DOCA-salt and Ang+HFD mouse models recapitulated clinical HFpEF features, including increased fibrosis compared to controls (6.38±0.67 vs 3.25±0.41, p<0.01 and 7.65±1.11 vs 2.83±0.91, p<0.01).
DOCA-salt and Ang-HFD mouse models better recapitulate clinical HFpEF features compared to the LNAME+HFD model, highlighting the need for careful model selection in preclinical studies.
There are various pre-clinical models of heart failure with preserved ejection fraction (HFpEF) designed to model different clinical phenotypes of HFpEF. However, detailed assessment and head-to-head comparison of these models is lacking. Our goal was to comprehensively evaluate the HFpEF phenotype in three previously-published HFpEF mouse models – deoxycortisterone acetate (DOCA)-salt, Nω-nitro-l-arginine methyl ester + high fat diet (LNAME+HFD), and aged female mice fed HFD with angiotensin II infusion (Ang+HFD) – in the commonly used C57BL/6J mouse, enabling direct comparisons between models. HFpEF features assessed included exercise testing, echocardiography, cardiac magnetic resonance (CMR) imaging, left ventricular catheterization, pulmonary congestion, cardiac hypertrophy and histological quantification. Mann-Whitney test was used for statistical testing within each model. All models exhibited decline in exercise capacity, evidence of diastolic dysfunction on echocardiography, preserved ejection fraction, and cardiac hypertrophy when measured by heart weight to tibia length ratio. CMR was notable for findings of reduced right ventricular ejection fraction (36.1±2.7% vs 49.8±1.4% in chow controls, p< 0.01) in the LNAME+HFD group. Only DOCA-salt and Ang-HFD demonstrated worsened diastolic function on invasive hemodynamics – DOCA-salt had a higher LV diastolic time constant (t, 11.7±1.4 vs 6.9±0.8 ms in sham controls, p=0.02) and Ang+HFD had a higher minimum rate of pressure change in the ventricle (dP/dtmin, -3506±342 vs -5268±227 in chow fed, vehicle infusion controls, p< 0.01).Pulmonary congestion was assessed by the lung wet-to-dry ratio and only DOCA-salt had a significantly higher ratio compared to sham controls (5.01±0.11 vs 4.55±0.16, p = 0.04). On histological analysis, all 3 models exhibited cardiomyocyte hypertrophy by cross-sectional area analysis; however, only DOCA-salt and Ang+HFD had increased fibrosis (6.38±0.67 vs 3.25±0.41, p < 0.01 and 7.65±1.11 vs 2.83±0.91, p < 0.01 respectively). In conclusion, we found that DOCA-salt and Ang-HFD model recapitulated nearly all features of clinical HFpEF. The LNAME+HFD model in the C57BL/6J mouse did not demonstrate diastolic dysfunction on invasive hemodynamics, pulmonary congestion, or cardiac fibrosis. Findings of decreased RV systolic function suggest significant pulmonary disease in the LNAME+HFD model. More broadly, these results highlight differences in HFpEF phenotype in mouse models and the need for comprehensive and systematic assessment in pre-clinical studies. This study is supported by the American Heart Association (24CDA1278132 to JWW) and the National Institutes of Health (1T32GM007569 to JWW, R01HL159487 to ACD, and R01HL161212 to MSM). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Wassenaar et al. (Fri,) conducted a other in Heart failure with preserved ejection fraction (HFpEF). DOCA-salt, LNAME+HFD, and Ang+HFD models vs. Sham or chow-fed vehicle infusion controls was evaluated on HFpEF phenotype features including exercise capacity, echocardiography, CMR, invasive hemodynamics, pulmonary congestion, and histology. DOCA-salt and Ang+HFD mouse models recapitulated clinical HFpEF features, including increased fibrosis compared to controls (6.38±0.67 vs 3.25±0.41, p<0.01 and 7.65±1.11 vs 2.83±0.91, p<0.01).
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