Prognostic Value of Elevated Levels of Intestinal Microbe-Generated Metabolite Trimethylamine-N-Oxide in Patients With Heart Failure
Open accessAbstract
Background Altered intestinal function is prevalent in patients with heart failure (HF), but its role in adverse outcomes is unclear. Objectives This study investigated the potential pathophysiological contributions of intestinal microbiota in HF. Methods We examined the relationship between fasting plasma trimethylamine-N-oxide (TMAO) and all-cause mortality over a 5-year follow-up in 720 patients with stable HF. Results The median TMAO level was 5.0 μM, which was higher than in subjects without HF (3.5 μM; p < 0.001). There was modest but significant correlation between TMAO concentrations and B-type natriuretic peptide (BNP) levels (r = 0.23; p < 0.001). Higher plasma TMAO levels were associated with a 3.4-fold increased mortality risk. Following adjustments for traditional risk factors and BNP levels, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio [HR]: 2.2; 95% CI: 1.42 to 3.43; p < 0.001), as well as following the addition of estimated glomerular filtration rate to the model (HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.001). Conclusions High TMAO levels were observed in patients with HF, and elevated TMAO levels portended higher long-term mortality risk independent of traditional risk factors and cardiorenal indexes.
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- Findingown data
In patients with heart failure, fasting plasma TMAO is strongly inversely correlated with eGFR.
“stronger inverse correlation between TMAO and eGFR (r = −0.55, p <0.001) in our study cohort.”
Quote in the paperNot a substantial claim - Findingown data
Adding TMAO to a model of traditional cardiovascular risk factors trends toward improvement in AUC (0.723 to 0.741, p = 0.096).
“and trended towards improvement in AUC (0.723 to 0.741, p = 0.096).”
Quote in the paperNot a substantial claim - Findingown data
In patients with heart failure, elevated TMAO remains predictive of 5-year mortality after adjustment for traditional risk factors and BNP (HR 2.2; 95% CI 1.42 to 3.43; p < 0.001).
“Following adjustments for traditional risk factors and BNP, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio [HR]: 2.2; 95% confidence interval [CI]: 1.42 to 3.43; p < 0.001)”
- Also stated in: § BASELINE CHARACTERISTICS · plain
“elevated fasting TMAO levels were associated with a 2.2-fold increase in mortality risk after adjusting for traditional risk factors and BNP (HR: 2.20; 95% CI: 1.42 to 3.43; p < 0.01)”
Quote in the paperSubstantial claim - Also stated in: § BASELINE CHARACTERISTICS · plain
- Findingown data
Within the intermediate BNP range, the lower two tertiles of TMAO are associated with a 3.3-fold increased mortality risk compared with both low BNP and TMAO levels.
“Interestingly within the intermediate BNP range (second tertile 160–505 pg/ml), the lower two tertiles of TMAO portend a 3.3-fold increase in mortality risk (95% CI: 1.4 to 8; p < 0.001), while the highest TMAO tertile (>7.2 μM) had a 5.7-fold increased mortality risk (95% CI: 2.5 to 13.2; p< 0.01) compared to both low BNP and TMAO levels.”
Quote in the paperSubstantial claim - Findingown data
In patients with heart failure, fasting plasma TMAO is modestly positively correlated with BNP.
“There was modest but significant correlation between TMAO and B-type natriuretic peptide (BNP) (r = 0.23; p < 0.001).”
- Also stated in: § BASELINE CHARACTERISTICS · plain
“We found relatively modest but significant correlation between TMAO and BNP (r = 0.23; p < 0.001)”
Quote in the paperNot a substantial claim - Also stated in: § BASELINE CHARACTERISTICS · plain
- Findingown data
In patients with heart failure, higher continuous TMAO is associated with increased 5-year all-cause mortality after adjustment for traditional cardiac risk factors (HR 1.18 per SD; 95% CI 1.06 to 1.31; p < 0.01).
“As a continuous variable, an increase in TMAO levels was associated with increased mortality risk at 5 years after adjusting for traditional cardiac risk factors (HR: 1.18; 95% CI: 1.06 to 1.31 per SD; p < 0.01)”
Quote in the paperSubstantial claim - Findingown data
Within the intermediate BNP range, the highest TMAO tertile is associated with a 5.7-fold increased mortality risk compared with both low BNP and TMAO levels.
