Dataset Information

Plasma Metabolites From Choline Pathway and Risk of Cardiovascular Disease in the PREDIMED (Prevention With Mediterranean Diet) Study.

ABSTRACT:

Background

The relationship between plasma concentrations of betaine and choline metabolism and major cardiovascular disease (CVD) end points remains unclear. We have evaluated the association between metabolites from the choline pathway and risk of incident CVD and the potential modifying effect of Mediterranean diet interventions.

Methods and results

We designed a case-cohort study nested within the PREDIMED (Prevention With Mediterranean Diet) trial, including 229 incident CVD cases and 751 randomly selected participants at baseline, followed up for 4.8 years. We used liquid chromatography-tandem mass spectrometry to measure, at baseline and at 1 year of follow-up, plasma concentrations of 5 metabolites in the choline pathway: trimethylamine N-oxide, betaine, choline, phosphocholine, and ?-glycerophosphocholine. We have calculated a choline metabolite score using a weighted sum of these 5 metabolites. We used weighted Cox regression models to estimate CVD risk. The multivariable hazard ratios (95% confidence intervals) per 1-SD increase in choline and ?-glycerophosphocholine metabolites were 1.24 (1.05-1.46) and 1.24 (1.03-1.50), respectively. The baseline betaine/choline ratio was inversely associated with CVD. The baseline choline metabolite score was associated with a 2.21-fold higher risk of CVD across extreme quartiles (95% confidence interval, 1.36-3.59; P<0.001 for trend) and a 2.27-fold higher risk of stroke (95% confidence interval, 1.24-4.16; P<0.001 for trend). Participants in the higher quartiles of the score who were randomly assigned to the control group had a higher risk of CVD compared with participants in the lower quartile and assigned to the Mediterranean diet groups (P=0.05 for interaction). No significant associations were observed for 1-year changes in individual plasma metabolites and CVD.

Conclusions

A metabolite score combining plasma metabolites from the choline pathway was associated with an increased risk of CVD in a Mediterranean population at high cardiovascular risk.

Clinical trial registration

URL: http://www.controlled-trials.com. Unique identifier: ISRCTN35739639.

SUBMITTER: Guasch-Ferre M

PROVIDER: S-EPMC5721752 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Publications

Plasma Metabolites From Choline Pathway and Risk of Cardiovascular Disease in the PREDIMED (Prevention With Mediterranean Diet) Study.

Guasch-Ferré Marta M Hu Frank B FB Ruiz-Canela Miguel M Bulló Mònica M Toledo Estefanía E Wang Dong D DD Corella Dolores D Gómez-Gracia Enrique E Fiol Miquel M Estruch Ramon R Lapetra José J Fitó Montserrat M Arós Fernando F Serra-Majem Lluís L Ros Emilio E Dennis Courtney C Liang Liming L Clish Clary B CB Martínez-González Miguel A MA Salas-Salvadó Jordi J

Journal of the American Heart Association 20171028 11

<h4>Background</h4>The relationship between plasma concentrations of betaine and choline metabolism and major cardiovascular disease (CVD) end points remains unclear. We have evaluated the association between metabolites from the choline pathway and risk of incident CVD and the potential modifying effect of Mediterranean diet interventions.<h4>Methods and results</h4>We designed a case-cohort study nested within the PREDIMED (Prevention With Mediterranean Diet) trial, including 229 incident CVD ...[more]

PMID: 29080862

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Project description:BACKGROUND:Although in vitro studies and investigations in animal models and small clinical populations have suggested that ceramides may represent an intermediate link between overnutrition and certain pathological mechanisms underlying cardiovascular disease (CVD), no prospective studies have investigated the association between plasma ceramides and risk of CVD. METHODS:The study population consisted of 980 participants from the PREDIMED trial (Prevención con Dieta Mediterránea), including 230 incident cases of CVD and 787 randomly selected participants at baseline (including 37 overlapping cases) followed for ?7.4 years. Participants were randomized to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with nuts, or a control diet. Plasma ceramide concentrations were measured on a liquid chromatography tandem mass spectrometry metabolomics platform. The primary outcome was a composite of nonfatal acute myocardial infarction, nonfatal stroke, or cardiovascular death. Hazard ratios were estimated with weighted Cox regression models using Barlow weights to account for the case-cohort design. RESULTS:The multivariable hazard ratios (HR) and 95% confidence intervals (CIs) comparing the extreme quartiles of plasma concentrations of C16:0, C22:0, C24:0, and C24:1 ceramides were 2.39 (1.49-3.83, Ptrend<0.001), 1.91 (1.21-3.01, Ptrend=0.003), 1.97 (1.21-3.20, Ptrend=0.004), and 1.73 (1.09-2.74, Ptrend=0.011), respectively. The ceramide score, calculated as a weighted sum of concentrations of four ceramides, was associated with a 2.18-fold higher risk of CVD across extreme quartiles (HR, 2.18; 95% CI, 1.36-3.49; Ptrend<0.001). The association between baseline ceramide score and incident CVD varied significantly by treatment groups (Pinteraction=0.010). Participants with a higher ceramide score and assigned to either of the 2 active intervention arms of the trial showed similar CVD risk to those with a lower ceramide score, whereas participants with a higher ceramide score and assigned to the control arm presented significantly higher CVD risk. Changes in ceramide concentration were not significantly different between Mediterranean diet and control groups during the first year of follow-up. CONCLUSIONS:Our study documented a novel positive association between baseline plasma ceramide concentrations and incident CVD. In addition, a Mediterranean dietary intervention may mitigate potential deleterious effects of elevated plasma ceramide concentrations on CVD. CLINICAL TRIAL REGISTRATION:URL: http://www.isrctn.com. Unique identifier: ISRCTN35739639.

