Biologically older cardiovascular system predicts adverse clinical outcome independently of chronological age

Background Cardiovascular ageing is the main biological driver of cardiovascular diseases, offering a unique opportunity to transform research and prevention strategies at both individual and population levels. Purpose We aimed to develop, and validate, a novel estimate of cardiovascular biological age (HeartAge) and its deviation from chronological age (HeartAge-gap) using XGBoost regression informed by readily extractable cardiovascular magnetic resonance phenotypes. Methods HeartAge and HeartAge-gap were estimated in 31,784 UK-Biobank participants (16,640 females, 64±7 years). A positive HeartAge-gap indicates an older cardiovascular system, conversely a negative HeartAge-gap indicates a younger one. Logistic regression assessed the association between HeartAge-gap and prevalent cardiovascular conditions, while Cox regression proportional hazard-ratio models evaluated its predictive value for the composite cardiovascular outcome and all-cause mortality. External validation was conducted in 897 participants (472 females, 60±10 years) from the Multi-Ethnic Study of Atherosclerosis (MESA). Results HeartAge-gap was independently associated hypertension, diabetes, and ischaemic heart disease in both sexes (P<0·05 for all). Over a median follow-up of nearly 6 years, an increased HeartAge-gap predicted the composite cardiovascular outcome in females (HR:1·022, 95%CI:1·000-1·044, P=0·048) and males (HR:1·017, 95%CI:1·002-1·033, P=0·027) independently of chronological age and other major baseline confounders including, body-mass-index, ischaemic heart disease, diabetes, and hypertension. In females, an increased HeartAge-gap also predicted all-cause mortality (HR:1·061, 95%CI:1·007-1·118, P=0·027) regardless of chronological age. In MESA females, increased HeartAge-gap predicted the cardiovascular outcome (HR:1·113, 95%CI:1·025-1·210, P=0·011) independently of chronological age and other key confounders. Conclusion Our framework offers an individualised approach to estimating cardiovascular biological ageing. A biologically older cardiovascular system emerged as a robust, independent predictor of adverse cardiovascular outcomes, irrespective of chronological age and traditional risk factors. Notably, in females, advanced cardiovascular ageing also predicted all-cause mortality regardless of chronological age.Figure-1.Study outline and main outcome