Circulating carotenoids are associated with favorable lipid and fatty acid profiles in an older population at high cardiovascular risk

© 2022 Marhuenda-Muñoz, Domínguez-López, Langohr, Tresserra Rimbau, Martínez González, Salas-Salvadó, Corella, Zomeño, Martínez, Alonso-Gómez, Wärnberg, Vioque, Romaguera, López-Miranda, Estruch, Tinahones, Lapetra, Serra-Majem, Bueno-Cavanillas, Tur, MartínSánchez, Pintó, Delgado-Rodríguez, Matía-Martín, Vidal, Vázquez, Daimiel, Ros, Toledo, Fernández de la Puente Cervera, Barragán, Fitó, Tojal-Sierra, Gómez-Gracia, Zazo, Morey, García-Ríos, Casas, GómezPérez, Santos-Lozano, Vázquez-Ruiz, Atzeni, Asensio, Gili-Riu, Bullon, Moreno-Rodriguez, Lecea, Babio, Peñas Lopez, Gómez Melis and Lamuela-Raventós. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).Carotenoid intake has been reported to be associated with improved cardiovascular health, but there is little information on actual plasma concentrations of these compounds as biomarkers of cardiometabolic risk. The objective was to investigate the association between circulating plasma carotenoids and different cardiometabolic risk factors and the plasma fatty acid profile. This is a cross-sectional evaluation of baseline data conducted in a subcohort (106 women and 124 men) of an ongoing multi-factorial lifestyle trial for primary cardiovascular prevention. Plasma concentrations of carotenoids were quantified by liquid chromatography coupled to mass spectrometry. The associations between carotenoid concentrations and cardiometabolic risk factors were assessed using regression models adapted for interval-censored variables. Carotenoid concentrations were cross-sectionally inversely associated with serum triglyceride concentrations [-2.79 mg/dl (95% CI: -4.25, -1.34) and -5.15 mg/dl (95% CI: -7.38, -2.93), p-values = 0.0002 and <0.00001 in women and men, respectively], lower levels of plasma saturated fatty acids [-0.09% (95% CI: -0.14, -0.03) and -0.15 % (95% CI: -0.23, -0.08), p-values = 0.001 and 0.0001 in women and men, respectively], and higher levels of plasma polyunsaturated fatty acids [(0.12 % (95% CI: -0.01, 0.25) and 0.39 % (95% CI: 0.19, 0.59), p-values = 0.065 and 0.0001 in women and men, respectively] in the whole population. Plasma carotenoid concentrations were also associated with higher plasma HDL-cholesterol in women [0.47 mg/dl (95% CI: 0.23, 0.72), p-value: 0.0002], and lower fasting plasma glucose in men [-1.35 mg/dl (95% CI: -2.12, -0.59), p-value: 0.001].Peer ReviewedArticle signat per 51 autors/es: María Marhuenda-Muñoz, Inés Domínguez-López, Klaus Langohr, Anna Tresserra-Rimbau, Miguel Ángel Martínez González1,4, Jordi Salas-Salvadó, Dolores Corella, María Dolores Zomeño, J. Alfredo Martínez, Angel M. Alonso-Gómez, Julia Wärnberg, Jesús Vioque, Dora Romaguera, José López-Miranda, Ramón Estruch, Francisco J. Tinahones, José Lapetra, Ll. Serra-Majem, Aurora Bueno-Cavanillas, Josep A. Tur, Vicente Martín-Sánchez, Xavier Pintó, Miguel Delgado-Rodríguez, Pilar Matía-Martín, Josep Vidal, Clotilde Vázquez, Lidia Daimiel, Emilio Ros, Estefanía Toledo, María Fernández de la Puente Cervera, Rocío Barragán, Montse Fitó, Lucas Tojal-Sierra, Enrique Gómez-Gracia, Juan Manuel Zazo, Marga Morey, Antonio García-Ríos, Rosa Casas, Ana M. Gómez-Pérez, José Manuel Santos-Lozano, Zenaida Vázquez-Ruiz, Alessandro Atzeni, Eva M. Asensio, M. Mar Gili-Riu, Vanessa Bullon, Anai Moreno-Rodriguez, Oscar Lecea, Nancy Babio, Francesca Peñas Lopez, Guadalupe Gómez Melis and Rosa M. Lamuela-Raventós.Postprint (published version

Impact of Consuming Extra-Virgin Olive Oil or Nuts within a Mediterranean Diet on DNA Methylation in Peripheral White Blood Cells within the PREDIMED-Navarra Randomized Controlled Trial: A Role for Dietary Lipids

