Intestinal Microbiota-Dependent Phosphatidylcholine Metabolites, Diastolic Dysfunction, and Adverse Clinical Outcomes in Chronic Systolic Heart Failure
Open accessAbstract
Background Trimethylamine-N-oxide (TMAO) has been linked to increased cardiovascular risk. We aimed to determine the prognostic value of TMAO and its dietary precursors, choline and betaine, in heart failure (HF). Methods and results In 112 patients with chronic systolic HF with comprehensive echocardiographic evaluation, we measured plasma TMAO, choline, and betaine by mass spectrometry. Median (interquartile range) TMAO levels, choline, and betaine levels were 5.8 (3.6-12.1) μmol/L, 10.9 (8.4-14.0) μmol/L, and 43.8 (37.1-53.0) μmol/L, respectively, and were correlated with each other (all P < .0001 for both). TMAO levels were significantly higher in patients with diabetes mellitus (9.4 [4.9-13.2] vs 4.8 [3.4-9.8] μmol/L; P = .005) and in subjects with New York Heart Association functional class III or greater (7.0 [4.7-14.8] vs 4.7 [3.4-11.3] μmol/L; P = .02). Elevated TMAO, choline, and betaine levels were each associated with higher plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and more advanced left ventricular diastolic dysfunction, but not systolic dysfunction or inflammatory and endothelial biomarkers. Higher choline (hazard ratio [HR] 1.64, 95% CI 1.22-2.20; P = .001), betaine (HR 1.51, 95% CI 1.10-2.08; P = .01), and TMAO (HR 1.48, 95% CI 1.10-1.96; P = .01) predicted increased risk for 5-year adverse clinical events (death/transplantation). Only higher TMAO levels predicted incident adverse clinical events independently from age, estimated glomerular filtration rate, mitral E/septal Ea, and NT-proBNP levels (HR 1.46, 95% CI 1.03-2.14; P = .03). Conclusion Elevated plasma TMAO, choline, and betaine levels are each associated with more advanced left ventricular diastolic dysfunction and portend poorer long-term adverse clinical outcomes in chronic systolic HF. However, only higher plasma TMAO was associated with poor prognosis after adjustment for cardiorenal indices.
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TMAO levels are associated with cardiovascular disease risks in a variety of cohorts.
“Numerous recent case–control and longitudinal studies have shown a striking association between trimethylamine N‐oxide (TMAO) levels and cardiovascular disease risks in a variety of cohorts.1, 2, 3, 4, 5, 6, 7, 8, 9, 10”
From Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB (2016) · cites this paper as [5]
High levels of TMAO precursors choline and betaine are independently associated with prevalence and poor prognosis in CVD even after adjustment for cardiovascular risk factors.
“High levels of TMAO precursors like choline and betaine also seem to be independently associated with prevalence and poor prognosis in CVD even after adjustment for cardiovascular risk factors [56].”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [56]
All included studies were clinical cohorts, including patients at higher cardiovascular risk, enriched for baseline heart disease, kidney disease, peripheral artery disease, or diabetes mellitus.
“All of the studies included clinical cohorts, including patients at higher cardiovascular risk, that is, enriched for baseline heart disease,3, 8, 12, 13, 14, 15, 16, 17, 21 kidney disease,10, 11, 18, 19, 20, 22, 23 peripheral artery disease,25 or diabetes mellitus.7, 26”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [12]
Multiple human and animal studies support mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks.
“multiple human and animal studies supporting both mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks have been reported8–16.”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [13]
TMAO functions as a protein conformation altering small molecule (protein chaperone mimetic).
“TMAO is known to function as a protein conformation altering small molecule (i.e., a protein chaperone mimetic)176.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [176]
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- Authors
- Tang, W. H. W., Wang, Z., Shrestha, K., Borowski, A. G., Wu, Y., Troughton, R. W., Klein, A. L., & Hazen, S. L.
- Affiliations
- Cleveland Clinic (US)
- Cleveland Clinic Research (US)
- Cleveland State University (US)
- Corresponding author
- Tang, W.H. Wilson
- Venue
- Journal of Cardiac Failure
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 21
- Issue
- 2
- Pages
- 91-96
- ISSN
- 1071-9164 (ISSN-L)
- PMC
- PMC4312712
- OpenAlex
- W2035241321
- Cited by
- 325
- References
- 19
- Citations by year
- 2026: 6 · 2025: 21 · 2024: 21 · 2023: 27 · 2022: 36 · 2021: 29 · 2020: 37 · 2019: 34 · 2018: 35 · 2017: 36 · 2016: 24 · 2015: 19
- FWCI
- 18.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cardiac Failure (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- EngagedScholarship @ Cleveland State University (Cleveland State University) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (UL1TR000439)
- National Heart, Lung, and Blood Institute (P01HL103453, R01HL103931, U10HL109250, P20HL113452, P01HL076491, P01HL098055, R24HL123767, R01HL103866)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- trimethylamine N-oxide, choline, betaine, chronic systolic heart failure, left ventricular diastolic dysfunction, prognosis, adverse clinical outcomes, gut microbiota, dietary precursors, diabetes mellitus, cardiovascular risk markers, echocardiography
- MeSH terms
- Adult, Aged, Betaine, Blood Pressure, Choline, Chronic Disease, Female, Humans, Intestinal Mucosa, Male, Methylamines, Middle Aged, Phosphatidylcholines, Prospective Studies, Risk Factors, Cohort Studies, Biomarkers, Treatment Outcome, Heart Failure, Systolic, Microbiota
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