Heart rate variability and atrial fibrillation in the general population: a longitudinal and mendelian randomization study

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. This study is further supported by the Gender and prevention grant (555003017) from ZonMw. Background Sex-differences and the causality of the association between heart rate variability (HRV) and atrial fibrillation (AF) remain unclear. Purpose To investigate the sex-differences and the causality of the association between heart rate variability and atrial fibrillation. Methods 12,334 participants free of AF from a large population-based cohort study were included. Measures of HRV including the standard deviation of normal RR-intervals (SDNN), SDNN corrected for heart rate (SDNNc), RR-interval differences (RMSSD), RMSSD corrected for heart rate (RMSSDc), and heart rate were assessed at baseline and follow-up examinations. Joint models, adjusted for cardiovascular risk factors, were used to determine the association between longitudinal measures of HRV with new-onset AF. Additionally, we evaluated sex-differences. Genetic variants for HRV were used as instrumental variables in a Mendelian randomization (MR) analysis using GWAS summary-level data. Results During a median follow-up of 9.4 years, 1,302 incident AF cases occurred. In joint models, higher SDNN (hazard ratio (HR), 95% confidence interval (CI), 1.24, 1.04-1.47, p=0.0213), and higher RMSSD (HR, 95% CI, 1.33, 1.13-1.54, p=0.0010) were significantly associated with new-onset AF. Sex-stratified analyses showed that the associations were mostly prominent among women. In MR analyses, genetically determined decreases in SDNN (odds ratio (OR), 95% CI, 1.60, 1.27-2.02, p=8.36x10-05), and RMSSD (OR, 95% CI, 1.56, 1.31-1.86, p= 6.32x10-07) were significantly associated with increased AF risk. Conclusions Longitudinal measures of uncorrected HRV were significantly associated with new-onset AF, in particular among women. MR analyses supported the causal relationship between uncorrected measures of HRV with AF. Our findings indicate that measures to modulate HRV might prevent AF in the general population, especially among women.