Elevated Trimethylamine N-oxide Levels Research Articles

Trimethylamine N-Oxide and Stroke Recurrence Depends on Ischemic Stroke Subtypes.

Trimethylamine N-oxide (TMAO) has been recognized as a risk factor for cardiovascular disease. However, the role of TMAO in ischemic stroke remains unclear. As we know, ischemic stroke is a heterogeneous disease with variable pathogenesis. Hence, we aimed to investigate the association between TMAO and stroke recurrence according to etiology subtypes. A total of 10 756 ischemic stroke/transient ischemic attack patients from the Third China National Stroke Registry were enrolled, and 1-year follow-up data for stroke recurrence were analyzed. TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria was used to classify the etiology subtypes. Plasma TMAO levels were quantified by liquid chromatography-mass spectrometry. The association between TMAO and stroke outcomes was analyzed using Cox regression models. We also conducted a meta-analysis on the association of TMAO levels and stroke risk. Elevated TMAO level was independently associated with the risk of stroke recurrence (Q4 versus Q1: adjusted hazard ratio, 1.37 [95% CI, 1.15-1.64]) in multivariate Cox regression model. After stratification by TOAST subtypes, there was a significant association between TMAO and stroke recurrence in small artery occlusion subtype (adjusted hazard ratio, 1.43 [95% CI, 1.03-2.00]) but not in the others subtype (large-artery atherosclerosis, 1.19 [0.95-1.48]; cardioembolism, 1.54 [0.95-2.48]; others, 1.19 [0.98-1.44]). The meta-analysis reported on stroke recurrence for the highest versus lowest TMAO levels with a pooled hazard ratio of 1.66 (95% CI, 0.91-3.01) and similarly found an increased risk of stroke recurrence. Elevated TMAO level is associated with increased risk of stroke recurrence in patients with small artery occlusion subtype, but this association seems to be attenuated in large-artery atherosclerosis, cardioembolism, and others subtypes.

TMAO (trimethylamine n-oxide) as a potential biomarker of individual severe stress perception in posttraumatic stress disorder (PTSD)-vulnerable patients after acute myocardial infarction

Abstract Background Acute myocardial infarction is not only a somatic disease but potentially triggers psychological effects, too. Post-traumatic stress disorder (PTSD) is a common stress-related disorder. It is characterized by numerous symptoms, such as flashbacks, intrusions, nightmares and severe anxiety, as well as uncontrollable, intense and disturbing thoughts and feelings related to the traumatic experience. However, with regard to the development of PTSD, individual stress perception might be crucial since not every serious traumatic experience leads to PTSD. To date, almost no biological correlates of an individual's perception of stress have been identified as being associated with the long-term development of PTSD. Objective The aim of the study was to determine whether blood levels of TMAO vary immediately after AMI (1) in patients with or without depression, and (2) in patients with AMI induced PTSD symptomatology (subsyndromal PTSD and full PTSD). Furthermore, we investigated whether TMAO is a potential biomarker that might be useful in the prediction of PTSD symptomatology in the long term. Method A total of 114 AMI patients were assessed with standardized clinical psychiatric interviews based on the Hamilton Depression Scale (HAMD-17) after admission to the hospital and 6 months later. In addition, the CAPS-5 was used to explore PTSD symptoms (subsyndromal PTSD and full PTSD) 6 months after AMI. To assess patients' TMAO status, serum samples were collected at hospitalization and 6 months after AMI. Results Study participants with post-myocardial infarction PTSD symptomatology (subsyndromal PTSD and full PTSD) had significantly higher TMAO levels immediately after AMI than patients without PTSD symptoms (ANCOVA: TMAO (PTSD x time), F = 4.544, df = 1, p=0.035). In contrast, depressive symptomatology 6 months after AMI had no influence on TMAO levels (TMAO (depression x time), F = 0.083, df = 1, p=0.774). With the inclusion of additional clinical predictors in a hierarchical logistic regression model, TMAO becomes a significant predictor of PTSD symptomatology. Conclusions An elevated TMAO level immediately after AMI might reflect severe stress in PTSD-vulnerable patients, which might also lead to a short-term increased gut permeability to trimethylamine (TMA), the precursor of TMAO. Thus, elevated TMAO might be a biological correlate for stress that is associated with vulnerability to PTSD and might help to identify patients at increased risk. Funding Acknowledgement Type of funding sources: None.

Trimethylamine-N-oxide (TMAO) Selectively Disrupts Endothelium-Dependent Hyperpolarization-Type Relaxations in a Time-Dependent Manner in Rat Superior Mesenteric Artery.

