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Heart failure with preserved ejection fraction (HFpEF) has a sex bias because it affects more women than men. We propose that this bias may be due to sex differences in the mitochondria. We find that heart mitochondrial DNA levels and function are typically lower in females than in males in genetic studies of heart failure in mice. In human cohorts, we also notice that males express more genes for mitochondrial proteins than females do. We test our theory using a panel of mice with a variety of genetic inbred strains, known as the Hybrid Mouse Diversity Panel (HMDP). Indeed, we discover a strong correlation between diastolic function, a crucial characteristic of HFpEF, and mitochondrial gene expression. Studies using a "two-hit" mouse model of HFpEF support this by showing that mitochondrial function varies between sexes and is closely linked to a variety of HFpEF characteristics. We identified the mitochondrial gene Acsl6 as a genetic predictor of diastolic function by combining data from human heart failure and the mouse HMDP cohort. We use adenoviral overexpression in the heart to confirm its function in HFpEF. We come to the conclusion that the sex bias in diastolic function is partially explained by sex differences in mitochondrial activity.
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