Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome linked to ageing, obesity and impaired nitric oxide signalling. Many preclinical models do not recapitulate the sex-specific and cardiometabolic features observed in patients. The study summarized here tested the hypothesis that biological sex and the degree of nitric oxide synthase (NOS) inhibition determine whether cardiometabolic stress produces HFpEF-like or heart failure with reduced ejection fraction (HFrEF)-like phenotypes.
The investigators used older C57BL/6J mice (>24 weeks) and exposed them to a high-fat diet (HFD) combined with pharmacological NOS inhibition using N(ω)-nitro-L-arginine methyl ester (L-NAME) for 15 weeks. Two dosing regimens of L-NAME were applied: a low dose (0.3 g/L) administered to female mice only, and a high dose (0.5 g/L) given to both male and female mice. Cardiac function, exercise capacity, blood pressure and ventricular pressures were assessed alongside molecular profiling. Circulating lipidomics and cardiac transcriptomics were performed to evaluate systemic and myocardial molecular remodeling associated with the interventions.
Female mice that received low-dose L-NAME combined with HFD developed a phenotype the authors describe as HFpEF-like. Key features reported in the source include impaired diastolic function, exercise intolerance, and preserved systolic function. These functional readouts align with clinical hallmarks of HFpEF, where diastolic dysfunction coexists with a normal ejection fraction and reduced exercise capacity.
When NOS inhibition was increased (high-dose L-NAME) in female mice on HFD, diastolic dysfunction did not show further worsening according to the source. However, higher NOS inhibition induced transcriptional activation of pathways linked to inflammation and cellular stress in female hearts. Thus, escalating NOS inhibition altered molecular signatures without proportionally exacerbating the measured diastolic phenotype in females.
Male mice treated with high-dose L-NAME combined with HFD developed a different cardiac outcome consistent with a HFrEF-like phenotype. The reported features included the development of hypertension, elevated ventricular pressures and impaired systolic function. These functional changes contrast with the female HFpEF-like response and indicate a sex-dependent divergence in cardiac remodeling under comparable cardiometabolic and NOS-inhibitory stress.
Despite the divergent functional phenotypes between sexes, circulating lipidomic profiling showed broadly conserved remodeling of major lipid classes, notably sphingolipid and phospholipid changes. The source reports sex-specific regulation within lipid subclasses, including differences in phosphatidylinositol and lysophosphatidylcholine species. Transcriptomic analyses of cardiac tissue identified shared regulation across sexes of extracellular matrix components, calcium-handling genes and metabolic pathways. Increased NOS inhibition correlated with transcriptional signatures indicative of inflammatory signalling, cellular stress responses and altered mitochondrial homeostasis.
The study supports the conclusion that cardiometabolic stress does not produce a single uniform heart failure phenotype. Instead, biological sex and the magnitude of NOS inhibition guide distinct functional and molecular remodeling trajectories. In older mice subjected to HFD and NOS inhibition, a HFpEF-like syndrome emerged in females under low-dose NOS inhibition, whereas males developed a HFrEF-like syndrome with high-dose NOS inhibition. Molecular profiling revealed both shared and dose- or sex-specific changes in lipid metabolism and gene expression, suggesting overlapping and divergent mechanisms underpinning these phenotypes.
These findings emphasize the importance of incorporating sex as a biological variable and considering the degree of nitric oxide signalling impairment when modelling cardiometabolic heart disease preclinically. They also suggest that therapies targeting nitric oxide pathways, inflammation or metabolic remodeling may have sex-dependent effects or require dose-specific consideration.
Details limited to those reported in the source: the study was conducted in older C57BL/6J mice under specified HFD and L-NAME dosing for 15 weeks. The source states the authors declared no competing interests. The summary here does not include additional methodological specifics, quantitative results, statistical values, or institutional details beyond those provided in the source article abstract and metadata because those were not reported in the extracted text.