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Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Complete blood count inflammatory markers (CBC-IMs) have been associated with cardiovascular diseases and mortality. We aimed to evaluate the relationship between preoperative CBC-IMs and 5-year survival after carotid endarterectomy (CEA). Retrospective analysis of 411 consecutive patients who underwent CEA between 2004 and 2018 was done. CBC-IM included the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte (LMR) ratio, and systemic immune-inflammation index (SII). Survival rate at 5 years was 79.8%. Age (hazard ratio (HR) = 1.05, P = .003), hemoglobin (HR = 0.78, P < .001), heart failure (HR = 2.91, P = .005), American Society of Anesthesiologists (ASA)-IV score (HR = 2.41, P = .043), and active neoplastic disease (HR = 2.61, P = .028) were independently related to survival. The discrimination of this model (C-statistic) was 0.698. Spline analysis showed a linear relationship between survival and NLR ( P < .001), PLR ( P < .001), and SII ( P < .001). After adjusting for the baseline predictive score, there was a significant relationship between survival and NLR (HR = 1.191, P = .001), PLR (HR = 1.004, P = .017), and SII (HR = 1.001, P < .001). The addition of NLR, PLR, and SII to the survival model improved the continuous net reclassification index (c-NRI) by 0.29 ( P = .028), 0.347 ( P = .008), and 0.481 ( P < .001), respectively, but not the C-statistic. CBC-IMs show a linear and independent relationship with 5-year survival after CEA and may moderately contribute to patient selection for this preventive intervention.

Background Ischemic stroke (IS) risk heritability is partly explained by genetics. Other heritable factors, such as epigenetics, could explain an unknown proportion of the IS risk. The objective of this study is to evaluate DNA methylation association with IS using epigenome-wide association studies (EWAS). Methods We performed a two-stage EWAS comprising 1,156 subjects. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) were assessed using the Infinium 450K and EPIC BeadChip in the discovery cohort (252 IS and 43 controls). Significant DMPs were replicated in an independent cohort (618 IS and 243 controls). Stroke subtype associations were also evaluated. Differentially methylated cell-type (DMCT) was analyzed in the replicated CpG sites using EpiDISH. We additionally performed pathway enrichment analysis and causality analysis with Mendelian randomization for the replicated CpG sites. Results A total of 957 CpG sites were epigenome-wide-significant (p ≤ 10 ) in the discovery cohort, being CpG sites in the top signals (logFC = 0.058, p = 2.35 × 10 ; logFC = 0.035, p = 3.22 × 10 , respectively). ZFHX3 and MAP3K1 were among the most significant DMRs. In addition, 697 CpG sites were replicated considering Bonferroni-corrected p -values (p < 5.22 × 10 ). All the replicated DMPs were associated with risk of cardioembolic, atherothrombotic, and undetermined stroke. The DMCT analysis demonstrated that the significant associations were driven by natural killer cells. The pathway enrichment analysis showed overrepresentation of genes belonging to certain pathways including oxidative stress. ZFHX3 and MAP3K1 methylation was causally associated with specific stroke-subtype risk. Conclusion Specific DNA methylation pattern is causally associated with IS risk. These results could be useful for specifically predicting stroke occurrence and could potentially be evaluated as therapeutic targets., The EPIGENESIS project (Carlos III Institute—PI17/02089, Marató TV3 and Fundació MútuaTerrassa), the MAESTRO project—PI18/01338 (Carlos III Institute), the iBioStroke project (Eranet-Neuron, European research grants), the EPINEXO project—PI20/00678 (Carlos III Institute), the SEDMAN Study (Boehringer Ingelheim), the APHAS project (Pfizer/Bristol-Myers Squibb), and the European Regional Development Fund (ERDF)/Fondo Europeo de Desarrollo Regional (FEDER) and 2017SGR-1427 (AGAUR). I.F.-C is the recipient of a research contract from the Miguel Servet Program (CP12/03298) from the Carlos III Institute. J.C.-M. is supported by an AGAUR contract (Agència de Gestió d'Ajuts Universitaris i de Recerca; FI_DGR 2019, grant number 2019_FI_B 00853) co-financed by Fons Social Europeu (FSE). M.L. is supported by a PFIS contract (Contratos Predoctorales de Formación en Investigación en Salud): FI19/00309. C.G.-F is supported by a Sara Borrell contract (CD20/00043) from the Carlos III Institute and Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). E.M. is supported by a Río Hortega contract (CM18/00198) from the Carlos III Institute.

