Combination of genetic eNOS deficiency and high-fat diet induces reproducible cardiometabolic HFpEF
- Design
- Animal study · Unknown outcome
- Match to healthy normal-weight adults aged 55–75
- Not human evidence[Auto] Non-human (animal or cellular) evidence; no direct inference to any human population.
- Could weight loss explain it?
- Unknown[Auto] Non-human study; weight-loss mediation not assessable.
- Study tier
- Study tier 4[Auto] Preclinical evidence; not clinical evidence for any human population.
- Assessment
- Version 1 · automatic, not yet reviewed by a person · Sep 20, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
[Auto, unreviewed; last sentences of abstract] In conclusion, this novel eNOS KO mouse + HFD model provides a rapidly developing, highly penetrant, and chemically unconfounded platform that ensures robust HFpEF induction across both sexes. This model can be readily adopted for the investigation of mechanistic insights into HFpEF pathobiology and for the study of novel HFpEF therapeutics.
01Findings
What the study reported
- Drugs
- Tirzepatide
- Primary outcome
- Not extracted
- Effect
- Not extracted
- 95% confidence interval
- Not extracted
- Follow-up
- 10 weeks
- Adverse events
- Not extracted
- Limitations
- Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.
Who was studied
- Cvd status
- cardiovascular disease present in population (see abstract)
- Metabolic syndrome
- mentioned
- Baseline condition
- heart failure with preserved ejection fraction
Study quality details
- Study design
- Preclinical (animal)
- Sample size
- not extracted
- Randomization
- no
- Blinding
- not stated
- Comparator
- not stated
- Follow up duration
- 10 weeks
- Outcome type
- unknown
- Replication
- not assessed (auto)
- Consistency with other evidence
- not assessed (auto)
- Population applicability
- VERY_INDIRECT
- Statistical precision
- not extracted
- Risk of bias
- not assessed (auto)
- Funding conflicts
- unclear
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- not reported in abstract
- Industry funded
- Unclear
- Manufacturer
- None identified
- Sponsor role
- not reported in abstract
- Author conflicts
- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a complex, multi-organ cardiometabolic syndrome lacking universally effective therapies. We developed and validated a robust murine model leveraging complete, constitutive genetic endothelial nitric oxide synthase deficiency (eNOS KO) coupled with metabolic stress via a high-fat diet (HFD) in both male and female cohorts. eNOS KO mice subjected to HFD (10 weeks for males; 15 weeks for females) developed a severe and highly reproducible cardiometabolic HFpEF phenotype. Despite preserved left ventricular ejection fraction, both sexes exhibited profound diastolic dysfunction, characterized by elevated E/e' ratios and left ventricular end-diastolic pressures (LVEDP), alongside severe exercise intolerance. Consistent with the systemic clinical syndrome, pathological remodeling extended to multi-organ damage, featuring prominent cardiac fibrosis, severe hepatic steatosis, and renal tubulointerstitial fibrosis. Finally, chronic administration of the dual GIP/GLP-1 receptor agonist tirzepatide largely reversed the hemodynamic, functional, and systemic fibrotic derangements. In conclusion, this novel eNOS KO mouse + HFD model provides a rapidly developing, highly penetrant, and chemically unconfounded platform that ensures robust HFpEF induction across both sexes. This model can be readily adopted for the investigation of mechanistic insights into HFpEF pathobiology and for the study of novel HFpEF therapeutics.