Intermittent Fasting Enhances Right Ventricular Function in Preclinical Pulmonary Arterial Hypertension

Abstract

Background Intermittent fasting (IF) confers pleiotropic cardiovascular benefits including restructuring of the gut microbiome and augmentation of cellular metabolism. Pulmonary arterial hypertension (PAH) is a rare and lethal disease characterized by right ventricular (RV) mitochondrial dysfunction and resultant lipotoxicity and microbiome dysbiosis. However, the effects of IF on RV function in PAH are unexplored. Therefore, we investigated how IF altered gut microbiota composition, RV function, and survival in the monocrotaline model of PAH. Methods and Results Male Sprague Dawley rats were randomly allocated into 3 groups: control, monocrotaline‐ad libitum feeding, and monocrotaline‐IF (every other day feeding). Echocardiography and invasive hemodynamics showed IF improved RV systolic and diastolic function despite no significant change in PAH severity. IF prevented premature mortality (30% mortality rate in monocrotaline‐ad libitum versus 0% in monocrotaline‐IF rats, P =0.04). IF decreased RV cardiomyocyte hypertrophy and reduced RV fibrosis. IF prevented RV lipid accrual on Oil Red O staining and ceramide accumulation as determined by metabolomics. IF mitigated the reduction in jejunum villi length and goblet cell abundance when compared with monocrotaline‐ad libitum. The 16S ribosomal RNA gene sequencing demonstrated IF changed the gut microbiome. In particular, there was increased abundance of Lactobacillus in monocrotaline‐IF rats. Metabolomics profiling revealed IF decreased RV levels of microbiome metabolites including bile acids, aromatic amino acid metabolites, and gamma‐glutamylated amino acids. Conclusions IF directly enhanced RV function and restructured the gut microbiome. These results suggest IF may be a non‐pharmacological approach to combat RV dysfunction, a currently untreatable and lethal consequence of PAH.

Metabolic Reprogramming of the Right Ventricle and Pulmonary Arteries in a Flow-Associated Pulmonary Arterial Hypertension Rat Model

“…PAH, a rare but lethal disease, has been increasingly recognized as a systemic disorder characterized by metabolic derangements. , Since the lungs are the primary target organ of PAH, the pathological alteration in PAs has been the traditional subject of most of the intensive research studies. However, the structural remodeling of the RV, which plays a pivotal role in controlling the clinical course of PAH, has not been sufficiently studied from the metabolic perspective.…”

Glyoxylase-1 combats dicarbonyl stress and right ventricular dysfunction in rodent pulmonary arterial hypertension

“…In addition, we show GLO1 overexpression increases the levels of both subunits of the mitochondrial trifunctional protein (HADHA and HADHB), which implies glycation of these proteins may alter their stability and subsequently impair FAO. This could be another mechanism underlying lipid accumulation observed in the RV in PAH (26,31). Finally, carnitine O-acetyltransferase (CRAT), an enzyme essential for import of acylcarnitines into the mitochondria for subsequent degradation, was also identified in the proteomics screen.…”

“…A high-fidelity catheter (Scisense 1.9F pressure-volume, Transonic Systems, Ithaca, NY) was placed into the RV via the right internal jugular vein in anesthetized rats as we have previously described ( 20 , 25 , 26 ). From PV loop recordings with and without pressure on the inferior vena cava, we determined pulmonary arterial elastance (Ea), RV contractility as represented by end-systolic elastance (Ees), and RV-PA coupling as assessed by Ees/Ea.…”

Intermittent Fasting Activates AMP-Kinase to Restructure Right Ventricular Lipid Metabolism and Microtubules in Two Rodent Models of Pulmonary Arterial Hypertension

“…Animals studies were performed as previously described 10 . Briefly, male Sprague Dawley rats, purchased from Charles River Laboratories, were randomized into three experimental groups: phosphate buffered saline (PBS) injected (control), monocrotaline- ad libitum , and monocrotaline-IF.…”

“…A highfidelity catheter (Scisense 1.9F pressure-volume, Transonic Systems, Ithaca, NY) was placed into the RV via the right internal jugular vein. RV pressure and volume were measured with the Transonic AV500 Pressure-Volume Measurement System and then analyzed on LabScribe version 4 (iWorx Systems, Dover, NH) as we have previously described 7,10,19 . Relative abundance of each protein in proteomics studies was determined with Scaffold Software and those values were used for both analyses.…”