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. 2023 Jul;11(7):810-821.
doi: 10.1016/j.jchf.2023.03.008. Epub 2023 Apr 26.

Microbially Produced Imidazole Propionate Is Associated With Heart Failure and Mortality

Antonio Molinaro  1 , Ina Nemet  2 , Pierre Bel Lassen  3 , Rima Chakaroun  4 , Trine Nielsen  5 , Judith Aron-Wisnewsky  3 , Per-Olof Bergh  6 , Lin Li  2 , Marcus Henricsson  6 , Lars Køber  7 , Richard Isnard  8 , Gerard Helft  9 , Michael Stumvoll  10 , Oluf Pedersen  5 , J Gustav Smith  11 , W H Wilson Tang  12 , Karine Clément  3 , Stanley L Hazen  12 , Fredrik Bäckhed  13 ; MetaCardis Consortium
Collaborators, Affiliations

Microbially Produced Imidazole Propionate Is Associated With Heart Failure and Mortality

Antonio Molinaro et al. JACC Heart Fail. 2023 Jul.

Abstract

Background: Over the past years, it has become clear that the microbial ecosystem in the gut has a profound capacity to interact with the host through the production of a wide range of bioactive metabolites. The microbially produced metabolite imidazole propionate (ImP) is clinically and mechanistically linked with insulin resistance and type 2 diabetes, but it is unclear how ImP is associated with heart failure.

Objectives: The authors aimed to explore whether ImP is associated with heart failure and mortality.

Methods: ImP serum measurements in 2 large and independent clinical cohorts of patients (European [n = 1,985] and North American [n = 2,155]) with a range of severity of cardiovascular disease including heart failure. Univariate and multivariate Cox regression analyses were performed to delineate the impact of ImP on 5-year mortality in the North American cohort, independent of other covariates.

Results: ImP is independently associated with reduced ejection fraction and heart failure in both cohorts, even after adjusting for traditional risk factors. Elevated ImP was a significant independent predictor of 5-year mortality (for the highest quartile, adjusted HR: 1.85 [95% CI: 1.20-2.88]; P < 0.01).

Conclusions: The gut microbial metabolite ImP is increased in individuals with heart failure and is a predictor of overall survival.

Keywords: heart failure; histidine; imidazole propionate; microbiota.

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Conflict of interest statement

Funding Support and Author Disclosures This study was supported by the Transatlantic Networks of Excellence Award from the Leducq Foundation (17CVD01), FP7-sponsored program MetaCardis (305312), JPI (A healthy diet for a healthy life; 2017-01996_3), Swedish Heart Lung Foundation (20210366), Swedish Research Council (2019-01599), AFA insurances (160337), Knut and Alice Wallenberg Foundation (2017.0026), the Novo Nordisk Foundation (NNF15OC0016798), grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-718101 and ALFGBG-934173), and Bengt Ihre fellowship program. This work was also supported in part by grants from the National Institutes of Health (NIH) and the Office of Dietary Supplements (P01-HL147823, R01-HL103866, R01HL126827). The European clinical study is sponsored by Assistance Publique Hopitaux de Paris. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research institution at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation. Drs Bäckhed and Molinaro are shareholders in Implexion pharma AB. Dr Bäckhed is Torsten Söderberg Professor in Medicine and Wallenberg Scholar; and has received research funds from Biogaia AB. Dr Clément is a consultant for Danone Research and LNC therapeutics for work unassociated with the present study; and has held a collaborative research contract with Danone Research in the context of MetaCardis project. Dr Hazen has been named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics; has been a paid consultant for Zehna Therapeutics; has received research funds from Zehna Therapeutics, Procter and Gamble, and Roche Diagnostics; and has been eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Zehna Therapeutics, Cleveland HeartLab, a fully owned subsidiary of Quest Diagnostics, and Procter and Gamble. Dr Tang is a consultant for Sequana Medical A.G., Cardiol Therapeutics Inc, and Genomics plc; and has received honorarium from Springer Nature for authorship and editorship and the American Board of Internal Medicine for examination writing committee participation, all unrelated to the subject and contents of this paper. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

FIGURE 1
FIGURE 1. Imidazole Propionate in Individuals With Cardiovascular Diseases in the European Cohort
(A) Serum levels of imidazole propionate in individuals without CVD and HF (n = 1,569), with CVD (n = 282), and with HF (n = 134). P values were calculated using Kruskal-Wallis H test, **P < 0.01, ***P < 0.001. (B) Serum levels of imidazole propionate according to percentage of LVEF; P values were calculated with linear regression model after adjustment for risk factors and other baseline covariates: age, sex, BMI, ethnicity, diabetes status, smoking status, systolic blood pressure, use of statins, serum levels of HDL, LDL, triglycerides, and eGFR). BMI = body mass index; CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; HDL = high-density lipoprotein; HF = heart failure; LDL = low-density lipoprotein; LVEF = left ventricular ejection fraction.
FIGURE 2
FIGURE 2. Imidazole Propionate in Individuals With Cardiovascular Diseases in the North American Cohort
(A) Serum levels of imidazole propionate in individuals without CVD and HF (n = 417), with CVD (n = 1,331), and with HF (n = 407) (P values were calculated using Kruskal-Wallis H test, ***P < 0.001). (B) Serum levels of imidazole propionate according to percentage of LVEF (P values were calculated with linear regression model after adjustment for risk factors and other baseline covariates: age, sex, BMI, ethnicity, diabetes status, smoking status, systolic blood pressure, use of statins, circulating levels of HDL, LDL, triglycerides, and eGFR). Abbreviations as in Figure 1.
FIGURE 3
FIGURE 3. Serum Imidazole Propionate Levels Affect Survival in the North American Cohort
(A) Serum levels of imidazole propionate levels among patients alive (Yes; n = 1,909) or not (No; n = 246) at 5-year follow-up (FU). P values were calculated using Mann-Whitney-U-test). Kaplan-Meier estimates (B) and Forrest plot (C) the risk of all-cause mortality at 5-year follow-up according to quartiles (Q) of imidazole propionate. The 5% to 95% CI is indicated by line length. *P < 0.05, **P < 0.01, ***P < 0.001. See Supplemental Table 5.
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