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Observational Study
. 2014 Dec 10;9(12):e114969.
doi: 10.1371/journal.pone.0114969. eCollection 2014.

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

Michael Lever  1 , Peter M George  1 , Sandy Slow  1 , David Bellamy  2 , Joanna M Young  3 , Markus Ho  2 , Christopher J McEntyre  2 , Jane L Elmslie  2 , Wendy Atkinson  2 , Sarah L Molyneux  2 , Richard W Troughton  3 , Christopher M Frampton  3 , A Mark Richards  3 , Stephen T Chambers  4
Affiliations
Observational Study

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

Michael Lever et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. 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.
Figure 2
Figure 2. Kaplan-Meier plots: trimethylamine-N-oxide.
Plasma trimethylamine-N-oxide concentrations and Kaplan-Meier plots of survival to events. TMAO: Trimethylamine N-oxide. Events: Top (A&B) death from all causes; (C&D) secondary myocardial infarction (MI); middle (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.
Figure 3
Figure 3. Hazard ratios.
Hazard ratios for low (left) or high (middle) plasma betaine concentrations, and for high plasma trimethylamine N-oxide concentrations (right). Model 1: just low and high marker (2 variables). Model 2: baseline eGFR added to model. Model 3: Model 2 plus baseline LVEF and plasma NT-proBNP added to model. A: in subjects without diabetes; B: in subjects with diagnosed diabetes. Events: MI: secondary myocardial infarction; HF: hospitalization for heart failure; UA: unstable angina; All: all cardiovascular events. Left side: low plasma betaine; middle: high plasma betaine; right side: high plasma trimethylamine N-oxide. Vertical dotted red lines: hazard ratio of 1.0. Ratios significantly (p<0.05) different from 1 are shown in red. All ratios are shown with 95% confidence intervals.
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References

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Publication types

Grants and funding

Support from the Heart Foundation of New Zealand (grant 1090) and the Maurice and Phyllis Paykel Trust are acknowledged. The parent CDCS study was funded by the Health Research Council of New Zealand (Programme 02/152). These funding bodies had no role in the conduct of the research or its interpretation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.