Emergence of heartbeat frailty in advanced age II: individual cardiovascular aging trajectories revealed by lifelong echocardiography in male mice.

Chronological age is the strongest risk factor for cardiovascular disease, yet individual trajectories of cardiovascular aging, particularly during late life, remain incompletely characterized. We performed quarterly echocardiography in 58 male C57BL/6 mice from 6 months until natural death, focusing on long-lived mice surviving beyond the cohort median of 24 months. Progressive body weight loss after 18-21 months defined the frailty transition and partitioned each mouse's lifespan into pre-frailty and frailty phases. Pulse wave velocity increased 15% across the lifespan, accompanied by luminal dilatation and declining fractional diameter change in all arterial segments, confirming arterial stiffening as a primary aging process. Left ventricular mass increased continuously, even as body weight declined, transitioning from concentric hypertrophy (wall thickening without chamber dilatation) in pre-frailty to eccentric hypertrophy (wall thickening plus chamber dilatation) in frailty. Ejection fraction declined from 51 to 27%; partial stroke volume preservation was achieved through Frank-Starling compensation. Heart rate increased during pre-frailty then declined during frailty, correlating with body weight loss rate. Critically, inter-individual variability in rates of change increased 2-threefold during frailty for all cardiac and arterial parameters despite genetic homogeneity and controlled housing, implicating stochastic mechanisms, including epigenetic drift, mitochondrial dysfunction, and heterogeneous senescent burden, as dominant determinants of late-life trajectories. These findings parallel human cardiovascular aging patterns and identify the frailty transition as a critical inflection point at which myocardial compensation yields to decompensation and individual divergence amplifies.