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Betaine and Trimethylamine-N-Oxide as Predictors of Cardiovascular Outcomes Show Different Patterns in Diabetes Mellitus: An Observational Study.

Lever M, George PM, Slow S, Bellamy D, Young JM, Ho M, McEntyre CJ, Elmslie JL, Atkinson W, Molyneux SL, Troughton RW, Frampton CM, Richards AM, Chambers ST - PLoS ONE (2014)

Bottom Line: In subjects with diabetes (n = 79), high plasma betaine was associated with increased frequencies of events; significantly for heart failure, hazard ratio 3.1 (1.2-8.2) and all cardiovascular events, HR 2.8 (1.4-5.5).In subjects without diabetes (n = 396), low plasma betaine was associated with events; significantly for secondary myocardial infarction, HR 2.1 (1.2-3.6), unstable angina, HR 2.3 (1.3-4.0), and all cardiovascular events, HR 1.4 (1.0-1.9).Adding the estimated glomerular filtration rate to Cox regression models tended to increase the apparent risks associated with low betaine.

View Article: PubMed Central - PubMed

Affiliation: Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand; Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand.

ABSTRACT

Background: Betaine is a major osmolyte, also important in methyl group metabolism. Concentrations of betaine, its metabolite dimethylglycine and analog trimethylamine-N-oxide (TMAO) in blood are cardiovascular risk markers. Diabetes disturbs betaine: does diabetes alter associations between betaine-related measures and cardiovascular risk?

Methods: Plasma samples were collected from 475 subjects four months after discharge following an acute coronary admission. Death (n = 81), secondary acute MI (n = 87), admission for heart failure (n = 85), unstable angina (n = 72) and all cardiovascular events (n = 283) were recorded (median follow-up: 1804 days).

Results: High and low metabolite concentrations were defined as top or bottom quintile of the total cohort. In subjects with diabetes (n = 79), high plasma betaine was associated with increased frequencies of events; significantly for heart failure, hazard ratio 3.1 (1.2-8.2) and all cardiovascular events, HR 2.8 (1.4-5.5). In subjects without diabetes (n = 396), low plasma betaine was associated with events; significantly for secondary myocardial infarction, HR 2.1 (1.2-3.6), unstable angina, HR 2.3 (1.3-4.0), and all cardiovascular events, HR 1.4 (1.0-1.9). In diabetes, high TMAO was a marker of all outcomes, HR 2.7 (1.1-7.1) for death, 4.0 (1.6-9.8) for myocardial infarction, 4.6 (2.0-10.7) for heart failure, 9.1 (2.8-29.7) for unstable angina and 2.0 (1.1-3.6) for all cardiovascular events. In subjects without diabetes TMAO was only significant for death, HR 2.7 (1.6-4.8) and heart failure, HR 1.9 (1.1-3.4). Adding the estimated glomerular filtration rate to Cox regression models tended to increase the apparent risks associated with low betaine.

Conclusions: Elevated plasma betaine concentration is a marker of cardiovascular risk in diabetes; conversely low plasma betaine concentrations indicate increased risk in the absence of diabetes. We speculate that the difference reflects control of osmolyte retention in tissues. Elevated plasma TMAO is a strong risk marker in diabetes.

No MeSH data available.


Related in: MedlinePlus

Kaplan-Meier plots: betaine.Plasma betaine concentrations and Kaplan-Meier plots of survival to events. Events: Top (A&B) death from all causes; (C&D) secondary myocardial infarction (MI); (E&F) hospitalization for heart failure (HF); (G&H) unstable angina (UA), and (H&I) all cardiovascular events. On left, A,C,E,G&H are subjects without diabetes; on right, B,D,F,H&J are subjects with diabetes. “High” (green) is the highest quintile of plasma betaine concentration, “Low” (red) the bottom quintile of plasma betaine concentration; “Middle” (black) the remaining 60% of the cohort. All significances are for comparisons with the middle group. Where no significance is shown, p for the difference is >0.3.
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pone-0114969-g001: Kaplan-Meier plots: betaine.Plasma betaine concentrations and Kaplan-Meier plots of survival to events. Events: Top (A&B) death from all causes; (C&D) secondary myocardial infarction (MI); (E&F) hospitalization for heart failure (HF); (G&H) unstable angina (UA), and (H&I) all cardiovascular events. On left, A,C,E,G&H are subjects without diabetes; on right, B,D,F,H&J are subjects with diabetes. “High” (green) is the highest quintile of plasma betaine concentration, “Low” (red) the bottom quintile of plasma betaine concentration; “Middle” (black) the remaining 60% of the cohort. All significances are for comparisons with the middle group. Where no significance is shown, p for the difference is >0.3.

Mentions: When the mean times to secondary events were compared between high (highest quintile) or low (lowest quintile) subjects and the central 60% of the total sample population, the most striking difference was in the predictive significance of plasma betaine (Fig. 1). In patients with diabetes, high (top quintile) plasma betaine concentrations were associated with an increased frequency of events when compared with patients with the middle 60% of betaine concentrations; the differences were large for some events, and despite the small number of patients the differences were significant for admissions for heart failure and for all cardiovascular events, with a trend (p = 0.054) in the case of secondary MI. In contrast (Fig. 1), in subjects without diabetes low plasma betaine was more likely to be associated with events, significantly so for MI, unstable angina and for all CVD, and there were no detectable differences in mean survival times between the middle and high plasma betaine groups.


