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Trimethylamine N-Oxide and Cardiovascular Events in Hemodialysis Patients.

ABSTRACT: Cardiovascular disease causes over 50% of the deaths in dialysis patients, and the risk of death is higher in white than in black patients. The underlying mechanisms for these findings are unknown. We determined the association of the proatherogenic metabolite trimethylamine N-oxide (TMAO) with cardiovascular outcomes in hemodialysis patients and assessed whether this association differs by race. We measured TMAO in stored serum samples obtained 3-6 months after randomization from a total of 1232 white and black patients of the Hemodialysis Study, and analyzed the association of TMAO with cardiovascular outcomes using Cox models adjusted for potential confounders (demographics, clinical characteristics, comorbidities, albumin, and residual kidney function). Mean age of the patients was 58 years; 35% of patients were white. TMAO concentration did not differ between whites and blacks. In whites, 2-fold higher TMAO associated with higher risk (hazard ratio [95% confidence interval]) of cardiac death (1.45 [1.24 to 1.69]), sudden cardiac death [1.70 (1.34 to 2.15)], first cardiovascular event (1.15 [1.01 to 1.32]), and any-cause death (1.22 [1.09 to 1.36]). In blacks, the association was nonlinear and significant only for cardiac death among patients with TMAO concentrations below the median (1.58 [1.03 to 2.44]). Compared with blacks in the same quintile, whites in the highest quintile for TMAO (?135 ?M) had a 4-fold higher risk of cardiac or sudden cardiac death and a 2-fold higher risk of any-cause death. We conclude that TMAO concentration associates with cardiovascular events in hemodialysis patients but the effects differ by race.

SUBMITTER: Shafi T

PROVIDER: S-EPMC5198291 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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Trimethylamine N-Oxide and Cardiovascular Events in Hemodialysis Patients.

Shafi Tariq T Powe Neil R NR Meyer Timothy W TW Hwang Seungyoung S Hai Xin X Melamed Michal L ML Banerjee Tanushree T Coresh Josef J Hostetter Thomas H TH

Journal of the American Society of Nephrology : JASN 20160719 1

Cardiovascular disease causes over 50% of the deaths in dialysis patients, and the risk of death is higher in white than in black patients. The underlying mechanisms for these findings are unknown. We determined the association of the proatherogenic metabolite trimethylamine N-oxide (TMAO) with cardiovascular outcomes in hemodialysis patients and assessed whether this association differs by race. We measured TMAO in stored serum samples obtained 3-6 months after randomization from a total of 123 ...[more]

PMID: 27436853

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Project description:Large size, protein binding and intracellular sequestration are well known to limit dialytic removal of compounds. In studying the normal renal and dialytic handling of trimethylamine oxide (TMAO), a molecule associated with cardiovascular disease in the general population, we discovered two largely unrecognized additional limitations to sustained reduction of a solute by chronic hemodialysis. We measured solute levels and handling in subjects on chronic hemodialysis (ESRD, n = 7) and compared these with levels and clearance in normal controls (NLS, n = 6). The ESRD patients had much higher peak predialysis plasma levels of TMAO than NLS (77 ± 26 vs 2±1 ?M, mean ± SD, p<0.05). For comparison, predialysis BUN levels in ESRD subjects were 45±11 mg/dl and 15±3 mg/dl in NLS. Thus TMAO levels in ESRD average about 40 fold those in NLS while BUN is 3 fold NLS. However, the fractional reduction of TMAO concentration during dialysis, was in fact greater than that of urea (86±3 vs 74±6%, TMAO vs urea, p < 0.05) and its dialytic clearance while somewhat lower than that of urea was comparable to creatinine's. Also production rates were similar (533±272 vs 606 ± 220 ? moles/day, ESRD vs NLS, p>0.05). However, TMAO has a volume of distribution about one half that of urea. Also in NLS the urinary clearance of TMAO was high (219±78 ml/min) compared to the urinary urea and creatinine clearances (55±14 and 119±21 ml/min, respectively). Thus, TMAO levels achieve multiples of normal much greater than those of urea due mainly to 1) TMAO's high clearance by the normal kidney relative to urea and 2) its smaller volume of distribution. Modelling suggests that only much more frequent dialysis would be required to lower levels Thus, additional strategies such as reducing production should be explored. Furthermore, using urea as the sole marker of dialysis adequacy may be misleading since a molecule, TMAO, that is dialyzed readily accumulates to much higher multiples of normal with urea based dialysis prescriptions.

