Indole-3-Propionic Acid Protects Against Heart Failure With Preserved Ejection Fraction

Area of Science:

• Cardiology
• Metabolomics
• Microbiome Research

Background:

• Heart failure with preserved ejection fraction (HFpEF) is a complex condition with impaired diastolic function.
• HFpEF is characterized by heterogeneity and multiple comorbidities like obesity and diabetes, complicating research.
• Reduced levels of indole-3-propionic acid (IPA), a gut bacteria metabolite, were observed in HFpEF models.

Purpose of the Study:

• To investigate the role of indole-3-propionic acid (IPA) in heart failure with preserved ejection fraction (HFpEF).
• To evaluate the therapeutic potential of IPA in HFpEF mouse models and human cohorts.

Main Methods:

• Metabolomic analysis in HFpEF mouse models to identify reduced IPA levels.
• Dietary supplementation with IPA in HFpEF mouse models.
• Examination of IPA levels in two independent human HFpEF cohorts.
• Investigated the mechanism involving nicotinamide N-methyl transferase (NNMT), nicotinamide adenine dinucleotide (NAD+)/NADH, and sirtuin 3 (SIRT3).

Main Results:

• IPA supplementation attenuated diastolic dysfunction, inflammation, oxidative stress, and gut dysbiosis in HFpEF mice.
• IPA restored nicotinamide, NAD+/NADH, and SIRT3 levels in the heart by suppressing NNMT.
• IPA's protective effects were mediated via aryl hydrocarbon receptor and SIRT3, confirmed by knockdown studies.
• Significantly reduced IPA levels were found in human HFpEF patients.

Conclusions:

• IPA demonstrates protective effects against diastolic dysfunction in HFpEF.
• IPA enhances the nicotinamide adenine dinucleotide salvage pathway.
• Therapeutic strategies could involve modulating gut microbiota or IPA dietary supplementation for HFpEF.