Association between frailty and chest pain: Insights from the 2009 to 2018 NHANES cross-sectional analysis and Mendelian randomization

Chest pain is a common clinical symptom with diverse etiologies, including cardiovascular, respiratory, digestive, and musculoskeletal disorders, and is one of the leading causes of emergency department visits. However, the association between frailty and chest pain has not been well characterized. We analyzed 1019 participants from the 2009 to 2018 National Health and Nutrition Examination Survey. Frailty was assessed using a 49-item frailty index (FI), evaluated as both a continuous variable and a categorical variable (frail: FI ≥ 0.21; non-frail: FI < 0.21). Chest pain was identified from a self-reported item in the National Health and Nutrition Examination Surve Health questionnaire, without distinguishing cardiac from noncardiac causes. Weighted logistic regression models were applied: model 1 (unadjusted), model 2 (adjusted for demographic variables), and model 3 (further adjusted for socioeconomic, lifestyle, medication use, clinical conditions, and metabolic markers). Sensitivity analyses included subgroup and interaction analyses, unweighted models, and multiple imputation. A 2-sample Mendelian randomization analysis, using genome-wide association study summary statistics, was conducted to explore potential causality. After adjusting for all covariates, FI was significantly associated with chest pain (odds ratio [OR] = 4.69, 95% confidence interval [CI]: 2.18-10.08, P < .001). In subgroup analyses, this association was significant in the frail population (OR = 2.78, 95% CI: 1.27-6.09, P = .017), but not in the non-frail group. Sensitivity analyses confirmed the robustness of these findings. Mendelian randomization analysis further indicated a potential causal relationship between FI and chest pain (inverse variance weighting OR = 1.12, 95% CI: 1.10-1.14, P < .001). Frailty is independently associated with self-reported chest pain, and genetic analyses suggest a possible causal relationship. However, these findings should be interpreted with caution, as chest pain may originate from multiple underlying conditions.