Background An association between interatrial block (IAB) (P wave duration ≥120 ms) and dementia has been suggested. Our objective was to assess the association of IAB with cognitive impairment (CI). Methods The prospective BAYES registry included 552 patients ≥70 years with structural heart disease without documented atrial fibrillation. Cognitive ability was assessed at baseline and every 6 months with the Pfeiffer test. The median follow-up was 22 months. Results Thirty patients (5.4%) had baseline CI, 20 patients with mild CI and 10 with moderate CI. Compared to patients without CI, patients with CI had higher mean age (80.4 ± 6.5 vs. 76.8 ± 5.4 years) and higher prevalence of advanced IAB (with biphasic P-wave ± in inferior leads) (14 [46.7%] vs. 122 [23.4%], p

The association between atrial fibrillation, stroke, and interatrial block (IAB) (P-wave duration ≥120 ms) is well recognized, particularly in the case of advanced IAB. We aimed to assess the association of IAB with mild cognitive impairment. Advanced Characterization of Cognitive Impairment in Elderly with Interatrial Block was a case-control multicenter study, conducted in subjects aged ≥70 years in sinus rhythm without significant structural heart disease. Diagnosis of mild cognitive impairment was performed by an expert geriatrician, internist, or neurologist in the presence of changes in cognitive function (Mini Mental State Examination score 20 to 25) without established dementia. A total of 265 subjects were included. Mean age was 79.6 ± 6.3 years and 174 (65.7%) were women; there were 143 cases with mild cognitive impairment and 122 controls with normal cognitive function. Compared with controls, cases had longer P-wave duration (116.2 ± 13.8 ms vs 112.5 ± 13.3 ms, p = 0.028), higher prevalence of IAB (73 [51.0%] vs 38 [31.1%], p = 0.001), higher prevalence of advanced IAB (28 [19.6%] vs 10 [8.2%], p = 0.002), and higher MVP ECG risk score (2.7 ± 1.4 vs 2.2 ± 1.3, p = 0.004). IAB was independently associated with mild cognitive impairment, both for partial (odds ratio 2.0, 95% CI: 1.1 to 3.9) and advanced IAB (odds ratio 2.8, 95% CI: 1.1 to 6.7). In conclusion, in subjects aged ≥70 years without significant structural heart disease, IAB is independently associated with mild cognitive impairment. This association is stronger in the case of advanced IAB. “Proyecto de la Sociedad Española de Cardiología para investigación clínica en cardiología 2019”, Spanish Society of Cardiology 2.778 JCR (2020) Q3, 81/142 Cardiac & Cardiovascular Systems 1.394 SJR (2020) Q1, 64/349 Cardiology and Cardiovascular Medicine No data IDR 2020 UEM

