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Background: Lifestyles influence atrial fibrillation (AF) risk. Blood biomarkers can characterize the atrial substrate that facilitates the development of AF. Therefore, determining the effect of lifestyle interventions on blood concentrations of biomarkers of AF-related pathways could help understand AF pathophysiology and contribute to AF prevention. Methods: The PREDIMED-PLUS study is a Spanish multicenter randomized trial in adults (55-75 years) with metabolic syndrome and body mass index between 27-40 kg/m 2 . Participants were randomized 1:1 to an intensive lifestyle intervention (ILI) program, emphasizing physical activity, weight loss, and adherence to the Mediterranean diet, or a control intervention. In a sub-sample, serum biomarkers including carboxy-terminal propeptide of procollagen type I (PICP), high-sensitivity troponin T (hsTnT), high-sensitivity C reactive protein (hsCRP), N-terminal propeptide of B-type natriuretic peptide (NT-proBNP), and 3-nitrotyrosine (3-NT) were measured at baseline and years 3 and 5 after randomization. Mixed models were used to evaluate the effect of ILI on changes in biomarkers through years 3 and 5. Follow-up time was modeled as a categorical and continuous variable. Results: Of 481 participants (65 mean age, 40% female, 49% assigned to ILI), 453 (94%) and 442 (92%) had available samples at years 3 and 5. After 5 years, mean changes in log-transformed biomarkers were -0.01 (PICP), 0.20 (hsTnT), -0.17 (hsCRP), 0.12 (3-NT), and 0.25 (NT-proBNP). Participants in the ILI group experienced greater decreases in hsCRP or smaller increases in 3-NT, NT-proBNP, and in hsTnT to a lesser extent, as compared to the control group (Table). The ILI did not affect PICP concentrations. Results were consistent when modeling follow-up time as a continuous variable. Conclusion: Over five years, an ILI favorably affected concentrations of hsCRP, 3-NT, and NT-proBNP, and of hs-TnT to a lesser degree, pointing to specific mechanisms in the pathways linking lifestyles and AF.

Background: Studies have failed to establish a clear link between high-density lipoprotein (HDL) cholesterol and cardiovascular disease, leading to the hypothesis that the atheroprotective role of HDL lies in its biological activity rather than in its cholesterol content. However, to date, the association between HDL functional characteristics and acute coronary syndrome has not been investigated comprehensively. Methods: We conducted a case-control study nested within the PREDIMED (Prevención con Dieta Mediterránea) cohort, originally a randomized trial in which participants followed a Mediterranean or low-fat diet. Incident acute coronary syndrome cases (N=167) were individually matched (1:2) to control patients by sex, age, intervention group, body mass index, and follow-up time. We investigated 2 individual manifestations (myocardial infarction, unstable angina) as secondary outcomes. We measured the following functional characteristics: HDL cholesterol concentration (in plasma); cholesterol efflux capacity; antioxidant ability, measured by the HDL oxidative-inflammatory index; phospholipase A2 activity; and sphingosine-1-phosphate, apolipoproteins A-I and A-IV, serum amyloid A, and complement 3 protein (in apolipoprotein B–depleted plasma). We used conditional logistic regression models adjusted for HDL cholesterol levels and cardiovascular risk factors to estimate odds ratios (ORs) between 1-SD increments in HDL functional characteristics and clinical outcomes. Results: Low values of cholesterol efflux capacity (OR 1SD , 0.58; 95% CI, 0.40–0.83) and low levels of sphingosine-1-phosphate (OR 1SD , 0.70; 95% CI, 0.52–0.92) and apolipoprotein A-I (OR 1SD , 0.58; 95% CI, 0.42–0.79) were associated with higher odds of acute coronary syndrome. Higher HDL oxidative inflammatory index values were marginally linked to acute coronary syndrome risk (OR 1SD , 1.27; 95% CI, 0.99–1.63). Low values of cholesterol efflux capacity (OR 1SD , 0.33; 95% CI, 0.18–0.61), sphingosine-1-phosphate (OR 1SD : 0.60; 95% CI: 0.40–0.89), and apolipoprotein A-I (OR 1SD , 0.59; 95% CI, 0.37–0.93) were particularly linked to myocardial infarction, whereas high HDL oxidative-inflammatory index values (OR 1SD , 1.53; 95% CI, 1.01–2.33) and low apolipoprotein A-I levels (OR 1SD , 0.52; 95% CI, 0.31–0.88) were associated with unstable angina. Conclusions: Low cholesterol efflux capacity values, pro-oxidant/proinflammatory HDL particles, and low HDL levels of sphingosine-1-phosphate and apolipoprotein A-I were associated with increased odds of acute coronary syndrome and its manifestations in individuals at high cardiovascular risk. Clinical Trial Registration: URL: https://www.controlled-trials.com/ISRCTN35739639 . Unique identifier: ISRCTN35739639.

