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Introduction and objectives Quantification of cardiovascular risk has been based on scores such as Framingham, Framingham-REGICOR, SCORE or Life's Simple 7 (LS7). In vitro, animal, and randomized clinical studies have shown that polyphenols may provide benefits to the vascular system and reduce the inflammatory response. However, some clinical-epidemiological studies have yielded inconsistent results. Our aim was to assess the possible association between intake of the various polyphenol classes and established cardiovascular scores. Methods This cross-sectional analysis involved 6633 PREDIMED-Plus study participants. Food polyphenol content was estimated by a semiquantitative food frequency questionnaire , adjusted for total energy intake according to the residual method. The association between polyphenol intake and cardiovascular risk was tested using linear regression analyses. Results Total polyphenol and flavonoid intake were directly and significantly associated only with the LS7 scale. Intake of lignans was directly and significantly associated with SCORE and LS7 scales, stilbene intake with SCORE, and phenolic acid intake with Framingham and Framingham-REGICOR scores. Other polyphenol classes were associated in a protective and significant manner in Framingham, SCORE and LS7 scores. In women, intake of all the polyphenol classes, except phenolic acids, showed a protective trend in the results of the Framingham, Framingham-REGICOR scores and LS7 scale. Conclusions An inverse association was found between consumption of the ‘other polyphenols’ class and, especially among women, with estimated cardiovascular risk. The results were similar to those of Framingham, Framingham-REGICOR and LS7 (after eliminating the diet component) and differed from those of SCORE, but the predictors included were limited in the latter case.

[Background & aims]: The Portfolio and Dietary Approaches to Stop Hypertension (DASH) diets have been shown to lower cardiometabolic risk factors in randomized controlled trials (RCTs). However, the Portfolio diet has only been assessed in RCTs of hyperlipidemic patients. Therefore, to assess the Portfolio diet in a population with metabolic syndrome (MetS), we conducted a longitudinal analysis of one-year data of changes in the Portfolio and DASH diet scores and their association with cardiometabolic risk factors in Prevención con Dieta Mediterránea (PREDIMED)-Plus trial. [Methods]: PREDIMED-Plus is an ongoing clinical trial (Trial registration: ISRCTN89898) conducted in Spain that includes 6874 older participants (mean age 65 y, 48% women) with overweight/obesity fulfilling at least three criteria for MetS. Data for this analysis were collected at baseline, six months and one year. Adherence to the Portfolio and DASH diet scores were derived from a validated 143-item food frequency questionnaire. We used linear mixed models to examine the associations of 1-SD increase and quartile changes in the diet scores with concomitant changes in cardiometabolic risk factors. [Results]: After adjusting for several potential confounders, a 1-SD increase in the Portfolio diet score was significantly associated with lower HbA1c (β [95% CI]: −0.02% [−0.02, −0.01], P < 0.001), fasting glucose (−0.47 mg/dL [−0.83, −0.11], P = 0.01), triglycerides (−1.29 mg/dL [−2.31, −0.28], P = 0.01), waist circumference (WC) (−0.51 cm [−0.59, −0.43], P < 0.001), and body mass index (BMI) (−0.17 kg/m2 [−0.19, −0.15], P < 0.001). A 1-SD increase in the DASH diet score was significantly associated with lower HbA1c (−0.03% [−0.04, −0.02], P < 0.001), glucose (−0.84 mg/dL [−1.18, −0.51], P < 0.001), triglycerides (−3.38 mg/dL [−4.37, −2.38], P < 0.001), non-HDL-cholesterol (−0.47 mg/dL [−0.91, −0.04], P = 0.03), WC (−0.69 cm [−0.76, −0.60 cm], P < 0.001), BMI (−0.25 kg/m2 [−0.28, −0.26 kg/m2], P < 0.001), systolic blood pressure (−0.57 mmHg [−0.81, −0.32 mmHg], P < 0.001), diastolic blood pressure (−0.15 mmHg [−0.29, −0.01 mmHg], P = 0.03), and with higher HDL-cholesterol (0.21 mg/dL [0.09, 0.34 mg/dL, P = 0.001]). Similar associations were seen when both diet scores were assessed as quartiles, comparing extreme categories of adherence. [Conclusions]: Among older adults at high cardiovascular risk with MetS, greater adherence to the Portfolio and DASH diets showed significant favourable prospective associations with several clinically relevant cardiometabolic risk factors. Both diets are likely beneficial for cardiometabolic risk reduction., The PREDIMED-Plus trial was supported by the Spanish government's official funding agency for biomedical research, ISCIII, through the Fondo de Investigación para la Salud (FIS) and co-funded by European Union ERDF/ESF, “A way to make Europe”/“Investing in your future” (five coordinated FIS projects led by JS-S and JVid, including the following projects: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183,PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, and PI19/01332), the Special Action Project entitled: Implementación y evaluación de una intervención intensiva sobre la actividad física Cohorte PREDIMED-Plus grant to JS-S, the European Research Council (Advanced Research Grant 2014–2019, 340918) to MÁM-G, the Recercaixa Grant to JS-S (2013ACUP00194), grants from the Consejería de Salud de la Junta de Andalucía (PI0458/2013, PS0358/2016, and PI0137/2018), a grant from the Generalitat Valenciana (PROMETEO/2017/017), a SEMERGEN grant, and funds from the European Regional Development Fund (CB06/03). This research was also partially funded by EU-H2020 Grant (EAT2BENICE/H2020-SFS-2016-2; Ref 728018). Study resulting from the SLT006/17/00246 grant, funded by the Department of Health of the Generalitat de Catalunya by the call “Acció instrumental de programes de recerca orientats en l'àmbit de la recerca i la innovació en salut”. We thank CERCA Programme/Generalitat de Catalunya for institutional support. This work is partially supported by ICREA under the ICREA Academia programme. IP-G receives a grant from the Spanish Ministry of Education, Culture and Sports (FPU 17/01925). MRBL was supported by “Miguel Servet Type I” program (CP15/00028) from the ISCIII-Madrid (Spain), cofinanced by the Fondo Europeo de Desarrollo Regional-FEDER. AJG was supported by the Nora Martin Fellowship in Nutritional Sciences, the Banting & Best Diabetes Centre Tamarack Graduate Award in Diabetes Research, the Peterborough K.M. Hunter Charitable Foundation Graduate Award and an Ontario Graduate Scholarship. PH-A was supported by a postdoctoral fellowship (Juan de la Cierva-Formación), FJCI-2017–32205, funded by the Ministry of Science and Innovation. RE group has been supported by the ‘Ajut 2017-2021 SGR 1717 from the Generalitat de Catalunya. DJAJ was funded by the Government of Canada through the Canada Research Chair Endowment. JK was supported by the ‘FOLIUM’ programme within the FUTURMed project from the Fundación Instituto de Investigación Sanitaria Illes Balears (financed by 2017 annual plan of the sustainable tourism tax and at 50% with charge to the ESF Operational Program 2014–2020 of the Balearic Islands). JLS was funded by a Diabetes Canada Clinician Scientist Award.

Background and aims Familial hypercholesterolemia (FH) is a codominant autosomal disease characterized by a high risk of cardiovascular disease when not in lipid-lowering treatment. However, there is a large variability in the clinical presentation in heterozygous subjects (HeFH). Maternal hypercholesterolemia has been proposed as a cardiometabolic risk factor later in life. Whether this phenotype variability depends on the mother or father origin of hypercholesterolemia is unknown. The objective of this study was to analyze potential differences in anthropometry, superficial lipid deposits, comorbidities, and lipid concentrations depending on the parental origin of hypercholesterolemia within a large group of HeFH. Methods This is a cross-sectional observational, multicenter, nation-wide study in Spain. We recruited adults with HeFH to study clinical differences according to the parental origin. Data on HeFH patients were obtained from the Dyslipidemia Registry of the Spanish Atherosclerosis Society. Results HeFH patients were grouped in 1231 HeFH-mother-offspring aged 45.7 (16.3) years and 1174 HeFH-father-offspring aged 44.8 (16.7) years. We did not find any difference in lipid parameters (total cholesterol, triglycerides, LDLc, HDLc, and Lp(a)), nor in the comorbidities studied (cardiovascular disease prevalence, age of onset of cardiovascular disease, obesity, diabetes, and hypertension) between groups. Lipid-lowering treatment did not differ between groups. The prevalence of comorbidities did not show differences when they were studied by age groups. Conclusions Our research with a large group of subjects with HeFH shows that a potential maternal effect is not relevant in FH. However, due to the size of our sample, potential differences between genders cannot be completely ruled out. This implies that severe maternal hypercholesterolemia during pregnancy is not associated with additional risk in the FH affected offspring.

Background & aims: Epidemiological data on iron status and cardiovascular disease (CVD) are still controversial. The aim of this study was to determine whether low serum iron (SI) levels are associated with an increased odds of first CVD event in a population at high cardiovascular risk. Methods: Case-control study design nested within the "PREvención con DIeta MEDiterránea" (PREDIMED) trial. A total of 207 participants diagnosed with CVD (myocardial infarction, stroke or cardiovascular death) during follow-up period (2003-2010) were matched by sex, age and intervention group to 436 controls by incidence density sampling. Median time between serum sample collection and subsequent CVD event occurrence was 0.94 years. Inductively coupled plasma mass spectrometry analysis was used to determine SI levels. In-person interviews, medical record reviews, and validated questionnaires were used to assess covariates. Multivariable-adjusted odds ratios (ORs) of CVD were calculated with conditional logistic regression. Results: Mean SI levels were higher in men than in women (1224.0 μg/L vs. 1093.8 μg/L; p < 0.001). Among women, but not in men, the mean SI concentration was lower in cases than in controls (1008.5 μg/L vs. 1132.9 μg/L; p = 0.030). There was a gradual decrease in the multivariable-adjusted ORs of CVD with increasing SI levels (highest vs. lowest quartile: OR = 0.55, 95% CI: 0.32-0.93; ptrend = 0.020). This inverse relationship was more pronounced among women (highest vs. lowest quartile: OR = 0.15, 95% CI: 0.03-0.69; ptrend = 0.011). Conclusions: The present findings are consistent with previously reported inverse associations between SI and CVD. SI levels as an independent marker of short-term cardiovascular risk may be useful for risk assessment in older populations. Trial registration: www.controlled-trials.com; International Standard Randomized Controlled Trial Number (ISRCTN): 35,739,639. Registered 5 October 2005. Retrospectively registered. This research was supported by the official funding agency for biomedical research of the Spanish government, Instituto de Salud Carlos III (ISCIII), through grants provided to research networks specifically developed for the trial (RTIC G03/140; RTIC RD 06/0045 “PREDIMED”), and JR14/00008, and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), the Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (Proyecto de Investigación (PI04-2239, PI05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505 and PI13/00462), the Ministerio de Ciencia e Innovación (Recursos y teconologia agroalimentarias (AGL)-2009-13906-C02 and AGL2010-22319-C03 and AGL2013-49083C3-1-R), the Ministerio de Economía y Competitividad-Fondos FEDER-Instituto de Salud Carlos III (UNGR15-CE-3380), the Fundación Mapfre 2010, the Consejería de Salud de la Junta de Andalucía (PI0105/2007), the Public Health Division of the Department of Health of the Autonomous Government of Catalonia, the Generalitat Valenciana (Generalitat Valenciana Ayuda Complementatia GVACOMP) 06109, GVACOMP2010-181, GVACOMP2011-151), Conselleria de Sanitat y AP; Atención Primaria (CS) 2010-AP-111, and CS2011-AP-042), Regional Government of Navarra (P27/2011), and Centre Català de la Nutrició de l'Institut d'Estudis Catalans. Hojiblanca and Patrimonio Communal Olivarero donated extra-virgin olive oil; the California Walnut Commission donated walnuts; Borges donated almonds; La Morella Nuts donated hazelnuts. ROLE OF THE FUNDERS: funding sources had no role in the designing and conducting of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Introduction: Large randomized trials testing the effect of a multifactorial weight-loss lifestyle intervention including Mediterranean diet (MedDiet) on renal function are lacking. Here, we evaluated the 1-year efficacy of an intensive weight-loss intervention with an energy-reduced MedDiet (erMedDiet) plus increased physical activity (PA) on renal function. Methods: Randomized controlled "PREvención con DIeta MEDiterránea-Plus"(PREDIMED-Plus) trial is conducted in 23 Spanish centers comprising 208 primary care clinics. Overweight/obese (n = 6,719) adults aged 55-75 years with metabolic syndrome were randomly assigned (1:1) to an intensive weight-loss lifestyle intervention with an erMedDiet, PA promotion, and behavioral support (intervention) or usual-care advice to adhere to an energy-unrestricted MedDiet (control) between September 2013 and December 2016. The primary outcome was 1-year change in estimated glomerular filtration rate (EGFR). Secondary outcomes were changes in urine albumin-to-creatinine ratio (UACR), incidence of moderately/severely impaired EGFR (, This work was supported by the official Spanish Institutions for funding scientific biomedical research, CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN) and Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigación para la Salud (FIS), which is cofunded by the European Regional Development Fund (5 coordinated FIS projects leaded by J.S.-S and J.V., including the following projects: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926; PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, and PI19/01332); the Especial Action Project entitled Implementación y evaluación de una intervención intensiva sobre la actividad física Cohorte PREDIMED-Plus grant to J.S.-S.; the European Research Council (Advanced Research Grant 2014–2019; agreement #340918) granted to M.Á.M.-G.; the Recercaixa (No. 2013ACUP00194) grant to J.S.-S.; grants from the Consejería de Salud de la Junta de Andalucía (PI0458/2013, PS0358/2016, and PI0137/2018); the PROMETEO/2017/017 grant from the Generalitat Valenciana; the SEMERGEN grant; funds from the European Regional Development Fund (CB06/03); International Nut & Dried Fruit Council – FESNAD (Long-term effects of an energyrestricted Mediterranean diet on mortality and cardiovascular disease 2014–2015, No. 201302) (PI: M.Á.M.-G.); the AstraZeneca Young Investigators Award in Category of Obesity and T2D 2017 (PI: D.R.); grant of support to research groups No. 35/2011 (Balearic Islands Gov.; FEDER funds) (J.A.T. and C.B.); the JR17/00022 (ISCIII) grant to O.C.; the Boosting young talent call grant program for the development of IISPV research projects 2019–2021 (Ref.: 2019/IISPV/03 grant to A.D.-L.); the Societat Catalana d’Endocrinologia i Nutrició (SCEN) Clinical-Research Grant 2019 (IPs: J.S.-S. and A.D.-L.). Collaborative Nutrition and/or Obesity Project for Young Researchers 2019 supported by CIBEROBN entitled Lifestyle Interventions and Chronic Kidney Disease: Inflammation, Oxidative Stress and Metabolomic Profile (LIKIDI study) grant to A.D.-L.

