Excitation-contraction coupling, cardiomyocyte electrophysiology, and transcriptome profiles in two HFpEF murine models: Etiology and sex-dependent differences

Heart failure (HF) with preserved ejection fraction (HFpEF) comprises heterogenous clinical phenotypes and variable co-morbidities. Recent two-hit translational animal models, including the hypertensive, nitrosative-stressed mice fed with high-fat diet and L-NAME (HFD+L-NAME) and the obese-diabetic leptin receptor-deficient db/db mice with excess aldosterone ( db/db+Aldo), may phenocopy select subgroups of HFpEF. We systematically compared mechanisms of excitation-contraction coupling (ECC), electrophysiology, and gene transcription in these preclinical HFpEF models and between sexes, including morphometry, echocardiography, cellular electrophysiology, intracellular Ca 2+ imaging, and RNA-sequencing. The multiorgan HFpEF phenotype showed key differences between the two models: db/db+Aldo mice were markedly obese, had severe hyperglycemia and hepatomegaly, whereas male HFD+L-NAME mice had more pronounced cardiac hypertrophy. Diastolic dysfunction (quantified as echocardiographic E/e’) was more severe in db/db+Aldo mice and worse in females, whereas females showed milder diastolic dysfunction in HFD+L-NAME. Marked proarrhythmic action potential (AP) changes (prolonged AP duration, increased short-term variability, and reduced alternans threshold) occurred in db/db+Aldo (in both sexes), while these AP changes were less severe in male HFD+L-NAME and absent in female HFD+L-NAME. In line with these findings, differential ionic current and Ca 2+ handling changes occurred between these two HFpEF models and between sexes. RNA-sequencing revealed highly distinctive gene expression profiles between HFpEF models. We conclude that marked differences exist in cardiomyocyte ECC, electrophysiology, and gene expression between HFD+L-NAME and db/db+Aldo mice and between sexes. This indicates that a combination of translational HFpEF models that mimic select HFpEF sub-phenogroups are critical to better understand HFpEF mechanisms for therapeutic drug development.