Exercise Training Reverses Cardiac Aging Phenotypes Associated With Heart Failure With Preserved Ejection Fraction

Abstract

Cardiac aging is associated with increased heart failure risk and is thought to contribute to heart failure with preserved ejection fraction (HFpEF) pathophysiology in older adults. Although no pharmacological therapy to date has improved survival in HFpEF, aerobic exercise training (ExT) consistently improves functional outcomes in older adults with HFpEF. We thus hypothesized that integrating cardiac aging transcriptomic analyses with ExT might provide novel mechanistic insights into age-related HFpEF that could also be used for therapeutic target discovery. Using comprehensive phenotyping, we first demonstrate that the aged C57BL/6 mouse recapitulates many hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic and diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy, that are induced in the absence of overt hypertension. Notably, similar to older humans, ExT in this aged HFpEF model improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion. Interestingly, cardiac transcriptomic analyses showed that ExT did not significantly modulate neurohormonal pathways targeted by current heart failure drugs, including the adrenergic, renin-angiotensinaldosterone, and nitric oxide systems. Rather, it reversed multiple cardiac aging processes, most notably the global age-related downregulation of cell cycle pathways, which was associated with increased capillary density without effects on cardiac mass or fibrosis. Taken together, our data suggest that the aged C57BL/6 mouse is a valuable model for studying cardiac aging biology in HFpEF pathophysiology and that targeting cell proliferation pathways that can potentially reverse microvascular rarefaction may be a more effective therapeutic strategy in age-related HFpEF.