Key result
Two-hit cardiometabolic stress triggers HFpEF in aged female mice, increasing pulmonary fluid ~40%.
Why the study?
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.
Absolute Event Rate: 21% vs 8%
p-value: p=0.24
Aging abolishes the known resistance of young female mice to cardiometabolic stress, resulting in severe HFpEF driven by mitochondrial dysfunction and disrupted proteostasis.
Aged female HFpEF model highlights mitochondrial proteostasis defects; extends two-hit paradigm but leaves open clinical relevance.
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.
No takes yet. Share an insight, caveat, or question.
Kobak et al. (2026) studied Heart failure with preserved ejection fraction (HFpEF). Two-hit cardiometabolic stress protocol vs. Age-matched controls was evaluated on Mortality (p=0.24). Aged female mice subjected to two-hit cardiometabolic stress lost their resilience and developed HFpEF, exhibiting a 16% increase in heart weight and 40% higher pulmonary fluid content.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: