Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors

May combine two claims.

Plasma TMAO levels were higher on average in the Cleveland cohort compared with the Swiss cohort, and the quartile cut-offs used for each cohort were different.

“Plasma TMAO levels were higher on average in the Cleveland cohort compared with the Swiss cohort, and the quartile cut-offs used for each cohort were thus different.”

May combine two claims.

Both plasma levels of TMAO and event rates were higher in US compared with Swiss patients.

“both the plasma levels of TMAO and the event rates were higher in the US compared with the Swiss patients”

May combine two claims.

In the Swiss ACS Cohort, inclusion of TMAO in the model for 1-year mortality resulted in significant improvement in NRI (0.45, P < 0.001) but no significant improvement in C-statistic (0.78 vs 0.77, P = 0.26).

“Inclusion of TMAO in the model for predicting 1-year mortality resulted in significant improvement in NRI (0.45 (0.25-0.65),P < 0.001), but no significant improvement in C-statistic (0.78 (0.72-0.84) with TMAO vs. 0.77 (0.71-0.83) without TMAO; P = 0.26)”

May combine two claims.

In the Swiss ACS Cohort, inclusion of TMAO in the model for MACE resulted in significant improvement in NRI (0.3, P < 0.001) but no significant improvement in C-statistic (0.66 vs 0.64, P = 0.15).

“The inclusion of TMAO as a variable to the model prediction of MACE resulted in a significant improvement in risk estimation over traditional risk factors (NRI, 0.3 (0.16-0.44),P < 0.001); but no significant improvement in C-statistic (C-statistic, 0.66 (0.62-0.7) (with TMAO) vs. 0.64 (0.6-0.68) (without TMAO); P = 0.15).”

May combine two claims.

This prognostic value was not only true for patients with elevated troponins due to STEMI or NSTEMI, but also observed for patients who did not suffer an infarction, but were negative for troponin at initial presentation.

“This was not only true for patients with elevated troponins due to a STEMI or NSTEMI, but also was observed for patients who did not suffer an infarction, but rather, were negative for troponin at initial presentation.”

May combine two claims.

On its own, our findings are hypothesis generating for such trials, but establish the prognostic information provided by TMAO in ACS patients.

“On its own, our findings are hypothesis generating for such trials, but establish the prognostic information provided by TMAO in ACS patients.”

Probably not a substantial claim: may not pass S3 (load-bearing).

TMAO promotes vascular inflammation, inducing aortic endothelial cell activation and up-regulation of adhesion proteins in animal models.

“Trimethylamine N-oxide was also recently shown in animal models to promote vascular inflammation, inducing aortic endothelial cell activation and up-regulation of adhesion proteins.23”

• cites [23] Seldin MM Meng Y Qi H Zhu W Wang Z Hazen SL Lusis AJ Shih DM. Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-kappaB. J Am Heart Assoc 2016;5:pii: e002767. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Platelet hyperreactivity is a risk factor for incident cardiovascular events.

“Numerous studies have reported platelet hyperreactivity is a risk factor for incident cardiovascular events.21,22”

• cites [21] sourceNot checked yet

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• cites [22] sourceNot checked yet

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Classified as probably not a substantial claim.

Elevated systemic levels of TMAO among stable subjects (n = 4007) undergoing elective diagnostic cardiac evaluations predict incident thrombotic event risks.

“Finally, recent clinical studies have shown that elevated systemic levels of TMAO among stable subjects (n = 4007) undergoing elective diagnostic cardiac evaluations predict incident thrombotic event risks.5”

• cites [5] sourceNot checked yet

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May combine two claims.

TMAO interacts with platelets, altering stimulus-dependent calcium signalling, fostering platelet hyperreactivity and enhanced thrombosis potential in vivo.

“This is particularly relevant given that recent human platelet and animal model studies reveal that TMAO interacts with platelets, altering stimulus-dependent calcium signalling, fostering platelet hyperreactivity and enhanced thrombosis potential in vivo.5”

• cites [5] sourceNot checked yet

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Classified as probably not a substantial claim.

Systemic TMAO levels are associated with cardiovascular risks in a variety of stable cohorts.

“Numerous studies reveal an association between systemic TMAO levels and cardiovascular risks in a variety of stable cohorts.[1][2][3]5,[7][8][9][10][11][12][13][14][15][16][17][18][19][20]”

• cites [1][2][3]5,[7][8][9][10][11][12][13][14][15][16][17][18][19][20]Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Adherence to a vegetarian or vegan diet compared with an omnivorous diet is associated with reduced plasma and urinary levels of TMAO.