Betaine and Trimethylamine-N-Oxide as Predictors of Cardiovascular Outcomes Show Different Patterns in Diabetes Mellitus: An Observational Study.

Lever M, George PM, Slow S, Bellamy D, Young JM, Ho M, McEntyre CJ, Elmslie JL, Atkinson W, Molyneux SL, Troughton RW, Frampton CM, Richards AM, Chambers ST - PLoS ONE (2014)

Kaplan-Meier plots: betaine.Plasma betaine concentrations and Kaplan-Meier plots of survival to events. Events: Top (A&B) death from all causes; (C&D) secondary myocardial infarction (MI); (E&F) hospitalization for heart failure (HF); (G&H) unstable angina (UA), and (H&I) all cardiovascular events. On left, A,C,E,G&H are subjects without diabetes; on right, B,D,F,H&J are subjects with diabetes. “High” (green) is the highest quintile of plasma betaine concentration, “Low” (red) the bottom quintile of plasma betaine concentration; “Middle” (black) the remaining 60% of the cohort. All significances are for comparisons with the middle group. Where no significance is shown, p for the difference is >0.3.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4262445&req=5

pone-0114969-g001: Kaplan-Meier plots: betaine.Plasma betaine concentrations and Kaplan-Meier plots of survival to events. Events: Top (A&B) death from all causes; (C&D) secondary myocardial infarction (MI); (E&F) hospitalization for heart failure (HF); (G&H) unstable angina (UA), and (H&I) all cardiovascular events. On left, A,C,E,G&H are subjects without diabetes; on right, B,D,F,H&J are subjects with diabetes. “High” (green) is the highest quintile of plasma betaine concentration, “Low” (red) the bottom quintile of plasma betaine concentration; “Middle” (black) the remaining 60% of the cohort. All significances are for comparisons with the middle group. Where no significance is shown, p for the difference is >0.3.
Mentions: When the mean times to secondary events were compared between high (highest quintile) or low (lowest quintile) subjects and the central 60% of the total sample population, the most striking difference was in the predictive significance of plasma betaine (Fig. 1). In patients with diabetes, high (top quintile) plasma betaine concentrations were associated with an increased frequency of events when compared with patients with the middle 60% of betaine concentrations; the differences were large for some events, and despite the small number of patients the differences were significant for admissions for heart failure and for all cardiovascular events, with a trend (p = 0.054) in the case of secondary MI. In contrast (Fig. 1), in subjects without diabetes low plasma betaine was more likely to be associated with events, significantly so for MI, unstable angina and for all CVD, and there were no detectable differences in mean survival times between the middle and high plasma betaine groups.

Bottom Line: In subjects with diabetes (n = 79), high plasma betaine was associated with increased frequencies of events; significantly for heart failure, hazard ratio 3.1 (1.2-8.2) and all cardiovascular events, HR 2.8 (1.4-5.5).In subjects without diabetes (n = 396), low plasma betaine was associated with events; significantly for secondary myocardial infarction, HR 2.1 (1.2-3.6), unstable angina, HR 2.3 (1.3-4.0), and all cardiovascular events, HR 1.4 (1.0-1.9).Adding the estimated glomerular filtration rate to Cox regression models tended to increase the apparent risks associated with low betaine.

View Article: PubMed Central - PubMed

Affiliation: Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand; Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand.

ABSTRACT

Background: Betaine is a major osmolyte, also important in methyl group metabolism. Concentrations of betaine, its metabolite dimethylglycine and analog trimethylamine-N-oxide (TMAO) in blood are cardiovascular risk markers. Diabetes disturbs betaine: does diabetes alter associations between betaine-related measures and cardiovascular risk?

Methods: Plasma samples were collected from 475 subjects four months after discharge following an acute coronary admission. Death (n = 81), secondary acute MI (n = 87), admission for heart failure (n = 85), unstable angina (n = 72) and all cardiovascular events (n = 283) were recorded (median follow-up: 1804 days).

Results: High and low metabolite concentrations were defined as top or bottom quintile of the total cohort. In subjects with diabetes (n = 79), high plasma betaine was associated with increased frequencies of events; significantly for heart failure, hazard ratio 3.1 (1.2-8.2) and all cardiovascular events, HR 2.8 (1.4-5.5). In subjects without diabetes (n = 396), low plasma betaine was associated with events; significantly for secondary myocardial infarction, HR 2.1 (1.2-3.6), unstable angina, HR 2.3 (1.3-4.0), and all cardiovascular events, HR 1.4 (1.0-1.9). In diabetes, high TMAO was a marker of all outcomes, HR 2.7 (1.1-7.1) for death, 4.0 (1.6-9.8) for myocardial infarction, 4.6 (2.0-10.7) for heart failure, 9.1 (2.8-29.7) for unstable angina and 2.0 (1.1-3.6) for all cardiovascular events. In subjects without diabetes TMAO was only significant for death, HR 2.7 (1.6-4.8) and heart failure, HR 1.9 (1.1-3.4). Adding the estimated glomerular filtration rate to Cox regression models tended to increase the apparent risks associated with low betaine.

Conclusions: Elevated plasma betaine concentration is a marker of cardiovascular risk in diabetes; conversely low plasma betaine concentrations indicate increased risk in the absence of diabetes. We speculate that the difference reflects control of osmolyte retention in tissues. Elevated plasma TMAO is a strong risk marker in diabetes.

No MeSH data available.


Related in: MedlinePlus