Abstract Body (Do not enter title and authors here): Introduction: Inflammation is a key driver in the development of pulmonary arterial hypertension (PAH). Recent studies have indicated that modulating the intestinal microbiome may be an innovative approach to mitigate systemic inflammation in PAH. The gut microbiome is a complex ecosystem consisting of trillions of organisms, 0.1% of which are fungi. The role of fungal species, or intestinal mycobiome, is undefined in PAH and is understudied in all diseases. We investigated whether the use of fluconazole, a broad-spectrum antifungal, affects the pulmonary vasculature in the monocrotaline (MCT) rat model.

Hypothesis: Fluconazole administration will alter PAH severity in a preclinical PAH model.

Methods: Three groups of male Sprague-Dawley rats were investigated: Control, MCT-vehicle (MCT-V), and MCT-fluconazole. MCT was given once subcutaneously at 60 mg/kg. Two weeks after MCT injection, MCT-fluconazole rats were administered fluconazole 20 mg/kg daily via oral gavage for ten days. Echocardiography and invasive hemodynamics defined right ventricular (RV) function and PAH severity. The pulmonary vasculature was evaluated histologically. RV hypertrophy was assessed by weight and cardiomyocyte area. Treadmill exercise testing assessed functional capacity.

Results: MCT-fluconazole rats had significantly decreased PAH disease severity with a significant reduction in RV systolic pressure (A), effective arterial elastance (B), and percent pulmonary medial wall thickness (C) compared to MCT-V. Rats administered fluconazole had augmented RV function with increased percent RV free wall thickness change (D), RV ejection fraction (E) and RV-pulmonary arterial coupling (F). Compared to MCT-V, MCT-fluconazole rats had diminished RV hypertrophy with a reduction in Fulton index (p<0.05), RV/body weight (p<0.05), and cardiomyocyte area (p<0.0001). Although MCT-fluconazole rats ran for a similar amount of time compared to MCT-V (6.5±2.6 and 5.2±3.4 seconds, respectively), they had significantly lower respiratory exchange ratios (G) and a trend towards higher maximum oxygen consumption (H)_.

Conclusion: Modulating the intestinal mycobiome may be a novel approach to diminish PAH severity.