The vascular action of trimethylamine-N-oxide (TMAO)-the gut microbiota-derived metabolite-in contributing cardiovascular disease is a controversial topic. A recent study has shown that acute exposure of TMAO at moderate concentrations inhibits endothelium-dependent hyperpolarization (EDH)-type relaxations selectively in rat isolated femoral arteries, but not in mesenteric arteries. Here we determined the efficacy of higher TMAO concentrations with longer exposure times on vascular reactivity in rat isolated superior mesenteric arteries. Acetylcholine-induced EDH-type relaxations were examined before and after incubation with TMAO (0.1-10 mM) at increasing exposure times (1-24 h). One- and 4-h-incubations with TMAO at 0.1-3 mM did not cause any change in EDH-type relaxations. However, when the incubation time was increased to 24 h, responses to acetylcholine were reduced in arteries incubated with 1-3 mM TMAO. In addition, at higher TMAO concentration (10 mM) the decrease in EDH relaxations could be detected both in 4-h- and 24-h-incubations. The EDH-relaxations were preserved in rings incubated with 10 mM TMAO for 24 h in the presence of SKA-31 (10 µM), the small (SKCa)- and intermediate (IKCa)-conductance calcium-activated potassium channel activator. Contractile responses to phenylephrine increased in arteries exposed to 10 mM TMAO for 24 h. Interestingly, nitric oxide (NO)-mediated relaxations remained unchanged in arteries treated for 24 h at any TMAO concentration. Our study revealed that TMAO selectively disrupted EDH-type relaxations time-dependently without interfering with NO-induced vasodilation in rat isolated mesenteric arteries. Disruption of these relaxations may help explain the causal role of elevated TMAO levels in certain vascular diseases.

Gut microbiota-generated metabolite, trimethylamine-N-oxide, and subclinical myocardial damage: a multicenter study from Thailand

Plasma Trimethylamine-N-oxide (TMAO), a gut microbiota metabolite from dietary phosphatidylcholine, is mechanistically linked to cardiovascular disease (CVD) and adverse cardiovascular events. We aimed to examine the relationship between plasma TMAO levels and subclinical myocardial damage using high-sensitivity cardiac troponin-T (hs-cTnT). We studied 134 patients for whom TMAO data were available from the Cohort Of patients at a high Risk of Cardiovascular Events—Thailand (CORE-Thailand) registry, including 123 (92%) patients with established atherosclerotic disease and 11 (8%) with multiple risk factors. Plasma TMAO was measured by NMR spectroscopy. In our study cohort (mean age 64 ± 8.9 years; 61% men), median TMAO was 3.81 μM (interquartile range [IQR] 2.89–5.50 μM), and median hs-cTnT was 15.65 ng/L (IQR 10.17–26.67). Older patients and those with diabetic or hypertension were more likely to have higher TMAO levels. Plasma TMAO levels correlated with those of hs-cTnT (r = 0.54; p < 0.0001) and were significantly higher in patients with subclinical myocardial damage (hs-cTnT ≥ 14 ng/L; 4.48 μM vs 2.98 μM p < 0.0001). After adjusting for traditional risk factors, elevated TMAO levels remained independently associated with subclinical myocardial damage (adjusted odds ratio [OR]: 1.58; 95% CI 1.24–2.08; p = 0.0007). This study demonstrated that plasma TMAO was an independent predictor for subclinical myocardial damage in this study population.

Gut Metabolite Trimethylamine N-oxide Protects β Cell Insulin Secretion by Reducing Oxidative Stress and Maintaining Insulin Granule Formation

Abstract Objectives Elevated circulating levels of the dietary metabolite trimethylamine N-oxide (TMAO) is associated with chronic diseases including cardiovascular disease (CVD) and obesity. While TMAO production via the gut microbiome-liver axis and distribution through the circulation is clear, its molecular effects on metabolic tissues are still unclear. Some clinical studies suggest that elevated TMAO levels increase the risk of type 2 diabetes (T2D) where pancreatic β cell insulin secretion is insufficient for blood glucose management. T2D promoting mechanisms limit functional β cell mass by reducing β cell viability and survival, inhibiting proliferation or decreasing insulin secretory function. We hypothesized that TMAO decreases functional β cell mass by one of these mechanisms to aggravate the T2D phenotype. Methods Using the INS-1 832/13 β cell line and primary murine islets, we screened the effect of various TMAO concentrations on cell viability, proliferation, and function. These parameters were measured under standard and glucolipotoxic (GLT) culture conditions to mimic T2D. We investigated TMAO effects, GLT effects and combined effects. Results TMAO minimally affected viability, proliferation or function under standard culture conditions across 96-hours of treatment. Culturing with GLT impaired viability, proliferation and function after 24 hours of treatment, mimicking T2D onset. Interestingly, adding 40–80 μM TMAO protected against GLT mediated functional impairments in cells and islets. Further, GLT increased oxidative stress by 2.5-fold and adding TMAO was significantly protective. Electron microscopy reveals that GLT alters insulin granule density whereas TMAO maintains proper granule structure. Conclusions These results reject our hypothesis. While TMAO has minor effects on β cells in standard culture conditions, TMAO is sufficient to improve GLT mediated β cell damage by decreasing oxidative stress and maintaining insulin granule formation. These results suggest an early compensatory role for TMAO in countering oxidative damage caused by glucolipotoxicity in β cell function during T2D onset. Funding Sources Funding for this study was provided by the Beatson Foundation and the US Department of Agriculture.