Project description:Objective- Gut microbiota-dependent metabolites, in particular trimethylamine N-oxide (TMAO), have recently been reported to promote atherosclerosis and thrombosis. Here, we examined for the first time the relation of TMAO and the risk of incident cardiovascular events in patients with recent first-ever ischemic stroke in 2 independent prospective cohorts. Moreover, the link between TMAO and proinflammatory monocytes as a potential contributing factor for cardiovascular risk in stroke patients was studied. Approach and Results- In a first study (n=78), higher TMAO plasma levels were linked with an increased risk of incident cardiovascular events including myocardial infarction, recurrent stroke, and cardiovascular death (fourth quartile versus first quartile; hazard ratio, 2.31; 95% CI, 1.25-4.23; P<0.01). In the second independent validation cohort (n=593), high TMAO levels again heralded marked increased risk of adverse cardiovascular events (fourth quartile versus first quartile; hazard ratio, 5.0; 95% CI, 1.7-14.8; P<0.01), and also after adjustments for cardiovascular risk factors including hypertension, diabetes mellitus, LDL (low-density lipoprotein) cholesterol, and estimated glomerular filtration rate (hazard ratio, 3.3; 95% CI, 1.2-10.9; P=0.04). A significant correlation was also found between TMAO levels and percentage of proinflammatory intermediate CD14++CD16+ monocytes ( r=0.70; P<0.01). Moreover, in mice fed a diet enriched with choline to increase TMAO synthesis, levels of proinflammatory murine Ly6Chigh monocytes were higher than in the chow-fed control group (choline: 9.2±0.5×103 per mL versus control: 6.5±0.5×103 per mL; P<0.01). This increase was abolished in mice with depleted gut microbiota (choline+antibiotics: 5.4±0.7×103 per mL; P<0.001 versus choline). Conclusions- The present study demonstrates for the first time a graded relation between TMAO levels and the risk of subsequent cardiovascular events in patients with recent prior ischemic stroke. Our data support the notion that TMAO-related increase of proinflammatory monocytes may add to elevated cardiovascular risk of patients with increased TMAO levels.

Project description:Background Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite of dietary choline, L-carnitine, and phosphatidylcholine-rich foods. On the basis of experimental studies and patients with prevalent disease, elevated plasma TMAO may increase risk of atherosclerotic cardiovascular disease (ASCVD). TMAO is also renally cleared and may interact with and causally contribute to renal dysfunction. Yet, how serial TMAO levels relate to incident and recurrent ASCVD in community-based populations and the potential mediating or modifying role of renal function are not established. Methods and Results We investigated associations of serial measures of plasma TMAO, assessed at baseline and 7 years, with incident and recurrent ASCVD in a community-based cohort of 4131 (incident) and 1449 (recurrent) older US adults. TMAO was measured using stable isotope dilution liquid chromatography-tandem mass spectrometry (laboratory coefficient of variation, <6%). Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, sudden cardiac death, or other atherosclerotic death) was centrally adjudicated using medical records. Risk was assessed by multivariable Cox proportional hazards regression, including time-varying demographics, lifestyle factors, medical history, laboratory measures, and dietary habits. Potential mediating effects and interaction by estimated glomerular filtration rate (eGFR) were assessed. During prospective follow-up, 1766 incident and 897 recurrent ASCVD events occurred. After multivariable adjustment, higher levels of TMAO were associated with a higher risk of incident ASCVD, with extreme quintile hazard ratio (HR) compared with the lowest quintile=1.21 (95% CI, 1.02-1.42; P-trend=0.029). This relationship appeared mediated or confounded by eGFR (eGFR-adjusted HR, 1.07; 95% CI, 0.90-1.27), as well as modified by eGFR (P-interaction <0.001). High levels of TMAO were associated with higher incidence of ASCVD in the presence of impaired renal function (eGFR <60 mL/min per 1.73 m2: HR, 1.56 [95% CI, 1.13-2.14]; P-trend=0.007), but not normal or mildly reduced renal function (eGFR ≥60 mL/min per 1.73 m2: HR, 1.03 [95% CI, 0.85-1.25]; P-trend=0.668). Among individuals with prior ASCVD, TMAO associated with higher risk of recurrent ASCVD (HR, 1.25 [95% CI, 1.01-1.56]; P-trend=0.009), without significant modification by eGFR. Conclusions In this large community-based cohort of older US adults, serial measures of TMAO were associated with higher risk of incident ASCVD, with apparent modification by presence of impaired renal function and with higher risk of recurrent ASCVD.

Dataset Information

Trimethylamine N-Oxide and Cardiovascular Events in Hemodialysis Patients.

Publications

Trimethylamine N-Oxide and Cardiovascular Events in Hemodialysis Patients.

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