Gastroesophageal Reflux Disease and Risk of Atrial Fibrillation/Flutter: Implications for Heart Failure Progression

AIMS: While observational studies suggest an association between gastroesophageal reflux disease (GERD) and atrial fibrillation/flutter (AF/AFL), the causal relationship and mechanisms remain undefined. This study employed Mendelian randomization (MR) to assess bidirectional causal relationships and explore potential implications for heart failure (HF) risk. METHODS AND RESULTS: A bidirectional two-sample MR analysis was conducted using genome-wide association study (GWAS) summary data from European populations (GERD: 129,080 cases and 473,524 controls; AF/AFL: 22,068 cases and 116,926 controls; Obesity: 4793 cases and 209,884 controls). Genetic instruments were selected for GERD and AF/AFL, with inverse variance weighting (IVW) as the primary analytical method to examine causality. Multivariable MR (MVMR) adjusted for obesity was performed to assess direct causal effects. RESULTS: IVW analysis demonstrated a significant causal effect of GERD on AF/AFL risk (OR = 1.373, 95% CI = 1.208-1.600, P = 0.017), which persisted after MVMR adjustment for obesity (OR = 1.303, 95% CI = 1.127-1.507, P < 0.001). Two-way analysis indicated no reverse causality. Sensitivity analyses supported result robustness with minimal pleiotropy. CONCLUSIONS: Genetic liability to GERD independently increases AF/AFL risk, unaffected by obesity pathways. Considering the well-established role of AF/AFL in the pathogenesis and progression of HF, our findings position GERD as a potential modifiable target within the causal pathway. Identification and management of GERD may therefore contribute to reducing atrial arrhythmia burden and subsequent HF risk.