DNA methylation could be reversible and mouldable by environmental factors, such as dietary exposures. The objective was to analyse whether an intervention with two Mediterranean diets, one rich in extra-virgin olive oil (MedDiet + EVOO) and the other one in nuts (MedDiet + nuts), was influencing the methylation status of peripheral white blood cells (PWBCs) genes. A subset of 36 representative individuals were selected within the PREvención con DIeta MEDiterránea (PREDIMED-Navarra) trial, with three intervention groups in high cardiovascular risk volunteers: MedDiet + EVOO, MedDiet + nuts, and a low-fat control group. Methylation was assessed at baseline and at five-year follow-up. Ingenuity pathway analysis showed routes with differentially methylated CpG sites (CpGs) related to intermediate metabolism, diabetes, inflammation, and signal transduction. Two CpGs were specifically selected: cg01081346–CPT1B/CHKB-CPT1B and cg17071192–GNAS/GNASAS, being associated with intermediate metabolism. Furthermore, cg01081346 was associated with PUFAs intake, showing a role for specific fatty acids on epigenetic modulation. Specific components of MedDiet, particularly nuts and EVOO, were able to induce methylation changes in several PWBCs genes. These changes may have potential benefits in health; especially those changes in genes related to intermediate metabolism, diabetes, inflammation and signal transduction, which may contribute to explain the role of MedDiet and fat quality on health outcomes

Mediterranean Diet and atherothrombosis biomarkers: a randomized controlled trial

Scope. To assess whether following a Mediterranean diet (MedDiet) improved atherothrombosis biomarkers in high cardiovascular risk individuals. Methods and results. In 358 random volunteers from the PREvención con DIeta MEDiterránea trial, we assessed the 1-year effects on atherothrombosis markers of an intervention with MedDiet, enriched with virgin olive oil (MedDiet-VOO; n=120) or nuts (MedDiet-Nuts; n=119) versus a low-fat control diet (n=119). We also studied whether large increments in MedDiet adherence (≥3 score points, relative to compliance decreases) and intake changes in key food items were associated with 1-year differences in biomarkers. We observed differences between 1-year changes in the MedDiet-VOO intervention and control diet on the activity of platelet activating factor acetylhydrolase in HDLs (+7.5% [95% confidence interval: 0.17; 14.8]) and HDL-bound α1-antitrypsin levels (- 6.1% [-11.8; -0.29]), and between the MedDiet-Nuts intervention and the control arm on non-esterified fatty acid concentrations (-9.3% [-18.1; -0.53]). Large MedDiet adherence increments were associated with less fibrinogen (-9.5% [-18.3; -0.60]) and non-esterified fatty acid concentrations (-16.7% [-31.7; -1.74]). Increases in nut, fruit, vegetable, and fatty fish consumption, and decreases in processed meat intake were linked to beneficial changes in atherothrombosis biomarkers. Conclusion. Following a MedDiet improved atherothrombosis biomarkers in high cardiovascular risk individual

Extra virgin olive oil consumption reduces the risk of osteoporotic fractures in the PREDIMED trial

BACKGROUND & AIMS: The incidence of osteoporotic fractures is lower in countries in the Mediterranean basin. Virgin olive oil, a key component of the Mediterranean Diet (MDiet), with recognised beneficial effects on metabolism and cardiovascular health, may decrease the risk of osteoporotic fractures. The aim to this study was to explore the effect of chronic consumption of total olive oil and its varieties on the risk of osteoporosis-related fractures in a middle-aged and elderly Mediterranean population. METHODS: We included all participants (n = 870) recruited in the Reus (Spain) centre of the PREvención con DIeta MEDiterránea (PREDIMED) trial. Individuals, aged 55-80 years at high cardiovascular risk, were randomized to a MedDiet supplemented with extra-virgin olive oil, a MedDiet supplemented with nuts, or a low-fat diet. The present analysis was an observational cohort study nested in the trial. A validated food frequency questionnaire was used to assess dietary habits and olive oil consumption. Information on total osteoporotic fractures was obtained from a systematic review of medical records. The association between yearly repeated measurements of olive oil consumption and fracture risk was assessed by multivariate Cox proportional hazards. RESULTS: We documented 114 incident cases of osteoporosis-related fractures during a median follow-up of 8.9 years. Treatment allocation had no effect on fracture risk. Participants in the highest tertile of extra-virgin olive oil consumption had a 51% lower risk of fractures (HR:0.49; 95% CI:0.29-0.81. P for trend = 0.004) compared to those in the lowest tertile after adjusting for potential confounders. Total and common olive oil consumption was not associated with fracture risk. CONCLUSIONS: Higher consumption of extra-virgin olive oil is associated with a lower risk of osteoporosis-related fractures in middle-aged and elderly Mediterranean population at high cardiovascular risk

Metabolites related to purine catabolism and risk of type 2 diabetes incidence; modifying efects of the TCF7L2-rs7903146 polymorphism

