Abstract
Heart failure with preserved ejection fraction (HFpEF) is a leading cause of morbidity and mortality in older adults. Exercise is the most effective intervention to improving cardiac performance and functional capacity in older HFpEF patients. The mechanisms by which exercise mediates these effects, however, remain unclear. Here, we show that aged C57BL/6 mice (24–30 months, n=42) largely recapitulate hallmark HFpEF phenotypes, including impaired diastolic function, systolic strain, cardiac reserves, and exercise capacity. Moreover, explanted hearts displayed classic HFpEF histopathology, including pathologic hypertrophy, increased myocardial fibrosis, inflammation, and microvascular rarefaction. In 28-month-old mice, eight weeks of moderate-intensity treadmill running improved exercise capacity (peak distance: 94 ± 14 vs. 181 ± 23 m, p=0.02), which was associated with improved contractile reserves (% fractional shortening change at peak exercise: -8.5 ± 3.0 vs. 9.3 ± 0.7, p=0.002) and trends toward improved diastolic function. No changes in resting systolic function or chronotropic reserves were observed. Although cardiac hypertrophy and fibrosis were unchanged, capillary density (1653 ± 66 vs. 1918 ± 89 capillaries/mm2, p=0.04) increased with exercise. RNAseq analyses of explanted hearts indeed showed that late-life exercise induces no significant changes in cardiac hypertrophy, fibrosis, or inflammatory pathways. However, it reversed age-related changes in proteasome, cell cycle, and fatty acid metabolism pathways toward more youthful levels, suggesting that these exercise-regulated pathways may improve microvascular growth and function in the aged heart. In summary, we propose that the aged C57BL/6 mouse is a valid preclinical model of HFpEF, and that late-life exercise training effectively mitigates some age-related microvascular and functional changes in the heart that lead to HFpEF.