Research related to sustainable diets is is highly relevant to provide better understanding of the impact of dietary intake on the health and the environment.To assess the association between the adherence to an energy-restricted Mediterranean diet and the amount of COUsing a cross-sectional design, the association between the adherence to an energy-reduced Mediterranean Diet (erMedDiet) score and dietary COFood intake and adherence to the erMedDiet was assessed using validated food frequency questionnaire and 17-item Mediterranean questionnaire. Sociodemographic characteristics were documented. Environmental impact was calculated through greenhouse gas emissions estimations, specifically COMore men than women induced higher dietary levels of COThe Mediterranean diet can be environmentally protective since the higher the adherence to the Mediterranean diet, the lower total dietary CO

Introduction and objectives Metabolic syndrome (MetS) is a combination of various cardiovascular risk factors with a major impact on morbidity and premature mortality. However, the impact of MetS on self-reported health-related quality of life (HRQoL) is unknown. This study evaluated the HRQoL in a Spanish adult population aged 55 years and older with MetS. Method A cross-sectional analysis was performed with baseline data from the PREDIMED-Plus multicentre randomized trial. The participants were 6430 men and women aged 55–75 years with overweight/obesity (body mass index ≥27 and ≤40 kg/m2) and MetS. The SF-36 questionnaire was used as a tool to measure HRQoL. Scores were calculated on each scale of the SF-36 by gender and age. Results Participants showed higher scores in the social function (mean 85.9, 95% CI; 85.4–86.4) and emotional role scales (mean 86.8, 95% CI; 86.0–87.5). By contrast, the worst scores were obtained in the aggregated physical dimensions. In addition, men obtained higher scores than women on all scales. Among men, the worst score was obtained in general health (mean 65.6, 95% CI; 65.0–66.2), and among women, in body pain (mean 54.3, 95%CI; 53.4–55.2). A significant decrease was found in the aggregated physical dimensions score among participants 70–75 years old, but an increased one in the aggregated mental dimensions, compared to younger participants. Conclusions Our results reflect that the MetS may negatively affect HRQoL in the aggregated physical dimensions, body pain in women, and general health in men. However, this adverse association was absent for the psychological dimensions of HRQoL, which were less affected.

Summary Background There is limited prospective evidence on the association between physical activity (PA) and inflammation in older adults. Our aim was to assess the associations between changes in PA and changes in the inflammatory profile in older individuals who are overweight or obese. Methods This prospective study included 489 men and women, aged 55–75 years, from the PREDIMED-Plus trial. Levels of interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 18 (IL-18), monocyte chemo-attractant protein-1 (MCP-1), C-peptide, high-sensitivity C-reactive protein (hs-CRP), leptin, and regulated on activation, normal T-cell expressed and secreted chemokine (RANTES) were obtained from fasting blood samples and a composite inflammatory score based on these biomarkers was calculated. Physical activity was measured by a validated questionnaire. All measures were taken at baseline and one-year follow-up. Results Multiple linear regression models showed an association between an increase in total PA and a decrease in the inflammatory score (p = 0.012), which was particularly driven by a decrease in C-peptide (p = 0.037). Similarly, the inflammatory score decreased with increasing moderate PA (p = 0.001), and moderate-to-vigorous PA (p = 0.006). Conclusions Increases in total PA, moderate and moderate-to-vigorous PA were associated with a decrease in the inflammatory profile of obese or overweight older individuals. This finding is relevant for PA recommendations and public health strategies. Clinical trial registry Clinical trial identifier: International Standard Randomized Controlled Trial 89898870.

Background: Socioeconomic disparities and lifestyle factors are likely to determine the overall quality of the diet. In addition, overeating is compatible with inadequate micronutrient intake and it can lead to adverse health outcomes. Objective: To assess adequacy of dietary nutrient intake and to investigate the influence of socioeconomic and lifestyle factors on nutrient density in a large primary cardiovascular prevention trial conducted in healthy participants with metabolic syndrome (MetS) to assess the cardiovascular effects of an energy-restricted Mediterranean diet (PREDIMED-Plus). Methods: Baseline cross-sectional analysis of the PREDIMED-Plus trial with 6646 Spanish participants (aged 55-75 years in men and 60-75 years in women) with overweight/obesity and MetS. Energy and nutrient intake (for 10 nutrients) were calculated using a validated 143-item Food Frequency Questionnaire (FFQ) and nutrient density was estimated dividing the absolute nutrient intake by total energy intake. The prevalence of inadequate intake was estimated according to dietary reference intakes. Multivariable linear regression models were fitted to examine associations between socioeconomic status or lifestyle factors and nutrient density. Results: A considerable proportion of the screened participants showed a deficient intake of vitamins A, D, E, B-9, calcium, magnesium and dietary fibre. Inadequate intake of four or more of the ten nutrients considered was present in 17% of participants. A higher nutrient density was directly and significantly associated with female sex, higher educational level and a better adherence to the Mediterranean diet. Lifestyle factors such as non-smoking and avoidance of sedentary lifestyles were also independently associated with better nutrient density. Conclusions: Patients with MetS, despite being overweight, exhibited suboptimal nutrient intake, especially among men. Low nutrient density diet can be largely explained by differences in socioeconomic and lifestyle factors. These results highlight the importance of focussing on nutritional education in vulnerable populations, taking into account nutrient requirements. (C) 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

[Background & aims]: Little is known about the impact of specific dietary patterns on the development of obesity phenotypes. We aimed to determine the association of longitudinal changes in adherence to the traditional Mediterranean diet (MedDiet) with the transition between different obesity phenotypes., [Methods]: Data of 5801 older men and women at high cardiovascular risk from PREDIMED trial were used. Adherence to MedDiet was measured with the validated 14p-Mediterranean Diet Adherence Screener (MEDAS). Using the simultaneous combination of metabolic health- and body size-related parameters participants were categorized into one of four phenotypes: metabolically healthy and abnormal obese (MHO and MAO), metabolically healthy and abnormal non-obese (MHNO and MANO). Cox regression models with yearly repeated measures during 5-year of follow-up were built with use of Markov chain assumption., [Results]: Each 2-point increase in MEDAS was associated with the following transitions: in MAO participants, with a 16% (95% CI 3–31%) greater likelihood of becoming MHO; in MHO participants with a 14% (3–23%) lower risk of becoming MAO; in MHNO participants with a 18% (5–30%) lower risk of becoming MHO. In MANO women, but not in men, MEDAS was associated with 20% (5–38%) greater likely of becoming MHNO (p for interaction by gender 0.014). No other significant associations were observed., [Conclusions]: Better adherence to the traditional MedDiet is associated with transitions to healthier phenotypes, promoting metabolic health improvement in MAO, MANO (only in women), and MHO, as well as protecting against obesity incidence in MHNO subjects., The research leading to these results was supported by the official Spanish Institutions for funding scientific biomedical research, CIBER de Fisiopatología de la Obesidad y Nutrición and Instituto de Salud Carlos III, and through specific grant - Juan de la Cierva-formación research grant (FJCI-2015-24058) of the Spanish Ministry of Economy, Industry and Competitiveness and European Social Funds (ESF) [K.J.], the “FOLIUM” program within the FUTURMe`d project. Talent for the medicine within the future from the Fundación Instituto de Investigación Sanitaria Illes Balears (financed by 2017 annual plan of the sustainable tourism tax and at 50% with charge to the ESF Operational Program 2014–2020 of the Balearic Islands) [K.J.].

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.

Objective: To evaluate the effect of Non-alcoholic fatty liver disease (NAFLD) status in the impact of lifestyle over Health-related quality of life (HRQoL) in patients with metabolic syndrome (MetS). Methods: Baseline and 1 year follow up data from the PREDIMED-plus cohort (men and women, 55-75 years old with overweight/obesity and MetS) were studied. Adherence to an energy-restricted Mediterranean Diet (er-MeDiet) and Physical Activity (PA) were assessed with a validated screeners. Hepatic steatosis index (HSI) was implemented to evaluate NAFLD while the SF-36 questionnaire provided HRQoL evaluation. Statistical analyses were performed to evaluate the influence of baseline NAFLD on HRQoL as affected by lifestyle during 1 year of follow up. Results: Data from 5205 patients with mean age of 65 years and a 48% of female participants. Adjusted linear multivariate mixed regression models showed that patients with lower probability of NAFLD (HSI < 36 points) were more responsive to er-MeDiet (b 0.64 vs b 0.05 per er-MeDiet adherence point, p< 0.01) and PA (b 0.05 vs b 0.01 per MET-h/week, p = 0.001) than those with high probability for NAFLD in terms Physical SF- 36 summary in the 1 year follow up. 10 points of er-MeDiet adherence and 50 MET-h/ week were thresholds for a beneficial effect of lifestyle on HRQoL physical domain in patients with lower probability of NAFLD. Conclusion: The evaluation of NAFLD by the HSI index in patients with MetS might identify subjects with different prospective sensitivity to lifestyle changes in terms of physical HRQoL (http://www.isrctn.com/ISRCTN89898870)., CIBER Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III (ISCIII) through the Fondo de Investigacion para la Salud (FIS), European Commission PI13/00673 PI13/00492 PI13/00272 PI13/01123 PI13/00462 PI13/00233 PI13/02184 PI13/00728 PI13/01090 PI13/01056 PI14/01722 PI14/00636 PI14/00618 PI14/00696 PI14/01206 PI14/01919 PI14/00853 PI14/01374 PI14/00972 PI14/00728 PI14/01471 PI16/00473 PI16/00662 PI16/01873 PI16/01094 PI16/00501 PI16/00533 PI16/00381 PI16/00366 PI16/01522 PI16/01120 PI17/00764 PI17/01183 PI17/00855 PI17/01347 PI17/00525 PI17/01827 PI17/00532 PI17/00215 PI17/01441 PI17/00508 PI17/01732 PI17/00926 PI19/00957 PI19/00386 PI19/00309 PI19/01032 PI19/00576 PI19/00017 PI19/01226 PI19/00781 PI19/01560 PI19/01332 PI20/01802 PI20/00138 PI20/01532 PI20/00456 PI20/00339 PI20/00557 PI20/00886 PI20/01158, Special Action Project "Implementacion y evaluacion de una intervencion intensiva sobre la actividad fisica Cohorte PREDIMED-Plus", La Caixa Foundation 2013ACUP00194, Junta de Andalucia PI0458/2013 PS0358/2016 PI0137/2018, SEMERGEN grant, Department of Health of the Government of Navarra 61/201, Fundacio La Marato de TV 201630.10, European Research Council (ERC) European Commission 340918, Ministerio de Ciencia e Investigacion RTI2018-095569-B-I00 PCI2018-093009 35/2011