We present the Spanish adaptation of the 2021 European Guidelines on Cardiovascular Disease (CVD) prevention in clinical practice. The current guidelines besides the individual approach greatly emphasize on the importance of population level approaches to the prevention of cardiovascular diseases. Systematic global CVD risk assessment is recommended in individuals with any major vascular risk factor. Regarding LDL-Cholesterol, blood pressure, and glycemic control in patients with diabetes mellitus, goals and targets remain as recommended in previous guidelines. However, it is proposed a new, stepwise approach (Step 1 and 2) to treatment intensification as a tool to help physicians and patients pursue these targets in a way that fits patient profile. After Step 1, considering proceeding to the intensified goals of Step 2 is mandatory, and this intensification will be based on 10-year CVD risk, lifetime CVD risk and treatment benefit, comorbidities and patient preferences. The updated SCORE algorithm (SCORE2, SCORE-OP) is recommended in these guidelines, which estimates an individual's 10-year risk of fatal and non-fatal CVD events (myocardial infarction, stroke) in healthy men and women aged 40-89 years. Another new and important recommendation is the use of different categories of risk according different age groups (50, 50-69,70 years). Different flow charts of CVD risk and risk factor treatment in apparently healthy persons, in patients with established atherosclerotic CVD, and in diabetic patients are recommended. Patients with chronic kidney disease are considered high risk or very high-risk patients according to the levels of glomerular filtration rate and albumin-to-creatinine ratio. New lifestyle recommendations adapted to the ones published by the Spanish Ministry of Health as well as recommendations focused on the management of lipids, blood pressure, diabetes and chronic renal failure are included.Presentamos la adaptación española de las Guías Europeas de Prevención Cardiovascular 2021. En esta actualización además del abordaje individual, se pone mucho más énfasis en las políticas sanitarias como estrategia de prevención poblacional. Se recomienda el cálculo del riesgo vascular de manera sistemática a todas las personas adultas con algún factor de riesgo vascular. Los objetivos terapéuticos para el colesterol LDL, la presión arterial y la glucemia no han cambiado respecto a las anteriores guías, pero se recomienda alcanzar estos objetivos de forma escalonada (etapas 1 y 2). Se recomienda llegar siempre hasta la etapa 2, y la intensificación del tratamiento dependerá del riesgo a los 10 años y de por vida, del beneficio del tratamiento, de las comorbilidades, de la fragilidad y de las preferencias de los pacientes. Las guías presentan por primera vez un nuevo modelo para calcular el riesgo (SCORE2 y SCORE2 OP) de morbimortalidad vascular en los próximos 10 años (infarto de miocardio, ictus y mortalidad vascular) en hombres y mujeres entre 40 y 89 años. Otra de las novedades sustanciales es el establecimiento de diferentes umbrales de riesgo dependiendo de la edad (50, 50-69,70 años). Se presentan diferentes algoritmos de cálculo del riesgo vascular y tratamiento de los factores de riesgo vascular para personas aparentemente sanas, pacientes con diabetes y pacientes con enfermedad vascular aterosclerótica. Los pacientes con enfermedad renal crónica se considerarán de riesgo alto o muy alto según la tasa del filtrado glomerular y el cociente albúmina/creatinina. Se incluyen innovaciones en las recomendaciones sobre los estilos de vida, adaptadas a las recomendaciones del Ministerio de Sanidad, así como aspectos novedosos relacionados con el control de los lípidos, la presión arterial, la diabetes y la insuficiencia renal crónica.

BACKGROUND: Epigenome-wide association studies identified the cg00574958 DNA methylation site at the carnitine palmitoyltransferase-1A (CPT1A) gene to be associated with reduced risk of metabolic diseases (hypertriglyceridemia, obesity, type 2 diabetes, hypertension, metabolic syndrome), but the mechanism underlying these associations is unknown. OBJECTIVES: We aimed to elucidate whether carbohydrate and fat intakes modulate cg00574958 methylation and the risk of metabolic diseases. METHODS: We examined associations between carbohydrate (CHO) and fat (FAT) intake, as percentages of total diet energy, and the CHO/FAT ratio with CPT1A-cg00574958, and the risk of metabolic diseases in 3 populations (Genetics of Lipid Lowering Drugs and Diet Network, n = 978; Framingham Heart Study, n = 2331; and REgistre GIroní del COR study, n = 645) while adjusting for confounding factors. To understand possible causal effects of dietary intake on the risk of metabolic diseases, we performed meta-analysis, CPT1A transcription analysis, and mediation analysis with CHO and FAT intakes as exposures and cg00574958 methylation as the mediator. RESULTS: We confirmed strong associations of cg00574958 methylation with metabolic phenotypes (BMI, triglyceride, glucose) and diseases in all 3 populations. Our results showed that CHO intake and CHO/FAT ratio were positively associated with cg00574958 methylation, whereas FAT intake was negatively correlated with cg00574958 methylation. Meta-analysis further confirmed this strong correlation, with β = 58.4 ± 7.27, P = 8.98 x 10(-16) for CHO intake; β = −36.4 ± 5.95, P = 9.96 x 10(-10) for FAT intake; and β = 3.30 ± 0.49, P = 1.48 x 10(-11) for the CHO/FAT ratio. Furthermore, CPT1A mRNA expression was negatively associated with CHO intake, and positively associated with FAT intake, and metabolic phenotypes. Mediation analysis supports the hypothesis that CHO intake induces CPT1A methylation, hence reducing the risk of metabolic diseases, whereas FAT intake inhibits CPT1A methylation, thereby increasing the risk of metabolic diseases. CONCLUSIONS: Our results suggest that the proportion of total energy supplied by CHO and FAT can have a causal effect on the risk of metabolic diseases via the epigenetic status of CPT1A. Study registration at https://www.clinicaltrials.gov/: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)—NCT01023750; and the Framingham Heart Study (FHS)—NCT00005121.

