Intermittent fasting enhances right ventricular function in preclinical pulmonary arterial hypertension

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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 monocrota-line-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.

Original languageEnglish (US)
Article numbere022722
JournalJournal of the American Heart Association
Volume10
Issue number22
DOIs
StatePublished - Nov 16 2021

Bibliographical note

Funding Information:
Echocardiography was completed at the University of Minnesota Imaging Center. We thank the University of Minnesota Histology and Research Laboratory in the Clinical and Translational Science Institute for their assis-tance with tissue processing and staining. S. Prisco is funded by National Institutes of Health (NIH) F32 HL154533, NIH T32 HL144472, a University of Minnesota Clinical and Translational Science award (NIH UL1 TR002494), and a University of Minnesota Medical School Academic Investment Educational Program Grant; Moutsoglou is funded by NIH T32 HL144472; A. Prisco is funded by NIH T32 HL144472, a University of Minnesota Institute for Engineering in Medicine COVID-19 Rapid Response Grant, a Climate Change Grant received jointly through the University of Minnesota Medical School and College of Science and Engineering, and a University of Minnesota Medical School Academic Investment Educational Program Grant; Thenappan is funded by the Cardiovascular Medical Research and Education Fund and the University of Minnesota Futures Grant; Prins is funded by NIH K08 HL140100, the Cardiovascular Medical Research and Education Fund, a Lillehei Heart Institute Cardiovascular Seed Grant, the University of Minnesota Faculty Research Development Grant, the United Therapeutics Jenesis Award, and an American Lung Association Innovative Award IA-816386.

Funding Information:
Prins served on an advisory board for Actelion and Edwards and receives grant funding from United Therapeutics. Thenappan served on an advisory board for Actelion, United Therapeutics, Altavant Sciences, and Aria CV. Thenappan receives research funding for clinical trials from United Therapeutics, Aria CV, Gossimer Bio, and Acceleron. The remaining authors have no disclosures to report.

Funding Information:
S. Prisco is funded by National Institutes of Health (NIH) F32 HL154533, NIH T32 HL144472, a University of Minnesota Clinical and Translational Science award (NIH UL1 TR002494), and a University of Minnesota Medical School Academic Investment Educational Program Grant; Moutsoglou is funded by NIH T32 HL144472; A. Prisco is funded by NIH T32 HL144472, a University of Minnesota Institute for Engineering in Medicine COVID-19 Rapid Response Grant, a Climate Change Grant received jointly through the University of Minnesota Medical School and College of Science and Engineering, and a University of Minnesota Medical School Academic Investment Educational Program Grant; Thenappan is funded by the Cardiovascular Medical Research and Education Fund and the University of Minnesota Futures Grant; Prins is funded by NIH K08 HL140100, the Cardiovascular Medical Research and Education Fund, a Lillehei Heart Institute Cardiovascular Seed Grant, the University of Minnesota Faculty Research Development Grant, the United Therapeutics Jenesis Award, and an American Lung Association Innovative Award IA-816386.

Publisher Copyright:
© 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Keywords

  • Lactobacillus
  • gut microbiome
  • intermittent fasting
  • lipotoxicity
  • metabolism
  • metabolomics
  • pulmonary arterial hypertension
  • right ventricular function

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Randomized Controlled Trial

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