Project description:AimsTo investigate whether metabolic signature composed of multiple plasma metabolites can be used to characterize adherence and metabolic response to the Mediterranean diet and whether such a metabolic signature is associated with cardiovascular disease (CVD) risk.Methods and resultsOur primary study cohort included 1859 participants from the Spanish PREDIMED trial, and validation cohorts included 6868 participants from the US Nurses' Health Studies I and II, and Health Professionals Follow-up Study (NHS/HPFS). Adherence to the Mediterranean diet was assessed using a validated Mediterranean Diet Adherence Screener (MEDAS), and plasma metabolome was profiled by liquid chromatography-tandem mass spectrometry. We observed substantial metabolomic variation with respect to Mediterranean diet adherence, with nearly one-third of the assayed metabolites significantly associated with MEDAS (false discovery rate < 0.05). Using elastic net regularized regressions, we identified a metabolic signature, comprised of 67 metabolites, robustly correlated with Mediterranean diet adherence in both PREDIMED and NHS/HPFS (r = 0.28-0.37 between the signature and MEDAS; P = 3 × 10-35 to 4 × 10-118). In multivariable Cox regressions, the metabolic signature showed a significant inverse association with CVD incidence after adjusting for known risk factors (PREDIMED: hazard ratio [HR] per standard deviation increment in the signature = 0.71, P < 0.001; NHS/HPFS: HR = 0.85, P = 0.001), and the association persisted after further adjustment for MEDAS scores (PREDIMED: HR = 0.73, P = 0.004; NHS/HPFS: HR = 0.85, P = 0.004). Further genome-wide association analysis revealed that the metabolic signature was significantly associated with genetic loci involved in fatty acids and amino acids metabolism. Mendelian randomization analyses showed that the genetically inferred metabolic signature was significantly associated with risk of coronary heart disease (CHD) and stroke (odds ratios per SD increment in the genetically inferred metabolic signature = 0.92 for CHD and 0.91 for stroke; P < 0.001).ConclusionsWe identified a metabolic signature that robustly reflects adherence and metabolic response to a Mediterranean diet, and predicts future CVD risk independent of traditional risk factors, in Spanish and US cohorts.

Project description:The usefulness of cardiovascular disease (CVD) predictive equations in different populations is debatable. We assessed the efficacy of the Framingham-REGICOR scale, validated for the Spanish population, to identify future CVD in participants, who were predefined as being at high-risk in the PREvención con DIeta MEDiterránea (PREDIMED) study-a nutrition-intervention primary prevention trial-and the impact of adherence to the Mediterranean diet on CVD across risk categories. In a post hoc analysis, we assessed the CVD predictive value of baseline estimated risk in 5966 PREDIMED participants (aged 55-74 years, 57% women; 48% with type 2 diabetes mellitus). Major CVD events, the primary PREDIMED end point, were an aggregate of myocardial infarction, stroke, and cardiovascular death. Multivariate-adjusted Cox regression was used to calculate hazard ratios for major CVD events and effect modification from the Mediterranean diet intervention across risk strata (low, moderate, high, very high). The Framingham-REGICOR classification of PREDIMED participants was 25.1% low risk, 44.5% moderate risk, and 30.4% high or very high risk. During 6-year follow-up, 188 major CVD events occurred. Hazard ratios for major CVD events increased in parallel with estimated risk (2.68, 4.24, and 6.60 for moderate, high, and very high risk), particularly in men (7.60, 13.16, and 15.85, respectively, versus 2.16, 2.28, and 3.51, respectively, in women). Yet among those with low or moderate risk, 32.2% and 74.3% of major CVD events occurred in men and women, respectively. Mediterranean diet adherence was associated with CVD risk reduction regardless of risk strata (P>0.4 for interaction). Incident CVD increased in parallel with estimated risk in the PREDIMED cohort, but most events occurred in non-high-risk categories, particularly in women. Until predictive tools are improved, promotion of the Mediterranean diet might be useful to reduce CVD independent of baseline risk. URL: http://www.Controlled-trials.com. Unique identifier: ISRCTN35739639.

