Blood Pressure and Risk of Atrial Fibrillation: A Mendelian Randomization Study

Abstract Importance: Observational studies have shown an association between hypertension and atrial fibrillation (AF). Aggressive blood pressure management in patients with known AF reduces overall arrhythmia burden, but it remains unclear whether hypertension is causative for AF. Objective: The primary objective of this study was to investigate the relationship between blood pressure and risk of AF using genetic proxies for blood pressure within a Mendelian randomization (MR) framework. We secondarily explored the relationship between genetically proxied use of anti-hypertensive drugs and risk of AF. Design: Two-sample MR was performed using an inverse-variance weighted meta-analysis with weighted median MR and Egger intercept tests performed as sensitivity analyses. Genetic proxies for the anti-hypertensive drug classes were used to investigate the impact of these therapies on the risk of AF. Setting: International Consortium of Blood Pressure, UK Biobank and Atrial Fibrillation Genetics Consortium. Participants: Summary statistics for systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) were obtained from the International Consortium of Blood Pressure and the UK Biobank discovery analysis (>750,000 individuals of European ancestry). Summary statistics for AF were obtained from the 2018 Atrial Fibrillation Genetics Consortium multi-ethnic GWAS (>65,000 AF cases and >522,000 referents). Exposure: Genetically predicted SBP, DBP and PP as quantified by risk scores. Main Outcome: Odds ratio for AF per 10 mmHg increase in genetically proxied blood pressure. Results: Ten mmHg increases in genetically proxied SBP, DBP or PP were associated with increased odds of AF (SBP: OR 1.17, 95% CI 1.11-1.22, p=1x10-11; DBP: OR 1.25, 95% CI 1.16-1.35, p=3x10-8; PP: OR 1.1, 95% CI 1.0-1.2, p=0.05). Ten mmHg decreases in SBP estimated by genetic proxies of anti-hypertensive medications showed calcium channel blockers (OR 0.66, 95% CI 0.57-0.76, p=8x10-9) and beta-blockers (OR 0.61, 95% CI 0.46-0.81, p=6x10-4) decreased the risk of AF. Conclusions and Relevance: Blood pressure-increasing genetic variants were associated with increased risk of AF, consistent with a causal relationship between blood pressure and AF. These data support the concept that blood pressure reduction through pharmacologic intervention, and specifically calcium channel blockade or beta blockade could reduce the risk of AF.