The Gut Microbiome and Cardiovascular Disease.

Cardiovascular disease (CVD) is currently the leading cause of death worldwide. Although many well-known conditions cause CVD, recent research has suggested that alterations to the gut microbiome may also promote CVD. The gastrointestinal tract houses trillions of bacteria, some of which in large numbers are considered to be part of a healthy gut microbiome profile. These “good” bacteria have the ability to process and digest complex carbohydrates into short-chain fatty acids (SFCA). These SCFA serve as signaling molecules, immune-modulating molecules, and sources of energy. However, with gut dysbiosis, there is an overgrowth of certain bacteria and these bacteria overly produce phosphatidylcholine, choline, and carnitine into the waste product trimethylamine-N-oxide (TMAO). Elevated TMAO levels are associated with an increased risk of atherosclerosis, myocardial infarction, thrombosis, and stroke. Therefore, introducing therapeutic interventions that alter a dysbiotic gut profile back to a healthy gut microbiome may be the key to reducing the incidence of cardiovascular disease in some conditions. The purpose of this review is to critically examine and consolidate the relevant information bearing on this concept. Our goal is to provide the informational framework for the possible use of microbiome modification as an optional therapeutic modality.

Trimethylamine N-oxide and outcomes in patients hospitalized with acute heart failure and preserved ejection fraction.

AimsTrimethylamine N‐oxide (TMAO) is a metabolite derived from the gut microbiota. Elevated TMAO levels are associated with a poor prognosis in patients with heart failure with reduced ejection fraction. However, the prognostic effect of elevated TMAO levels on heart failure with preserved ejection fraction (HFpEF) remains unclear.Methods and resultsWe consecutively enrolled 146 patients who were hospitalized and discharged from Tottori University Hospital with the primary diagnosis of HFpEF (ejection fraction ≥ 50%). High TMAO levels were defined as those greater than the median value in the patients (20.37 μmol/L). Patients with high TMAO levels had a significantly higher prevalence of prior hospitalization for heart failure and severe renal dysfunction than those with low TMAO levels. They also had a significantly higher acylcarnitine to free carnitine ratio than those with low TMAO levels, which indicated abnormal fatty acid metabolism and relative carnitine deficiency. After adjustment for differences in the patients' background in multivariate analysis, high TMAO levels remained independently associated with a high incidence of the composite endpoints of death due to cardiac causes and hospitalization for heart failure (adjusted hazard ratio, 1.91; 95% confidence interval, 1.01 to 3.62; P < 0.05). There was a significant interaction between TMAO and nutritional status on the primary outcome, and the prognostic effect of TMAO was enhanced in patients with malnutrition.ConclusionsElevated TMAO levels at discharge are associated with an increased risk of post‐discharge cardiac events in patients with HFpEF, especially those with the complication of malnutrition.

Plasma trimethylamine N-oxide (TMAO) levels predict future risk of coronary artery disease in apparently healthy individuals in the EPIC-Norfolk prospective population study

BackgroundRecent studies show a mechanistic link between gut microbiota-dependent formation of the atherosclerosis- and thrombosis-promoting metabolite trimethylamine N-oxide (TMAO) and cardiovascular disease (CVD). The clinical utility of TMAO in apparently healthy subjects for predicting incident CVD risks is unclear. Methods and ResultsIn the EPIC-Norfolk community-based study, we examined baseline fasting levels of TMAO and two of its nutrient precursors, choline and betaine, in a case:control design study comparing apparently European healthy middle-aged participants who subsequently develop CVD (Cases, n = 908) vs those who did not (Controls, n = 1,273) over an ensuing average follow-up period of 8 years. In participants who developed CVD vs controls, higher plasma TMAO (3.70 [IQR 2.50-6.41]μM vs 3.25 [IQR 2.19-52,1.15]μM; P < .001) and choline levels (9.09 [IQR 7.87-10.53]μM vs 8.89 [IQR 7.66-10.13]μM; P = .001) were observed. Following adjustments for traditional risk factors, elevated TMAO (adjusted odds ratio (OR) 1.58 [95% confidence interval (CI) 1.21-2.06], P < .001) and choline levels (adjusted OR 1.31 [95%CI 1.00-1.72], P < .05) remained predictive of incident CVD development. The clinical prognostic utility of TMAO remained significant and essentially unchanged regardless of the level of cutoff chosen between 1.5 uM (10%ile) to 10.5 uM (90%ile). ConclusionIn apparently healthy participants of the community-based middle-aged EPIC-Norfolk population, elevated plasma levels of the gut microbe-dependent metabolite TMAO, and its nutrient precursor choline, predict incident risk for CVD development independent of traditional risk factors.

