Assessment Of The Causal Relevance Of Ecg Parameters For Risk Of Atrial Fibrillation: A Mendelian Randomisation Study

Background Atrial electrical and structural remodelling in older individuals with cardiovascular risk factors has been associated with changes in surface electrocardiographic (ECG) parameters (e.g., prolongation of the PR interval) and higher risks of atrial fibrillation (AF). However, it has been difficult to establish whether altered ECG parameters are the cause or a consequence of the myocardial substrate leading to AF. This study aimed to examine the potential causal relevance of ECG parameters on risk of AF using mendelian randomisation (MR).Methods and findings Weighted genetic scores explaining lifelong differences in P-wave duration, PR interval, and QT interval were constructed, and associations between these ECG scores and risk of AF were estimated among 278,792 UK Biobank participants (mean age: 57 years at recruitment; 19,132 AF cases). The independent genetic variants contributing to each of the separate ECG scores, and their corresponding weights, were based on published genome-wide association studies. In UK Biobank, genetic scores representing a 5 ms longer P-wave duration or PR interval were significantly associated with lower risks of AF (odds ratio [OR] 0.91; 95% confidence interval [CI]: 0.87-0.96, P = 2 x 10(-4) and OR 0.94; 95% CI: 0.93-0.96, P = 2 x 10(-19), respectively), while longer QT interval was not significantly associated with AF. These effects were independently replicated among a further 17,931 AF cases from the AFGen Consortium. Investigation of potential mechanistic pathways showed that differences in ECG parameters associated with specific ion channel genes had effects on risk of AF consistent with the overall scores, while the overall scores were not associated with changes in left atrial size. Limitations of the study included the inherent assumptions of MR, restriction to individuals of European ancestry, and possible restriction of results to the normal ECG ranges represented in UK Biobank.Conclusions In UK Biobank, we observed evidence suggesting a causal relationship between lifelong differences in ECG parameters (particularly PR interval) that reflect longer atrial conduction times and a lower risk of AF. These findings, which appear to be independent of atrial size and concomitant cardiovascular comorbidity, support the relevance of varying mechanisms underpinning AF and indicate that more individualised treatment strategies warrant consideration.Author summaryWhy was this study done?Atrial fibrillation (AF) is the most common arrhythmia worldwide and associated with higher risk of stroke, dementia, heart failure, and death. Incomplete understanding of the underlying substrates for AF has hampered therapeutic advances and effective risk stratification, with current anti-arrhythmic drug therapy and a variety of catheter ablation strategies for AF still showing high medium-term failure rates and no material effects on the risk of stroke. Observational studies have suggested associations between electrocardiographic (ECG) parameters and risk of AF, but these associations may be subject to confounding and reverse causality, and thus the causal relevance of ECG parameters for AF remains unclear.What did the researchers do and find?We used a mendelian randomisation (MR) approach to examine the potential causal relevance of lifelong differences in ECG parameters for AF among approximately 300,000 individuals in UK Biobank. Unexpectedly, we found evidence supporting a causal association between lifelong differences in ECG parameters representing longer atrial conduction times within the normal range and a lower risk of AF. The relationship between ECG parameters and AF appeared to be independent of atrial size and cardiovascular comorbidities.What do these findings mean?These findings further emphasise that substantial variation in the mechanisms underpinning AF exists and warrants the consideration of more individualised treatment strategies.