Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice

Abstract

Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age‐related disease. The molecular mechanisms by which ExT induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that ExT 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, ExT in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion. Interestingly, RNAseq of explanted hearts showed that ExT 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 ExT potentially reverses cardiac aging phenotypes in HFpEF.

Multiple-Tissue and Multilevel Analysis on Differentially Expressed Genes and Differentially Correlated Gene Pairs for HFpEF

“…Furthermore, the common biological processes among the three tissues were mainly related to cell cycle and immune response. These findings were consistent with those of previous studies, which demonstrated that cell cycle and immune response are closely related to diastolic dysfunction and impaired cardiac reserves ( Roh et al, 2020 ; Sava et al, 2020 ). Heart function is related to the flow dynamics of the cerebral artery, which may influence the gene expression in the cerebral artery and increase the incidence of cerebrovascular events ( Karahan et al, 2020 ).…”

Gestational diabetes triggers postpartum cardiac hypertrophy via activation of calcineurin/NFAT signaling

“…The reasons for this are unclear but might reflect reduced ability of the heart to undergo physiological hypertrophy due to a more advanced age (~ 5.5 months of age). This is in line with studies reporting lack of exercise-induced hypertrophy in aged animals 45 , 46 . In contrast, our data suggest that GDM is associated with concentric remodeling/hypertrophy, both at term and postpartum, as HIP females showed increased diastolic thickness of both interventricular septum (Fig.…”

Heart failure with preserved ejection fraction in humans and mice: embracing clinical complexity in mouse models

“… 170 At an age of 24–30 months, mice recapitulate many hallmarks of human HFpEF pathophysiology, including diastolic dysfunction, concentric hypertrophy with fibrosis and reduced exercise capacity. 171 , 172 This mice furthermore have lung congestion and increased natriuretic peptide levels. Hypertension or T2DM, however, have not been described.…”