Elevated Serum Trimethylamine N-Oxide Levels Are Associated with Mortality in Male Patients on Peritoneal Dialysis

Background: Elevated levels of serum trimethylamine N-oxide (TMAO) have been previously linked to adverse cardiovascular (CV) and all-cause mortality in hemodialysis patients. However, the clinical significance of serum TMAO levels in patients treated with peritoneal dialysis (PD) is unclear. Methods: A total of 1,032 PD patients with stored serum samples at baseline were enrolled in this prospective study. Serum concentrations of TMAO were quantified by ultra-performance liquid chromatography-tandem mass spectrometry. Cox proportional hazards and competing-risk regression models were performed to examine the association of TMAO levels with all-cause and CV mortality. Results: The median level of serum TMAO in our study population was 34.5 (interquartile range (IQR), 19.8–61.0) μM. During a median follow-up of 63.7 months (IQR, 43.9–87.2), 245 (24%) patients died, with 129 (53%) deaths resulting from CV disease. In the entire cohort, we observed an association between elevated serum TMAO levels and all-cause mortality (adjusted subdistributional hazard ratio [SHR], 1.22; 95% confidence interval [95% CI], 1.01–1.48; p = 0.039) but not CV mortality. Further analysis revealed such association differed by sex; the elevation of serum TMAO levels was independently associated with increased risk of both all-cause (SHR, 1.37; 95% CI, 1.07–1.76; p = 0.013) and CV mortality (SHR, 1.41; 95% CI, 1.02–1.94; p = 0.038) in men but not in women. Conclusions: Higher serum TMAO levels were independently associated with all-cause and CV mortality in male patients treated with PD.

Microbiota-Derived Metabolite Trimethylamine N-Oxide Protects Mitochondrial Energy Metabolism and Cardiac Functionality in a Rat Model of Right Ventricle Heart Failure.

Aim: Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite synthesized in host organisms from specific food constituents, such as choline, carnitine and betaine. During the last decade, elevated TMAO levels have been proposed as biomarkers to estimate the risk of cardiometabolic diseases. However, there is still no consensus about the role of TMAO in the pathogenesis of cardiovascular disease since regular consumption of TMAO-rich seafood (i.e., a Mediterranean diet) is considered to be beneficial for the primary prevention of cardiovascular events. Therefore, the aim of this study was to investigate the effects of long-term TMAO administration on mitochondrial energy metabolism in an experimental model of right ventricle heart failure.Methods: TMAO was administered to rats at a dose of 120 mg/kg in their drinking water for 10 weeks. Then, a single subcutaneous injection of monocrotaline (MCT) (60 mg/kg) was administered to induce right ventricular dysfunction, and treatment with TMAO was continued (experimental groups: Control; TMAO; MCT; TMAO+MCT). After 4 weeks, right ventricle functionality was assessed by echocardiography, mitochondrial function and heart failure-related gene and protein expression was determined.Results: Compared to the control treatment, the administration of TMAO (120 mg/kg) for 14 weeks increased the TMAO concentration in cardiac tissues up to 14 times. MCT treatment led to impaired mitochondrial function and decreased right ventricular functional parameters. Although TMAO treatment itself decreased mitochondrial fatty acid oxidation-dependent respiration, no effect on cardiac functionality was observed. Long-term TMAO administration prevented MCT-impaired mitochondrial energy metabolism by preserving fatty acid oxidation and subsequently decreasing pyruvate metabolism. In the experimental model of right ventricle heart failure, the impact of TMAO on energy metabolism resulted in a tendency to restore right ventricular function, as indicated by echocardiographic parameters and normalized organ-to-body weight indexes. Similarly, the expression of a marker of heart failure severity, brain natriuretic peptide, was substantially increased in the MCT group but tended to be restored to control levels in the TMAO+MCT group.Conclusion: Elevated TMAO levels preserve mitochondrial energy metabolism and cardiac functionality in an experimental model of right ventricular heart failure, suggesting that under specific conditions TMAO promotes metabolic preconditioning-like effects.