INTRODUCTION: DNA methylation may be one of the biological mechanisms underlying the health benefits of physical activity (PA). Our objective was to determine the association between PA and genome-wide DNA methylation at CpG level. METHODS: We designed a two-stage epigenome wide association study. In the discovery stage, we used 619 individuals from the REGICOR cohort. Next, we validated the CpGs suggestively associated with PA (p-value

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.

Assessment of individual cardiovascular risk, distinguishing primary and secondary prevention, would improve the clinical management of the population with familial hypercholesterolemia. We aimed to develop and validate two risk functions to predict incident and recurrent atherosclerotic cardiovascular disease (ASCVD) in a primary care-based population with familial hypercholesterolemia phenotype (FHP), and to compare their predictive capacity with that of the SpAnish Familial hypErcHolEsterolemiA cohoRT (SAFEHEART) risk equation (SAFEHEART-RE).Data from the Catalan primary care system database (SIDIAP) of patients ≥18 years old with FHP in 2006-2013 were used to develop and validate two risk functions to predict incident and recurrent ASCVD. A validation dataset was also used to compare the model predictive capacity to that of SAFEHEART-RE.The new model (SIDIAP-FHP) included age, diabetes, smoking, sex (male), hypertension, and baseline low-density lipoprotein cholesterol in the primary prevention cohort and age, diabetes, smoking, and disease characteristics (progressive, recent, polyvascular, or included myocardial infarction) in the secondary prevention cohort. The models demonstrated a fair fit: C-Statistic: 0.71 (95%CI:0.68-0.75) in primary prevention and 0.65 (95%CI:0.60-0.70) in secondary prevention (higher than that of SAFEHEART-RE: 0.64 [95%CI:0.60-0.68] and 0.55 [95%CI:0.51-0.59], respectively; both p 0.01). The Brier scores obtained with the SIDIAP-FHP score were significantly lower than that obtained with SAFEHEART-RE in both the primary and secondary prevention cohorts.The SIDIAP-FHP score provides accurate ASCVD risk estimates for primary and secondary prevention in the FHP population, with better predictive capacity than that of SAFEHEART-RE in this general population, especially in persons with previous ASCVD.

