Targeting RUNX1 protects against diastolic dysfunction in a two-hit mouse model of heart failure with preserved ejection fraction

AIMS: Heart failure with preserved ejection fraction (HFpEF) continues to increase in prevalence and has limited treatment options. HFpEF is a systemic condition with a broad phenotype including diastolic dysfunction, pulmonary oedema, exercise intolerance, and left ventricular (LV) hypertrophy, collectively resulting in enhanced morbidity and mortality. The transcription factor RUNX1 has recently been identified as a mediator of pathological changes in multiple cardiac diseases, however its role in HFpEF remained unknown. METHODS AND RESULTS: Here we show that inhibition of Runx1 limits adverse cardiac remodelling in a clinically relevant mouse model of HFpEF. Cardiomyocyte-specific tamoxifen-inducible Runx1-deficient mice with HFpEF are protected, with preservation of diastolic function, and attenuation of pulmonary oedema, exercise intolerance, and hypertrophy. Furthermore, targeting Runx1 in HFpEF by using gene transfer or small molecule inhibitor Ro5-3335 improves diastolic function and reduces pulmonary oedema, both in female and male mice. CONCLUSION: Overall, our research enhances our understanding of RUNX1 in cardiac disease and presents a novel translational target for the treatment of HFpEF.