Inhibition of microbiota-dependent TMAO production attenuates chronic kidney disease in mice

Patients with chronic kidney disease (CKD) have elevated circulating levels of trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes and associated with cardiovascular diseases. High circulating levels of TMAO and its dietary precursor, choline, predict increased risk for development of CKD in apparently healthy subjects, and studies in mice fed TMAO or choline suggest that TMAO can contribute to kidney impairment and renal fibrosis. Here we examined the interactions between TMAO, kidney disease, and cardiovascular disease in mouse models. We observed that while female hyperlipidemic apoE KO mice fed a 0.2% adenine diet for 14 weeks developed CKD with elevated plasma levels of TMAO, provision of a non-lethal inhibitor of gut microbial trimethylamine (TMA) production, iodomethylcholine (IMC), significantly reduced multiple markers of renal injury (plasma creatinine, cystatin C, FGF23, and TMAO), reduced histopathologic evidence of fibrosis, and markedly attenuated development of microalbuminuria. In addition, while the adenine-induced CKD model significantly increased heart weight, a surrogate marker for myocardial hypertrophy, this was largely prevented by IMC supplementation. Surprisingly, adenine feeding did not increase atherosclerosis and significantly decreased the expression of inflammatory genes in the aorta compared to the control groups, effects unrelated to TMAO levels. Our data demonstrate that inhibition of TMAO production attenuated CKD development and cardiac hypertrophy in mice, suggesting that TMAO reduction may be a novel strategy in treating CKD and its cardiovascular disease complications.

Assessment of trimethylamine N-oxide (TMAO) as a potential biomarker of severe stress in patients vulnerable to posttraumatic stress disorder (PTSD) after acute myocardial infarction

ABSTRACT Background: Posttraumatic stress disorder (PTSD) is a frequently observed stress-related disorder after acute myocardial infarction (AMI) and it is characterized by numerous symptoms, such as flashbacks, intrusions and anxiety, as well as uncontrollable thoughts and feelings related to the trauma. Biological correlates of severe stress might contribute to identifying PTSD-vulnerable patients at an early stage. Objective: Aims of the study were (1) to determine whether blood levels of trimethylamine N-oxide (TMAO) vary immediately after AMI in patients with/without AMI-induced PTSD symptomatology, (2) to investigate whether TMAO is a potential biomarker that might be useful in the prediction of PTSD and the PTSD symptom subclusters re-experiencing, avoidance and hyperarousal, and (3) to investigate whether TMAO varies immediately after AMI in patients with/without depression 6 months after AMI. Method: A total of 114 AMI patients were assessed with the Hamilton-Depression Scale after admission to the hospital and 6 months later. The Clinician Administered PTSD Scale for DSM-5 was used to explore PTSD-symptoms at the time of AMI and 6 months after AMI. To assess patients’ TMAO status, serum samples were collected at hospitalization and 6 months after AMI. Results: Participants with PTSD-symptomatology had significantly higher TMAO levels immediately after AMI than patients without PTSD-symptoms (ANCOVA: TMAO(PTSD x time), F = 4.544, df = 1, p = 0.035). With the inclusion of additional clinical predictors in a hierarchical logistic regression model, TMAO became a significant predictor of PTSD-symptomatology. No significant differences in TMAO levels immediately after AMI were detected between individuals with/without depression 6 months after AMI. Conclusions: An elevated TMAO level immediately after AMI might reflect severe stress in PTSD-vulnerable patients, which might also lead to a short-term increase in gut permeability to trimethylamine, the precursor of TMAO. Thus, an elevated TMAO level might be a biological correlate for severe stress that is associated with vulnerability to PTSD.

Relationship between Plasma Trimethylamine N-Oxide Levels and Renal Dysfunction in Patients with Hypertension

Introduction: Trimethylamine N-oxide (TMAO) is a metabolite produced by gut bacteria. Although increased TMAO levels have been linked to hypertension (HTN) and chronic kidney disease (CKD) with poor prognosis, no clinical studies have directly addressed the relationship between them. In this study, we investigated the relationship between TMAO and renal dysfunction in hypertensive patients. Methods: We included healthy controls (n = 50), hypertensive patients (n = 46), and hypertensive patients with renal dysfunction (n = 143). Their blood pressure values were taken as the highest measured blood pressure. Renal function was evaluated using the estimated glomerular filtration rate. Plasma TMAO levels were measured using high-performance liquid chromatography tandem mass spectrometry. Results: We found significant differences in plasma TMAO levels among the 3 groups (p < 0.01). The plasma TMAO of patients with HTN was significantly higher than that of healthy people, and the plasma TMAO of patients with HTN complicated by renal dysfunction was significantly higher than either of the other groups. Patients in the highest TMAO quartile were at a higher risk of developing CKD stage 5 than those in the lowest quartile. In the receiver operating characteristic curve, the area under the curve of TMAO combined with β 2-macroglobulin for predicting renal dysfunction in patients with HTN was 0.85 (95% confidence interval 0.80–0.90). Conclusion: An elevated TMAO level reflects higher levels of HTN and more severe renal dysfunction. TMAO, combined with β 2-macroglobulin levels, may assist in diagnosing CKD in hypertensive patients. Plasma TMAO has predictive value for early kidney disease in hypertensive patients.

