Abstract 4366302: Specific Fungal Species Supplementation Augments Right Ventricular Function in Preclinical Pulmonary Arterial Hypertension

Abstract

Introduction: Right ventricular dysfunction (RVD) is the greatest predictor of outcomes in pulmonary arterial hypertension (PAH). Inflammation is a major driver of RVD. The intestinal tract is the body’s largest immune organ and emerging evidence is linking the gut microbiome to RVD. Although there are trillions of microorganisms in the gut, little is known about role of the fungal species, or mycobiome, in RVD. We recently demonstrated that supplementation of the bacteria Lactobacillus directly augments RV function in the monocrotaline (MCT) rat model of PAH. Lactobacillus was positively correlated with abundance of the fungus Blumeria . In this study, we investigated whether supplementation of Blumeria could recapitulate the benefits of Lactobacillus . Hypothesis: Supplementation with the fungus Blumeria will enhance RV function in the monocrotaline (MCT) PAH rat model. Methods: Blumeria , which is a powdery mildew, was collected from crops in St. Paul, Minnesota. These spores were subsequently freeze-dried. Male Sprague-Dawley rats were randomly allocated to three groups: Control, MCT-Water, and MCT- Blumeria . Two weeks after MCT injection (60 mg/kg), rats received a daily oral gavage of 10 mg Blumeria or 1 mL water for ten days. Echocardiography and invasive pressure-volume loops assessed RV function and PAH severity. Small pulmonary arteriole remodeling, RV cardiomyocyte area, and RV fibrosis were evaluated histologically. Results: Despite having unaltered PAH disease severity as assessed by right ventricular systolic pressure (A, Con: 21±4, MCT-Water: 80±15, MCT- Blumeria : 77±10 mmHg, p =0.85 between MCT-Water and MCT- Blumeria ), effective arterial elastance (Ea) (B, Con: 0.04±0.01, MCT-Water: 0.34±0.09, MCT- Blumeria : 0.32±0.15, p =0.94 between MCT-Water and MCT- Blumeria ), and small pulmonary arteriole percent medial wall thickness (C, Con: 28±01, MCT-Water: 46±4, MCT- Blumeri a: 42±5%, p =0.36 between MCT-Water and MCT- Blumeria ), supplementation of Blumeria augmented RV function as assessed by elevated RV ejection fraction (RVEF) (D, Con: 91±5, MCT-Water: 71±12, MCT- Blumeria : 91±5%, p =0.0003 between MCT-Water and MCT- Blumeria ) and RV-pulmonary artery coupling (Ees/Ea) (E, Con: 1.3±0.3, MCT-Water: 0.4±0.1, MCT- Blumeria : 1.0±0.3 p =0.01 between MCT-Water and MCT- Blumeria ), and diminished RV fibrosis (F) and RV cardiomyocyte area (G). Conclusion: Altering the gut ecosystem via fungal supplementation may be a novel approach to enhancing RV function in PAH.