The following funding bodies contributed to study concept and design, research, and data collection for the PREDIMED-Plus study. The PREDIMED-Plus trial was supported by the European Research Council (Advanced Research grant 2014-2019; agreement #340918; granted to M.A.M-G.); the official Spanish institutions for funding scientific biomedical research, CIBER Fisiopatologia de la Obesidad y Nutricion (CIBEROBN) and Instituto de Salud Carlos III (ISCIII) through the Fondo de Investigacion para la Salud (FIS) which is co-funded by the European Regional Development Fund (coordinated FIS projects led by J.S-S. and J.V., including the following projects: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, PI19/01332), and the Especial Action Project "Implementacion y evaluacion de una intervencion intensiva sobre la actividad fisica Cohorte PREDIMED-Plus" (J.S-S.); the Recercaixa (grant number 2013ACUP00194) (J.S-S.). Moreover, J.S-S. gratefully acknowledges the financial support by ICREA under the ICREA Academia program; the SEMERGEN grant; Department of Health of the Government of Navarra (61/2015), the Fundacio La Marato de TV (Ref. 201630.10); the AstraZeneca Young Investigators Award in Category of Obesity and T2D 2017 (D.R.); grants from the Consejeria de Salud de la Junta de Andalucia (PI0458/2013; PS0358/2016; PI0137/2018), the PROMETEO/2017/017 grant from the Generalitat Valenciana, the SEMERGEN grant; grant of support to research groups 35/2011 (Balearic Islands Government; FEDER funds) (J.A.T.). J.K. was financially supported by the Juan de la Cierva-Incorporacion research grant (IJC2019-042420-I) of the Spanish Ministry of Economy, Industry and Competitiveness and the European Social Funds. The following funding bodies contributed to data preparation and analysis, bibliographic research, and manuscript writing. The METHYL-UP project was supported by the Spanish Ministry of Science and Innovation (RTI2018-095569-B-I00, Programa de Proyectos Orientados a los Retos de la Sociedad "Projects Toward Society Challenges Program"). R.S.-C. acknowledges financial support from the Juan de la Cierva Program Training Grants of the Spanish State Research Agency of the Spanish Ministerio de Ciencia e Innovacion y Ministerio de Universidades (FJC2018-038168-I). C.M.-P. was financially supported by a joint grant from the Community of Madrid and the European Social Fund (PEJD-2019-POST/SAL-15892). C. C.-M. was financially supported by the Formacion de Personal Investigador (FPI) grant from the Spanish Ministerio de Ciencia, Innovacion y Universidades (PRE2019-087643)., Background: Recent lifestyle changes include increased consumption of highly processed foods (HPF), which has been associated with an increased risk of non-communicable diseases (NCDs). However, nutritional information relies on the estimation of HPF consumption from food-frequency questionnaires (FFQ) that are not explicitly developed for this purpose. We aimed to develop a short screening questionnaire of HPF consumption (sQ-HPF) that integrates criteria from the existing food classification systems. Methods: Data from 4400 participants (48.1% female and 51.9% male, 64.9 ± 4.9 years) of the Spanish PREDIMED-Plus (“PREvention with MEDiterranean DIet”) trial were used for this analysis. Items from the FFQ were classified according to four main food processing-based classification systems (NOVA, IARC, IFIC and UNC). Participants were classified into tertiles of HPF consumption according to each system. Using binomial logistic regression, food groups associated with agreement in the highest tertile for at least two classification systems were chosen as items for the questionnaire. ROC analysis was used to determine cut-off points for the frequency of consumption of each item, from which a score was calculated. Internal consistency of the questionnaire was assessed through exploratory factor analysis (EFA) and Cronbach’s analysis, and agreement with the four classifications was assessed with weighted kappa coefficients. Results: Regression analysis identified 14 food groups (items) associated with high HPF consumption for at least two classification systems. EFA showed that items were representative contributors of a single underlying factor, the “HPF dietary pattern” (factor loadings around 0.2). We constructed a questionnaire asking about the frequency of consumption of those items. The threshold frequency of consumption was selected using ROC analysis. Comparison of the four classification systems and the sQ-HPF showed a fair to high agreement. Significant changes in lifestyle characteristics were detected across tertiles of the sQ-HPF score. Longitudinal changes in HPF consumption were also detected by the sQ-HPF, concordantly with existing classification systems. Conclusions: We developed a practical tool to measure HPF consumption, the sQ-HPF. This may be a valuable instrument to study its relationship with NCDs., European Research Council (ERC) European Commission 340918, CIBER Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III (ISCIII) through the Fondo de Investigacion para la Salud (FIS) - European Regional Development Fund PI13/00673 PI13/00492 PI13/00272 PI13/01123 PI13/00462 PI13/00233 PI13/02184 PI13/00728 PI13/01090 PI13/01056 PI14/01722 PI14/00636 PI14/00618 PI14/00696 PI14/01206 PI14/01919 PI14/00853 PI14/01374 PI14/00972 PI14/00728 PI14/01471, Especial Action Project "Implementacion y evaluacion de una intervencion intensiva sobre la actividad fisica Cohorte PREDIMED-Plus", La Caixa Foundation 2013ACUP00194, ICREA, SEMERGEN grant, Department of Health of the Government of Navarra 61/2015, Fundacio La Marato de TV 201630.10, AstraZeneca T2D 2017, Junta de Andalucia PI0458/2013 PS0358/2016 PI0137/2018, Generalitat Valenciana European Commission General Electric PROMETEO/2017/017, Balearic Islands Government 35/2011, European Commission 35/2011, Juan de la Cierva-Incorporacion research grant of the Spanish Ministry of Economy, Industry and Competitiveness and the European Social Funds IJC2019-042420-I, Spanish Ministry of Science and Innovation (Programa de Proyectos Orientados a los Retos de la Sociedad "Projects Toward Society Challenges Program") RTI2018-095569-B-I00, Juan de la Cierva Program Training Grants of the Spanish State Research Agency of the Spanish Ministerio de Ciencia e Innovacion y Ministerio de Universidades FJC2018-038168-I, Comunidad de Madrid, European Social Fund (ESF) PEJD-2019-POST/SAL-15892, Formacion de Personal Investigador (FPI) grant from the Spanish Ministerio de Ciencia, Innovacion y Universidades PRE2019-087643, The Instituto de Salud Carlos III (ISCIII) through the Fondo de Investigacion para la Salud (FIS) - European Regional Development Fund PI16/00473 PI16/00662 PI16/01873 PI16/01094 PI16/00501 PI16/00533 PI16/00381 PI16/00366 PI16/01522 PI16/01120 PI17/00764 PI17/01183 PI17/00855 PI17/01347 PI17/00525 PI17/01827 PI17/00532 PI17/00215 PI17/01441 PI17/00508 PI19/00309 PI19/01560 PI19/01332, A Instituto de Salud Carlos III (ISCIII) through the Fondo de Investigacion para la Salud (FIS) - European Regional Development Fund PI17/01732 PI17/00926 PI19/00957 PI19/00386 PI19/01032 PI19/00576 PI19/00017 PI19/01226 PI19/00781

Purpose Low-density lipoprotein (LDL) cholesterol reduction by statin therapy is dose-dependent, varies among different statins, and has wide inter-individual variability. The present study aimed to compare mean LDL cholesterol reduction and its variability achieved with different doses of the three statins most frequently used in monotherapy or combined with ezetimibe in a real clinical setting. Methods Of 5620 cases with primary hypercholesterolemia on the Spanish Arteriosclerosis Society Registry, 1004 with non-familial hypercholesterolemia and complete information on drug therapy and lipid profile were included. Results The lowest mean percentage LDL cholesterol reduction was observed with simvastatin 10 mg (32.5 +/- 18.5%), while the highest mean percentage LDL reduction was obtained with rosuvastatin 40 mg (58.7 +/- 18.8%). As to combined treatment, the lowest and highest mean percentage LDL cholesterol reductions were obtained with simvastatin 10 mg combined with ezetimibe (50.6 +/- 24.6%) and rosuvastatin 40 mg combined with ezetimibe (71.6 +/- 11.1%), respectively. Factors associated with a suboptimal response were male sex, lower age, body mass index, and baseline LDL cholesterol levels. Combined treatment was associated with less variability in LDL cholesterol reduction (OR 0.603, p < 0.001). Conclusion In a real clinical setting, rosuvastatin was superior to the other statins in lowering LDL cholesterol, both as monotherapy or combined with ezetimibe. Factors associated with a suboptimal response in LDL cholesterol decline were male sex, age, body mass index, and baseline LDL cholesterol levels. Combined treatment was associated with less variability in LDL cholesterol improvement.

BACKGROUND: Cardio-vascular disease and depression are thought to be closely related, due to shared risk factors. The aim of the study was to determine the association between cardio-vascular risk (CVR) factors and depressive status in a population (55-75 years) with metabolic syndrome (MetS) from the PREDIMED-Plus trial. METHODS AND FINDINGS: Participants were classified into three groups of CVR according to the Framingham-based REGICOR function: (1) low (LR), (2) medium (MR) or (3) high/very high (HR). The Beck Depression Inventory-II (BDI-II) was used to assess depressive symptoms at baseline and after 2 years. The association between CVR and depressive status at baseline (n = 6545), and their changes after 2 years (n = 4566) were evaluated through multivariable regression models (logistic and linear models). HR women showed higher odds of depressive status than LR [OR (95% CI) = 1.78 (1.26, 2.50)]. MR and HR participants with total cholesterol

Background Consumption of certain foods is associated with long-term weight gains and abdominal fat accumulation in healthy, middle-aged and young, non-obese participants. Whether the same foods might be associated with changes in adiposity in elderly population at high cardiovascular risk is less known. Objective Using yearly repeated measurements of both food habits and adiposity parameters, we aimed to investigate how changes in the consumption of specific foods were associated with concurrent changes in weight or waist circumference (WC) in the PREDIMED trial. Design We followed-up 7009 participants aged 55-70 years at high cardiovascular risk for a median time of 4.8 years. A validated 137-item semi-quantitative Food Frequency Questionnaire was used for dietary assessment with yearly repeated measurements. We longitudinally assessed associations between yearly changes in food consumption (serving/d) and concurrent changes in weight (kg) or WC (cm). Results Yearly increments in weight were observed with increased consumption (kg per each additional increase in 1 serving/d) for refined grains (0.32 kg/serving/d), red meat (0.24), potatoes (0.23), alcoholic beverages (0.18), processed meat (0.15), white bread (0.07) and sweets (0.04); whereas inverse associations were detected for increased consumption of low-fat yogurt (- 0.18), and low-fat milk (- 0.06). Annual WC gain (cm per each additional increase in 1 serving/d) occurred with increased consumption of snacks, fast-foods and pre-prepared dishes (0.28), processed meat (0.18), alcoholic beverages (0.13), and sweets (0.08); whereas increased consumption of vegetables (- 0.23), and nuts (- 0.17), were associated with reductions in WC. Conclusions In this assessment conducted in high-risk subjects using yearly repeated measurements of food habits and adiposity, some ultra-processed foods, refined carbohydrates (including white bread), potatoes, red meats and alcohol were associated with higher weight and WC gain, whereas increases in consumption of low-fat dairy products and plant foods were associated with less gain in weight and WC., The research leading to these results was supported by the official Spanish Institutions for funding scientific biomedical research, CIBER Fisiopatologia de la Obesidad y Nutricion (CIBEROBN) and Instituto de Salud Carlos III (ISCIII), and through specific grants/contracts: the FOLIUM program within the FUTURMed project. Talent for the medicine within the future from the Fundacion Instituto de Investigacion Sanitaria Illes Balears (financed by 2017 annual plan of the sustainable tourism tax and at 50% with charge to the ESF Operational Program 2014-2020 of the Balearic Islands) [JK]; ERC Advanced Research Grant (340918) [MAM-G as PI]. None of the funding sources took part in the design, collection, analysis or interpretation of the data, or in the decision to submit the manuscript for publication.

The authors wish to thank the PREDIMED-Plus participants and staff for their engagement, as well as to the primary care centers involved in the study. We also thank the Cerca Programme of the Generalitat de Catalunya, and the CIBEROBN, CIBERESP and CIBERDEM initiatives of Instituto de Salud Carlos III in Spain, and the collaborators in the PRIME consortium for helpful input. The first version of the present article has been published in the public repository Research Square as a preprint publication of our work (44). We particularly thank Stephanie Nishi for her assistance with manuscript language revision., Introduction: Type 2 diabetes has been linked to greater cognitive decline, but other glycemic parameters such as prediabetes, diabetes control and treatment, and HOMA-IR and HbA1c diabetes-related biomarkers have shown inconsistent results. Furthermore, there is limited research assessing these relationships in short-term studies. Thus, we aimed to examine 2-year associations between baseline diabetes/glycemic status and changes in cognitive function in older participants at high risk of cardiovascular disease. Methods: We conducted a 2-year prospective cohort study (n=6,874) within the framework of the PREDIMED-Plus study. The participants (with overweight/obesity and metabolic syndrome; mean age 64.9 years; 48.5% women) completed a battery of 8 cognitive tests, and a global cognitive function Z-score (GCF) was estimated. At baseline, participants were categorized by diabetes status (no-diabetes, prediabetes, and, CIBERESP, Generalitat de Catalunya, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición

[EN]Objective: To examine associations between intake of simple sugars and cancer incidence, cancer mor-tality, and total mortality in a prospective cohort study based on the PREDIMED trial conducted from 2003 to 2010. Methods: Participants were older individuals at high cardiovascular risk. Exposures were total sugar, glucose and fructose from solid or liquid sources, and fructose from fruit and 100% fruit juice. Cancer incidence was the primary outcome; cancer mortality and all-cause mortality were secondary outcomes. Multivariable-adjusted, time-dependent Cox proportional hazard models were used. Results: Of 7447 individuals enrolled, 7056 (94.7%) were included (57.6% women, aged 67.0 +/- 6.2 years). 534 incident cancers with 152 cancer deaths and 409 all-cause deaths were recorded after a median follow-up of 6 years. Intake of simple sugars in solid form was unrelated to outcomes. Higher cancer incidence was found per 5 g/day increase in intake of liquid sugars, with multivariable-adjusted HR of 1.08 (95% CI, 1.03-1.13) for total liquid sugar, 1.19 (95% CI, 1.07-1.31) for liquid glucose, 1.14 (95% CI, 1.05-1.23) for liquid fructose, and 1.39 (95% CI, 1.10-1.74) for fructose from fruit juice. Cancer and all-cause mortality increased to a similar extent with intake of all sugars in liquid form. In categorical models, cancer risk was dose-related for all liquid sugars. Conclusions: Simple sugar intake in drinks and fruit juice was associated with an increased risk of overall cancer incidence and mortality and all-cause mortality. This suggests that sugary beverages are a modifiable risk factor for cancer and all-cause mortality. This work was supported by the official Spanish Institutions for funding scientific biomedical research, CIBER Fisiopatologia de la Obesidad y Nutricion (CIBEROBN) and Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigaciones Sanitarias (FIS), which is co-funded by the European Regional Development Fund (FIS projects, PI04-2239, PI05/2368, PI05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, and P11/02505), Spanish Ministry of Economy, Industry and Competitiveness (SAF2017-82369-R, AGL-2009-13906-C02, and AGL2010-22319-C03), Generalitat de Catalunya (2017 SGR 38), Generalitat Valenciana (GV2016-141), Fundacion Mapfre 2010, Consejeria de Salud de la Junta de Andalucia (PI0105/2007), and Regional Government of Navarra (P27/2011). The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

[Background]: Short dietary assessment tools can be useful to estimate food intake and diet quality in large-scale epidemiological studies with time constraints. [Objective]: To determine the concurrent validity of the 17-item energy-restricted Mediterranean Adherence Screener (er-MEDAS) used in the PREDIMED (PREvención con DIeta MEDiterránea)-Plus trial and to analyse its capacity to detect 1-year changes in diet and cardiometabolic risk factors. [Methods]: Validation study nested in the PREDIMED-Plus (n = 6760, 55–75 years). Dietary data were collected by the 17-item er-MEDAS and a 143-item validated semiquantitative food frequency questionnaire (FFQ) at baseline and after 1-year intervention. Cardiometabolic risk markers were measured at both time points. A Mediterranean diet (MedDiet) score was derived from both instruments. Concurrent validity was evaluated by Pearson and intra-class correlation coefficients (ICC) and Bland and Altman limits of agreement. Construct validity was evaluated by assessing 1-year changes in FFQ-reported dietary intake and cardiometabolic profile changes in relation to changes in er-MEDAS. [Results]: A moderate to good correlation between the MedDiet score calculated by both measurement instruments was found: r = 0.61 and ICC = 0.60 (both p < 0.001). Agreement of each of the er-MEDAS items ranged from 55.4% to 85.0% with a moderate mean concordance (kappa = 0.41). Between baseline and 1-year follow-up, energy intake measured by the FFQ decreased by 242 kcal, while Mediterranean food consumption increased in participants with the highest increase in the er-MEDAS MedDiet score. An increase in the er-MEDAS MedDiet score ratings was associated with a decrease in BMI, waist circumference, triglycerides, fasting glucose, diastolic blood pressure, and triglycerides/HDL-cholesterol ratio (p < 0.001 for all), and with an increase in HDL-cholesterol (p = 0.006). [Conclusion]: The er-MEDAS shows a modest to good concurrent validity compared with FFQ data. It shows acceptable construct validity, as a greater er-MEDAS score was associated with more favourable dietary and cardiometabolic profiles over time., The PREDIMED-Plus trial was supported by the official funding agency for biomedical research of the Spanish government, ISCIII through the Fondo de Investigación para la Salud (FIS), which is co-funded by the European Regional Development Fund four coordinated FIS projects led by Jordi Salas-Salvadó and Josep Vidal, including the following projects: PI13/00673, PI13/ 00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/ 00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/ 00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926; the Special Action Project entitled Implementación y evaluación de una intervención intensiva sobre la actividad física cohorte" PREDIMED-Plus grant to Jordi Salas-Salvadó; the Recercaixa grant to Jordi Salas-Salvadó (2013ACUP00194); the European Research Council Advanced Research Grant 2013–2018 (340918) granted to Miguel Ángel Martínez-Gonzalez, grants from the Consejería de Salud de la Junta de Andalucía (PI0458/2013; PS0358/2016, PI0137/2018), the PROMETEO/2017/017 grant from the Generalitat Valenciana, the SEMERGEN grant and FEDER funds (CB06/03) to Josep A. Tur; the Astra Zeneca Young Investigators Award in Category of Obesity and Diabetes 2017 to Dora Romaguera; the ‘FOLIUM’ programme within the FUTURMed project from the Fundación Instituto de Investigación Sanitaria Illes Balears (financed by 2017annual plan of the sustainable tourism tax and at 50% with charge to the ESF Operational Program 2014–2020 of the Balearic Islands). JR17/00022 contract to Olga Castaner from ISCIII. CIBERobn (Centros de Investigación Biomedica en Red: Obesidad y Nutrición), CIBEResp (Centros de Investigación Biomedica en Red: Epidemiología y Salud Publica) and CIBERdem (Centros de Investigación Biomedica en Red: Diabetes y Enfermedades). J. Salas-Salvadó gratefully acknowledges the financial support provided by the ICREA Academia programme. None of the funding sources took part in the design, collection, analysis, or interpretation of the data; in writing the manuscript; or in the decision to submit the manuscript for publication.