Drug Discovery and Development of Novel Therapeutics for Inhibiting TMAO in Models of Atherosclerosis and Diabetes.

Diabetes mellitus exists as a comorbidity with congestive heart failure (CHF). However, the exact molecular signaling mechanism linking CHF as the major form of mortality from diabetes remains unknown. Type 2 diabetic patients display abnormally high levels of metabolic products associated with gut dysbiosis. One such metabolite, trimethylamine N-oxide (TMAO), has been observed to be directly related with increased incidence of cardiovascular diseases (CVD) in human patients. TMAO a gut-liver metabolite, comes from the metabolic degenerative product trimethylamine (TMA) that is produced from gut microbial metabolism. Elevated levels of TMAO in diabetics and obese patients are observed to have a direct correlation with increased risk for major adverse cardiovascular events. The pro-atherogenic effect of TMAO is attributed to enhancing inflammatory pathways with cholesterol and bile acid dysregulation, promoting foam cell formation. Recent studies have revealed several potential therapeutic strategies for reducing TMAO levels and will be the central focus for the current review. However, few have focused on developing rational drug therapeutics and may be due to the gaps in knowledge for understanding the mechanism by which microbial TMA producing enzymes and hepatic flavin-containing monoxygenase (FMO) can work together in preventing elevation of TMAO levels. Therefore, it is critical to understand the advantages of developing a novel rational drug design strategy that manipulates FMO production of TMAO and TMA production by microbial enzymes. This review will focus on the inspection of FMO manipulation, as well as gut microbiota dysbiosis and its influence on metabolic disorders including cardiovascular disease and describe novel potential pharmacological therapeutic development.

Gut microbiota-derived trimethylamine N-oxide is associated with poor prognosis in patients with heart failure.

Gut microbiota-produced trimethylamine N-oxide (TMAO) is a risk factor for cardiovascular events. However, conflicting findings regarding the link between plasma TMAO level and prognosis for patients with heart failure have been reported. We examined the association of plasma TMAO concentration with risk of major adverse cardiac events (MACEs) and all-cause mortality in patients with heart failure. Meta-analysis of prospective clinical studies. We searched electronic databases (PubMed, EMBASE) for published prospective studies examining associations between plasma TMAO level and MACEs and all-cause mortality in adults with heart failure. Hazard ratios (HRs) with 95% confidence intervals for associations between TMAO level and outcomes were estimated in random effects models. In seven eligible studies including a total of 6879 patients (median follow-up, 5.0 years) and adjusted for multiple risk factors, higher plasma TMAO level was associated with greater risks of MACEs (TMAO tertile 3 v tertile 1: HR, 1.68; 95% CI, 1.44-1.96; per SD increment: HR, 1.26; 95% CI, 1.18-1.36) and of all-cause mortality (TMAO tertile 3 v tertile 1: HR, 1.67; 95% CI, 1.17-2.38; per SD increment: HR, 1.26; 95% CI, 1.07-1.48). Higher TMAO level was also associated with greater risk of MACEs after adjusting for estimated glomerular filtration rate (eGFR; six studies included); however, the heterogeneity of studies in which risk was adjusted for eGFR was significant (I2 =76%). Elevated plasma TMAO level in patients with heart failure is associated with poorer prognoses. This association is only partially mediated by renal dysfunction.

Ethnic differences in association of outcomes with trimethylamine N-oxide in acute heart failure patients.