“Moreover, adherence to a vegetarian or vegan diet compared with an omnivorous diet is reported to be associated with reduced plasma and urinary levels of TMAO.3,44”

• cites [3] sourceNot checked yet

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• cites [44] sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

DMB, by inhibiting microbial choline and carnitine TMA lyase activities in vivo, appears to prevent foam cell formation and aortic atherosclerotic plaque formation while maintaining normal gut flora.

“Particularly promising is the effective experimental use of 3,3-dimethyl-1-butanol (DMB), which by inhibiting microbial choline and carnitine TMA lyase activities in vivo appears to prevent foam cell formation and aortic atherosclerotic plaque formation, while maintaining a normal gut flora.38”

• cites [38] sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The higher burden of comorbidities in the Cleveland cohort may account in part for the higher TMAO levels and event rates in the US.

“and this may account in part for these observations.”

Classified as probably not a substantial claim.

The findings suggest a potential basis for a novel therapeutic target in the management of ACS patients.

“These findings not only broaden the potential clinical utility of TMAO as an independent prognostic marker to those presenting with suspected ACS, but also suggest, in combination with the recent studies linking this metabolite to platelet function, a potential basis for a novel therapeutic target in the management of ACS patients.”

Classified as probably not a substantial claim. May combine two claims.

The Swiss ACS Cohort was a prospective multicentre cohort based on consecutive recruitment and follow-up at 30 days and 1 year of subjects with adjudicated ACS.

“This prospective multicentre cohort was based on consecutive recruitment and follow-up performed at 30 days (phone call) and 1 year (clinical visit) of subjects with adjudicated ACS.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The Cleveland Cohort was a single-center, prospective cohort study.

“The Cleveland Cohort (n = 530) was a single-center, prospective cohort study approved by the Cleveland Clinic Institutional Review Board.”

May combine two claims.

The present study demonstrates for the first time that systemic TMAO levels are associated with both near-term risk of MACE and long-term mortality among sequential patients presenting with complaint of chest pain and suspected ACS in two independent ACS cohorts.

“The present study demonstrates for the first time that systemic TMAO levels are associated with both near-term risk of MACE and long term mortality, among sequential patients presenting with complaint of chest pain and suspected ACS in two independent ACS cohorts.”

May combine two claims.

TMAO has a prothrombotic effect by altering platelet calcium signalling, rendering platelets more responsive to agonists, increasing the risk of in vivo thrombus formation.

“In addition, TMAO has a prothrombotic effect by altering platelet calcium signalling, rendering platelets more responsive to agonists, increasing the risk of in vivo thrombus formation.5”

• cites [5] sourceNot checked yet

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May combine two claims.

TMAO may serve as a clinically useful and potentially modifiable prognostic marker for both near-term and long-term cardiovascular outcomes beyond currently used risk factors and laboratory testing.

“These studies thus add to the growing body of data demonstrating that the gut microbiota dependent metabolite, TMAO, may serve as a clinically useful and potentially modifiable prognostic marker for both near-term and long-term cardiovascular outcomes beyond currently used risk factors and laboratory testing.”

Classified as probably not a substantial claim.

Adjustments were made for individual traditional cardiac risk factors including age, gender, HDL, LDL, smoking, diabetes, hypertension, hyperlipidaemia, revascularization or coronary artery disease, high sensitivity C-reactive protein, eGFR, initial cTnT, and diagnosis of STEMI, NSTEMI or unstable angina.

“Adjustments were made for individual traditional cardiac risk factors including but not limited to age, gender, HDL, LDL, smoking, presence or absence of a history of diabetes mellitus, hypertension, hyperlipidaemia, revascularization or coronary artery disease, high sensitivity C-reactive protein level, eGFR, initial cTnT level, and diagnosis of either STEMI, NSTEMI or unstable angina.”

Probably not a substantial claim: may not pass S3 (load-bearing).

TMAO levels are highly related to coronary atherosclerotic burden and plaque complexity as monitored by the SYNTAX score.

“In line with these findings, recent studies reveal that TMAO levels are highly related to the coronary atherosclerotic burden and plaque complexity as monitored by the SYNTAX score.19”

• cites [19] sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Mediterranean diet has been shown to decrease the risk of adverse cardiovascular events in both observational and prospective studies.

