Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype

Our study shows that three independent pathological stressors (increased Ca 2+ influx, high-fat diet, and l-NAME) together produce a profound HFpEF phenotype. The primary mechanisms include HDAC-dependent-CM hypertrophy, necrosis, increased M 2 -macrophage population, fibroblast activation, and myocardial fibrosis. A role for HDAC activation in the HFpEF phenotype was shown in studies with SAHA treatment, which prevented the severe HFpEF phenotype. This “3-Hit” mouse model could be helpful in identifying novel therapeutic strategies to treat HFpEF.