Background: Metabolomics technologies can efficiently profile a large number of structurally diverse lipids, e.g., glycerophospholipids, sphingolipids, and glycerolipids, that may play differential roles in pathogenesis of cardiovascular disease (CVD). However, existing studies were focused more on discovering individual lipid metabolites for CVD risk prediction than inferring perturbed pathways responsible for the pathological processes. Hypothesis: We hypothesized that different lipid metabolic pathways, captured by network analysis, were divergently associated with CVD risk; the associations could be modified by the Mediterranean diet (MedDiet) intervention. Methods: We conducted this study in the PREDIMED trial with participants randomized to three intervention diets: MedDiet with extra-virgin olive oil, MedDiet with nuts, or a low-fat control diet. This study comprises a subcohort of 788 participants randomly selected from the PREDIMED cohort and 230 cases. The outcome was a composite endpoint of non-fatal acute myocardial infarction, non-fatal stroke and cardiovascular death. We performed network analysis using Gaussian graphic model among 200 targeted lipid metabolites and subsequent dimensionality reduction using Greedy Modularity Optimization to detect subnetworks. We calculated the subnetwork scores by summing up the products of the topological connectivity weight (representing network structure) and metabolite level and included the scores into Cox proportional hazards model with simultaneous adjustment for other subnetwork scores and covariates. The Benjamini-Hochberg procedure was applied to detect smaller subnetworks of specific interest for further investigation. Results: We detected 4 major subnetworks of lipid metabolic pathway. Most lipid metabolites with larger numbers of carbon atom and double bond clustered within a same subnetwork (subnetwork 2), while those with smaller numbers of carbon atom and double bond clustered within other 3 subnetworks (subnetworks 1, 3 and 4). The hazard ratio (HR) of CVD across quartiles of the subnetwork score 2 was 0.56 (95% CI, 0.35, 0.91, P trend =0.008) after multivariable adjustment. The HRs of CVD comparing extreme quartiles of subnetwork scores 3 and 4 were 1.85 (95% CI, 1.15, 2.97, P trend =0.02) and 1.93 (95% CI, 1.19, 3.14, P trend =0.01), respectively. The MedDiet appeared to enhance the inverse association between subnetwork score 2 and CVD ( P interaction =0.03). We detected several smaller subnetworks with functional interpretation related to CVD pathogenesis such as the ceramide pathway and the pathway including phospholipids with high unsaturation. Conclusions: Based on topological structure of lipid metabolic pathways, we detected biologically meaningful pathways. We found divergent associations between subnetworks and CVD and smaller subnetworks with functional interpretation.

Background: Metabolites associated with betaine and choline metabolism and the gut-microbiota-dependent metabolite trimethylamine N-oxide (TMAO) have been linked to the risk of cardiovascular disease (CVD). However, the relationship between plasma concentrations of other gut microbiota-related metabolites and major CVD endpoints remains unclear. Objectives: To evaluate the association between gut microbiota-related metabolites and risk of incident CVD and the potential modifying effect of Mediterranean diet (MedDiet) interventions. Methods: We designed a case-cohort study nested within the PREDIMED trial. We used liquid chromatography–tandem mass spectrometry to measure plasma gut microbiota-related metabolites. A score including the sum of quartile values of 8 metabolites was constructed (TMAO, betaine, choline, phosphocholine, alphaglycerophosphocholine, proline, hydroxyproline, allantoin). The primary outcome was a composite of myocardial infarction, stroke, and cardiovascular death. Blood samples from a randomly selected PREDIMED sub-cohort (n=751) and all available incident CVD cases (n=229) after 4.8-y of follow-up were included in the analysis. We used weighted Cox regression models to estimate multivariable-adjusted hazard ratios (HR) and their 95% confidence intervals (CI). Models were adjusted for age, sex, BMI, family history of premature heart disease, and smoking, physical activity (metabolic equivalent tasks in min/d), hypertension, dyslipidemia, diabetes and was stratified by intervention group. Results: Baseline plasma concentrations of choline and hydroxyproline were associated with higher CVD risk independent of traditional risk factors, while no significant association between plasma concentrations of TMAO and CVD was found. The HRs comparing extreme quartiles (lowest quartile as the reference) were 1.72 (95% CI: 1.05, 2.81; P for trend=0.01) and 1.65 (95% CI: 1.03, 2.65; P for trend =0.04), respectively. The microbiota metabolite score was associated with a 2.13-fold higher risk of CVD across extreme quartiles (95% CI: 1.32, 3.43; P for trend Conclusions: Plasma gut microbiota-related metabolites were associated with an increased risk of CVD in a Mediterranean population at high cardiovascular risk, independent of traditional CVD risk factors.