AimsThe aim of this study was to investigate whether ethnicity influences the associations between trimethylamine N‐oxide (TMAO) levels and heart failure (HF) outcomes.Methods and resultsTrimethylamine N‐oxide levels were measured in two cohorts with acute HF at two sites. The UK Leicester cohort consisted mainly of Caucasian (n = 842, 77%) and South Asian (n = 129, 12%) patients, whereas patients in the Japanese cohort (n = 116, 11%) were all Japanese. The primary endpoint was the measurement of all‐cause mortality and/or HF rehospitalization within 1 year post‐admission. Association of TMAO levels with outcome was compared in the entire population and between ethnic groups after adjustment for clinical parameters. TMAO levels were significantly higher in Japanese patients [median (interquartile range): 9.9 μM (5.2–22.8)] than in Caucasian [5.9 μM (3.6–10.8)] and South Asian [4.5 μM (3.1–8.4)] (P < 0.001) patients. There were no differences in the rate of mortality and/or HF rehospitalization between the ethnic groups (P = 0.096). Overall, higher TMAO levels showed associations with mortality and/or rehospitalization after adjustment for confounders ( P = 0.002). Despite no differences between ethnicity and association with mortality/HF after adjustment (P = 0.311), only in Caucasian patients were TMAO levels able to stratify for a mortality/HF event (P < 0.001).ConclusionsDifferences were observed in the association of mortality and/or rehospitalization based on circulating TMAO levels. Elevated TMAO levels in Caucasian patients showed increased association with adverse outcomes, but not in non‐Caucasian patients.

Abstract P205: Long-term Changes in Microbiota-dependent Metabolite Trimethylamine N-oxide and Risks of Hypertension and Coronary Heart Disease, and Their Modulation by Diet: The Nurses' Health Study and the POUNDS Lost Trial

Introduction: A gut microbiota-related metabolite, trimethylamine N-oxide (TMAO) has been related to risks of cardiovascular events, however, whether changes in TMAO may contribute to the incidence of hypertension remains unknown. Gut microbiome may be affected by sodium intake and dietary patterns linked to blood pressure control, while little is known about whether these dietary factors may modify associations between TMAO changes and risks of hypertension and cardiovascular events. Hypothesis: To test whether long-term changes in TMAO are associated with increased risks of hypertension and coronary heart disease (CHD), and whether sodium intake and adherence to the DASH (Dietary Approaches to Stop Hypertension) dietary pattern may modulate these associations. Methods: A prospective nested case-control study was performed in 730 women (including 362 incident cases of fatal CHD and nonfatal myocardial infarction). We measured blood levels of TMAO at 2 time points (in 1989-90 and 2000-01), and prospectively examined associations of 10-year changes in TMAO with CHD events after the date of the second blood collection (through 2016). For the hypertension outcome, we assessed prevalent hypertension at 2nd time point among total participants, as well as the incidence of hypertension over 10 years (between 1989-90 and 2000-01) among people who were initially free of hypertension (n=410). In overweight and obese participants (n=429) from a randomized dietary intervention, we also investigated whether diet-induced changes in TMAO were related to blood pressure changes considering 24-hr urinary sodium excretion as a marker of sodium intake. Results: Elevated TMAO levels were significantly associated with hypertension at the 2nd time point (relative risk (RR): 1.30 (95% CI: 1.09, 1.56) per 1 SD increment). Also, greater 10-year increases in TMAO were significantly associated with increased risks of incident hypertension and CHD, with evidence of significant modification by adherence to the DASH diet (P-interaction =0.02 for hypertension; P-interaction =0.01 for CHD). Among people with lower adherence to the DASH diet (i.e., having unhealthy dietary patterns and higher sodium intake), every 1 SD increase in TMAO was associated with a RR of 2.13 (1.30, 3.49) for hypertension, and a RR of 2.03 (1.42, 2.89) for CHD. Such significantly increased risks of hypertension and CHD by TMAO increases were not found for women with higher adherence to the DASH diet. In a dietary intervention, we also found similar associations; diet-induced changes in TMAO levels with blood pressure changes were modified by urinary sodium excretion. Conclusion: Increases in TMAO, an atherogenic microbial metabolite, were associated with higher risks of hypertension and CHD among women, and heart-healthy dietary patterns and sodium intake modified the unfavorable associations of TMAO with the risks of these diseases.

Gut microbial taxa as potential predictive biomarkers for acute coronary syndrome and post-STEMI cardiovascular events

Plasma trimethylamine N-oxide (TMAO) is associated with coronary atherosclerotic plaque and cardiovascular disease risk, but associations between gut microbes in acute coronary syndrome (ACS) and post-ST-segment elevation myocardial infarction (post-STEMI) events are unknown. We investigated associations between gut microbial taxa and systemic TMAO levels and the possible TMAO contribution to incident post-STEMI cardiovascular events. Patients and Methods. A total of 60 patients, including 30 with unstable angina pectoris (UAP), 30 post-STEMI and 30 healthy controls, were enrolled from June to November 2017. Metagenomic sequencing was performed and TMAO and IL-6 were detected. Results. Minimal discriminators of gut microbial taxa (top 40) distinguished ACS patients from controls. Serum TMAO levels were positively associated with increased abundance of Aerococcaceae, Ruminococcaceae_UCG.005, Ruminococcaceae_UCC.014 and X. Eubacterium_fissicatena, and decreased abundance of Lachnospiraceae_FCS020 (P < 0.05). Elevated serum TMAO levels correlated independently with ACS (P < 0.05). Risk stratification for incident major adverse cardiovascular events (MACE) improved at one year in patients with serum TMAO levels ≦2.19 µM. Serum interleukin-6 levels were not significantly increased in patients with ACS and post-STEMI MACE. Conclusions. ACS and incident post-STEMI MACE may be associated with the gut bacteria choline metabolite TMAO. The specific gut microbial taxa identified in association with serum TMAO levels may be potential predictive biomarkers for accurate diagnosis of ACS onset.