“Interestingly within the intermediate BNP range (second tertile 160–505 pg/ml), the lower two tertiles of TMAO portend a 3.3-fold increase in mortality risk (95% CI: 1.4 to 8; p < 0.001), while the highest TMAO tertile (>7.2 μM) had a 5.7-fold increased mortality risk (95% CI: 2.5 to 13.2; p< 0.01) compared to both low BNP and TMAO levels.”
Quote in the paperSubstantial claim - Findingown data
In patients with heart failure, median fasting plasma TMAO level is higher than in non-HF healthy controls.
“Median TMAO level was 5.0 μM, which was higher than in non-HF subjects (3.5 -μM; p < 0.001).”
- Also stated in: § BASELINE CHARACTERISTICS · plain
“The median TMAO level within the HF cohort was 5.0 μM (IQR 3.0 to 8.5 μM), which is higher than that in the healthy control cohort (3.5 μM [IQR 2.3 to 5.7 μM]; p < 0.001; Central Illustration).”
- Also stated in: § CONCLUSIONS · plain
“Patients with HF have elevated TMAO levels compared to those without HF.”
Quote in the paperSubstantial claim- Rests on an assumption: The healthy control cohort is comparable to the heart failure cohort except for heart failure status, so the observed TMAO difference reflects heart failure.
- Also stated in: § BASELINE CHARACTERISTICS · plain
- Findingown data
In patients with heart failure, elevated TMAO remains predictive of mortality after additional adjustment for eGFR (HR 1.75; 95% CI 1.07 to 2.86; p < 0.05).
“and a 1.80-fold increase in mortality risk even after adjusting for traditional risk factors and BNP plus eGFR (HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.05)”
Quote in the paperSubstantial claim - Findingown data
Adding TMAO to a model of traditional cardiovascular risk factors improves net reclassification for mortality (IDI 16.0%, p < 0.001; NRI 10.9%, p < 0.001).
“Addition of TMAO to a model of traditional cardiovascular risk factors showed elevated TMAO levels significantly improved net reclassification (integrated discrimination improvement 16.0%; p < 0.001; net reclassification index 10.9%; p < 0.001)”
Quote in the paperSubstantial claim - Findingown data
In patients with heart failure, elevated TMAO remains predictive of mortality after additional adjustment for hsCRP (HR 1.85; 95% CI 1.14 to 3.00; p < 0.05).
“and plus hsCRP (HR: 1.85; 95% CI: 1.14 to 3.00; p < 0.05)”
Quote in the paperSubstantial claim - Findingown data
In patients with heart failure, higher plasma TMAO level is associated with a 3.4-fold increased mortality risk in the highest versus lowest quartile.
“Higher plasma TMAO level was associated with a 3.4-fold increased mortality risk.”
- Also stated in: § BASELINE CHARACTERISTICS · plain
“elevated TMAO levels are associated with increased mortality risk within the HF cohort (quartile 4 vs. 1, HR: 3.42; 95% CI: 2.24 to 5.23; p < 0.001).”
Quote in the paperSubstantial claim - Also stated in: § BASELINE CHARACTERISTICS · plain
- Interpretationown data
Elevated TMAO portends higher long-term mortality in heart failure patients independent of traditional risk factors, BNP, and renal function.
“Elevated fasting TMAO levels portend higher long-term mortality risk independent of traditional risk factors, BNP, and renal function.”
- Also stated in: § CONCLUSION · plain
“High TMAO levels are observed in patients with HF and elevated TMAO levels portend higher long-term mortality risk independent of traditional risk factors.”
Quote in the paperSubstantial claim - Also stated in: § CONCLUSION · plain
- Interpretationreasoning
The equivalent adverse prognostic value of elevated TMAO in ischemic and nonischemic heart failure suggests that mechanisms other than pro-atherogenic effects may contribute to increased mortality.
“the equivalent adverse prognostic value of elevated TMAO levels in both ischemic and nonischemic HF suggests the possibility that other potential mechanisms contribute to the increased mortality risks observed in HF subjects with elevated TMAO levels.”
