The impact of age and frailty on ventricular structure and function in C57BL/6

Abstract

Background: On average, cardiac hypertrophy and contractile dysfunction increase with age. Still, individuals age at different rates and their health status varies from fit to frail. We investigated the influence of frailty on age-dependent ventricular remodeling. Methods: Frailty was quantified as deficit accumulation in adult (≈7 mos) and aged (≈27 mos) C57BL/6 mice by adapting a validated frailty index (FI) tool. Hypertrophy and contractile function were evaluated in Langendorff-perfused hearts; cellular correlates/mechanisms were investigated in ventricular myocytes. Results: FI scores increased with age. Mean cardiac hypertrophy increased with age, but values in the adult and aged groups overlapped. When plotted as a function of frailty, hypertrophy was graded by FI score (r=0.67-0.55, p<0.0003). Myocyte area also correlated positively with FI (r=0.34; p=0.03). Left ventricular developed pressure (LVDP) plus rates of pressure development (+dP/dt) and decay (-dP/dt) declined with age and this was graded by frailty (r=-0.51, p=0.0007; r=-0.48, p=0.002; r=-0.56, p=0.0002 for LVDP, +dP/dt and -dP/dt). Smaller, slower contractions graded by FI score were also seen in ventricular myocytes. Contractile dysfunction in cardiomyocytes isolated from frail mice was attributable to parallel changes in underlying Ca2+ transients. These changes were not due to reduced sarcoplasmic reticulum stores, but were graded by smaller Ca2+ currents (r=-0.40, p=0.008), lower gain (r=-0.37, p=0.02) and reduced expression of Cav1.2 protein (r=-0.68, p=0.003). Conclusions: These results show that cardiac hypertrophy and contractile dysfunction in naturally-ageing mice are graded by overall health and suggest that frailty, in addition to chronological age, can help explain heterogeneity in cardiac ageing. This model system can ultimately be used to test interventions designed to improve cardiovascular outcomes in frail older adults.