Male BPH/2J Mice Develop Heart Failure With Mildly Reduced Ejection Fraction and Cardiac Microvascular Rarefaction Later in Life

Introduction: Heart failure (HF) is a growing health and economic burden in the United States, affecting approximately 6.7 million adults. Although there is no consensus about sex differences in HF with mildly reduced ejection fraction (HFmrEF) prevalence, this condition is aggravated by endothelial cell (EC) microvascular rarefaction. HF with preserved ejection fraction (HFpEF) is prevalent in women, and although several animal models of HFpEF exist, there are still limitations in understanding how hypertension triggers the development of this disease. We hypothesize that male but not female BPH/2J mice develop HFmrEF later in life with cardiac EC microvascular rarefaction. Our goals were to determine the spontaneous development of HF in BPH/2J mice, and the contribution of cardiac ECs in the sex-dependent outcomes of HF. Methods: Male and female BPN/3J and BPH/2J mice (6 weeks and 1.5 years of age) were investigated for their blood pressure by carotid artery catheterization (1% of isoflurane) or radiotelemetry. Cardiac function (left vetricular ejection fraction - LVEF, cardiac output - CO, myocardial performance index – (MPI) were assessed by echocardiography. Cardiac EC were evaluated in the LV by immunofluorescence. Data are shown as mean S.E.M., and analyzed by Two-way ANOVA, with Tukey post-hoc ( p <0.05). Results: Normotensive BPH/2J mice at 6 weeks of age showed systolic and diastolic dysfunction compared to the control (LVEF male BPN/3J: 81.05±1.27%; BPH/2J: 63.67±3.50%*; female BPN/3J: 77.68±2.18%; BPH/2J: 68.75±2.86%; CO male BPN/3J: 10.23±0.68mL/min; BPH/2J: 12.95±0.61mL/min*; female BPN/3J: 10.38±0.57mL/min; BPH/2J: 11.40±0.55mL/min; MPI male BPN/3J: 0.69±0.03; BPH/2J: 0.70±0.04; female BPN/3J: 0.69±0.03; BPH/2J: 0.86±0.06*; n=6-13 * p <0.05). However, at 1.5 years of age, both male and female BPH/2J mice were hypertensive (systolic blood pressure BPN/3J male: 127.1±1.4mmHg; female: 115.6±1.9mmHg; BPH/2J male: 158.0±1.7mmHg # ; female: 152.7±2.5 # ; n=4 # p <0.05), and developed HF in a sex-dependent manner. Specifically, male BPH/2J mice showed HFmrEF (LVEF male BPN/3J: 69.43±3.56%; BPH/2J: 43.28±1.21% # ; CO male BPN/3J: 11.84±1.37mL/min; BPH/2J: 14.69±1.00mL/min # ; n=6-14 # p <0.05), and female BPH/2J developed HFpEF (LVEF female BPN/3J: 63.38±5.60%; BPH/2J: 51.35±3.13% # ; CO female BPN/3J: 12.49±1.77mL/min; BPH/2J: 13.70±1.17mL/min; n=6-11 # p <0.05). Cardiac EC rarefaction was only observed in males (BPN/3J male: 7.36±0.31%; BPH/2J male: 5.20±0.36% # ; n=8 # p <0.05). Conclusion: Taken together, the results reveal for the first time that male and female BPH/2J mice spontaneously develop HF induced by hypertension. Cardiac microvascular rarefaction may contribute to the sex-dependent outcomes of HF in BPH/2J mice. Funding: 1R01HL149762; 1R21AG085331-01; AARG-NTF-23-114509. This abstract was presented at the American Physiology Summit 2025 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.