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Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Senior Scientist Grant from the Dutch Heart Foundation. Aims Due to their dependence on temporality, current atrial fibrillation (AF) classifications are inaccurate and impractical in large cohort studies, resulting in scarce evidence on prognostic differences between AF patterns in the general population. Using our recently developed AF classification, we investigated potential differences in cardiovascular prognosis among participants with various AF patterns and matched non-AF individuals from the general population. Methods 1,111 individuals from the general population were classified as 'single-documented AF episode' (sAF), 198 as 'multiple-documented AF episodes' (mAF), and 52 as 'longstanding persistent AF' (lpAF). Each group was independently matched with non-AF participants through propensity score matching. Participants were followed for the development of coronary heart syndrome (CHD), stroke, heart failure (HF), and cardiovascular mortality. Cox proportional hazards regression analyses were performed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for each AF pattern. Results Stroke risk was 1.01; 0.82-1.28 (HR; 95% CI) for sAF, 1.36; 0.87-2.11 for mAF, and 1.44; 0.79-3.54 for lpAF, as compared to their matched participants. HF risk was larger in all AF patterns, with the gradient corresponding to AF severity: 3.48; 1.61-7.55 for lpAF, 2.78; 1.94-3.98 for mAF, and 1.71; 1.44-2.03 for sAF. Compared to non-AF participants, cardiovascular mortality risk was larger in the sAF (1.56; 1.37-1.79) and mAF (1.53; 1.11-2.12) categories, but not for lpAF (0.85; 0.40-1.82). Conclusion More severe AF patterns in the general population carried a larger HF risk. We observed a trend regarding a larger stroke risk in more severe AF patterns, albeit statistically not significant. Our new AF classification method may benefit comorbidity and mortality risk stratification associated with AF in a general population.

Background Digoxin is one of the oldest cardiovascular medications still used to treat heart failure and atrial fibrillation. Due to its narrow therapeutic window, it is associated with life threatening intoxication and arrhythmias, and with QTc-shortening. Common genetic variation in the nitric oxide synthase-1 adaptor protein (NOS1AP) has been associated with QTc interval prolongation. Purpose We investigated whether the rs10494366 variant of the NOS1AP gene modified the risk of SCD in patients using digoxin. Methods In a prospective population-based cohort study, we included data of the three cohorts, started as of January 1st, 1991 until January 1st 2014. Digoxin current use on the date of cardiac death in cases and the same day of follow-up in the remainder of the cohort was a time-dependent exposure. The main outcome was SCD defined as sudden and unexpected death as a result of cardiac causes, according to international criteria. Identification and adjudication of SCD was performed independently, before the start of this study. We used Cox proportional hazard regression analysis to investigate the associations between NOS1AP rs10494366 variant and incident SCD among digoxin users compared to non-users. Associations were adjusted for age, sex (model 1) in addition to BMI, prevalent diabetes, myocardial infarction, baseline hypertension and smoking status (past, current, never) (model 2). Results We included 14,594 individuals, with a mean age of 65.3 (SD 10.3) years. Almost 59% were female. The cumulative incidence of SCD was 9.5% (609 cases) by the end of follow up. Among them, 98 (16%) individuals were exposed to digoxin at the time of death. In model 1, NOS1AP rs10494366 variant was not associated with SCD in the total study population. However, an interaction term of the gene with the daily dose of digoxin was significantly associated with increased risk of SCD (p-value 0.0001). In model 2, the risk of SCD in current users of digoxin was 4.2 [95% CI 1.3–13.8] for the GG genotype; 2.1 [95% CI 1.1–4.2] for the GT genotype, and 1.5 [95% CI 0.7–3.2] for the TT genotype. Conclusion NOS1AP rs10494366 variant modified the risk of sudden cardiac death in users of digoxin. Our study suggests that individuals with the homozygous minor GG allele have a fourfold increased risk of sudden cardiac death. Funding Acknowledgement Type of funding source: None

Purpose: Chronic heart failure is often a manifestation of long-standing underlying cardiac conditions, such as coronary heart disease (CHD) and left ventricular hypertrophy (LVH). Atrial fibrillation (AF) is a well-recognized consequence of heart failure which can be prevented by timely pharmacological treatment. However, limited data exists on the role of AF in the etiology of heart failure in the general population. We sought to evaluate the long-term risk of heart failure associated with new onset AF; in addition, we evaluated the interplay between AF and other cardiac conditions (CHD and LVH) in the development of heart failure. Methods: Within the Rotterdam Study, a prospective population-based cohort, we followed 6178 persons (mean age 68.6 years, 41% men) free of heart disease at baseline (1990-1993) for the occurrence of AF, CHD (defined as myocardial infarction or revascularization), and heart failure. We constructed time-dependent Cox models adjusted for traditional cardiovascular risk factors to study the effect of newly-diagnosed AF (and CHD) during follow-up and subsequent heart failure risk. Since both AF and heart failure can have a substantial time-lag between the occurrence of first symptoms and clinical diagnosis, we modeled various time-lags of up to 5 years since first diagnosis of AF in order to ascertain that AF preceded heart failure symptoms. Results: During a median 14.2 years of follow-up 584 diagnoses of AF were made and 994 participants developed heart failure. New onset AF was associated with an increased risk of heart failure (adjusted HR 3.16 [95% CI: 2.63-3.79]), which persisted even 5 years after AF diagnosis (adjusted HR 2.60 [95% CI: 1.88-3.58]). Regarding the interplay between AF and CHD, the presence of AF only, CHD only, and concomitant AF and CHD showed a graded increase in heart failure risk (adjusted HRs 3.52 [95% CI: 2.85-4.34], 4.30 [95% CI: 3.40-5.45], and 6.23 [95% CI: 3.56-10.88], respectively). A similar graded increase in risk estimates was observed for the presence of ECG detected LVH and concurrent AF. Population attributable risks were 12.2% for AF, 6.3% for CHD, and 5.2% for LVH. Conclusions: New onset AF was a strong risk factor for incident heart failure in the general population, with long-term relative risks close to those of manifest CHD. Absolute and relative risk estimates were especially high for persons with concomitant AF and CHD. Persons with AF may well constitute an important part of the general population that could potentially benefit from timely introduced intensive preventive measures to reduce the growing burden of chronic heart failure.