Assessment of Cardiac Frailty in Preclinical Models of Heart Failure and Ageing – Parallels Between Discovery and the Clinic

Frailty is a state of reduced physiological reserve and has been identified as a prognostic indicator in older people with cardiovascular disease and heart failure (HF). Frailty contributes to increased vulnerability and worse outcomes, leading to increased morbidity and mortality. Clinical screening for frailty is increasingly recognised as an essential factor for risk stratification in HF and geriatric care, however its adoption in preclinical research and its uptake into clinical practice remains limited. In clinical practice, biomarkers are often not incorporated into routine frailty assessment. Nevertheless, several emerging biomarkers-reflecting inflammation, metabolic dysregulation, sarcopenia, and cardiovascular stress-are increasingly recognised as valuable adjuncts to established frailty assessment tools. Given that facilitating healthy ageing requires enhancing strategies to delay, slow, or reverse cardiac frailty, this discussion paper examines the current landscape of frailty assessment across the translational spectrum, advocating for an integration of frailty measures and biomarkers into preclinical discovery across the domains of physical/cognitive, systemic and cardiac phenotype. We call on cardiac preclinical discovery researchers to include or assess measures of frailty across these domains in their animal models of cardiomyopathy (heart failure with reduced ejection fraction [HFrEF], myocardial infarction [MI], heart failure with preserved ejection fraction [HFpEF], diabetes, cardiovascular-kidney metabolic disease), as well as prioritising sex-inclusive cohorts and inclusion of older animals, hence enhancing translational relevance and aligning discovery science with clinical priorities. Requiring the incorporation of these frailty measures by funding agencies and journals, alongside current measures of altered cardiac phenotype and function, into preclinical discovery, will be critical for identifying novel drivers of frailty and developing interventions that improve both lifespan and functional health in an ageing population with HF.