Gut-Heart Axis Dysfunction Drives Systemic Inflammation in a Murine HFpEF Model

Background: Heart failure with preserved ejection fraction (HFpEF) affects half of the 6.7 million HF patients in the U.S. and is often accompanied by hypertension, obesity, and diabetes. This debilitating syndrome is marked by low-grade, chronic systemic inflammation that drives endothelial dysfunction, reducing nitric oxide (NO) bioavailability for cardiomyocytes. However, the underlying source of this inflammation remains largely unclear. Methods: We established a HFpEF model in 8-week-old male and female C57BL6/J mice by administering 1% saline in drinking water, subcutaneous Deoxycorticosterone acetate pellets (0.83 mg/day), and a high-fat diet (60% fat) for 6 weeks. Control mice received a chow diet and regular water. Cardiac function was evaluated via echocardiography, while colon measurements and histological analyses (H&E for crypt length, Periodic Acid–Schiff staining for mucus thickness) assessed gut morphology. Plasma levels of lipopolysaccharides (LPS) and C-reactive protein (CRP) were quantified using ELISA, and eNOS phosphorylation and NOX2 expression were analyzed by Western blotting. Results: Echocardiography confirmed the HFpEF phenotype, characterized by preserved ejection fraction (EF > 50%) and diastolic dysfunction, including reduced e’ velocity (23.1±1.5 vs. 17.8±0.8 mm/s, p<0.01), elevated E/e' ratio (26.1±1.0 vs. 36.5±1.5, p<0.0001), and decreased isovolumetric relaxation time (IVRT: 17.9±0.8 vs. 20.8±0.9 ms, p<0.01). Additionally, cardiac output (CO) was significantly reduced (17.4±0.8 vs. 14.2±0.2 ml/min, p<0.01), reflecting the presence of heart failure. HFpEF mice exhibited significant gut dysfunction, as evidenced by reduced colon length (78.9±1.6 vs. 65.3±0.9 mm, p<0.0001), decreased colon mass (0.2±0.01 vs. 0.15±0.01 g, p<0.0001), and histological abnormalities, including crypt atrophy (89.2±3.8 vs. 50.7±2.7 µm, p<0.0001), fewer goblet cells (145.3±5.6 vs. 118.8±5.9, p<0.01), and a thinner mucus layer (5.9±0.2 vs. 3.4±0.5 µm, p<0.0001). Plasma markers of gut-derived endotoxemia, such as LPS, were significantly elevated (115±13 vs. 182±23, ng/ml p<0.05), along with systemic inflammatory markers like CRP (2.59±0.02 vs. 2.68±0.03, mg/dl p<0.05). Additionally, increased NOX2 expression (0.02±0.004 vs. 1.9±0.41 a.u., p<0.01) and reduced eNOS phosphorylation (0.45±0.04 vs. 0.12±0.01, a.u. p<0.0001) were observed, suggesting increased ROS production and diminished NO bioavailability. Control vs. HFpEF data are presented as mean ± SEM and analyzed using Student’s t-test. Conclusions: Our data suggests that in this model, the reduced CO in HFpEF triggers intestinal hypoperfusion, resulting in intestinal atrophy, reduced mucus thickness and compromising the integrity of the intestinal lining. This compromised mucus and intestinal barrier facilitate bacterial translocation into the bloodstream, leading to a pro-inflammatory state, oxidative stress and impaired NO signaling further exacerbate HFpEF pathophysiology. K01HL155241 and AHA CDA849387 to PCR 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.