Quote in the paperSubstantial claim - Interpretationown data
The study provides direct evidence that systemic accumulation of TMAO, a downstream metabolite of gut microbiota, heralds increased long-term adverse clinical outcomes in heart failure subjects independent of multiple cardiorenal indices.
“Our current observations therefore provided direct evidence that accumulation in the systemic circulation of TMAO, an obligatory down-stream metabolite of gut microbiota, heralds increased long-term adverse clinical outcomes in subjects with HF independent of multiple cardiorenal indices.”
Quote in the paperSubstantial claim - Premisecitation
Features of altered intestinal function have been observed in patients with heart failure.
“Several of these features of altered intestinal function have been observed in patients with HF (3,4).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [3] Rauchhaus, 2000, Plasma concentrations of bacterial lipopolysaccharide: a marker of infection or inflammation?, J Am Coll Cardiol source
Not checked in the free run.
- cites [4] Sandek, 2007, Altered intestinal function in patients with chronic heart failure, J Am Coll Cardiol source
Not checked in the free run.
- Interpretationown data
The study findings provide mechanistic links between gut microbiota-associated metabolism involved in TMAO formation and cardiorenal pathophysiology.
“Despite these limitations, our findings point to novel insights that provide mechanistic links between gut microbiota-associated metabolism involved in TMAO formation and cardiorenal pathophysiology.”
Quote in the paperNot a substantial claim - Study design and conductown data
The study did not have complete information on New York Heart Association functional class, cachexia, or atrial fibrillation.
“We also did not have complete information regarding New York Heart Association functional class, presence of cachexia, or atrial fibrillation in our study population”
Quote in the paperNot a substantial claim - Interpretationown data
The study findings suggest that gut microbiota composition and functional consequence may contribute to disease progression during heart failure.
“by demonstrating the association between TMAO and mortality risks in patients with HF, our findings suggest that gut microbiota composition and functional consequence may contribute to disease progression during HF.”
Quote in the paperSubstantial claim - Premisecitation
Intestinal microbe-dependent generation of TMAO is mechanistically linked to increased risk for future cardiovascular events via dietary nutrients such as phosphatidylcholine, choline, and carnitine.
“Our group has recently described a mechanistic link between intestinal microbe-dependent generation of trimethylamine-N-oxide (TMAO) and increased risk for future cardiovascular events (death, myocardial infarction, and stroke) by a pathway involving dietary nutrients such as phosphatidylcholine, choline, and carnitine (10,11).”
Quote in the paperSubstantial claim0 of 2 sources checked
- May combine two claims. 7
- Classified as probably not a substantial claim. 10
- The quote only partly states this claim. 1
May combine two claims.
Findingown dataIn patients with heart failure, mortality risk associated with elevated TMAO is similar among ischemic and nonischemic subjects and other clinical subgroups.
“mortality risks were similar among ischemic and nonischemic HF subjects, as well as other clinical subgroups (Figure 2).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataIn patients with heart failure, plasma TMAO is weakly inversely correlated with serum arylesterase activity (r = −0.135; p < 0.001).
“plasma TMAO levels were weakly but significantly inversely correlated with serum arylesterase activity (r = −0.135; p < 0.001)”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.
Findingown dataOver 5-year follow-up, 207 deaths occurred in the heart failure cohort.
“Over 5-year follow-up, a total of 207 deaths occurred in our study cohort.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataIn patients with heart failure, plasma TMAO is positively correlated with serum uric acid levels (r = 0.29; p < 0.001).
“and positively correlated with serum uric acid levels (r = 0.29; p < 0.001)”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe study findings refine the gut hypothesis and suggest a potential association between the gut microbiota pathway and adverse prognosis in heart failure subjects.
“These observations further refine in a large HF patient population the notion of a “gut hypothesis,” and suggest a potential association between the gut microbiota pathway of known pro-atherogenic potential to adverse prognosis in HF subjects.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductreasoningThis single-center study recruited patients at the point of cardiac evaluation for coronary angiography, so selection bias may identify a higher proportion of patients with ischemic cardiomyopathy.
