TY - JOUR
T1 - Intermittent fasting enhances right ventricular function in preclinical pulmonary arterial hypertension
AU - Prisco, Sasha Z.
AU - Eklund, Megan
AU - Moutsoglou, Daphne M.
AU - Prisco, Anthony R.
AU - Khoruts, Alexander
AU - Weir, E. Kenneth
AU - Thenappan, Thenappan
AU - Prins, Kurt W.
N1 - Publisher Copyright:
© 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
PY - 2021/11/16
Y1 - 2021/11/16
N2 - 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.
AB - 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.
KW - Lactobacillus
KW - gut microbiome
KW - intermittent fasting
KW - lipotoxicity
KW - metabolism
KW - metabolomics
KW - pulmonary arterial hypertension
KW - right ventricular function
UR - http://www.scopus.com/inward/record.url?scp=85120774736&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85120774736&partnerID=8YFLogxK
U2 - 10.1161/JAHA.121.022722
DO - 10.1161/JAHA.121.022722
M3 - Article
C2 - 34747187
AN - SCOPUS:85120774736
SN - 2047-9980
VL - 10
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 22
M1 - e022722
ER -