[ES] Presentamos la adaptación española de las Guías Europeas de Prevención Cardiovascular 2021. En esta actualización además del abordaje individual, se pone mucho más énfasis en las políticas sanitarias como estrategia de prevención poblacional. Se recomienda el cálculo del riesgo vascular de manera sistemática a todas las personas adultas con algún factor de riesgo vascular. Los objetivos terapéuticos para el colesterol LDL, la presión arterial y la glucemia no han cambiado respecto a las anteriores guías, pero se recomienda alcanzar estos objetivos de forma escalonada (etapas 1 y 2). Se recomienda llegar siempre hasta la etapa 2, y la intensificación del tratamiento dependerá del riesgo a los 10 años y de por vida, del beneficio del tratamiento, de las comorbilidades, de la fragilidad y de las preferencias de los pacientes. Las guías presentan por primera vez un nuevo modelo para calcular el riesgo (SCORE2 y SCORE2 OP) de morbimortalidad vascular en los próximos 10 años (infarto demiocardio, ictus y mortalidad vascular) en hombres y mujeres entre 40 y 89 años. Otra de las novedades sustanciales es el estable cimiento de diferentes umbrales de riesgo dependiendo de la edad (70 años). Se presentan diferentes algoritmos de cálculo del riesgo vascu lar y tratamiento de los factores de riesgo vascular para personas aparentemente sanas, pacientes con diabetes y pacientes con enfermedad vascular aterosclerótica. Los pacientes con enfermedad renal crónica se considerarán de riesgo alto o muy alto según la tasa del filtrado glomerular y el cociente albúmina/creatinina. Se incluyen innovaciones en las recomendaciones sobre los estilos de vida, adaptadas a las recomendaciones del Ministerio de Sanidad, así como aspectos novedosos relacionados con el control de los lípidos, la presión arterial, la diabetes y la insuficiencia renal crónica. [EN] We present the Spanish adaptation of the 2021 European Guidelines on Cardiovascular Disease (CVD) prevention in clinical practice. The current guidelines besides the individual approach greatly emphasize on the importance of population level approaches to the prevention of cardiovascular diseases. Systematic global CVD risk assessment is recommended in individuals with any major vascular risk factor. Regarding LDL-Cholesterol, blood pressure, and glycemic control in patients with diabetes mellitus, goals and targets remain as recommended in previous guidelines. However, it is proposed a new, stepwise approach (Step 1 and 2) to treatment intensification as a tool to help physicians and patients pursue these targets in a way that fits patient profile. After Step 1, considering proceeding to the intensified goals of Step 2 is mandatory, and this intensification will be based on 10-year CVD risk, lifetime CVD risk and treatment benefit, comorbidities and patient preferences. The updated SCORE algorithm (SCORE2, SCORE-OP) is recommended in these guidelines, which estimates an individual's 10-year risk of fatal and non-fatal CVD events (myocardial infarction, stroke) in healthy men and women aged 40-89 years. Another new and important recommendation is the use of different categories of risk according different age groups (70 years). Different flow charts of CVD risk and risk factor treatment in apparently healthy persons, in patients with established atherosclerotic CVD, and in diabetic patients are recommended. Patients with chronic kidney disease are considered high risk or very high-risk patients according to the levels of glomerular filtration rate and albumin-to-creatinine ratio. New lifestyle recommendations adapted to the ones published by the Spanish Ministry of Health as well as recommendations focused on the management of lipids, blood pressure, diabetes and chronic renal failure are included. Sí

Cardiovascular diseases are the leading causes of morbidity and mortality. Overweight, obesity, and accelerated growth during early childhood have been associated with adverse cardiovascular outcomes in later life. Few studies have assessed whether trajectories of accelerated growth in early childhood are associated with preclinical cardiovascular measurements. We aimed to evaluate the associations between childhood body mass index (BMI) growth trajectories and measures of macro- and microvascular function in early adolescence. Measurements of macrovascular function (systolic and diastolic blood pressure (SBP and DBP), pulse wave velocity (PWV), and microvascular function (central retinal arteriolar/veinular equivalent) were assessed at 11 years old in a Spanish birth cohort study (n = 489). BMI trajectories from birth to 9 years were identified using latent class growth analysis. Multiple linear regression assessed the associations between the BMI trajectories and macro- and microvascular function. Compared to children with average birth size and slower BMI gain (reference), children with a lower birth size and accelerated BMI gain had increased SBP [β = 6.57; (95% CI 4.00, 9.15)], DBP [β = 3.65; (95% CI 1.45, 5.86)], and PWV [β = 0.14; (95% CI 0.01, 0.27)]. Children with higher birth size and accelerated BMI gain had increased SBP [β = 4.75; (95% CI 1.79, 7.71) compared to the reference. No significant associations between BMI trajectories and the microvascular measurements were observed. In conclusion, we found that childhood BMI trajectories characterized by accelerated growth are associated with preclinical macrovascular measurements in young adolescents.

