Excitation-contraction coupling, cardiomyocyte electrophysiology, and transcriptome changes in two translational HFpEF murine models: Aetiology and sex-dependent differences

Heart failure (HF) with preserved ejection fraction (HFpEF) comprises heterogenous clinical phenotypes and presence of various 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 key preclinical HFpEF models and between sexes to advance translation. We performed morphometry, echocardiography, cellular electrophysiology, intracellular Ca2+ imaging, and RNA-sequencing. The multiorgan HFpEF phenotype showed key differences between the 2 models, db/db+Aldo mice were markedly obese, had severe hyperglycaemia and hepatomegaly, whereas male HFD+L-NAME mice had more pronounced cardiac hypertrophy. Diastolic dysfunction was more severe in db/db+Aldo mice and worse in females therein, whereas female sex was protective in HFD+L-NAME. Marked proarrhythmic action potential (AP) changes (AP prolongation, increased short-term variability and alternans threshold) occurred in db/db+Aldo (in both sexes), these AP changes were less severe in male HFD+L-NAME and absent in female HFD+L-NAME. In line with these, differential ionic current and Ca2+ handling changes occurred between these two HFpEF models and between sexes in each model. 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 needed to better understand HFpEF mechanisms for therapeutic drug development.