“a change in dietary habits, specifically to that of the Mediterranean type, 46 which has been shown to decrease the risk of adverse cardiovascular events in both observational and prospective studies, 47,48”

• cites [47] sourceNot checked yet

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• cites [48] sourceNot checked yet

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May combine two claims.

TMAO is modifiable both with diet and with potential therapeutics under development.

“The importance of our findings is underlined by the modifiable nature of TMAO, both with diet, and with potential therapeutics under development, offering new prospects for treatment strategies at both levels of primary and secondary prevention.”

• cites [38] sourceNot checked yet

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• cites [3] sourceNot checked yet

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• cites [44] sourceNot checked yet

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Classified as probably not a substantial claim.

All events were adjudicated with medical record checks.

“All events were adjudicated with medical record checks.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All-cause mortality at 7 years was available in 89% (n = 474) of the Cleveland Cohort subjects.

“All-cause mortality at 7 years was available in 89% (n = 474) of the Cleveland Cohort subjects.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Follow-up in the Cleveland Cohort was completed for 30-day and 6-month outcomes.

“Follow-up in the Cleveland Cohort was completed for 30-day and 6-month outcomes.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Model validation and calibration are shown in the Supplemental Statistical Methods section.

“Model validation and calibration are shown in the Supplemental Statistical Methods section (Supplementary material online, Table S1 and Figures S1-S3).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Animal model studies suggest that inhibition of gut microbial participants involved in metabolic production of TMAO could be an approach for high TMAO ACS patients.

“Animal model studies suggest another approach to the high TMAO ACS patient could involve inhibition of the gut microbial participants involved in metabolic production of TMAO.49”

• cites [49] sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

For both cohorts, electrocardiographic data were verified independently by personnel at electrocardiography core facilities who were unaware of the patients' diagnoses.

“For both the Cleveland Cohort and the Swiss ACS Cohort, electrocardiographic data were verified independently by personnel at electrocardiography core facilities who were unaware of the patients' diagnoses.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Plasma samples from subjects presenting with suspected ACS were not necessarily fasting, and no information was collected on timing of presentation relative to last meal, or dietary patterns preceding presentation in either the Cleveland or Swiss ACS cohorts.

“Another limitation of the present study is that plasma samples from subjects presenting with suspected ACS were not necessarily fasting, and no information was collected on timing of presentation relative to last meal, or dietary patterns preceding presentation in either the Cleveland or Swiss ACS cohorts.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The diagnosis of ACS was confirmed by a chart review by an investigator who was unaware of the patients' diagnoses.

“The diagnosis of an acute coronary syndrome (ACS) was based on the presence of MI or unstable angina, as defined in the protocol, and confirmed by a chart review by an investigator who was unaware of the patients' diagnoses.”

May combine two claims.

Our results are consistent with other clinical studies in showing that elevated levels of TMAO may serve as an independent risk factor of MACE and long-term all-cause mortality, including in those presenting with ACS.

“Our results are consistent with these other clinical studies in that they show that elevated levels of TMAO may serve as an independent risk factor of MACE and long-term all-cause mortality, including in those presenting with ACS.”

Classified as probably not a substantial claim.

Sequential consenting adult subjects presenting to the emergency department with chest pain of suspected cardiac origin within 24 h of onset were eligible.

“Sequential consenting adult subjects (ages 18 years and above) who presented to the emergency department (ED) with chest pain of suspected cardiac origin within 24 h of onset were eligible.”

May combine two claims.

TMAO appears to be not only a risk marker but also may serve as a potential therapeutic target to improve outcomes in patients, including subjects with ACS.

“Thus, TMAO appears to not only be a risk marker, but also may serve as a potential therapeutic target to improve outcomes in patients, including subjects with ACS.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Phosphatidylcholine consumption is associated with increased all-cause and cardiovascular mortality independent of traditional risk factors.

“recent large-scale epidemiological studies examining phosphatidylcholine ingestion, a nutrient that is more abundant in animal products, and mortality risks in >100 000 subjects with over a quarter century of follow-up, revealed phosphatidylcholine consumption is associated with increased all-cause and cardiovascular mortality independent of traditional risk factors.43”

• cites [43] sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Cause of death was not available for the Cleveland cohort, so all-cause death was used as the mortality end point.

“Cause of death was not available for the Cleveland cohort, so all-cause death was used as the mortality end point.”