Cardiometabolic stress induces HFpEF with impaired bioenergetics and disrupted proteostasis in aged female mice.

Heart failure with preserved ejection fraction (HFpEF) predominantly affects older women. The widely used two-hit model of HFpEF has mostly been applied to young animals and fails to induce HFpEF in female mice, limiting clinical and epidemiologic relevance. We challenged 19-month-old female mice with the two-hit protocol. Unlike young female mice, aged mice developed HFpEF, coinciding with impaired cardiac mitochondrial function and disrupted mitochondrial proteostasis. Our findings connect aging with increased female susceptibility to cardiometabolic stress and demonstrate the contribution of mitochondrial dysfunction in HFpEF. Incorporating aging into the two-hit model enables future investigation of sex-specific mechanisms of HFpEF.