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

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Background: Sex differences and causality of the association between heart rate variability (HRV) and atrial fibrillation (AF) in the general population remain unclear. Methods: 12,334 participants free of AF from the population-based Rotterdam 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. Genetic variants for HRV were used as instrumental variables in a Mendelian randomization (MR) analysis using genome-wide association studies (GWAS) summary-level data. Results: During a median follow-up of 9.4 years, 1302 incident AF cases occurred among 12,334 participants (mean age 64.8 years, 58.3% women). In joint models, higher SDNN (fully-adjusted hazard ratio (HR), 95% confidence interval (CI) 1.24, 1.04–1.47, p = 0.0213), and higher RMSSD (fully-adjusted 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, a genetically determined increase in SDNN (odds ratio (OR), 95% CI 1.60, 1.27–2.02, p = 8.36 × 10 –05), and RMSSD (OR, 95% CI 1.56, 1.31–1.86, p = 6.32 × 10 –07) were significantly associated with an increased odds of AF. Conclusion: Longitudinal measures of uncorrected HRV were significantly associated with new-onset AF, especially 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, in particular in women. Graphical abstract: [Figure not available: see fulltext.] AF; atrial fibrillation, GWAS; genome-wide association study, IVW; inverse variance weighted, MR; Mendelian randomization, MR-PRESSO; MR-egger and mendelian randomization pleiotropy residual sum and outlier, RMSSD; root mean square of successive RR interval differences, RMSSDc; root mean square of successive RR interval differences corrected for heart rate, SDNN; standard deviation of normal to normal RR intervals, SDNNc; standard deviation of normal to normal RR intervals corrected for heart rate, WME; weighted median estimator.

Original languageEnglish
Pages (from-to)747–758
Number of pages12
JournalClinical Research in Cardiology
Issue number6
Early online date13 Aug 2022
Publication statusPublished - Jun 2023

Bibliographical note

Funding Information:
The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the 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 Senior Scientist Grant from Dutch Heart Foundation (03-004-2021-T050).

Funding Information:
The authors are grateful for the dedication, commitment and contribution of the study participants, the general practitioners, pharmacists and the staff from the Rotterdam Study. Furthermore, the authors would like to thank the Genetic Variance in Heart Rate Variability (Vg HRV), HUNT, deCODE, MGI, DiscovEHR, UK Biobank, AFGen Consortium, and individual studies for sharing their summary statistics in GWAS.

Publisher Copyright:
© 2022, The Author(s).


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