“First, this is a single-center study that recruited patients at the point of cardiac evaluation for coronary angiography; hence selection bias may ensue to identify a higher proportion of patients with ischemic cardiomyopathy.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIntestinal microbiota are implicated in regulating multiple host metabolic pathways that contribute to phenotypes such as obesity and insulin resistance.
“Intestinal microbiota are implicated in the regulation of multiple host metabolic pathways that contribute to phenotypes such as obesity and insulin resistance (9).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Nicholson, 2012, Host-gut microbiota metabolic interactions, Science source
Not checked in the free run.
May combine two claims.
Study design and conductreasoningThe cohort has relatively preserved renal function and few patients with advanced cardiorenal disease or advanced heart failure, with an annualized mortality of 5.8%.
“Also, because of this catchment, the large majority of patients have relatively preserved renal function, and few have advanced cardiorenal diseases or advanced HF (annualized mortality of 5.8%).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductreasoningRight heart catheterization was not performed in a large majority of subjects and was not readily available.
“Also, this is a cohort of patients who underwent elective coronary angiography, thus right heart catheterization was not performed in a large majority of subjects and was not readily available.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe study did not have information on gastrointestinal symptoms and pathology, prior antibiotic use, or prior supplements other than those taken on the day of enrollment.
“Specifically, we do not have any information regarding gastrointestinal symptoms and pathology or prior antibiotic use or knowledge of prior supplements other than those taken the day of enrollment.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationChanges in bacterial composition serve as a primary driver of TMAO levels in other studies.
“Changes in bacterial composition have been shown to serve as a primary driver of TMAO levels in other studies (10,15).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [10] Wang, 2011, Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease, Nature source
Not checked in the free run.
- cites [15] Hanley, 1983, A method of comparing the areas under receiver operating characteristic curves derived from the same cases, Radiology source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenInterim events and treatment may influence the primary outcome of all-cause mortality.
“As in most outcome studies, interim events and treatment also may influence the primary outcome of all-cause mortality.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTMAO has pro-atherogenic properties.
“While TMAO has been shown to possess pro-atherogenic properties (10,11,17)”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [10] Wang, 2011, Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease, Nature source
Not checked in the free run.
- cites [11] Tang, 2013, Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk, N Engl J Med source
Not checked in the free run.
- cites [17] Anker, 2003, Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging, Circulation source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenOnly a single time-point blood draw after overnight fast was available, and no dietary history was available to confirm or refute the impact of diet on TMAO levels or their cardiorenal consequences.
“Another potential limitation is that only a single time-point blood draw after overnight fast was available, and we do not have dietary history to confirm or refute the impact of diet on TMAO levels or their cardiorenal consequences.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Before this study, the relationship between TMAO and cardiorenal indices and long-term prognosis in chronic systolic heart failure had not been examined, and the association between elevated TMAO and poor prognosis in heart failure had not been demonstrated.
“In chronic systolic HF, the relationship between the intestinal microbiota-generated metabolite TMAO and both cardiorenal indices and long-term clinical prognosis have not been examined.”
“The present study is the first demonstration of an association between elevated TMAO levels and poor prognosis in patients with HF.”
The paper relies on this without support.
The healthy control cohort is comparable to the heart failure cohort except for heart failure status, so the observed TMAO difference reflects heart failure.
“We also performed a cross-sectional comparison of TMAO levels between our cohort of stable systolic HF patients and an independent set of 300 prospectively recruited, apparently healthy individuals without known cardiac disease from a health-screening program at various locations across Cleveland, Ohio.”
The paper relies on this without support.
Renal clearance of TMAO may be impaired beyond what eGFR estimates.
“though recognize that the kidneys may be physiologically impaired in eliminating TMAO beyond estimates of glomerular filtration rates.”
The paper relies on this without support.
Inclusion of BNP can integrate many risk profiles associated with missing New York Heart Association functional class, cachexia, and atrial fibrillation.
“even though we believe that the inclusion of BNP can integrate many of these risk profiles.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Multiple clinical studies have found associations between plasma TMAO and coronary atherosclerotic plaque burden and cardiovascular disease risk.
