Cardiometabolic multimorbidity and mortality in calcific aortic valve stenosis: the ARISTOTLE cohort study

Abstract Background Cardiometabolic multimorbidity (CMM), defined as the coexistence of two or more cardiometabolic diseases (CMDs), is highly prevalent in patients with calcific aortic valve stenosis (CAVS). However, its association with mortality in this population remains poorly characterized. Methods This retrospective cohort study analyzed 1175 adults with echocardiographically confirmed CAVS from the ARISTOTLE (Aortic valve diseases RISk facTOr assessmenT and prognosis modeL construction) registry. Participants were stratified by baseline CMD count into pre-specified primary exposure groups: CMM0 (no CMD), CMM1 (one CMD), and CMM2–3 (≥ 2 CMDs). CMDs included type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), and ischemic stroke. Cause-specific Cox proportional-hazards models were applied; non-cardiovascular deaths were treated as censoring events for cardiovascular mortality analyses. Fine–Gray competing-risk models were constructed, with non-cardiovascular death set as the competing event. Formal interaction testing with Bonferroni correction was conducted for pre-defined subgroup analyses. Exploratory four-category CMD stratification and analyses of distinct CMD combinations were presented in supplementary materials. Results During a median follow-up of 3.23 years, 329 all-cause deaths and 179 cardiovascular deaths occurred. Mortality risk tended to increase with higher cardiometabolic multimorbidity burden. In the fully adjusted model, participants with ≥ 2 CMDs showed higher risk of all-cause mortality (HR 1.74, 95% CI 1.23–2.48; P = 0.002) and cardiovascular mortality (HR 2.24, 95% CI 1.39–3.61; P < 0.001), compared with patients without CMD. Each incremental rise in CMD count was associated with 30% higher all-cause death risk (HR 1.30, 95% CI 1.10–1.53, P = 0.002) and 47% higher cardiovascular death risk (HR 1.47, 95% CI 1.18–1.84, P < 0.001). Fine–Gray competing-risk analyses yielded consistent findings (subdistribution HR 2.07, 95% CI 1.30–3.28, P = 0.002 for CMM2–3 versus CMM0). Associations between CMD burden and mortality were directionally uniform across most predefined subgroups; no statistically significant interaction remained after Bonferroni correction for multiple comparisons. Conclusions Among patients with calcific aortic valve stenosis, higher cumulative cardiometabolic multimorbidity burden was independently associated with elevated all‑cause and cardiovascular mortality. These observational findings suggest that assessment of cumulative cardiometabolic comorbidity burden may add prognostic context for patients with CAVS.