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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE284354 | GEO | 2025/12/02

REPOSITORIES: GEO

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Project description:BACKGROUND: Clinical management of heart failure with preserved ejection fraction (HFpEF) is hindered by a lack of disease-modifying therapies capable of altering its distinct pathophysiology. Despite the widespread implementation of a 2-hit model of cardiometabolic HFpEF to inform precision therapy, which utilizes HFD+L-NAME (ad libitum high-fat diet and 0.5% N[ω]-nitro-L-arginine methyl ester), we observe that C57BL6/J mice exhibit less cardiac diastolic dysfunction in response to HFD+L-NAME. METHODS: Genetic strain-specific single-nucleus transcriptomic analysis identified disease-relevant genes that enrich oxidative metabolic pathways within cardiomyocytes. Because C57BL/6J mice are known to harbor a loss-of-function mutation affecting the inner mitochondrial membrane protein Nnt (nicotinamide nucleotide transhydrogenase), we established an isogenic model of Nnt loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of HFD+L-NAME. Twelve-week-old mice cross-bred to isolate wild-type (Nnt+/+) or loss-of-function (Nnt−/−) Nnt in the C57BL/6N background were challenged with HFD+L-NAME for 9 weeks (N=6–10). RESULTS: Nnt+/+ mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via noninvasive echocardiographic quantification of early diastolic pulse-wave velocity (E) to mitral annular velocity (e′) ratio (E/e′) (42.8 versus 21.5, P=1.2×10−10), E/A (early-to-late mitral inflow velocity ratio) (2.3 versus 1.4, P=4.1×10−2), diastolic stiffness (0.09 versus 0.04 mm Hg/μL, P=5.1×10−3), and myocardial fibrosis (P=2.3×10−2). Liquid chromatography and mass spectroscopy exposed a 40.0% reduction in NAD+ (P=8.4×10−3) and a 38.8% reduction in the ratio of reduced-to-oxidized glutathione (GSH: GSSG, P=2.6×10−2) among Nnt+/+ mice after HFD+L-NAME feeding. Using single-nucleus ligand-receptor analysis, we implicate Fgf1 (fibroblast growth factor 1) as a putative NNT-dependent mediator of cardiomyocyte-to-fibroblast signaling in myocardial fibrosis. CONCLUSIONS: Together, these findings underscore the pivotal role of mitochondrial dysfunction in HFpEF pathogenesis, implicating both NNT and Fgf1 as novel therapeutic targets.

Project description:Aims: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like Glucagon Like Peptide Receptor Agonist (GLP-1RA) and Sodium Glucose Transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide and a SGLT2i dapagliflozin. Methods&Results: Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high fat diet (HFD) for 12 weeks. After 8 weeks HFD, Angiotensin-II (ANGII), was administered for 4 weeks via osmotic mini-pumps. HFD+ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling and metabolic dysregulation with inflammation. The multiple-hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement lung congestion, and elevated blood pressures. Treatment with liraglutide attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapagliflozin treatment improved glucose handling, but had mild effects on the HFpEF phenotype. Conclusions: We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for treatment of HFpEF.

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

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