“Finally, an association between plasma TMAO levels and both the extent of coronary atherosclerotic plaque burden and CVD risks has been observed in multiple distinct clinical studies (Wang et al., 2011; Tang et al., 2013; Tang et al., 2014; Lever et al., 2014; Tang et al., 2015).”
From Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk (2016) · cites this paper as Tang et al., 2014
Trimethylamine-N-oxide (TMAO) is produced by gut microbes from dietary choline, phosphatidylcholine and L-carnitine.
“Specifically, gut microbiota-mediated metabolism of phosphatidylcholine, choline or L-carnitine each have been shown to ultimately produced trimethylamine-N-oxide (TMAO), and in multiple clinical studies, TMAO levels have been shown to be associated with cardiovascular risks8–10, 13.”
Multiple clinical studies have linked TMAO levels to cardiovascular risk.
“in multiple clinical studies, TMAO levels have been shown to be associated with cardiovascular risks8–10, 13.”
Plasma TMAO levels in subjects are associated with prevalent and incident cardiovascular disease risks.
“plasma levels in subjects are associated with prevalent and incident cardiovascular disease risks (5, 7, 9, 10).”
From Transmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation (2015) · cites this paper as [10]
Of the 19 publications, 16 publications, including 19 data points, were eligible for the main analysis to calculate a pooled RR of elevated TMAO levels as compared with low levels.
“Of the 19 publications, a total of 16 publications, including 19 data points, were eligible for our main analysis to calculate a pooled RR of elevated TMAO levels as compared with low levels3, 7, 8, 10, 11, 13, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26 (Table 1 and Figure 1).”
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”
For all-cause mortality, 15 data from 12 articles were available, including 2498 deaths among 11,676 participants.
“For calculating the risk for only all‐cause mortality, 15 data from 12 articles7, 8, 10, 11, 18, 19, 21, 22, 23, 24, 25, 26 were available, including 2498 deaths among 11 676 participants.”
Median TMAO concentrations in healthy individuals were reported as ranges of 3 to 6 μmol/L.
“Nonetheless, median values of TMAO concentrations in healthy individuals were reported as ranges of 3 to 6 μmol/L,8, 17, 18, 19 and the study by Shafi et al22 consisted of hemodialysis patients with the substantially high mean vale of TMAO (101.9 μmol/L among total participants).”
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 [11]
In humans, elevated plasma levels of TMAO are positively correlated with an increased risk for major adverse cardiovascular events and death.
“In humans, a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events and death is reported.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [34]
In patients with stable heart failure, TMAO levels were increased and elevated levels were associated with increased risk of death.
“In another study, TMAO levels were increased in patients with stable heart failure and elevated levels were associated with increased risk of death [34].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [34]
Substantial evidence indicates that elevated TMAO levels are associated with cardiovascular disease.
“Thus, substantial evidence indicates that elevated TMAO levels are associated with cardiovascular disease (CVD).”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [34]
Blood TMAO level is positively correlated with long-term mortality risk in patients with atherosclerosis, heart failure, and chronic kidney disease.
“The blood TMAO level has been reported to be positively correlated with long‐term mortality risk in patients with atherosclerosis, heart failure, and chronic kidney disease.5, 6, 7”
From Dysbiosis of gut microbiota with reduced trimethylamine-N-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack (2015) · cites this paper as [6]
Many cohort studies have suggested that an increased number of adverse outcomes are associated with high TMAO levels.
“many cohort studies have suggested that an increased number of adverse outcomes are associated with high TMAO levels,4, 5, 6, 7”
From Dysbiosis of gut microbiota with reduced trimethylamine-N-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack (2015) · cites this paper as [6]
A pro-inflammatory signaling effect of TMAO has been independently replicated in human umbilical vein endothelial cells and in studies exploring the NLRP3 inflammasome.
“A pro-inflammatory signaling effect of TMAO has been independently replicated in studies utilizing human umbilical vein endothelial cells, as well as in studies exploring additional mechanisms such as the NLRP3 inflammasome174,175.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [175]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Adjusted mortality estimate has two values
MinorFor the model adjusted for traditional risk factors, BNP, and eGFR, the text calls the increase 1.80-fold but gives a hazard ratio of 1.75. Both are presented to two decimal places.