South Asian (SA) individuals represent a large, growing population in a number of European countries. These individuals, particularly first-generation SA immigrants, are at higher risk of developing type 2 diabetes, atherogenic dyslipidaemia, and coronary heart disease than most other racial/ethnic groups living in Europe. SAs also have an increased risk of stroke compared to European-born individuals. Despite a large body of conclusive evidence, SA-specific cardiovascular health promotion and preventive interventions are currently scarce in most European countries, as well as at the European Union level. In this narrative review, we aim to increase awareness among clinicians and healthcare authorities of the public health importance of cardiovascular disease among SAs living in Europe, as well as the need for tailored interventions targeting this group - particularly, in countries where SA immigration is a recent phenomenon. To this purpose, we review key studies on the epidemiology and risk factors of cardiovascular disease in SAs living in the United Kingdom, Italy, Spain, Denmark, Norway, Sweden, and other European countries. Building on these, we discuss potential opportunities for multi-level, targeted, tailored cardiovascular prevention strategies. Because lifestyle interventions often face important cultural barriers in SAs, particularly for first-generation immigrants; we also discuss features that may help maximise the effectiveness of those interventions. Finally, we evaluate knowledge gaps, currently available risk stratification tools such as QRISK-3, and future directions in this important field.

Early smoking onset age (SOA) is a public health concern with scant empirical evidence of its role in health outcomes. The study had two aims: i) to assess whether an early SOA was associated with the risk of fatal and non-fatal CVD and all-cause and CVD mortality and ii) to explore the linear and non-linear association between SOA and the outcomes of interest. Data from 4499 current or former smokers, recruited from 1995 to 2005, aged 25 to 79 years, and with a median 7.02 years of follow-up, were obtained from the REGICOR population-based cohort. In the present analysis, performed in 2018, the independent variable was SOA and the dependent variables were CVD events, CVD mortality, and all-cause mortality. Penalized smoothing spline methods were used to assess the linear and non-linear association. During follow-up, 361 deaths and 210 CVD events were recorded. A significant non-linear component was identified in the association between SOA and CVD outcomes with a cut-off point at 12 years: In the group aged ≤12 years, each year of delay in SOA was inversely associated with CVD risk (HR = 0.71; 95%CI = 0.53 – 0.96) and CVD mortality (HR = 0.58; 95%CI = 0.37 – 0.90). No association was observed in the older SOA group. A linear association was observed between SOA and all-cause mortality, and each year of delay was associated with 4% lower risk of mortality (HR = 0.96; 95%CI = 0.93 – 0.98). The associations were adjusted for lifelong exposure to tobacco and cardiovascular risk factors. These results reinforce the value of preventing tobacco use among teenagers and adolescents.

Adequate LDL cholesterol (LDLc) control after an acute coronary syndrome (ACS) is a crucial secondary prevention strategy to minimize the incidence of recurrent myocardial infarction and cardiovascular death. There are tables that predict the necessary dosage of lipid-lowering treatment from the initial LDLc but have not been tested in ACS. Variables associated with optimal LDLc after an ACS were analyzed and the therapeutic yield of the use of Masana's recommendations in this setting.A total number of 326 ACS-patients were included between January-2015 and May-2016. Baseline LDLc concentration and prescribed hypolipemiant treatment at hospital discharge were registered. We analyzed the variables associated with optimal LDLc levels (70mg/dL) control during follow-up.Among our patient population (72% male, age 66±13 years), the hypolipemiant treatment at hospital discharge fulfilled the Masana's recommendations in 196 (60%) patients. After a follow-up period of 122 [66-184] days the targeted LDLc levels were achieved in 148 (45%) patients, being this percentage greater among those in whom the Masana's recommendations were fulfilled (109/196, 56%), as compared with the remaining (39/130, 30%; P.001). The male gender (P.001), the absence of prior history of dyslipemia (P.001) and the adherence to Masana's recommendations (P=.007) were independent predictors for the achievement of targeted LDLc levels during follow-up.In less than half of ACS-patients adequate mid-term LDLc control is obtained. The dosage of the lipid-lowering therapy according to Masana's recommendations helps to achieve this important therapeutic goal.