Studies examining associations between purine metabolites and type 2 diabetes (T2D) are limited. We prospectively examined associations between plasma levels of purine metabolites with T2D risk and the modifying effects of transcription factor-7-like-2 (TCF7L2) rs7903146 polymorphism on these associations. This is a case-cohort design study within the PREDIMED study, with 251 incident T2D cases and a random sample of 694 participants (641 non-cases and 53 overlapping cases) without T2D at baseline (median follow-up: 3.8 years). Metabolites were semi-quantitatively profiled with LC-MS/MS. Cox regression analysis revealed that high plasma allantoin levels, including allantoin-to-uric acid ratio and high xanthine-to-hypoxanthine ratio were inversely and positively associated with T2D risk, respectively, independently of classical risk factors. Elevated plasma xanthine and inosine levels were associated with a higher T2D risk in homozygous carriers of the TCF7L2-rs7903146 T-allele. The potential mechanisms linking the aforementioned purine metabolites and T2D risk must be also further investigated

Circulating citric acid cycle metabolites and risk of cardiovascular disease in the PREDIMED study

Background and aim Plasma citric acid cycle (CAC) metabolites might be likely related to cardiovascular disease (CVD). However, studies assessing the longitudinal associations between circulating CAC-related metabolites and CVD risk are lacking. The aim of this study was to evaluate the association of baseline and 1-year levels of plasma CAC-related metabolites with CVD incidence (a composite of myocardial infarction, stroke or cardiovascular death), and their interaction with Mediterranean diet interventions. Methods and results Case-cohort study from the PREDIMED trial involving participants aged 55–80 years at high cardiovascular risk, allocated to MedDiets or control diet. A subcohort of 791 participants was selected at baseline, and a total of 231 cases were identified after a median follow-up of 4.8 years. Nine plasma CAC-related metabolites (pyruvate, lactate, citrate, aconitate, isocitrate, 2-hydroxyglutarate, fumarate, malate and succinate) were measured using liquid chromatography-tandem mass spectrometry. Weighted Cox multiple regression was used to calculate hazard ratios (HRs). Baseline fasting plasma levels of 3 metabolites were associated with higher CVD risk, with HRs (for each standard deviation, 1-SD) of 1.46 (95%CI:1.20–1.78) for 2-hydroxyglutarate, 1.33 (95%CI:1.12–1.58) for fumarate and 1.47 (95%CI:1.21–1.78) for malate (p of linear trend <0.001 for all). A higher risk of CVD was also found for a 1-SD increment of a combined score of these 3 metabolites (HR = 1.60; 95%CI: 1.32–1.94, p trend <0.001). This result was replicated using plasma measurements after one-year. No interactions were detected with the nutritional intervention. Conclusion Plasma 2-hydroxyglutarate, fumarate and malate levels were prospectively associated with increased cardiovascular risk

The Effect of a Mediterranean Diet on the Incidence of Cataract Surgery

Background: Cataract is a leading cause of vision impairment worldwide, and surgery is the only available treatment. The process that initiates lens opacification is dependent on the oxidative stress experienced by the lens components. A healthy overall dietary pattern, with the potential to reduce oxidative stress, has been suggested as a means to decrease the risk of developing cataract. We aimed to investigate the hypothesis that an intervention with a Mediterranean diet (MedDiet) rather than a low-fat diet could decrease the incidence of cataract surgery in elderly subjects. Methods: We included 5802 men and women (age range: 55–80 years) from the Prevención con Dieta Mediterránea study (multicenter, parallel-group, randomized controlled clinical trial) who had not undergone cataract surgery. They were randomly assigned to one of three intervention groups: (1) a MedDiet enriched with extra-virgin olive oil (EVOO) (n = 1998); (2) a MedDiet enriched with nuts (n = 1914), and a control group recommended to follow a low-fat diet (n = 1890). The incidence of cataract surgery was recorded yearly during follow-up clinical evaluations. Primary analyses were performed on an intention-to-treat basis. Cox regression analyses were used to assess the relationship between the nutritional intervention and the incidence of cataract surgery. Results: During a follow-up period of 7.0 years (mean follow-up period: 5.7 years; median: 5.9 years), 559 subjects underwent cataract surgery. Two hundred and six participants from the MedDiet + EVOO group, 174 from the MedDiet + Nuts group, and 179 from the control group underwent cataract surgery. We did not observe a reduction in the incidence of cataract surgery in the MedDiet groups compared to the control group. The multivariable adjusted hazard ratios were 1.03 (95% confidence interval [CI]: 0.84–1.26, p = 0.79) for the control group versus the MedDiet + EVOO group and 1.06 (95% CI: 0.86–1.31, p = 0.58) for the control group versus the MedDiet + Nuts group. Conclusions: To our knowledge, this is the first large randomized trial assessing the role of a MedDiet on the incidence of cataract surgery. Our results showed that the incidence of cataract surgery was similar in the MedDiet with EVOO, MedDiet with nuts, and low-fat diet groups. Further studies are necessary to investigate whether a MedDiet could have a preventive role in cataract surgery

