Elevated Plasma Bilirubin Improves Cardiac Function In Mice with Heart Failure with Preserved Ejection Fraction (HFpEF)

Heart failure with preserved ejection fraction (HFpEF) represents approximately 50% of heart failure cases. This is exacerbated by aging as a predisposing factor and the increase in prevalence of obesity and hypertension. In HFpEF, metabolic remodeling, amongst other changes, increases oxidative stress and impairs mitochondrial energetics. Bilirubin, due to its potent antioxidant and anti-inflammatory role, has been suggested to be a mediator of metabolic cardiac remodeling to regulate energy expenditure during HFpEF. Moreover, clinical studies show an inverse correlation between bilirubin and HFpEF severity. Therefore, we investigated the potential effects of bilirubin on cardiac function in a mouse model of HFpEF. HFpEF was induced using a 2-hit HFpEF mouse model (High Fat Diet;60% Kcal + L-NAME 1g/L; ) in wild-type mice (C57BL/6N), n=4-6 mice/group. Mice were then randomly assigned for vehicle or pegylated bilirubin treatment (30mg/kg, i.p., every second day) for 8 weeks. All data were analyzed with GraphPad Prism using Welch’s t-test. P values < 0.05 were considered statistically significant. There was no change in ejection fraction as expected in HFpEF (50.9±2.3 % vs 51.1±1.6 %). Yet, bilirubin-treated mice had decreased isometric volume relaxation time (IVRT, 22.1±0.4 ms vs 17.3±1.0 ms, p< 0.05), increased E/e’ (-35.1±1.6 vs -26.7±1.4, p< 0.05) and a trend to increase in cardiac output (12.2±1.0 ml/min vs 15.1±1.1 ml/min, p=0.086). Moreover, vascular compliance assessed via pulse wave measurement was improved in bilirubin-treated mice (4.9±0.4 ms vs 3.5±0.1 ms, p< 0.05). Together, our findings show that elevated bilirubin improves cardiovascular outcomes in HFpEF and could be a potential treatment for HFpEF patients. Ongoing studies will investigate the mechanism by which elevated levels of bilirubin improve cardiac metabolic and cardiovascular outcomes in HFpEF, which is poorly understood. 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.