Background: \ud Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.\ud \ud Objectives: \ud This study sought to test the association between the rs9349379 genotype and SCAD.\ud \ud Methods: \ud Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.\ud \ud Results: \ud The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.\ud \ud Conclusions: \ud The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

Introduction and objectives PCSK9 inhibitors (PCSK9i) are safe and effective lipid-lowering drugs . Their main limitation is their high cost. The aim of this study was to estimate the number of patients eligible for treatment with PCSK9i according to distinct published criteria. Methods Data were obtained from the Information System for the Development of Research in Primary Care. Included patients were equal to or older than 18 years and had at least 1 low-density lipoprotein cholesterol measurement recorded between 2006 and 2014 (n = 2 500 907). An indication for treatment with PCSK9i was assigned according to the following guidelines: National Health System, Spanish Society of Arteriosclerosis , Spanish Society of Cardiology, National Institute for Health and Care Excellence, and the European Society of Cardiology/European Atherosclerosis Society Task Force. Lipid-lowering treatment was defined as optimized if it reduced low-density lipoprotein levels by ≥ 50% and adherence was > 80%. Results Among the Spanish population aged 18 years or older, the number of possible candidates to receive PCSK9i in an optimal lipid-lowering treatment scenario ranged from 0.1% to 1.7%, depending on the guideline considered. The subgroup of patients with the highest proportion of potential candidates consisted of patients with familial hypercholesterolemia , and the subgroup with the highest absolute number consisted of patients in secondary cardiovascular prevention. Conclusions The number of candidates to receive PCSK9i in conditions of real-world clinical practice is high and varies widely depending on the recommendations of distinct scientific societies.

Background DNA methylation is associated with atherosclerosis and cardiovascular risk factors. However, little evidence regarding its association with cardiovascular diseases in large studies is currently available. We aimed to assess the association between DNA methylation and cardiovascular events, and to determine both the predictive capacity of the identified loci and the causality of those associations. Methods We defined two strategies: epigenome-wide (EWAS) and candidate-gene association studies. In both strategies, we designed one approach with prevalent cases of coronary heart disease (CHD) and another with incident cases of CHD and cardiovascular disease. We used data from three independent cohorts: the REgistre GIroní del COR (REGICOR) study, the Framingham Offspring Study and the Women’s Health Initiative. We also assessed the association between the identified CpGs and cardiovascular risk factors in the three populations. Then, we developed methylation risk scores to evaluate whether their inclusion in the Framingham risk function improved its predictive capacity. Finally, we performed a Mendelian randomization study to determine the causality of the identified associations. Results We found 17 CpGs related to prevalent CHD and/or incident cardiovascular events, two of them observed using both approaches ( p

Background The integration of different layers of omics information is an opportunity to tackle the complexity of cardiovascular diseases (CVD) and to identify new predictive biomarkers and potential therapeutic targets. Our aim was to integrate DNA methylation and gene expression data in an effort to identify biomarkers related to cardiovascular disease risk in a community-based population. We accessed data from the Framingham Offspring Study, a cohort study with data on DNA methylation (Infinium HumanMethylation450 BeadChip; Illumina) and gene expression (Human Exon 1.0 ST Array; Affymetrix). Using the MOFA2 R package, we integrated these data to identify biomarkers related to the risk of presenting a cardiovascular event. Results Four independent latent factors (9, 19, 21—only in women—and 27), driven by DNA methylation, were associated with cardiovascular disease independently of classical risk factors and cell-type counts. In a sensitivity analysis, we also identified factor 21 as associated with CVD in women. Factors 9, 21 and 27 were also associated with coronary heart disease risk. Moreover, in a replication effort in an independent study three of the genes included in factor 27 were also present in a factor identified to be associated with myocardial infarction (CDC42BPB, MAN2A2 and RPTOR). Factor 9 was related to age and cell-type proportions; factor 19 was related to age and B cells count; factor 21 pointed to human immunodeficiency virus infection-related pathways and inflammation; and factor 27 was related to lifestyle factors such as alcohol consumption, smoking and body mass index. Inclusion of factor 21 (only in women) improved the discriminative and reclassification capacity of the Framingham classical risk function and factor 27 improved its discrimination. Conclusions Unsupervised multi-omics data integration methods have the potential to provide insights into the pathogenesis of cardiovascular diseases. We identified four independent factors (one only in women) pointing to inflammation, endothelium homeostasis, visceral fat, cardiac remodeling and lifestyles as key players in the determination of cardiovascular risk. Moreover, two of these factors improved the predictive capacity of a classical risk function.