Primary prevention of cardiovascular disease with a Mediterranean diet

BACKGROUND: Observational cohort studies and a secondary prevention trial have shown an inverse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary prevention of cardiovascular events. METHODS: In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years. RESULTS: A total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, according to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, versus the control group (109 events). No diet-related adverse effects were reported. CONCLUSIONS: Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events

Lysine pathway metabolites and the risk of type 2 diabetes and cardiovascular disease in the PREDIMED study: results from two case-cohort studies

Background: The pandemic of cardiovascular disease (CVD) and type 2 diabetes (T2D) requires the identifcation of new predictor biomarkers. Biomarkers potentially modifable with lifestyle changes deserve a special interest. Our aims were to analyze: (a) The associations of lysine, 2-aminoadipic acid (2-AAA) or pipecolic acid with the risk of T2D or CVD in the PREDIMED trial; (b) the efect of the dietary intervention on 1-year changes in these metabolites, and (c) whether the Mediterranean diet (MedDiet) interventions can modify the efects of these metabolites on CVD or T2D risk. Methods: Two unstratifed case-cohort studies nested within the PREDIMED trial were used. For CVD analyses, we selected 696 non-cases and 221 incident CVD cases; for T2D, we included 610 non-cases and 243 type 2 diabetes incident cases. Metabolites were quantifed using liquid chromatography–tandem mass spectrometry, at baseline and after 1-year of intervention. Results: In weighted Cox regression models, we found that baseline lysine (HR+1 SD increase=1.26; 95% CI 1.06–1.51) and 2-AAA (HR+1 SD increase=1.28; 95% CI 1.05–1.55) were both associated with a higher risk of T2D, but not with CVD. A signifcant interaction (p=0.032) between baseline lysine and T2D on the risk of CVD was observed: subjects with prevalent T2D and high levels of lysine exhibited the highest risk of CVD. The intervention with MedDiet did not have a signifcant efect on 1-year changes of the metabolites. Conclusions: Our results provide an independent prospective replication of the association of 2-AAA with future risk of T2D. We show an association of lysine with subsequent CVD risk, which is apparently diabetes-dependent. No evidence of efects of MedDiet intervention on lysine, 2-AAA or pipecolic acid changes was found

Arginine catabolism metabolites and atrial fibrillation or heart failure risk: 2 case-control studies within the Prevención con Dieta Mediterránea (PREDIMED) trial

Background Arginine-derived metabolites are involved in oxidative and inflammatory processes related to endothelial functions and cardiovascular risks. Objectives We prospectively examined the associations of arginine catabolism metabolites with the risks of atrial fibrillation (AF) or heart failure (HF), and evaluated the potential modifications of these associations through Mediterranean diet (MedDiet) interventions in a large, primary-prevention trial. Methods Two nested, matched, case-control studies were designed within the Prevención con Dieta Mediterránea (PREDIMED) trial. We selected 509 incident cases and 547 matched controls for the AF case-control study and 326 cases and 402 matched controls for the HF case-control study using incidence density sampling. Fasting blood samples were collected at baseline and arginine catabolism metabolites were measured using LC-tandem MS. Multivariable conditional logistic regression models were applied to test the associations between the metabolites and incident AF or HF. Interactions between metabolites and intervention groups (MedDiet groups compared with control group) were analyzed with the likelihood ratio test. Results Inverse association with incident AF was observed for arginine (OR per 1 SD, 0.83; 95% CI: 0.73–0.94), whereas a positive association was found for N1-acetylspermidine (OR for Q4 compared with Q1 1.58; 95% CI: 1.13–2.25). For HF, inverse associations were found for arginine (OR per 1 SD, 0.82; 95% CI: 0.69–0.97) and homoarginine (OR per 1 SD, 0.81; 95% CI: 0.68–0.96), and positive associations were found for the asymmetric dimethylarginine (ADMA) and symmetric dimethlyarginine (SDMA) ratio (OR per 1 SD, 1.19; 95% CI: 1.02–1.41), N1-acetylspermidine (OR per 1 SD, 1.34; 95% CI: 1.12–1.60), and diacetylspermine (OR per 1 SD, 1.20; 95% CI: 1.02–1.41). In the stratified analysis according to the dietary intervention, the lower HF risk associated with arginine was restricted to participants in the MedDiet groups (P-interaction = 0.044). Conclusions Our results suggest that arginine catabolism metabolites could be involved in AF and HF. Interventions with the MedDiet may contribute to strengthen the inverse association between arginine and the risk of HF. This trial was registered at controlled-trials.com as ISRCTN35739639