Objectives: To assess the association between potato consumption, blood pressure changes and the risk of hypertension in two Mediterranean populations. Design: Separate analyses were performed in the PREDIMED (PREvención con DIeta MEDiterránea), a multicenter nutrition intervention trial, and the SUN (“Seguimiento Universidad de Navarra”) project, an open, prospective cohort, both in Spain. Participants: The PREDIMED trial included 6,940 participants aged 55-80 years at high risk for cardiovascular disease. The SUN project included 13,837 middle-aged participants who were university graduates. Main outcome measures: In PREDIMED, generalized estimating equations adjusted for lifestyle and dietary characteristics were used to assess changes in blood pressure across quintiles of total potato consumption during a 4-year follow-up. Controlled blood pressure levels during follow-up were also assessed. For SUN, multivariable-adjusted hazard ratios (HR) for incident hypertension during an average 6.7-year follow-up were calculated. Results: In PREDIMED, the mean (SD) total potato intake was 81.9 (40.6) g/day. No overall significant differences in blood pressure changes were detected based on consumption of potatoes. For total potatoes, the mean change in systolic BP after multivariate adjustment was quintile 5 (Q5) vs. quintile 1 (Q1): -0.90, 95% CI: (-2.56 to 0.76) mmHg, p for trend=0.14 and for diastolic BP it was Q5 vs. Q1: -0.02, 95% CI: (-0.93 to 0.89) mmHg, p for trend=0.81. In SUN, the mean (SD) total potato consumption was 52.7 (33.6) g/day and no significant association between potato consumption and hypertension incidence was observed: HR: for total potato consumption, Q5 vs. Q1: 0.98, 95% CI: (0.80 to 1.19), p for trend=0.84. Conclusions: Potato consumption is not associated with changes in blood pressure or risk of hypertension in Mediterranean populations and this might be explained by relatively low consumption of potatoes and characteristics of the traditional Mediterranean diet, particularly the custom of accompanying potatoes with vegetables or legumes and dressing them with olive oil.

Background: Glutamate metabolism may play a role in the pathophysiology of cardiometabolic disorders. However, there is limited evidence on the association between glutamate-related metabolites and, moreover, changes in these metabolites, and risk of cardiovascular disease (CVD). Methods and Results: Plasma levels of glutamate and glutamine were measured at baseline and 1-year follow-up in a case-cohort study including 980 participants (mean age: 67 years; 46% male) from the PREDIMED randomized trial, which assessed a Mediterranean diet intervention in the primary prevention of CVD. During median 4.8 years of follow-up, there were 229 incident CVD events (non-fatal stroke, non-fatal myocardial infarction, or CVD death). In fully-adjusted models, per 1-SD, baseline glutamate was associated with 43% (95% CI: 16-76%) and 81% (39-137%) increased risk of composite CVD and stroke alone, respectively, and baseline glutamine-to-glutamate ratio with 25% (6-40%) and 44% (25-58%) decreased risk of composite CVD and stroke alone, respectively. Associations appeared linear for stroke (both Plinear trend≤0.005). Among participants with high baseline glutamate, the interventions lowered CVD risk by 37% compared to the control diet; the intervention effects were not significant when baseline glutamate was low (Pinteraction=0.02). No significant effect of the intervention on year-1 changes in metabolites was observed, and no effect of changes themselves on CVD risk was apparent. Conclusions: Baseline glutamate was associated with increased CVD risk, particularly stroke, and glutamine-to-glutamate ratio was associated with decreased risk. Participants with high glutamate levels may obtain greater benefits from the Mediterranean diet than those with low levels.

We appreciate the interest and kind comments by Gonzalez-Salvado et al regarding our published article on extravirgin olive oil (EVOO) consumption and a reduced risk of atrial fibrillation (AF).1 The answer to their questions about the quantity of EVOO that should be consumed to observe a reduction in the risk of AF and the between-subject variability in EVOO consumption can be found in our online-only Data Supplement published in Circulation. In the per protocol analyses shown in Table II in the online-only Data Supplement (including the 3 arms of the trial together), we demonstrated that the risk of AF was only 6.6 cases/1000 person-years when the attained consumption reached the 3 upper quintiles of consumption, whereas it was 15.5 when the consumption was in the 2 lower quintiles. This cutoff corresponded to a consumption of at least 25 g/d. More specifically, and taking into account the between-subject variability in total energy intake and after controlling for other potential confounding factors, we observed a significant reduction in the risk of AF when EVOO consumption represented ≥15% of total energy intake (please check Figure IB in the online-only Data Supplement). We acknowledge that we did not specify whether EVOO was consumed raw or cooked. Specifically we included both possibilities in our educational recommendations to participants, but we also gave the advice to our participants to frequently consume EVOO for salad dressings and as a spread. Please check http://www.predimed.es, and previous articles on our interventions in the Prevención con Dieta …