“a 1.80-fold increase in mortality risk even after adjusting for traditional risk factors and BNP plus eGFR”
“(HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.05)”
Abstract overstates significance of the eGFR-adjusted result
MinorThe abstract reports p < 0.001 for the HR of 1.75, whereas its 95% confidence interval implies a two-sided p-value of approximately 0.025 under the usual Cox-model calculation. The results section reports the same estimate as p < 0.05.
“(HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.001)”
“(HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.05)”
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Cited by
Sorted by citations
Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk
Zhu, W., Gregory, J. C., Org, E., Buffa, J. A., Gupta, N., Wang, Z., Li, L., Fu, X., Wu, Y., Mehrabian, M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.02.011 · Cited by 1,968 · see citing works
Self-citationWang, Z., Roberts, A. B., Buffa, J. A., Levison, B. S., Zhu, W., Org, E., Gu, X., Huang, Y., Zamanian-Daryoush, M., Culley, M. K., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.055 · Cited by 1,317 · see citing works
Self-citationTang, W. H. W., Wang, Z., Kennedy, D. J., Wu, Y., Buffa, J. A., Agatisa-Boyle, B., Li, X. S., Levison, B. S., & Hazen, S. L. (2015) · Circulation Research · doi:10.1161/circresaha.116.305360 · Cited by 1,223 · see citing works
Self-citationGut microbiota and cardiovascular disease.
Witkowski, M., Weeks, T. L., & Hazen, S. L. (2020) · Circulation Research · doi:10.1161/circresaha.120.316242 · Cited by 1,051 · see citing works
Self-citationPostler, T. S., & Ghosh, S. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.05.008 · Cited by 876 · see citing works
“These observations were further corroborated and extended by subsequent studies from the same group and others (Li et al., 2017; Mente et al., 2015; Tang et al., 2013, 2014, 2015; Trøseid et al., 2015; Wang et al., 2014b).”
ResultDietary metabolism, the gut microbiome, and heart failure
Tang, W. H. W., Li, D. Y., & Hazen, S. L. (2019) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0108-7 · Cited by 789 · see citing works
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Schiattarella, G. G., Sannino, A., Toscano, E., Giugliano, G., Gargiulo, G., Franzone, A., Trimarco, B., Esposito, G., & Perrino, C. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx342 · Cited by 563 · see citing works
Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential
Roberts, A. B., Gu, X., Buffa, J. A., Hurd, A. G., Wang, Z., Zhu, W., Gupta, N., Skye, S. M., Cody, D. B., Levison, B. S., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0128-1 · Cited by 552 · see citing works
Self-citationγ-Butyrobetaine Is a Proatherogenic Intermediate in Gut Microbial Metabolism of L-Carnitine to TMAO
Koeth, R. A., Levison, B. S., Culley, M. K., Buffa, J. A., Wang, Z., Gregory, J. C., Org, E., Wu, Y., Li, L., Smith, J. D., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.006 · Cited by 546 · see citing works
Self-citationHeianza, Y., Ma, W., Manson, J. E., Rexrode, K. M., & Qi, L. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.116.004947 · Cited by 544 · see citing works
Trimethylamine N-oxide: the good, the bad and the unknown.
