The influence of accelerated aging-related cardiac remodeling on cardiovascular outcomes: an observational study

BACKGROUND: This study aimed to investigate the associations between phenotypic age acceleration (PhenoAgeAccel) and different CVD outcomes and mortality, examine its relationship with cardiac structure and function using cardiac magnetic resonance imaging (CMR), and explore potential mediating pathways involving cardiac remodeling and cardiometabolic diseases. METHODS: PhenoAgeAccel was defined as the residual of PhenoAge, derived from 9 biomarkers, regressed on chronological age. We included 31 722 UK Biobank participants (mean age 54.6 years; 48.1% male) with complete baseline biomarker and CMR data. Multiple Cox proportional hazards models were used to assess associations with CVD outcomes and mortality. Multivariable linear regression examined associations with CMR-derived cardiac measures, and multiple mediation analyses were performed to evaluate potential mediating roles. RESULTS: Higher PhenoAgeAccel was independently associated with increased risks of any CVD, ischemic heart disease (IHD), heart failure, all-cause mortality, and CVD mortality. Each standard deviation increase in PhenoAgeAccel (4.63 years) was associated with 7%, 9%, 29%, 14%, and 16% higher risks of these outcomes, respectively, but not with arrhythmias or cerebrovascular disease. Associations with any CVD, IHD, and CVD mortality were stronger in women. Higher PhenoAgeAccel was also associated with adverse cardiac remodeling, including lower left ventricular volume, stroke volume, mass, LVGFI, and ejection fraction. Cardiac remodeling and cardiometabolic diseases partially mediated these associations. CONCLUSIONS: Our study examines the association between accelerated aging and cardiac phenotypes and their important independent mediating role in the accelerated aging-cardiovascular outcome relationship. Improving cardiac remodeling and metabolic health may mitigate the effects of biological aging on CVD risk.