EXPLORING THE BIDIRECTIONAL CAUSAL ASSOCIATION BETWEEN FRAILTY AND CARDIOVASCULAR DISEASES: INSIGHTS FROM A BIDIRECTIONAL MENDELIAN RANDOMIZATION STUDY

Objective: Observational studies have consistently shown a robust association between frailty and cardiovascular diseases. However, it remains uncertain whether this association reflects causality. We performed a bidirectional Mendelian randomized (MR) study to assess the bidirectional causality between frailty, as measured by the frailty index (FI), and hypertension(HTN), atrial fibrillation(AF), coronary artery disease (CAD) and heart failure(HF). Design and method: Using the latest genome-wide association study (GWAS) summary data on individuals of European descent, we extracted independent single nucleotide polymorphisms (SNPs) for each phenotype at genome-wide significance levels as instrument variables, including FI (N=175,226), HTN (N=462,933), AF (N=138,994) and HF (N= 977,323). The inverse variance weighting method in two-sample MR analysis was primarily used, followed by various sensitivity and validation analyses such as MRPRESSO. Results: Higher FI significantly increased the risk of HTN (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.07-1.16 P<0.001) and CAD (OR 2.57, 95% CI 1.72-3.84 P<0.001). FI was suggestively associated with a higher risk of AF (OR 1.83 95%CI 1.11-3.01 P<0.05). No association between FI and HF was observed (OR 1.30, 95% CI 1.00-1.71 P>0.05). In the reverse analysis, genetic predisposition to HTN (OR 1.94 95% CI 1.71, 2.19 P<0.001) and CAD (OR 1.07 95% CI 1.05-1.09 P<0.001) was significantly associated with higher FI. A suggestive correlation between genetic susceptibility to HF (OR 1.09 95% CI 1.00-1.19 P<0.05) and higher FI was also observed. No association between AF and FI was observed (OR 1.01 95% CI 1.00-1.03 P>0.05). Results of sensitivity and validation analyses were stable. Conclusions: Our findings support a bidirectional causal association between frailty and HTN and CAD and a possible causal association between frailty and the development of AF and HF. A deeper exploration of this association is imperative to optimize the management of elderly patients.