Interacting and joint effects of frailty and depressive symptoms in relation to risk of cardio-oncology comorbidity in older adults from three prospective cohorts

BACKGROUND: While cardiovascular disease and cancer share common risk factors and exhibit complex bidirectional interplay, evidence regarding the interacting and joint effects of frailty and depressive symptoms on the risk of cardio-oncology comorbidity in older adults remains scarce. OBJECTIVES: This study aimed to examine the association between frailty and depressive symptoms with the risk of cardio-oncology comorbidity, and to explore their interacting and joint effects. METHODS: This study harmonized data from three prospective, nationally representative cohort studies: China Health and Retirement Longitudinal Study (CHARLS), the English Longitudinal Study of Ageing (ELSA), and the Health and Retirement Study (HRS). The final analytical sample included 10,937 participants aged ≥ 65 years without baseline cardio-oncology comorbidity. Frailty and depressive symptoms were assessed at baseline. Cardio-oncology comorbidity was ascertained based on self-reported physician diagnoses of cardiovascular disease and cancer. Cox proportional hazards models were utilized to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Multiplicative and additive interaction analyses were conducted, followed by joint association evaluations. RESULTS: Frailty (CHARLS HR = 1.71; ELSA HR = 1.41; HRS HR = 1.38) and depressive symptoms (CHARLS HR = 1.27; ELSA HR = 1.20; HRS HR = 1.18) were independently associated with significantly increased cardio-oncology comorbidity risk. While interaction analyses demonstrated the absence of significant multiplicative or additive interactions, the joint effect analysis revealed that cardio-oncology comorbidity risk was elevated among individuals with both frailty and depressive symptoms by 80% in CHARLS, 57% in ELSA, and 47% in HRS compared to those with neither condition. CONCLUSIONS: Concurrent frailty and depressive symptoms constitute the highest-risk phenotype for cardio-oncology comorbidity in community-dwelling older adults. These findings suggest that combined assessment of frailty and depressive symptoms may improve baseline risk stratification of cardio-oncology comorbidity.