Long-Term Changes in Gut Microbial Metabolite Trimethylamine N-Oxide and Coronary Heart Disease Risk

BackgroundA gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with coronary atherosclerotic burden. No previous prospective study has addressed associations of long-term changes in TMAO with coronary heart disease (CHD) incidence. ObjectivesThe purpose of this study was to investigate whether 10-year changes in plasma TMAO levels were significantly associated with CHD incidence. MethodsThis prospective nested case-control study included 760 healthy women at baseline. Plasma TMAO levels were measured both at the first (1989 to 1990) and the second (2000 to 2002) blood collections; 10-year changes (Δ) in TMAO were calculated. Incident cases of CHD (n = 380) were identified after the second blood collection through 2016 and were matched to controls (n = 380). ResultsRegardless of the initial TMAO levels, 10-year increases in TMAO from the first to second blood collection were significantly associated with an increased risk of CHD (relative risk [RR] in the top tertile: 1.58 [95% confidence interval (CI): 1.05 to 2.38]; RR per 1-SD increment: 1.33 [95% CI: 1.06 to 1.67]). Participants with elevated TMAO levels (the top tertile) at both time points showed the highest RR of 1.79 (95% CI: 1.08 to 2.96) for CHD as compared with those with consistently low TMAO levels. Further, we found that the ΔTMAO-CHD relationship was strengthened by unhealthy dietary patterns (assessed by the Alternate Healthy Eating Index) and was attenuated by healthy dietary patterns (p interaction = 0.008). ConclusionsLong-term increases in TMAO were associated with higher CHD risk, and repeated assessment of TMAO over 10 years improved the identification of people with a higher risk of CHD. Diet may modify the associations of ΔTMAO with CHD risk.

Dynamic Changes and Prognostic Value of Gut Microbiota-Dependent Trimethylamine-N-Oxide in Acute Ischemic Stroke.

Background: Acute ischemic stroke (AIS) is an atherothrombotic disease. Trimethylamine-N-oxide (TMAO), a gut microbiota-dependent metabolite, has been shown to be proatherogenic and prothrombotic. However, the involvement of TMAO in AIS remains unclear. This study aimed to observe the dynamic changes of TMAO in AIS patients and identify the prognostic value of TMAO for major ischemic events and unfavorable functional outcomes.Methods: This study included 204 AIS patients and 108 healthy controls. Blood samples for TMAO analyses were drawn at admission, 2 and 7 days of admission. Logistic regression models and receiver operating characteristic curves were established to identify associations between TMAO levels and major ischemic events (ischemic stroke, myocardial infarction, or death from an ischemic vascular event), as well as unfavorable functional outcomes (modified Rankin Scale score ≥3), at 90 days and 12 months.Results: TMAO levels showed no significant changes before and within 24 h of AIS treatment (at admission) but decreased significantly thereafter. Elevated log2-transformed baseline TMAO levels were associated with increased risks of 90-day [odds ratio (OR), 2.62; 95% confidence interval (CI), 1.55–4.45; p < 0.001] and 12-month (OR, 3.59; 95% CI, 2.12–6.09; p < 0.001) major ischemic events, as well as 90-day (OR, 2.89; 95% CI, 1.46–5.71; p = 0.002) and 12-month (OR, 2.58; 95% CI, 1.50–4.46; p = 0.001) unfavorable functional outcomes, after adjustments for confounding factors. The areas under curve of baseline TMAO levels for predicting 90-day and 12-month major ischemic events were 0.72 (95% CI, 0.61–0.83; p < 0.001) and 0.76 (95% CI, 0.66–0.85; p < 0.001). Baseline TMAO levels improved the prognostic accuracy of conventional risk factors, National Institutes of Health Stroke Scale (NIHSS) score and N-terminal B-type natriuretic peptide (NT-proBNP) level.Conclusions: TMAO levels decreased with time since stroke onset. Elevated TMAO levels at an earlier period portended poor stroke outcomes, broadening the potential clinical utility of TMAO as an independent prognostic marker and therapeutic target.