The PREDIMED-Plus trial was supported by the European Research Council (Advanced Research grant 2014–2019; agreement #340918; granted to M.Á.M.-G.); the official Spanish institutions for funding scientific biomedical research, CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN) and Instituto de Salud Carlos III (ISCIII) through the Fondo de Investigación para la Salud (FIS) which is co-funded by the European Regional Development Fund (coordinated FIS projects led by J.S-S. and J.V., including the following projects: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, PI19/01332), and the Especial Action Project “Implementación y evaluación de una intervención intensiva sobre la actividad física Cohorte PREDIMED-Plus” (J.S.-S.); the Recercaixa (grant number 2013ACUP00194) (J.S.-S.). Moreover, J.S-S. gratefully acknowledges the financial support by ICREA under the ICREA Academia program; the SEMERGEN grant; Department of Health of the Government of Navarra (61/2015), the Fundació La Marató de TV (Ref. 201630.10); the AstraZeneca Young Investigators Award in Category of Obesity and T2D 2017 (D.R.); grants from the Consejería de Salud de la Junta de Andalucía (PI0458/2013; PS0358/2016; PI0137/2018), the PROMETEO/2017/017 grant from the Generalitat Valenciana, the SEMERGEN grant; grant of support to research groups 35/2011 (Balearic Islands Government; FEDER funds) (J.A.T.). R.S.-C. acknowledges financial support from the Juan de la Cierva Program Training Grants of the Spanish State Research Agency of the Spanish Ministerio de Ciencia e Innovación y Ministerio de Universidades (FJC2018-038168- I). N.B.-T. acknowledges financial support from the Juan de la Cierva Formación Program Training Grants of the Spanish State Research Agency of the Spanish Ministerio de Ciencia e Innovación y Ministerio de Universidades (FJC2018-036016-I). M.R.B.-L. was supported by “Miguel Servet Type I” program (CP15/00028) from the ISCIII-Madrid (Spain), cofinanced by the Fondo Europeo de Desarrollo Regional-FEDER. S.K.N. acknowledges financial support from the Canadian Institute for Health Research, CIHR Fellowship. J.K. was supported by the ‘FOLIUM’ programme within the FUTURMed project from the Fundación Instituto de Investigación Sanitaria Illes Balears (financed by 2017 annual plan of the sustainable tourism tax and at 50% with charge to the ESF Operational Program 2014–2020 of the Balearic Islands. C.M.-P. was financially supported by a joint grant from the Community of Madrid and the European Social Fund (grant PEJD-2019- POST/SAL-15892). The METHYL-UP project was supported by the Spanish Ministry of Science and Innovation (RTI2018-095569-B-I00, Programa de Proyectos Orientados a los Retos de la Sociedad “Projects Toward Society Challenges Program”)., The association between ultra-processed food (UPF) and risk of cardiometabolic disorders is an ongoing concern. Different food processing-based classification systems have originated discrepancies in the conclusions among studies. To test whether the association between UPF consumption and cardiometabolic markers changes with the classification system, we used baseline data from 5636 participants (48.5% female and 51.5% male, mean age 65.1 4.9) of the PREDIMEDPlus (“PREvention with MEDiterranean DIet”) trial. Subjects presented with overweight or obesity and met at least three metabolic syndrome (MetS) criteria. Food consumption was classified using a 143-item food frequency questionnaire according to four food processing-based classifications: NOVA, International Agency for Research on Cancer (IARC), International Food Information Council (IFIC) and University of North Carolina (UNC). Mean changes in nutritional and cardiometabolic markers were assessed according to quintiles of UPF consumption for each system. The association between UPF consumption and cardiometabolic markers was assessed using linear regression analysis. The concordance of the different classifications was assessed with intra-class correlation coefficients (ICC3, overall = 0.51). The highest UPF consumption was obtained with the IARC classification (45.9%) and the lowest with NOVA (7.9%). Subjects with high UPF consumption showed a poor dietary profile. We detected a direct association between UPF consumption and BMI (p = 0.001) when using the NOVA system, and with systolic (p = 0.018) and diastolic (p = 0.042) blood pressure when using the UNC system. Food classification methodologies markedly influenced the association between UPF consumption and cardiometabolic risk markers., European Research Council (ERC) European Commission #340918, Centro de Investigacion Biomedica en Red-Fisiopatologia de la Obesidad y Nutricion PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441 PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471 PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, PI19/01332

According to the food addiction (FA) model, the consumption of certain types of food could be potentially addictive and can lead to changes in intake regulation. We aimed to describe metabolic parameters, dietary characteristics, and affective and neurocognitive vulnerabilities of individuals with and without FA, and to explore its influences on weight loss progression. The sample included 448 adults (55-75 years) with overweight/obesity and metabolic syndrome from the PREDIMED-Plus cognition sub-study. Cognitive and psychopathological assessments, as well as dietary, biochemical, and metabolic measurements, were assessed at baseline. Weight progression was evaluated after a 3-year follow up. The presence of FA was associated with higher depressive symptomatology, neurocognitive decline, low quality of life, high body mass index (BMI), and high waist circumference, but not with metabolic comorbidities. No differences were observed in the dietary characteristics except for the saturated and monounsaturated fatty acids consumption. After three years, the presence of FA at baseline resulted in a significantly higher weight regain. FA is associated with worse psychological and neurocognitive state and higher weight regain in adults with metabolic syndrome. This condition could be an indicator of bad prognosis in the search for a successful weight loss process. We thank CERCA Programme/Generalitat de Catalunya for institutional support and partial support was also provided by SLT006/17/00246, funded by the Department of Health of the Generalitat de Catalunya by the calls “Acció instrumental de programes de recerca orientats en l’àmbit de la recerca i la innovació en salut” and “Pla estratègic de recerca i innovació en salut (PERIS)”. This research was also partially funded by EU-H2020 Grants (Eat2beNICE/ H2020-SFS-2016-2; Ref 728018; and PRIME/ H2020-SC1-BHC-2018-2020; Ref: 847879). IP-G receives a grant from the Spanish Ministry of Education, Culture and Sports (FPU 17/01925). C.G.-M. receives a predoctoral grant from the University of Rovira i Virgili (2020PMF-PIPF-37); J.S-S. is partially supported by ICREA under the ICREA Academia program.

Postmenopausal women are at higher risk of developing cardiovascular diseases due to changes in lipid profile and body fat, among others. The aim of this study was to evaluate the association of urinary tartaric acid, a biomarker of wine consumption, with anthropometric (weight, waist circumference, body mass index (BMI), and waist-to-height ratio), blood pressure, and biochemical variables (blood glucose and lipid profile) that may be affected during the menopausal transition. This sub-study of the PREDIMED (Prevención con Dieta Mediterránea) trial included a sample of 230 women aged 60–80 years with high cardiovascular risk at baseline. Urine samples were diluted and filtered, and tartaric acid was analyzed by liquid chromatography coupled to electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Correlations between tartaric acid and the study variables were adjusted for age, education level, smoking status, physical activity, BMI, cholesterol-lowering, antihypertensive, and insulin treatment, total energy intake, and consumption of fruits, vegetables, and raisins. A strong association was observed between wine consumption and urinary tartaric acid (0.01 μg/mg (95% confidence interval (CI): 0.01, 0.01), p-value &lt, 0.001). Total and low-density lipoprotein (LDL) cholesterol were inversely correlated with urinary tartaric acid (−3.13 μg/mg (−5.54, −0.71), p-value = 0.016 and −3.03 μg/mg (−5.62, −0.42), p-value = 0.027, respectively), whereas other biochemical and anthropometric variables were unrelated. The results suggest that wine consumption may have a positive effect on cardiovascular health in postmenopausal women, underpinning its nutraceutical properties.

Introduction and objectives The cardiovascular benefits of the Mediterranean diet have usually been assessed under assumptions of ad libitum total energy intake (ie, no energy restriction). In the recently launched PREDIMED-Plus, we conducted exploratory analyses to study the baseline associations between adherence to an energy-restricted Mediterranean diet (MedDiet) and the prevalence of cardiovascular risk factors (CVRF). Methods Cross-sectional assessment of all PREDIMED-Plus participants (6874 older adults with overweight/obesity and metabolic syndrome) at baseline. The participants were assessed by their usual primary care physicians to ascertain the prevalence of 4 CVRF (hypertension, obesity, diabetes, and dyslipidemia). A 17-point PREDIMED-Plus score was used to measure adherence to the MedDiet. Multivariable models were fitted to estimate differences in means and prevalence ratios for individual and clustered CVRF. Results Better adherence to a MedDiet pattern was significantly associated with lower average triglyceride levels, body mass index, and waist circumference. Compared with low adherence (≤ 7 points in the 17-point score), better adherence to the MedDiet (11-17 points) showed inverse associations with hypertension (prevalence ratio = 0.97; 95%CI, 0.94-1.00) and obesity (prevalence ratio = 0.96; 95%CI, 0.92-1.00), but positive associations with diabetes (prevalence ratio = 1.19; 95%CI, 1.07-1.32). Compared with the lowest third of adherence, women in the upper third showed a significantly lower prevalence of the clustering of 3 or more CVRF (prevalence ratio = 0.91; 95%CI, 0.83-0.98). Conclusions Among participants at high cardiovascular risk, better adherence to a MedDiet showed significant inverse associations with CVRF among women, and improved lipid profiles and adiposity measures. This trial was registered in 2014 at the International Standard Randomized Controlled Trial Registry (ISRCTN89898870).

Introduction: The Multidimensional Weight Locus of Control Scale (MWLCS) measures a person's beliefs regarding the locus of control or lack of locus of control over his/her body weight. Purpose: We aim to evaluate the factorial structure and psychometric properties of the MWLCS with Spanish normal weight, overweight and obese samples. Methods: The research was carried out in two different studies. The first included a sample of 140 normal weight participants, selected out of a 274 sample recruited with an online survey. Study 2 was carried out in a sample of 633 participants recruited from the PREDIMED-Plus study. Out of them, 558 participants fulfilled the weight criteria and were categorized into: overweight (BMI 25 - < 29.99; N = 170), obese class I (BMI 30 - < 34.99; N = 266), and obese class II (BMI 35 - < 39.99; N = 122). Exploratory (EFA) and confirmatory (CFA) factor analyses were used to evaluate the factor structure of the MWLCS, and reliabilities and Spearman's correlations were estimated. Invariance measurement was tested across the three subgroups of weight in Study 2. Results: A three-factor structure indicating weight locus of control factors (internal, chance, and powerful others) was supported, both via EFA in the normal weight sample and CFA in the overweight and obese samples. In the normal weight sample, the powerful others dimension was positively related to BMI and the dimensions of the Dutch Eating Behaviors Questionnaire. Additionally, the scale showed evidence of scalar invariance across the groups with different weight conditions. Conclusions: This scale seems to be a psychometrically appropriate instrument and its use is highly recommended when designing interventions for overweight or obese individuals. Level of evidence: Level V, descriptive study. CIBEROBN is an initiative of the ISCIII (Instituto de Salud Carlos III, Spain). We thank the PREDIMEDPLUS Biobank Network, part of the National Biobank Platform of Instituto de Salud Carlos III for storing and managing biological samples. We thank to Research Council (Grant 340918) and PROMETEO Grant (17/2017) from the Generalitat Valenciana.