Project description:AIMS/HYPOTHESIS:Branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) are associated with type 2 diabetes. However, repeated measurements of BCAA/AAA and their interactions with dietary interventions have not been evaluated. We investigated the associations between baseline and changes at 1 year in BCAA/AAA with type 2 diabetes in the context of a Mediterranean diet (MedDiet) trial. METHODS:We included 251 participants with incident type 2 diabetes and a random sample of 694 participants (641 participants without type 2 diabetes and 53 overlapping cases) in a case-cohort study nested within the PREvención con DIeta MEDiterránea (PREDIMED) trial. Participants were randomised to a MedDiet+extra-virgin olive oil (n = 273), a MedDiet+nuts (n = 324) or a control diet (n = 295). We used LC-MS/MS to measure plasma levels of amino acids. Type 2 diabetes was a pre-specified secondary outcome of the PREDIMED trial. RESULTS:Elevated plasma levels of individual BCAAs/AAAs were associated with higher type 2 diabetes risk after a median follow-up of 3.8 years: multivariable HR for the highest vs lowest quartile ranged from 1.32 for phenylalanine ([95% CI 0.90, 1.92], p for trend = 0.015) to 3.29 for leucine ([95% CI 2.03, 5.34], p for trend<0.001). Increases in BCAA score at 1 year were associated with higher type 2 diabetes risk in the control group with HR per SD = 1.61 (95% CI 1.02, 2.54), but not in the MedDiet groups (p for interaction <0.001). The MedDiet+extra-virgin olive oil significantly reduced BCAA levels after 1 year of intervention (p = 0.005 vs the control group). CONCLUSIONS/INTERPRETATION:Our results support that higher baseline BCAAs and their increases at 1 year were associated with higher type 2 diabetes risk. A Mediterranean diet rich in extra-virgin olive oil significantly reduced the levels of BCAA and attenuated the positive association between plasma BCAA levels and type 2 diabetes incidence. Clinical trial number: SRCTN35739639 ( www.controlled-trials.com ).

Project description:The aim of this study was to examine the validity of the English version of the PREvencion con DIetaMEDiterranea (PREDIMED) 14-item Mediterranean Diet Adherence Screener (MEDAS), a brief questionnaire assessing adherence to the Mediterranean diet (MedDiet), which was used in the PREDIMED trial for assessment and immediate feedback. This instrument (MEDAS) was administered to 96 adults with a high cardiovascular risk (66% women, mean age 68.3 ± 6.0 years), recruited from general practices in Bristol, UK. Participants then completed a 3-day estimated food record, and the MEDAS was administered again one month later. A MedDiet score (range = 0-14) was calculated from the MEDAS' administrations and food record to assess concurrent validity and test-retest reliability. Predictive validity was assessed by examining the association of the MEDAS-derived score with cardiometabolic risk factors and dietary intakes derived from the food records. The MEDAS-derived MedDiet score was higher by 1.47 points compared to food records (5.47 vs.4.00, p < 0.001), correlated moderately with the record-derived score (r = 0.50, p < 0.001; ICC = 0.53, p < 0.001) and there was borderline fair agreement between the two methods (? = 0.19, 95% CI 0.07-0.31, p = 0.002; 95% limits of agreement -2.2, 5.1). Exact agreement within score categories and gross misclassificationwere 45.8% and 21.9%, respectively. The distribution of dietary intakes, reported on the food records by the MEDAS-derived total MedDiet score, was in the expected direction, but no association was observed with cardiometabolic risk factors. The two administrations of the MEDAS produced similar mean total MedDiet scores (5.5 vs. 5.4, p = 0.706), which were correlated (r and ICC = 0.69, p < 0.001) and agreed fairly (? = 0.38, 95% CI 0.24-0.52, p < 0.001; 95% limits of agreement -3.1, 3.2). The English version of the MEDAS has acceptable accuracy and reliability for assessing MedDiet adherence among individuals with a high cardiovascular risk, in the UK, and can be used to rank individuals according to MedDiet adherence in research and practice.

Dataset Information

Plasma Metabolites From Choline Pathway and Risk of Cardiovascular Disease in the PREDIMED (Prevention With Mediterranean Diet) Study.

Background

Methods and results

Conclusions

Clinical trial registration

Publications

Plasma Metabolites From Choline Pathway and Risk of Cardiovascular Disease in the PREDIMED (Prevention With Mediterranean Diet) Study.

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