Abstract 9773: Intermittent Fasting Enhances Right Ventricular Function in Preclinical Pulmonary Arterial Hypertension

Abstract

Introduction: Intermittent fasting (IF) confers pleotropic cardiovascular benefits including restructuring the gut microbiome and augmenting metabolism. Pulmonary arterial hypertension (PAH) is a rare and lethal disease characterized by right ventricular (RV) mitochondrial dysfunction and resultant lipotoxicity and microbiome dysbiosis. The effects of IF on RV function in PAH are unexplored. Hypothesis: IF restructures the gut microbiome, normalizes the microbiota metabolites in the RV, and improves RV function and survival in monocrotaline (MCT) rats. Methods: Male SD rats were randomly allocated into 3 groups: control, MCT- ad lib feeding, and MCT-IF (every other day feeding). 16S ribosomal RNA sequencing of stool evaluated the microbiome. Jejunal epithelium was evaluated with H&E staining. RV metabolomics assessed microbiome metabolites. RV Oil Red O, H&E, and trichrome staining evaluated lipotoxicity, cardiomyocyte hypertrophy, and fibrosis, respectively. RV function was determined by echocardiography and closed-chest pressure-volume (PV) loops. Lung H&E staining evaluated pulmonary vascular remodeling. Results: IF changed the microbiome, with increased abundance of Lactobacillus . IF mitigated the reduction in jejunum villi length and goblet cell abundance when compared to MCT- ad lib . Metabolomics profiling revealed IF decreased RV levels of microbiome metabolites (bile acids, aromatic amino acid metabolites, and γ-glutamylated amino acids). When probing RV metabolism, IF prevented RV lipid accrual on Oil Red O staining and ceramide accumulation as determined by metabolomics. IF decreased RV cardiomyocyte hypertrophy and reduced RV fibrosis. Echocardiography and PV loops showed IF improved RV systolic and diastolic function despite no significant change in PAH severity. There was a slight but significant decline in histological pulmonary vascular remodeling (MCT- ad lib : 52±11 vs MCT-IF: 47±12%). IF ultimately prevented premature mortality (30% mortality rate in MCT- ad lib vs 0% in MCT-IF rats). Conclusions: IF restructured the microbiome and directly enhanced RV function. These results suggest IF may be a non-pharmacological approach to combat RV dysfunction, a currently untreatable and lethal consequence of PAH.