[Background] Because of the high density of fat, high-fat diets are perceived as likely to lead to increased bodyweight, hence health-care providers are reluctant to recommend them to overweight or obese individuals. We assessed the long-term effects of ad libitum, high-fat, high-vegetable-fat Mediterranean diets on bodyweight and waist circumference in older people at risk of cardiovascular disease, most of whom were overweight or obese., [Methods] PREDIMED was a 5 year parallel-group, multicentre, randomised, controlled clinical trial done in primary care centres affiliated to 11 hospitals in Spain. 7447 asymptomatic men (aged 55–80 years) and women (aged 60–80 years) who had type 2 diabetes or three or more cardiovascular risk factors were randomly assigned (1:1:1) with a computer-generated number sequence to one of three interventions: Mediterranean diet supplemented with extra-virgin olive oil (n=2543); Mediterranean diet supplemented with nuts (n=2454); or a control diet (advice to reduce dietary fat; n=2450). Energy restriction was not advised, nor was physical activity promoted. In 2016, we reported the 5 year changes in bodyweight and waist circumference, but because of a subsequently identified protocol deviation (including enrolment of household members without randomisation, assignment to a study group without randomisation of some participants at one of 11 study sites, and apparent inconsistent use of randomisation tables at another site; 866 [11·6%] participants were affected in total), we have withdrawn our previously published report and now report revised effect estimates based on reanalyses that do not rely exclusively on the assumption that all the participants were randomly assigned. In this analysis of the trial, we measured bodyweight and waist circumference at baseline and yearly for 5 years in the intention-to-treat population. The PREDIMED trial is registered with ISRCTN.com, number ISRCTN35739639., [Findings] After a median 4·8 years (IQR 2·8–5·8) of follow-up, participants in all three groups had marginally reduced bodyweight and increased waist circumference. After multivariable adjustment, including adjustment for propensity scores and use of robust variance estimators, the difference in 5 year changes in bodyweight in the Mediterranean diet with olive oil group was −0·410 kg (95% CI −0·830 to 0·010; p=0·056) and in the nut group was −0·016 kg (–0·453 to 0·421; p=0·942), compared with the control group. The adjusted difference in 5 year changes in waist circumference was −0·466 cm (–1·109 to 0·176; p=0·154) in the Mediterranean diet with olive oil group and −0·923 cm (–1·604 to −0·241; p=0·008) in the nut group, compared with the control group., [Interpretation] A long-term intervention with an unrestricted-calorie, high-vegetable-fat Mediterranean diet was associated with no significant difference in bodyweight and some evidence of less gain in central adiposity compared with a control diet. These results lend support to advice not restricting intake of healthy fats for bodyweight maintenance., Funding: Spanish Government, CIBERobn, Instituto de Salud Carlos III, Hojiblanca, Patrimonio Comunal Olivarero, California Walnut Commission, Borges SA, and Morella Nuts.

Objective To assess the prevalence of gallstone disease and identify associated risk factors in rheumatoid arthritis (RA) patients compared to the general population. Methods Eighty-four women with rheumatoid arthritis were included in the study. Each patient was assessed via a structured interview, physical examination, abdominal ultrasound and blood test including lipid profile. The prevalence of gallstone disease in rheumatoid arthritis was compared with data from a study of the Spanish population matched by age groups. Results Twenty-eight of the 84 women had gallstone disease (33.3%). RA women with and without gallstone disease were similar in most of the variables assessed, except for older age and menopausal status in the former. A greater prevalence of gallstone disease was seen in rheumatoid arthritis patients compared to the general population of the same age; however, the differences were significant only in women aged 60 or older (45.5% versus 23.1% respectively, P-value .008). The age-adjusted OR of developing gallstone disease in RA women compared with general population women was 2,3 (95% CI: 1.3–4.1). A significantly higher HDL3-c subfraction and higher apoA-I/HDL and HDL3-c/TC ratios were observed in patients with gallstone disease. Conclusion Women with rheumatoid arthritis may have a predisposition to gallstones that can manifest in middle or older age compared with women in the general population. This situation could be related to chronic inflammation and HDL metabolism.

ObjectiveSLE is associated with increased cardiovascular risk (CVR). High serum concentrations of triglyceride-rich lipoproteins and apolipoprotein B-rich particles constitute the characteristic dyslipidaemia of SLE.MethodsA cross-sectional study was conducted to study the relationship between genetic variants involved in polygenic hypertriglyceridaemia, subclinical atherosclerosis and lipoprotein abnormalities. 73 women with SLE and 73 control women age-matched with the case group were recruited (age range 30–75 years). Serum analysis, subclinical atherosclerosis screening studies for the detection of plaque, and genetic analysis of the APOE, ZPR1, APOA5 and GCKR genes were performed.ResultsTriglyceride concentrations and the prevalence of hypertension, dyslipidaemia and carotid atherosclerosis were higher in women with SLE than in the control group. Multivariate logistic regression showed that CC homozygosity for the GCKR rs1260326 gene (OR=0.111, 95% CI 0.015 to 0.804, p=0.030) and an increase of 1 mmol/L in triglyceride concentrations were associated with a greater risk of carotid plaque in women with SLE (OR=7.576, 95% CI 2.415 to 23.767, p=0.001).ConclusionsGCKR CC homozygosity (rs1260326) and serum triglyceride concentrations are independently associated with subclinical carotid atherosclerosis in women with SLE. Subclinical carotid atherosclerosis is also more prevalent in these women compared with the control group. The study of GCKR rs1260326 gene variants may contribute to more precise assessment of CVR and modulation of the intensity of lipid-lowering treatment in patients with SLE.

The PREDIMEDPlus trial was supported by the Spanish government's official funding agency for biomedical research, ISCIII, through the Fondo de Investigacion para la Salud (FIS) and cofunded by European Union ERDF/ESF, "A way to make Europe"/"Investing in your future" (five coordinated FIS projects led by JS-S and JVid, including the following: PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/00728, PI14/01722, PI14/00636, PI14/01206, PI14/01919, PI14/01374, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00366, PI17/00764, PI17/01827, PI17/01441, PI17/01732, PI17/00926, PI19/00309, PI19/01032, PI19/00576, PI19/00017, and PI19/00781) , the Special Action Project entitled: Implementacion y evaluacion de una intervencion intensiva sobre la actividad fisica Cohorte PREDIMED-Plus grant to JSS, the European Research Council (Advanced Research Grant 2013-2018, 340918) to MAMG, the Recercaixa Grant to JS-S (2013ACUP00194) , a grant from the Generalitat Valenciana (PROMETEO/2017/017) , a SEMER-GEN grant, and funds from the European Regional Development Fund (CB06/03) . Study resulting from the SLT006/17/00246 grant, funded by the Department of Health of the Generalitat de Catalunya by the call "Accio instrumental de programes de recerca orientats en l'ambit de la recerca i la innovacio en salut". We thank the CERCA Programme/Generalitat de Catalunya for institutional support. This publication has been possible with the support of the Ministerio de Ciencia, Innovacion y Universidades (MICINN) (FPU 17/01925) . Jordi SalasSalvado, senior author of this study, is partially supported by ICREA under the ICREA Academia programme. IP-G receives a grant from the Spanish Ministry of Education, Culture and Sports (FPU 17/01925) . Dr. NB-T is supported by a postdoctoral fellowship (Juan de la Cierva-Formacion, FJC2018-036016-I) . I.M GimenezAlba received an FPU grant from the Ministry of Science, Innovation and Universities (reference FPU 18/01703) . C.B. received a Fernando Tarongi Bauza PhD Grant., Background & aims: The association between drinking water consumption and adiposity has been poorly explored. Therefore, we aimed to analyse the associations between the frequency of drinking water consumption and body weight and waist circumference changes in an elderly Mediterranean cohort. Methods: A total of 1832 elderly participants (aged 55e75 years) with metabolic syndrome from the PREDIMED-Plus study with baseline data on drinking water and other beverages assessed by a validated 32-item Spanish fluid-intake questionnaire and with data on body weight (BW) and waist circumference (WC) at 1-year and 2-year were included in these prospective analyses. Multivariable linear regression models were fitted to assess the b-coefficients and 95% confidence interval (CI) for BWand WC changes in terms of categories of baseline drinking water consumption (tap water and bottled water). The theoretical effect on BWand WC of replacing several beverages with drinking water was assessed using mathematical models. Results: The baseline frequency of drinking water consumptionwas inversely associated with 1-year and 2- year changes in BW. b-coefficients (95%CI) across categories ofwater consumption (, Spanish Government European Commission, European Union ERDF/ESF, "A way to make Europe"/"Investing in your future" PI13/00272 PI13/01123 PI13/00462 PI13/00233 PI13/00728 PI14/01722 PI14/00636 PI14/01206 PI14/01919 PI14/01374 PI16/01873 PI16/01094 PI16/00501 PI16/00533 PI16/00366, Special Action Project entitled: Implementacion y evaluacion de una intervencion intensiva sobre la actividad fisica Cohorte PREDIMED-Plus grant, European Research Council (ERC), European Commission 340918, Recercaixa Grant 2013ACUP00194, Generalitat Valenciana European Commission PROMETEO/2017/017, SEMER-GEN grant European Commission CB06/03, Department of Health of the Generalitat de Catalunya SLT006/17/00246, Ministerio de Ciencia, Innovacion y Universidades (MICINN) FPU 17/01925, ICREA under the ICREA Academia programme, Spanish Ministry of Education, Culture and Sports FPU 17/01925, Juan de la Cierva-Formacion FJC2018-036016-I, Ministry of Science, Innovation and Universities FPU 18/01703, Fernando Tarongi Bauza PhD Grant, The European Union ERDF/ESF, "A way to make Europe"/"Investing in your future" PI17/00764 PI17/01827 PI17/01441 PI17/01732 PI17/00926 PI19/00309 PI19/01032 PI19/00576 PI19/00017 PI19/00781

We thank all the volunteers for the participation and personnel for the contribution in the PREDIMED-Plus trial. CIBEROBN, CIBERESP and CIBERDEM are initiatives of ISCIII, Madrid, Spain. The authors also thank the PREDIMED-Plus Biobank Network as a part of the National Biobank Platform of the ISCIII for storing and managing the PREDIMED-Plus biological samples. This work was supported by the official Spanish Institutions for funding scientific biomedical research, CIBER Fisiopatologia de la Obesidad y Nutricion (CIBEROBN) and Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigacion para la Salud (FIS), which is co-funded by the European Regional Development Fund (five coordinated FIS projects leaded by JS-S and JVi, including the following projects: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, PI19/01332, PI20/01802, PI20/00138, PI20/01532, PI20/00456, PI20/00339, PI20/00557, PI20/00886, PI20/01158); the Especial Action Project entitled: Implementacion y evaluacion de una intervencion intensiva sobre la actividad fisica Cohorte PREDIMED-Plus Grant to JS-S; the European Research Council (Advanced Research Grant 2014-2019; Agreement #340918) granted to MaM-G.; the Recercaixa (Number 2013ACUP00194) grant to JS-S; grants from the Consejeria de Salud de la Junta de Andalucia (PI0458/2013, PS0358/2016, PI0137/2018); the PROMETEO/2017/017 grant from the Generalitat Valenciana; the SEMERGEN grant; funds from the European Regional Development Fund (CB06/03); International Nut & Dried Fruit Council - FESNAD (Long-term effects of an energy-restricted Mediterranean diet on mortality and cardiovascular disease 2014 -2015, No. 201302) (PI: MaM-G); the AstraZeneca Young Investigators Award in Category of Obesity and T2D 2017 (PI: DR); grant of support to research groups no. 35/2011 (Balearic Islands Gov.; FEDER funds) (JAT and CB); the JR17/00022 (ISCIII) grant to OC; the Boosting young talent call grant program for the development of IISPV research projects 2019-2021 (Ref.: 2019/IISPV/03 grant to AD-L); the Societat Catalana d'Endocrinologia i Nutricio (SCEN) Clinical-Research Grant 2019 (IPs: JS-S and AD-L). Collaborative Nutrition and/or Obesity Project for Young Researchers 2019 supported by CIBEROBN entitled: Lifestyle Interventions and Chronic Kidney Disease: Inflammation, Oxidative Stress and Metabolomic Profile (LIKIDI study) grant to AD-L. IP-G receives a grant from the Spanish Ministry of Education, Culture and Sports (FPU17/01925). Jordi Salas-Salvado, the senior author of this work, gratefully acknowledges the financial support by ICREA under the ICREA Academia programme. None of the funding sources took part in the design, collection, analysis, interpretation of the data, or writing the report, or in the decision to submit the manuscript for publication., It remains unclear whether caffeinated beverages could have deleterious renal effects in elderly population with underlying comorbid conditions. We investigated the associations between coffee, tea, or caffeine intake and 1-year changes in glomerular filtration rate (eGFR) in a large Spanish cohort of overweight/obese elderly with metabolic syndrome (MetS). This prospective analysis includes 5851 overweight/obese adults (55-75 years) with MetS from the PREDIMED-Plus study. We assessed coffee, tea, and caffeine consumption from a validated food-frequency questionnaire and creatinine-based eGFR using the Chronic Kidney Disease Epidemiology Collaboration equation. Multivariate-adjusted regression models were applied to test associations between baseline coffee, tea, or caffeine intake and 1-year eGFR changes. Caffeinated coffee (> 2 cups/day) and tea (at least 1 cup/day) drinkers had 0.88 and 0.93 mL/min/1.73 m(2) greater eGFR decrease respectively, compared to those with less than 1 cup/day of coffee consumption or non-tea drinkers. Furthermore, caffeinated coffee consumption of > 2 cups/day was associated with 1.19-fold increased risk of rapid eGFR decline > 3 mL/min/1.73 m(2) (95% CI 1.01-1.41). Similarly, individuals in the highest (median, 51.2 mg/day) tertile of caffeine intake had a 0.87 mL/min/1.73 m(2) greater eGFR decrease. Decaffeinated coffee was not associated with eGFR changes. In conclusion, higher consumption of caffeinated coffee, tea, and caffeine was associated with a greater 1-year eGFR decline in overweight/obese adults with MetS., CIBER Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigacion para la Salud (FIS) - European Regional Development Fund PI13/00673 PI13/00492 PI13/00272 PI13/01123 PI13/00462 PI13/00233 PI13/02184 PI13/00728 PI13/01090 PI13/01056 PI14/01722 PI14/00636 PI14/00618 PI14/00696 PI14/01206 PI14/01919 PI14/00853 PI14/01374 PI14/00972 PI14/00728 PI14/01471 PI16/00473, European Research Council (ERC) European Commission 340918, La Caixa Foundation 2013ACUP00194, Junta de Andalucia PI0458/2013 PS0358/2016 PI0137/2018, Generalitat Valenciana European Commission PROMETEO/2017/017, European Commission CB06/03, International Nut & Dried Fruit Council - FESNAD (Long-term effects of an energy-restricted Mediterranean diet on mortality and cardiovascular disease 2014 -2015) 201302, SEMERGEN grant, AstraZeneca, Balearic Islands Gov.; FEDER funds 35/2011, (ISCIII) grant JR17/00022, Boosting young talent call grant program for the development of IISPV research projects 2019-2021 2019/IISPV/03, Societat Catalana d'Endocrinologia i Nutricio (SCEN) Clinical-Research Grant 2019, Collaborative Nutrition and/or Obesity Project for Young Researchers 2019 - CIBEROBN, Spanish Ministry of Education, Culture and Sports FPU17/01925, ICREA, the Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigacion para la Salud (FIS) - European Regional Development Fund PI17/01441 PI17/00508 PI17/01732 PI17/00926 PI19/00957 PI19/00386 PI19/00309 PI19/01032 PI19/00576 PI19/00017 PI19/01226 PI19/00781 PI19/01560 PI19/01332 PI20/01802 PI20/00138 PI20/01532 PI20/00456 PI20/00339 PI20/00557 PI20/00886 PI20/01158, 'Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigacion para la Salud (FIS) - European Regional Development Fund' PI16/00662 PI16/01873 PI16/01094 PI16/00501 PI16/00533 PI16/00381 PI16/00366 PI16/01522 PI16/01120 PI17/00764 PI17/01183 PI17/00855 PI17/01347 PI17/00525 PI17/01827 PI17/00532 PI17/00215

