Exercise is known to improve outcomes in heart failure patients, but there is a limit as to the data that can be obtained on mechanisms of action from human patients. Here researchers use a mouse model of heart failure to show that exercise doesn't impact the harmful presence of fibrosis in heart tissue, but does increase capillary density. The density of capillaries in tissues throughout the body declines with age, and this progressive loss is probably quite important in a number of aspects of aging, particularly in tissues that have high energy demands, such as the heart. That fibrosis isn't affected suggests that exercise doesn't do much to reduce the burden of cellular senescence, however, given that senescent cells are strongly implicated in age-related fibrosis.
Heart failure with preserved ejection fraction (HFpEF) is the most common type of heart failure in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training has emerged as the most effective intervention to improving functional outcomes in this age-related disease. The molecular mechanisms by which exercise training induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that exercise training might reverse cardiac aging phenotypes that contribute to HFpEF pathophysiology and additionally provide a platform for novel mechanistic and therapeutic discovery.
Here, we show that aged (24-30 months) C57BL/6 male mice recapitulate many of the hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic dysfunction, diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy. Similar to older humans, exercise training in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion.
Interestingly, RNAseq showed that exercise training did not significantly modulate biological pathways targeted by conventional HF medications. However, it reversed multiple age-related pathways, including the global downregulation of cell cycle pathways seen in aged hearts, which was associated with increased capillary density, but no effects on cardiac mass or fibrosis. Taken together, these data demonstrate that the aged C57BL/6 male mouse is a valuable model for studying the role of aging biology in HFpEF pathophysiology, and provide a molecular framework for how exercise training potentially reverses cardiac aging phenotypes in HFpEF.