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

Yu-Chen Wang; Yen Chin Koay; Calvin Pan; Zhiqiang Zhou; Wilson Tang; Jennifer Wilcox; Xinmin S Li; Alexia Zagouras; Francine Marques; Hooman Allayee; Federico E Rey; David M Kaye; John F O'Sullivan; Stanley L Hazen; Yang Cao; Aldons J Lusis

doi:10.1161/CIRCRESAHA.123.322381

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

Circ Res. 2024 Feb 16;134(4):371-389. doi: 10.1161/CIRCRESAHA.123.322381. Epub 2024 Jan 24.

Authors

Yu-Chen Wang¹, Yen Chin Koay^{2

3}, Calvin Pan¹, Zhiqiang Zhou¹, Wilson Tang, Jennifer Wilcox⁴, Xinmin S Li⁴, Alexia Zagouras⁵, Francine Marques⁶, Hooman Allayee⁷, Federico E Rey⁸, David M Kaye^{9

10}, John F O'Sullivan^{2

3

11

12}, Stanley L Hazen^{13

4}, Yang Cao^{14

15}, Aldons J Lusis¹

Affiliations

¹ Department of Medicine, Division of Cardiology, Department of Microbiology, Immunology and Molecular Genetics, and Department of Human Genetics, University of California, Los Angeles (Y.-C.W., C.P., Z.Z., A.J.L.).
² Cardiometabolic Medicine, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, New South Wales, Australia (Y.C.K., J.F.O.).
³ Charles Perkins Centre, Sydney, New South Wales, Australia (Y.C.K., J.F.O.).
⁴ Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, OH (J.W., X.S.L., S.L.H.).
⁵ Stanford Department of Medicine, CA (A.Z.).
⁶ School of Biological Sciences, Faculty of Medicine, Monash University, Clayton, VIC, Australia (F.M.).
⁷ Departments of Population & Public Health Sciences and Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles (H.A.).
⁸ Department of Bacteriology, University of Wisconsin-Madison (F.E.R.).
⁹ Baker Heart and Diabetes Institute, Melbourne, Australia (D.M.K.).
¹⁰ Department of Cardiology, Alfred Hospital, Melbourne, Australia (D.M.K.).
¹¹ Department of Cardiology, Royal Prince Alfred Hospital, New South Wales, Australia (J.F.O.).
¹² Faculty of Medicine, TU Dresden, Germany (J.F.O.).
¹³ Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, OH (W.H.W.T., S.L.H.).
¹⁴ Department of Cardiology, the First Affiliated Hospital of USTC (Y.C.), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
¹⁵ School of Basic Medical Sciences (Y.C.), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.

PMID: 38264909
PMCID: PMC10923103 (available on 2025-02-16)
DOI: 10.1161/CIRCRESAHA.123.322381

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is a common but poorly understood form of heart failure, characterized by impaired diastolic function. It is highly heterogeneous with multiple comorbidities, including obesity and diabetes, making human studies difficult.

Methods: Metabolomic analyses in a mouse model of HFpEF showed that levels of indole-3-propionic acid (IPA), a metabolite produced by gut bacteria from tryptophan, were reduced in the plasma and heart tissue of HFpEF mice as compared with controls. We then examined the role of IPA in mouse models of HFpEF as well as 2 human HFpEF cohorts.

Results: The protective role and therapeutic effects of IPA were confirmed in mouse models of HFpEF using IPA dietary supplementation. IPA attenuated diastolic dysfunction, metabolic remodeling, oxidative stress, inflammation, gut microbiota dysbiosis, and intestinal epithelial barrier damage. In the heart, IPA suppressed the expression of NNMT (nicotinamide N-methyl transferase), restored nicotinamide, NAD⁺/NADH, and SIRT3 (sirtuin 3) levels. IPA mediates the protective effects on diastolic dysfunction, at least in part, by promoting the expression of SIRT3. SIRT3 regulation was mediated by IPA binding to the aryl hydrocarbon receptor, as Sirt3 knockdown diminished the effects of IPA on diastolic dysfunction in vivo. The role of the nicotinamide adenine dinucleotide circuit in HFpEF was further confirmed by nicotinamide supplementation, Nnmt knockdown, and Nnmt overexpression in vivo. IPA levels were significantly reduced in patients with HFpEF in 2 independent human cohorts, consistent with a protective function in humans, as well as mice.

Conclusions: Our findings reveal that IPA protects against diastolic dysfunction in HFpEF by enhancing the nicotinamide adenine dinucleotide salvage pathway, suggesting the possibility of therapeutic management by either altering the gut microbiome composition or supplementing the diet with IPA.

Keywords: NAD; heart failure, diastolic; microbiota; niacinamide; receptors, aryl hydrocarbon.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cardiomyopathies*
Heart Failure* / metabolism
Humans
Indoles / pharmacology
Mice
NAD
Niacinamide
Propionates*
Sirtuin 3* / genetics
Stroke Volume / physiology

Substances

propionic acid
NAD
Sirtuin 3
Indoles
Niacinamide
Propionates

Abstract

Publication types

MeSH terms

Substances

Grants and funding