Background and aims: Modifiable lifestyle factors, such as physical activity (PA) and Mediterranean diet (MD), decrease metabolic syndrome (MetS). The aim was to assess 1-year changes of leisure-time physical activity (LTPA), sedentary behavior, and diet quality according to MetS severity in older population at high cardiovascular risk. Methods and results: Prospective analysis of 55-75-year-old 4359 overweight/obese participants with MetS (PREDIMED-Plus trial) categorized in tertiles according to 1-year changes of a validated MetS severity score (MetSSS). Anthropometrics, visceral adiposity index, triglycerides and glucose index, dietary nutrient intake, biochemical marker levels, dietary inflammatory index, and depression symptoms were measured. Diet quality was assessed by 17-item MD questionnaire. PAs were self-reported using the Minnesota-REGICOR Short Physical Activity Questionnaire and 30-s chair stand test. Sedentary behaviors were measured using the Spanish version of the Nurses' Health Study questionnaire. After 1-year follow-up, decreasing MetSSS was associated with an anti-inflammatory dietary pattern, high intake of vegetables, fruits, legumes, nuts, whole grain cereals, white fish, and bluefish and low intake of refined cereals, red and processed meat, cookies/sweets, and snacks/ready-to-eat-meals. It resulted in high intake of polyunsaturated fatty acids, omega-3 fatty acids, protein, fiber, vitamins B1, B6, B9, C, D, potassium, magnesium, and phosphorus and low glycemic index and saturated fatty acid, trans fatty acid, and carbohydrates intake. Regarding PA and sedentary behavior, decreasing MetSSS was associated with increased moderate-to-vigorous LTPA, chair stand test, and decreased sedentary and TV-viewing time. Conclusion: Decreasing MetSSS was associated with an anti-inflammatory dietary pattern, high LTPA, high MD adherence, low sedentary time, and low depression risk. 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Background: Lipid metabolism disorders, especially hypertriglyceridemia (HTG), are risk factors for non-alcoholic fatty liver disease (NAFLD). However, the association between genetic factors related to HTG and the risk of NAFLD has been scarcely studied. Methods: A total of 185 subjects with moderate HTG were prospectively included. We investigated the association between genetic factors’ (five allelic variants with polygenic hypertriglyceridemia) clinical and biochemical biomarkers with NAFLD severity. The five allelic variants’ related clinical and biochemical data of HTG were studied in all the subjects. NAFLD was assessed by abdominal ultrasound and patients were divided into two groups, one with no or mild NAFLD and another with moderate/severe NAFLD. Results: Patients with moderate/severe NAFLD had higher weight and waist values and a higher prevalence of insulin resistance than patients with no or mild NAFLD. Moderate/severe NAFLD was independently associated with APOA5 rs3134406 and ZPR1 rs964184 variants, and also showed a significant inverse relationship with lipoprotein(a) [Lp(a)] concentrations. Conclusions: APOA5 rs3135506 and ZPR1 rs964184 variants and lipoprotein(a) are associated with moderate/severe NAFLD. This association was independent of body weight, insulin resistance, and other factors related to NAFLD. info:eu-repo/semantics/publishedVersion

Background In the last years, evidence that dietary vitamin K could have a role in the cognitive domain has increased. However, data from large trials are limited. The objective of this study was to assess the association of 2 year changes in the dietary intake of vitamin K with cognitive function measured through neuropsychological performance tests. Methods In 5,533 participants of the multicentre PREDIMED-Plus study (48.1% women, age 65.1 ± 4.9 years with overweight/obesity and metabolic syndrome), we assessed the adjusted odds ratios of cognitive function decline according to 2 year changes in vitamin K intake. Participants answered a battery of cognitive function tests and Food Frequency Questionnaires (FFQs) in order to estimate the vitamin K dietary intake. Results After adjusting for potential cofounders, the highest tertile of change of dietary vitamin K intake (median [IQR]; 194.4 μg/d [120.9, 373.1]) was inversely associated with a Mini-Mental State Examination (MMSE) score ≤24 (OR [95% CI]; 0.53 [0.35, 0.79] P for trend = 0.002) compared with a decrease in the intake of vitamin K (median [IQR]; −97.8 μg/d [−292.8, −51.5]). A significant positive association between changes in dietary vitamin K intake and the semantic verbal fluency test scores (OR [95% CI]; 0.69 [0.51, 0.94] P for trend = 0.019) was found. Conclusions An increase of the intake of dietary vitamin K was associated with better cognitive function scores, independently of recognised risk factors for cognitive decline, in an older adult Mediterranean population with high cardiovascular risk.

This study examines if overweight/obesity are related to higher impulsivity, food addiction and depressive symptoms, and if these variables could be modified after 1 year of a multimodal intervention (diet, physical activity, psychosocial support). 342 adults (55-75 years) with overweight/obesity and metabolic syndrome (MetS) from the PREDIMED-Plus Cognition study were randomized to the intervention or to the control group (lifestyle recommendations). Cognitive and psychopathological assessments were performed at baseline and after 1-year follow-up. At baseline, higher impulsivity was linked to higher food addiction and depressive symptoms, but not to body mass index (BMI). Food addiction not only predicted higher BMI and depressive symptoms, but also achieved a mediational role between impulsivity and BMI/depressive symptoms. After 1 year, patients in both groups reported significant decreases in BMI, food addiction and impulsivity. BMI reduction and impulsivity improvements were higher in the intervention group. Higher BMI decrease was achieved in individuals with lower impulsivity. Higher scores in food addiction were also related to greater post-treatment impulsivity. To conclude, overweight/obesity are related to higher impulsivity, food addiction and depressive symptoms in mid/old age individuals with MetS. Our results also highlight the modifiable nature of the studied variables and the interest of promoting multimodal interventions within this population. This project was funded by Instituto de Salud Carlos III (ISCIII), the Spanish Government Official Agency for funding biomedical research—with competitive grants leaded by Jordi Salas-Salvadó and Josep Vidal for the periods 2014–2016, 2015–2017, 2017–2019 and 2018–2020, through the Fondo de Investigación para la Salud (FIS), which is co-funded by the European Regional Development Fund [grants: PI13/00233, PI13/00728, PI13/01123, PI13/00462, PI16/00533, PI16/00366, PI16/01094, PI16/00501, PI19/00017, PI19/00781, PI19/01032, PI19/00576]; the Especial Action Project entitled: Implementación y evaluación de una intervención intensiva sobre la actividad física Cohorte PREDIMED-Plus grant to Jordi Salas-Salvadó; the European Research Council [Advanced Research Grant 2014–2019; agreement #340918] granted to Miguel Ángel Martínez-González; the Recercaixa (number 2013ACUP00194) grant to Jordi Salas-Salvadó. This research was also partially funded by EU-H2020 Grants (Eat2beNICE/H2020-SFS-2016-2; Ref 728018; and PRIME/H2020-SC1-BHC-2018-2020; Ref: 847879) and Instituto Salud Carlos III (Fondo Investigación Sanitario, FIS: PI17/01167), Grant PROMETEO/2017/017 (Generalitat Valenciana) and Grant FEA/SEA 2017 for Primary Care Research. This work is also partially supported by ICREA under the ICREA Academia programme.

Background and aims: Total fruit consumption is important for cardiovascular disease prevention, but also the variety and form in which is consumed. The aim of the study was to assess the associations between total fruit, subgroups of fruits based on their color and fruit juices consumption with different cardiometabolic parameters. Methods and results: A total of 6633 elderly participants (aged 55-75 years) with metabolic syndrome from the PREDIMED-Plus study were included in this analysis. Fruit and fruit juice consumption was assessed using a food frequency questionnaire. Linear regression models were fitted to evaluate the association between exposure variables (total fruit, subgroups based on the color, and fruit juices) and different cardiometabolic risk factors. Individuals in the highest category of total fruit consumption (>3 servings/d) had lower waist circumference (WC) (13 = -1.04 cm; 95%CI:-1.81,-0.26), fasting glucose levels (13 =-2.41 mg/dL; 95%CI(-4.19,-0.63) and LDL-cholesterol (13 =-4.11 mg/dL; 95%CI:-6.93,-1.36), but, unexpectedly, higher systolic blood pressure (BP) (13 = 1.84 mmHg; 95%CI: 0.37, 3.30) and diastolic BP (13 = 1.69 mmHg; 95%CI:0.83, 2.56) when compared to those in the lowest category of consumption (1 serving/day of total fruit juice had lower WC (13 = -0.92 cm; 95%CI:-1.56,-0.27) and glucose levels (13 =-1.59 mg/dL; 95%CI:-2.95,-0.23) than those consuming

Clinical data on the direct health effects of energy deficit or surplus beyond its impact on body weight are scarce. We aimed to assess the association with all-cause, cardiovascular and cancer mortality of (1) sustained energy deficit or surplus, calculated according to each individual’s en-ergy intake (EI) and theoretical energy expenditure (TEE), and (2) mid-term change in total EI in a prospective study. In 7119 participants in the PREDIMED Study (PREvención con DIeta MEDi-terránea) with a mean age of 67 years, energy intake was derived from a 137-item food frequency questionnaire. TEE was calculated as a function of age, sex, height, body weight and physical ac-tivity. The main exposure was the proportion of energy requirement covered by energy intake, cumulative throughout the follow-up. The secondary exposure was the change in energy intake from baseline. Cox proportional hazard models were used to estimate hazard ratios and 95% con-fidence intervals for all-cause, cardiovascular and cancer mortality. Over a median follow-up of 4.8 years, there were 239 deaths (excluding the first 2 years). An energy intake exceeding energy needs was associated with an increase in mortality risk (continuous HR10% over energy needs = 1.10, 95% CI 1.02, 1.18), driven by cardiovascular death (HR = 1.26, 95% CI 1.11, 1.43). However, consum-ing energy below estimated needs was not associated with a lower risk. Increments over time in energy intake were associated with greater all-cause mortality (HR10% increase = 1.09, 95% CI 1.02, 1.17). However, there was no evidence that a substantial negative change in energy intake would reduce mortality risk. To conclude, in an older Mediterranean cohort, energy surplus or increase over a 5-year period was associated with greater risk of mortality, particularly cardiovascular mortality. Energy deficit, or reduction in energy intake over time were not associated with mortal-ity risk.

Goals To explore affective and cognitive status, later in life, in individuals with and without previous history of eating disorder (ED), and also its association with higher risk for metabolic syndrome (MetS) symptomatology. Methods A cross-sectional analysis of 6756 adults, aged 55-75 years with overweight/obesity and MetS participating in the Predimed-Plus study was conducted. Participants completed self-reported questionnaires to examine lifetime history of ED, according to DSM-5 criteria, and other psychopathological and neurocognitive factors. Anthropometric and metabolic measurements were also collected. Results Of the whole sample, 24 individuals (0.35%) reported a previous history of ED. In this subsample, there were more women and singles compared to their counterparts, but they also presented higher levels of depressive symptoms and higher cognitive impairment, but also higher body mass index (BMI) and severe obesity, than those without lifetime ED. Conclusions This is one of the first studies to analyse the cognitive and metabolic impact of a previous history of ED. The results showed that previous ED was associated with greater affective and cognitive impairment, but also with higher BMI, later in life. No other MetS risk factors were found, after controlling for relevant variables.