Velasquez, M., Ramezani, A., Manal, A., & Raj, D. (2016) · Toxins · doi:10.3390/toxins8110326 · Cited by 504 · see citing works
Transmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation
Gregory, J. C., Buffa, J. A., Org, E., Wang, Z., Levison, B. S., Zhu, W., Wagner, M. A., Bennett, B. J., Li, L., DiDonato, J. A., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.618249 · Cited by 486 · see citing works
Self-citationLi, X. S., Obeid, S., Klingenberg, R., Gencer, B., Mach, F., Räber, L., Windecker, S., Rodondi, N., Nanchen, D., Muller, O., et al. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehw582 · Cited by 479 · see citing works
Self-citationRole of the Gut Microbiome in Uremia: A Potential Therapeutic Target
Ramezani, A., Massy, Z. A., Meijers, B., Evenepoel, P., Vanholder, R., & Raj, D. S. (2016) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2015.09.027 · Cited by 394 · see citing works
Organ, C. L., Otsuka, H., Bhushan, S., Wang, Z., Bradley, J., Trivedi, R., Polhemus, D. J., Tang, W. H. W., Wu, Y., Hazen, S. L., et al. (2016) · Circulation: Heart Failure · doi:10.1161/circheartfailure.115.002314 · Cited by 382 · see citing works
Self-citationTang, W. H. W., Wang, Z., Shrestha, K., Borowski, A. G., Wu, Y., Troughton, R. W., Klein, A. L., & Hazen, S. L. (2015) · Journal of Cardiac Failure · doi:10.1016/j.cardfail.2014.11.006 · Cited by 325 · see citing works
Self-citationTrimethylamine‐<i>N</i>‐oxide promotes brain aging and cognitive impairment in mice
Li, D., Ke, Y., Zhan, R., Liu, C., Zhao, M., Zeng, A., Shi, X., Ji, L., Cheng, S., Pan, B., et al. (2018) · Aging Cell · doi:10.1111/acel.12768 · Cited by 304 · see citing works
Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction
Boini, K. M., Hussain, T., Li, P.-L., & Koka, S. S. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000484623 · Cited by 302 · see citing works
Trimethylamine N-oxide promotes atherosclerosis via CD36-dependent MAPK/JNK pathway
Geng, J., Yang, C., Wang, B., Zhang, X., Hu, T., Gu, Y., & Li, J. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.11.016 · Cited by 297 · see citing works
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Intersections Between Microbiome and Heart Failure: Revisiting the Gut Hypothesis
Nagatomo, Y., & Tang, W. H. W. (2015) · Journal of Cardiac Failure · doi:10.1016/j.cardfail.2015.09.017 · Cited by 259 · see citing works
Self-citationLinking the Microbiota, Chronic Disease, and the Immune System
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Trimethylamine <i>N</i>-oxide and prognosis in acute heart failure
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Self-citationGut Microbiota and Ischemic Stroke: The Role of Trimethylamine N-Oxide
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Trimethylamine N‐oxide: breathe new life
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Lifestyle modifications for preventing and treating heart failure
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Self-citationTMAO is Associated with Mortality: Impact of Modestly Impaired Renal Function
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- Authors
- Tang, W. H. W., Wang, Z., Fan, Y., Levison, B., Hazen, J. E., Donahue, L. M., Wu, Y., & Hazen, S. L.
- Affiliations
- Cleveland Clinic (US)
- Cleveland State University (US)
- Corresponding author
- Tang, W.H. Wilson
- ORCID
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 64
- Issue
- 18
- Pages
- 1908-1914
- ISSN
- 0735-1097 (ISSN-L)
- PMC
- PMC4254529
- OpenAlex
- W2118024623
- Cited by
- 681
- References
- 20
- Citations by year
- 2026: 29 · 2025: 61 · 2024: 49 · 2023: 49 · 2022: 86 · 2021: 75 · 2020: 82 · 2019: 55 · 2018: 67 · 2017: 55 · 2016: 35 · 2015: 30 · 2014: 7
- FWCI
- 17.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EngagedScholarship @ Cleveland State University (Cleveland State University) (submittedVersion, cc-by-nc-nd)
- Funders
- Office of Dietary Supplements (R01 HL103866, P20 HL113452)
- American Heart Association (12SDG12050473)
- Abbott Laboratories
- Cleveland Clinic
- Case Western Reserve University (UL1TR000439)
- Georgia Clinical and Translational Science Alliance
- National Institutes of Health (UL1TR000439)
- National Heart, Lung, and Blood Institute (R01HL103931, P20HL113452, P01HL076491, P01HL098055, R01HL103866)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Keywords
- trimethylamine N-oxide, heart failure, gut microbiota, all-cause mortality, prognostic factors, brain natriuretic peptide, estimated glomerular filtration rate, cardiorenal risk, gut-heart axis
- MeSH terms
- Aged, Female, Follow-Up Studies, Heart Failure, Humans, Intestinal Mucosa, Intestines, Male, Methylamines, Middle Aged, Ohio, Prognosis, Prospective Studies, Mass Spectrometry, Time Factors, Biomarkers, Survival Rate, Risk Assessment, Kaplan-Meier Estimate, Microbiota
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.
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