I.D.-L. is supported by the [FI_B 00256] from the FI-AGAUR Research Fellowship Program, Generalitat de Catalunya and M.M.-M is supported by the FPU17/00513 grant. a.-H. is supported by the [CD17/00122] grant and S.K.N. is supported by a Canadian Institutes of Health Research (CIHR) Fellowship. We also thank all the volunteers for their participation in and the personnel for their contribution to the PREDIMED-Plus trial. This research was funded by CiCYT [AGL2016-75329-R] and CIBEROBN from the Instituto de Salud Carlos III, ISCIII from the Ministerio de Ciencia, Innovacion y Universidades, (AEI/FEDER, UE), Generalitat de Catalunya (GC) [2017SGR196]. The PREDIMED-Plus trial was supported by the official Spanish Institutions for funding scientific biomedical research, CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn) and Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigacion para la Salud (FIS), which is co-funded by the European Regional Development Fund (four coordinated Fondo de Investigaciones Sanitarias projects lead by J.S.-S. and J.V., including the following projects: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926 and PI19/00781), the Especial Action Project entitled Implementacion y evaluacion de una intervencion intensiva sobre la actividad fisica Cohorte PREDIMED-Plus grant to J.S.-S., European Research Council (Advanced Research Grant 2014-2019, 340918) to M.a.M.-G., the Recercaixa grant to J.S.-S. (2013ACUP00194), grants from the Consejeria de Salud de la Junta de Andalucia (PI0458/2013, PS0358/2016, and PI0137/2018), a grant from the Generalitat Valenciana (PROMETEO/2017/017), a SEMERGEN grant, Fundacio la Marato de TV3 (PI044003), 2017 SGR 1717 from Generalitat de Catalunya, a CICYT grant provided by the Ministerio de Ciencia, Innovacion y Universidades (AGL2016-75329-R), and funds from the European Regional Development Fund (CB06/03 and CB12/03). Food companies Hojiblanca (Lucena, Spain) and Patrimonio Comunal Olivarero (Madrid, Spain) donated extra virgin olive oil, and the Almond Board of California (Modesto, CA, USA), American Pistachio Growers (Fresno, CA, USA), and Paramount Farms (Wonderful Company, LLC, Los Angeles, CA, USA) donated nuts. J.K. was supported by the "FOLIUM" program within the FUTURMed project entitled Talent for the medicine within the future from the Fundacio Institut d'Investigacio Sanitaria Illes Balears. This call was co-financed at 50% with charge to the Operational Program FSE 2014-2020 of the Balearic Islands. This work is partially supported by ICREA under the ICREA Academia programme to J.S.-S., Scope: Plasma fatty acids (FAs) are associated with the development of cardiovascular diseases and metabolic syndrome. The aim of our study is to assess the relationship between fruit and vegetable (F&V) consumption and plasma FAs and their subtypes. Methods and Results: Plasma FAs are assessed in a cross-sectional analysis of a subsample of 240 subjects from the PREDIMED-Plus study. Participants are categorized into four groups of fruit, vegetable, and fat intake according to the food frequency questionnaire. Plasma FA analysis is performed using gas chromatography. Associations between FAs and F&V consumption are adjusted for age, sex, physical activity, bodymass index (BMI), total energy intake, and alcohol consumption. Plasma saturated FAs are lower in groups with high F&V consumption (-1.20 mg cL−1 [95% CI: [-2.22, - 0.18], p-value = 0.021), especially when fat intake is high (-1.74 mg cL−1 [95% CI: [-3.41, -0.06], p-value = 0.042). Total FAs and n-6 polyunsaturated FAs tend to be lower in high consumers of F&V only in the high-fat intake groups. Conclusions: F&V consumption is associated with lower plasma saturated FAs when fat intake is high. These findings suggest that F&V consumption may have different associations with plasma FAs depending on their subtype and on the extent of fat intake., Generalitat de Catalunya FI_B 00256, Canadian Institutes of Health Research (CIHR), Consejo Interinstitucional de Ciencia y Tecnologia (CICYT), European Commission AGL2016-75329-R, CIBEROBN from the Instituto de Salud Carlos III ISCIII from the Ministerio de Ciencia, Innovacion y Universidades, (AEI/FEDER, UE), Generalitat de Catalunya 2017SGR196, CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigacion para la Salud (FIS), European Commission PI13/00673 PI13/00492 PI13/00272 PI13/01123 PI13/00462 PI13/00233 PI13/02184 PI13/00728 PI13/01090 PI13/01056 PI14/01722 PI14/00636 PI14/00618 PI14/00696 PI14/01206 PI14/01919 PI14/00853 PI14/01374, Especial Action Project entitled Implementacion y evaluacion de una intervencion intensiva sobre la actividad fisica Cohorte PREDIMED-Plus grant, European Research Council (ERC) European Commission 340918, Recercaixa grant 2013ACUP00194, Junta de Andalucia PI0458/2013 PS0358/2016 PI0137/2018, Generalitat Valenciana European Commission PROMETEO/2017/017, SEMERGEN grant, Fundacio la Marato de TV3 PI044003, Generalitat de Catalunya 2017 SGR 1717, Ministerio de Ciencia, Innovacion y Universidades AGL2016-75329-R, "FOLIUM" program within the FUTURMed project within Fundacio Institut d'Investigacio Sanitaria Illes Balears, ICREA under the ICREA Academia programme, The European Regional Development Fund PI17/01347 PI17/00525 PI17/01827 PI17/00532 PI17/00215 PI17/01441 PI17/00508 PI17/01732 PI17/00926 PI19/00781 CB06/03 CB12/03, European Commission PI14/00972 PI14/00728 PI14/01471 PI16/00473 PI16/00662 PI16/01873 PI16/01094 PI16/00501 PI16/00533 PI16/00381 PI16/00366 PI16/01522 PI16/01120 PI17/00764 PI17/01183 PI17/00855 FPU17/00513 CD17/00122

Background and aims: Previous studies, mainly focused on quantity rather than variety, have shown beneficial associations between the amount of fruit and vegetable consumed, diet quality and healthy lifestyle. The aim is to evaluate the association between fruit and vegetable consumption, diet quality and lifestyle in an elderly Mediterranean population, considering both variety and the combination of quantity and variety (QV). Methods: A cross-sectional analysis of 6647 participants (51.6% of males) was conducted in the framework of the PREDIMED-Plus study. A variety score was created as the sum of vegetables and/or fruits consumed at least once per month using food frequency questionnaires. Dietary Reference Intakes (EAR and IA values) were used to estimate the prevalence of inadequate intake of dietary fiber and micro nutrients. Logistic regression models were performed to examine the association between fruit and vegetable consumption and not meeting the DRIs, by tertiles of fruit and vegetable variety and QV categories. Results: Participants with higher fruit and vegetable variety score reported a significant higher intake of fiber, vitamins, minerals and flavonoids and were significantly more likely to be physically active and non-smoker. Besides, higher variety in fruit and vegetable consumption was associated with lower prevalence of having an inadequate intake of fiber [(0.13 (0.11-0.16)], two or more [(0.17 (0.14-0.21)], three or more [(0.15 (0.13-0.18)] and four or more [(0.11 (0.10-0.14)] micronutrients in our participants. Higher quantity and variety in fruit and vegetable consumption was associated with lower prevalence of having an inadequate intake of fiber [(0.05 (0.04-0.06)], two or more [(0.08 (0.06-0.10)], three or more [(0.08 (0.06-0.09)] and four or more [(0.06 (0.05-0.07)] micronutrients. Conclusion: Greater variety in fruit and vegetable intake was associated with better nutrient adequacy, diet quality and healthier lifestyle in an elderly Mediterranean population. (c) 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

This baseline cross-sectional analysis from data acquired in a sub-sample of the PREDIMED-Plus study participants aimed to evaluate the relation between the Composite Socioeconomic Index (CSI) and lifestyle (diet and physical activity). This study involved 1512 participants (759 (52.2%) women) between 55 and 80 years with overweight/obesity and metabolic syndrome assigned to 137 primary healthcare centers in Catalonia, Spain. CSI and lifestyle (diet and physical activity) were assessed. Multiple linear regression or multinomial regression were applied to the data. Cluster analysis was performed to identify dietary patterns. The multiple linear regression model showed that a high deprivation index was related to a higher consumption of refined cereals (11.98 g/d, p-value = 0.001) and potatoes (6.68 g/d, p-value = 0.001), and to a lower consumption of fruits (−17.52 g/d, p-value = 0.036), and coffee and tea (−8.03 g/d, p-value = 0.013). Two a posteriori dietary patterns were identified by cluster analysis and labeled as “healthy” and “unhealthy”. In addition, the multinomial regression model showed that a high deprivation index was related to an unhealthy dietary pattern and low physical activity (OR 1.42 [95% CI 1.06–1.89], p-value &lt, 0.05). In conclusion, a high deprivation index was related to an unhealthy lifestyle (diet and physical activity) in PREDIMED-Plus study participants.

Cardiovascular risk in heterozygous familial hypercholesterolaemia (HeFH) is driven by LDL cholesterol levels. Since lipid response to statin therapy presents individual variation, this study aimed to compare mean LDL and non-HDL cholesterol reductions and their variability achieved with different types and doses of the most frequently prescribed statins.Among primary hypercholesterolaemia cases on the Spanish Arteriosclerosis Society registry, 2894 with probable/definite HeFH and complete information on drug therapy and lipid profile were included. LDL cholesterol reduction ranged from 30.2 ± 17.0% with simvastatin 10 mg to 48.2 ± 14.7% with rosuvastatin 40 mg. After the addition of ezetimibe, an additional 26, 24, 21 and 24% reduction in LDL cholesterol levels was obtained for rosuvastatin, 5, 10, 20 and 40 mg, respectively. Subjects with definite HeFH and a confirmed genetic mutation had a more discrete LDL cholesterol reduction compared to definite HeFH subjects with no genetic mutation. A suboptimal response (15% or30% reduction in LDL cholesterol levels, respectively with low-/moderate-intensity and high-intensity statin therapy) was observed in 13.5% and, respectively, 20.3% of the subjects.According to the LDL cholesterol reduction in HeFH patients, the ranking for more to less potent statins was rosuvastatin, atorvastatin and simvastatin; however, at maximum dosage, atorvastatin and rosuvastatin were nearly equivalent. HeFH subjects with positive genetic diagnosis had a lower lipid-lowering response. Approximately 1 in 5 patients on high-intensity statin therapy presented a suboptimal response.

Highlights • Dexamethasone, or alternative steroids, are recommended in severe COVID-19. • The use of tocilizumab in COVID-19, with or without steroids, is still controversial. • Risk for mortality was assessed in 186 COVID-19 patients receiving tocilizumab. • Mortality was associated with older age, chronic heart failure and liver disease. • In tocilizumab-treated patients, the additional use of steroids was beneficial., Objectives To assess the characteristics and risk factors for mortality in patients with severe COVID-19 treated with tocilizumab (TCZ), alone or in combination with corticosteroids (CS). Methods From March 17 to April 7, 2020, a real-world observational retrospective analysis of consecutive hospitalized adult patients receiving TCZ to treat severe COVID-19 was conducted at our 750-bed university hospital. The main outcome was all-cause in-hospital mortality. Results A total of 1,092 COVID-19 patients were admitted during the study period. Of them, 186 (17%) were treated with TCZ, of which 129 (87.8%) in combination with CS. Of the total 186, 155 (83.3 %) patients were receiving non-invasive ventilation when TCZ was initiated. Mean time from symptoms onset and hospital admission to TCZ use was 12 (± 4.3) and 4.3 days (± 3.4), respectively. Overall, 147 (79%) survived and 39 (21%) died. By multivariate analysis, mortality was associated with older age (HR = 1.09, p

Dietary polyphenol intake is associated with improvement of metabolic disturbances. The aims of the present study are to describe dietary polyphenol intake in a population with metabolic syndrome (MetS) and to examine the association between polyphenol intake and the components of MetS. This cross-sectional analysis involved 6633 men and women included in the PREDIMED (PREvenci&oacute, n con DIeta MEDiterranea-Plus) study. The polyphenol content of foods was estimated from the Phenol-Explorer 3.6 database. The mean of total polyphenol intake was 846 &plusmn, 318 mg/day. Except for stilbenes, women had higher polyphenol intake than men. Total polyphenol intake was higher in older participants (&gt, 70 years of age) compared to their younger counterparts. Participants with body mass index (BMI) &gt, 35 kg/m2 reported lower total polyphenol, flavonoid, and stilbene intake than those with lower BMI. Total polyphenol intake was not associated with a better profile concerning MetS components, except for high-density lipoprotein cholesterol (HDL-c), although stilbenes, lignans, and other polyphenols showed an inverse association with blood pressure, fasting plasma glucose, and triglycerides. A direct association with HDL-c was found for all subclasses except lignans and phenolic acids. To conclude, in participants with MetS, higher intake of several polyphenol subclasses was associated with a better profile of MetS components, especially HDL-c.

A low prevalence of type 2 diabetes mellitus has been reported in familial hypercholesterolaemia. Whether a healthier lifestyle could explain it has not been explored. This cross-sectional study determines the prevalence of lifestyle-related cardiovascular risk factors in heterozygous familial hypercholesterolaemia (HeFH) from the Dyslipidaemia Registry of the Spanish Atherosclerosis Society and in the ENRICA study, a representative sample of the adult Spanish general population, weighted to match the age and sex distribution of the HeFH sample. A total of 2185 HeFH patients and 11,856 individuals from ENRICA were included. HeFH had lower body mass index and fewer of them were smokers than in the reference population. A model adjusted for age, sex and body mass index showed that HeFH more frequently had cardiovascular disease (odds ratio (OR) 23.98; 95% confidence interval (CI) 18.40–31.23) and hypertension (OR 1.20; 95% CI 1.07–1.35), and took anti-hypertensive medication (OR 1.36; 95% CI 1.18–1.56) and anti-diabetic medication (OR 1.25; 95% CI 1.00–1.56), but less frequently were smokers (OR 0.79; 95% CI 0.71–0.89). In a HeFH subsample ( n = 513) with complete blood glucose information, those patients without cardiovascular disease showed lower prevalence of smoking and type 2 diabetes mellitus, lower body mass index and glucose, and higher diastolic blood pressure than the Spanish population. The differences in type 2 diabetes mellitus were justified mostly by the difference in body mass index. Body mass index adjustment also showed higher prevalence of hypertension and use of anti-hypertensive drugs in HeFH. In summary, HeFH patients had lower body mass index, which may contribute to explaining the lower prevalence of diabetes, and lower current smoking but higher hypertension.

Background & aims: Few studies have compared micronutrient intake and fulfilment of average requirements (EAR) in non-diabetic, pre-diabetic and diabetic adults at high cardiovascular risk. We assessed these variables in a large sample of participants in the PREDIMED-PLUS randomized trial of primary cardiovascular prevention with diet and physical activity. Design: Baseline assessment of nutritional adequacy in n = 5792 men and women, aged 55-75 years, with overweight/obesity and some metabolic syndrome features. Methods: Participants were categorised as non-diabetic (n = 2390), pre-diabetic (n = 1322) or diabetic (n = 2080) by standard criteria. Food and nutrient intake were assessed using a validated food frequency questionnaire. Micronutrients examined were vitamins B1, B2, B3, B6, B12, A, C, D, E and folic acid; Ca, K, P, Mg, Fe, Se, Cr, Zn, and iodine. The proportion of micronutrient inadequacy was evaluated using the EAR or adequate intake (AI) cut-offs. Diet quality was also determined using a 17-item energy-restricted Mediterranean diet (MedDiet) questionnaire. Results: Compared to non-diabetic participants, those with pre-diabetes had lower intakes of total carbohydrates (CHO) and higher intakes of total fat and saturated fatty acids (SFA) and were more likely to be below EAR for folic, while diabetic participants had lower intakes of total CHO and higher intakes of protein, total fat, monounsaturated fatty acids, SFA and cholesterol and were less likely to be below EAR for vitamins B2, and B6, Ca, Zn and iodine. Diabetic participants disclosed higher adherence to the MedDiet than the other two groups. Conclusions: Older Mediterranean individuals with metabolic syndrome and diabetes had better nutrient adequacy and adherence to the MedDiet than those with pre-diabetes or no diabetes. (C) 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

[EN] Introduction and objectives The Life's Simple 7 strategy of the American Heart Association proposes 7 metrics of ideal cardiovascular health: body mass index (BMI) < 25 mg/m2, not smoking, healthy diet, moderate physical activity ≥ 150 min/wk, total blood cholesterol < 200 mg/dL, systolic and diastolic blood pressures < 120 and < 80 mmHg, respectively, and fasting blood glucose < 100 mg/dL. It is important to assess the combined effect of these 7 metrics in the Spanish population. We prospectively analyzed the impact of baseline Life's Simple 7 metrics on the incidence of major cardiovascular events in the PREDIMED cohort (57.5% women, average baseline age, 67 years). Methods The healthy diet metric was defined as attaining ≥ 9 points on a validated 14-item Mediterranean diet adherence screener. An incident major cardiovascular event was defined as a composite of myocardial infarction, stroke, or cardiovascular death. Cox regression was used to calculate multivariable adjusted hazard ratios (HR) and their 95% confidence intervals (95%CI) for successive categories of health metrics. Results After a median follow-up of 4.8 years in 7447 participants, there were 288 major cardiovascular events. After adjustment for age, sex, center, and intervention group, HRs (95%CI) were 0.73 (0.54-0.99), 0.57 (0.41-0.78), and 0.34 (0.21-0.53) for participants with 2, 3, and ≥ 4 metrics, respectively, compared with participants with only 0 to 1 metrics. Conclusions In an elderly Spanish population at high cardiovascular risk, better adherence to Life's Simple 7 metrics was progressively associated with a substantially lower rate of major cardiovascular events., [ES] Introducción y objetivos La estrategia Life's Simple 7 de la American Heart Association propuso 7 métricas de salud cardiovascular ideal: índice de masa corporal (IMC) < 25, no fumar, dieta saludable, actividad física moderada ≥ 150 min a la semana, colesterol total < 200 mg/dl, presión arterial sistólica < 120 mmHg y diastólica < 80 mmHg y glucemia basal < 100 mg/dl. Resulta de gran interés valorar el efecto combinado de estas 7 metas. Se analizó prospectivamente el impacto de las métricas basales Life's Simple 7 en la incidencia de eventos cardiovasculares mayores en la cohorte PREDIMED (el 57,5% mujeres; media de edad inicial, 67 años). Métodos La métrica de dieta saludable se definió como alcanzar al menos 9 puntos en una escala validada de 14 puntos de adhesión a dieta mediterránea. Se definió evento cardiovascular mayor incidente como infarto de miocardio, ictus o muerte de causa cardiovascular. Se usó regresión de Cox para estimar hazard ratios (HR) ajustadas multivariables con intervalos de confianza del 95% (IC95%) para categorías sucesivas de métricas de salud cardiovascular. Resultados Tras seguir a 7.447 participantes durante una mediana de 4,8 años, se registraron 288 eventos. Respecto a los participantes con solo 0-1 métricas, tras ajustar por edad, sexo, centro y grupo de intervención, se observaron HR (IC95%) 0,73 (0,54-0,99), 0,57 (0,41-0,78) y 0,34 (0,21-0,53), para 2, 3 y 4 o más métricas respectivamente. Conclusiones En una población española con alto riesgo cardiovascular, la presencia de un mayor número de métricas se asoció progresivamente con una reducción sustancial en la tasa de eventos cardiovasculares mayores., This study was funded by the Instituto de Salud Carlos III, Spanish Ministry of Health through the support provided to research networks especially developed for the study (RTIC G03/140, to R. Estruch and RTIC RD 06/0045 to M.Á. Martínez González), the Biomedical Research Networking Center for Physiopathology of Obesity and Nutrition, the Spanish National Center for Cardiovascular Research (CNIC 06/2007), Spanish Health Research Fund-European Fund for Regional Development (PI04-2239, PI05/2584, CP06/00100, PI06/00100, PI07/0240,PI07/1138, PI07/0473, PI10/01407, PI10/02658, PI11/02505), Ministry of Science and Innovation (AGL-2009-13906-C02 and AGL-2010-22319-C03), Mapfre Foundation 2010, Regional Health Ministry of Andalusia (PI0105/2007), Public Health Division of the Department of Health of the Generalitat of Catalonia and Generalitat of Valencia (ACOMP06109, GVACOMP201-181,GVACOMP2011-151, CS2010-AP-111, and CS2011-AP-042), and the Regional Government of Navarre (P27/2011).

Purpose Cardiovascular disease remains the global leading cause of death. We evaluated at baseline the association between the adherence to eight a priori high-quality dietary scores and the prevalence of individual and clustered cardiovascular risk factors (CVRF) in the PREDIMED-Plus cohort. Methods All PREDIMED-Plus participants (6874 men and women aged 55-75 years, with overweight/obesity and metabolic syndrome) were assessed. The prevalence of 4 CVRF (hypertension, obesity, diabetes, and dyslipidaemia), using standard diagnoses criteria, were considered as outcomes. The adherence to eight a priori-defined dietary indexes was calculated. Multivariable models were fitted to estimate differences in mean values of factors and prevalence ratios for individual and clustered CVRF. Results Highest conformity to any dietary pattern did not show inverse associations with hypertension. The modified Mediterranean Diet Score (PR = 0.95; 95% CI 0.90-0.99), Mediterranean Diet Adherence Score (MEDAS) (PR = 0.94; 95% CI 0.89-0.98), the pro-vegetarian dietary pattern (PR = 0.95; 95% CI 0.90-0.99) and the Alternate Healthy Eating Index 2010 (PR = 0.92; 95% CI 0.87-0.96) were inversely associated with prevalence of obesity. We identified significant inverse trend among participants who better adhered to the MEDAS and the Prime Diet Quality Score (PDQS) in the mean number of CVRF across categories of adherence. Better adherence to several high-quality dietary indexes was associated with better blood lipid profiles and anthropometric measures. Conclusions Highest adherence to dietary quality indexes, especially Mediterranean-style and PDQS scores, showed marginal associations with lower prevalence of individual and clustered CVRF among elderly adults with metabolic syndrome at high risk of cardiovascular disease

Purpose: We aimed to evaluate associations between compliance with recommendations for total water intake (TWI) and total water intake from fluids (TWIF), and some socio-demographic and lifestyle factors of a senior Mediterranean population at high cardiovascular risk. Methods: Cross-sectional analysis with data of 1902 participants from the PREDIMED-Plus study. A validated 32-item Spanish fluid-intake questionnaire was used to assess beverage consumption and water intake. Multivariable logistic regression models were used to assess the odds ratio (OR) and the 95% confidence interval (CI) for complying with European Food Safety Agency recommendations for TWI and TWIF according to various socio-demographic and lifestyle factors, and for the joint associations of Mediterranean diet (MedDiet) adherence and moderate-vigorous physical activity (MVPA). Results: The mean total volume of fluid intake in the population studied was 1934 ± 617 mL/day. Water was the most frequently consumed beverage. Significant differences between sex were only observed in alcoholic and hot beverage consumption. Compliance with TWIF was associated with being women (OR 3.02; 2.40, 3.80), high adherence to MedDiet (OR 1.07; 1.02, 1.12), and participants who were more engaged in physical activity (PA) (OR 1.07; 1.02, 1.13). Age was inversely associated (OR 0.96; 0.94, 0.98). Similar results for TWI recommendations compliance were observed in relation to being women (OR 5.34; 3.85, 7.42), adherence to MedDiet (OR 1.16; 1.02, 1.31) and PA (OR 1.07; 1.00, 1.15). The joint association of PA and MedDiet, showed that participants with higher adherence to MedDiet and meeting WHO recommendations for MVPA complied better with the TWI recommendations (OR 1.66; 1.19, 2.32). Conclusions: High compliance with recommendations for TWI was associated with being a woman, and a healthy lifestyle characterized by high adherence to the MedDiet and PA.

[Background]: Overall quality of dietary carbohydrate intake rather than total carbohydrate intake may determine the risk of cardiovascular disease (CVD)., [Objective]: We examined 6- and 12-mo changes in carbohydrate quality index (CQI) and concurrent changes in several CVD risk factors in a multicenter, randomized, primary-prevention trial (PREDIMED-Plus) based on an intensive weight-loss lifestyle intervention program., [Methods]: Prospective analysis of 5373 overweight/obese Spanish adults (aged 55–75 y) with metabolic syndrome (MetS). Dietary intake information obtained from a validated 143-item semiquantitative food-frequency questionnaire was used to calculate 6- and 12-mo changes in CQI (categorized in quintiles), based on 4 criteria (total dietary fiber intake, glycemic index, whole grain/total grain ratio, and solid carbohydrate/total carbohydrate ratio). The outcomes were changes in intermediate markers of CVD., [Results]: During the 12-mo follow-up, the majority of participants improved their CQI by increasing their consumption of fruits, vegetables, legumes, fish, and nuts and decreasing their consumption of refined cereals, added sugars, and sugar-sweetened beverages. After 6 mo, body weight, waist circumference (WC), systolic and diastolic blood pressure (BP), fasting blood glucose, glycated hemoglobin (HbA1c), triglyceride levels, triglycerides and glucose (TyG) index, and TyG-WC decreased across successive quintiles of improvement in the CQI. After 12 mo, improvements were additionally observed for HDL cholesterol and for the ratio of total to HDL cholesterol. Favorable improvements (expressed in common units of SD and 95% CI) for quintile 5 compared with quintile 1 of CQI change were observed for most risk factors, including TyG-WC (SD −0.20; 95% CI −0.26, −0.15), HbA1c (SD −0.16; 95% CI −0.23, −0.10), weight (SD −0.12; 95% CI −0.14, −0.09), systolic BP (SD −0.11; 95% CI −0.19, −0.02) and diastolic BP (SD −0.11; 95% CI −0.19, −0.04)., [Conclusions]: Improvements in CQI were strongly associated with concurrent favorable CVD risk factor changes maintained over time in overweight/obese adults with MetS. This trial was registered as ISRCTN 89898870., The PREDIMED-Plus trial was supported by the European Research Council (advanced research grant 2013–2018, 340918 to MAM-G as PI) and by the official Spanish Institutions for funding scientific biomedical research, CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn) and Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigación en Salud (FIS), which is cofunded by the European Regional Development Fund (4 coordinated FIS projects), the Especial Action Project entitled Implementación y evaluación de una intervención intensiva sobre la actividad física Cohorte PREDIMED-Plus grant, the Recercaixa grant (2013ACUP00194), grants from the Consejería de Salud de la Junta de Andalucía, a grant from the Generalitat Valenciana, a SEMERGEN grant, and funds from the European Regional Development Fund (CB06/03)

PREDIMED-PLUS investigators: et al., [Background]: High nut consumption has been previously associated with decreased prevalence of metabolic syndrome (MetS) regardless of race and dietary patterns., [Objectives]: The aim of this study was to assess whether changes in nut consumption over a 1-y follow-up are associated with changes in features of MetS in a middle-aged and older Spanish population at high cardiovascular disease risk., [Methods]: This prospective 1-y follow-up cohort study, conducted in the framework of the PREvención con DIeta MEDiterránea (PREDIMED)-Plus randomized trial, included 5800 men and women (55–75 y old) with overweight/obesity [BMI (in kg/m2) ≥27 and, [Results]: As nut consumption increased, between each tertile there was a significant decrease in WC, TG, systolic blood pressure, weight, and BMI (P < 0.05), and a significant increase in HDL cholesterol (only in women, P = 0.044). The interaction effect between time and group was significant for total energy intake (P < 0.001), adherence to the Mediterranean diet (MedDiet) (P < 0.001), and nut consumption (P < 0.001). Across tertiles of increasing nut consumption there was a significant increase in extra virgin olive oil intake and adherence to the MedDiet; change in energy intake, on the other hand, was inversely related to consumption of nuts., [Conclusions]: Features of MetS and excess weight were inversely associated with nut consumption after a 1-y follow-up in the PREDIMED-Plus study cohort. This trial was registered at isrctn.com as ISRCTN89898870., The PREDIMED-Plus trial was supported by the official funding agency for biomedical research of the Spanish government, Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigación para la Salud (FIS), which is cofunded by the European Regional Development Fund (5 coordinated FIS projects led by JS-S and J Vidal, including projects PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, and PI19/01332); the Special Action Project entitled Implementación y evaluación de una intervención intensive sobre la actividad física Cohorte PREDIMED-Plus grant (to JS-S); European Research Council Advanced Research Grant 2013–2018, 340918 (to MÁM-G); Recercaixa Grant 2013ACUP00194 (to JS-S); Consejería de Salud de la Junta de Andalucía grants PI0458/2013, PS0358/2016, and PI0137/2018; Generalitat Valenciana grant PROMETEO/2017/017; a SEMERGEN grant; EU-COST Action CA16112; Balearic Islands Government grant of support to research groups 35/2011; Balearic Islands Health Research Institute (IdISBa) grants; European Regional Development Fund funds CIBEROBN CB06/03 and CB12/03; and European Commission fund EAT2BENICE_H2020_SFS2016. PH-A is supported by Juan de la Cierva-Formación postdoctoral fellowship FJCI-2017-32205. AC is supported by IdISBa “TECH” fellowship TECH18/03, funded by the 2018 Sustainable Tourism Tax annual plan. LG-A is supported by a FPU PhD program from the Spanish Ministry of Education.

Introduction and objectives: The SAFEHEART study was designed to analyze the situation of familial heterozygous hypercholesterolemia (FHH) and improve knowledge of this disease in Spain. Our objective was to determine the incidence rate of cardiovascular events, the estimated risk of developing an event and its modification, the use of lipid-lowering treatment, and the achievement of low-density lipoprotein cholesterol targets in patients with FHH. Methods: SAFEHEART is a prospective, open, multicenter, nationwide cohort study, with long-term protocol-based follow-up in a population of individuals with molecularly-characterized FHH. We analyzed patients older than 18 years with complete follow-up. Results: We included 2648 patients with FHH. The median follow-up was 6.6 (4.8-9.7) years. The overall incidence rate of cardiovascular events was 1.3 events/100 patient-years. After the follow-up, the 10-year estimated risk of developing a cardiovascular event was reduced from 1.6% to 1.3% (P