To explore the role of chronic inflammation inherent to autoimmune diseases in the development of subclinical atherosclerosis and arterial stiffness, this study recruited two population-based samples of individuals with and without autoimmune disease (ratio 1:5) matched by age, sex, and education level and with a longstanding (≥6 years) diagnosis of autoimmune disease. Common carotid intima-media thickness (IMT) and arterial distensibility and compliance were assessed with carotid ultrasound. Multivariable linear and logistic regression models were adjusted for 10-year cardiovascular risk. In total, 546 individuals with and without autoimmune diseases (91 and 455, respectively) were included. The mean age was 66 years (standard deviation 12), and 240 (43.9%) were women. Arterial stiffness did not differ according to the presence of autoimmune diseases. In men, the diagnosis of autoimmune diseases significantly increased common carotid IMT [beta-coefficient (95% confidence interval): 0.058 (0.009; 0.108); p value = 0.022] and the percentage with IMT ≥ 75th percentile [1.012 (0.145; 1.880); p value = 0.022]. Women without autoimmune disease were more likely to have IMT ≥ the 75th percentile [-2.181 (-4.214; -0.149); p value = 0.035], but the analysis of IMT as a continuous variable did not yield significant results. In conclusion, subclinical carotid atherosclerosis, but not arterial stiffness, was more common in men with autoimmune diseases. Women did not show significant differences in any of these carotid features. Sex was an effect modifier in the association between common carotid IMT values and the diagnosis of autoimmune diseases.

Background Coronary artery disease remains a major cause of death despite better outcomes of ST‐segment–elevation myocardial infarction (STEMI). We aimed to analyze data from the Ruti‐STEMI registry of in‐hospital, 28‐day, and 1‐year events in patients with STEMI over the past 3 decades in Catalonia, Spain, to assess trends in STEMI prognosis. Methods and Results Between February 1989 and December 2017, a total of 7589 patients with STEMI were admitted consecutively. Patients were grouped into 5 periods: 1989 to 1994 (period 1), 1995 to 1999 (period 2), 2000 to 2004 (period 3), 2005 to 2009 (period 4), and 2010 to 2017 (period 5). We used Cox regression to compare 28‐day and 1‐year STEMI mortality and in‐hospital complication trends across these periods. Mean patient age was 61.6±12.6 years, and 79.3% were men. The 28‐day all‐cause mortality declined from period 1 to period 5 (10.4% versus 6.0%; P P P =0.001), with a 24% reduction after multivariable adjustment (HR, 0.76; 95% CI, 0.60–0.98; P =0.036). A significant temporal reduction was observed for in‐hospital complications including postinfarct angina (−78%), ventricular tachycardia (−57%), right ventricular dysfunction (−48%), atrioventricular block (−45%), pericarditis (−63%), and free wall rupture (−53%). Primary ventricular fibrillation showed no significant downslope trend. Conclusions In‐hospital STEMI complications and 28‐day and 1‐year mortality rates have dropped markedly in the past 30 years. Reducing ischemia‐driven primary ventricular fibrillation remains a major challenge.

Background:Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency—homozygous loss-of-function (LoF) variants—in theABCG5orABCG8genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency ofABCG5orABCG8—as occurs in heterozygous carriers of LoF variants—on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.Methods:We first recruited 9 sitosterolemia families, identified causative LoF variants inABCG5orABCG8, and evaluated the associations of theseABCG5orABCG8LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants inABCG5orABCG8in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants inABCG5orABCG8with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency ABCG5orABCG8.Results:In sitosterolemia families, 7 pedigrees harbored causative LoF variants inABCG5and 2 pedigrees inABCG8. Homozygous LoF variants in eitherABCG5orABCG8led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers ofABCG5LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants inABCG5and inABCG8was ≈0.1% each.ABCG5heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14–35];P=1.1×10−6) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27–3.35];P=0.004). By contrast,ABCG8heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.Conclusions:Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant inABCG5had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.

Background: To assess whether genetically determined quantitative and qualitative HDL characteristics were independently associated with coronary artery disease (CAD). Methods: We designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I levels, HDL size, particle levels, and lipid content to define our genetic instrumental variables in one sample (Kettunen et al. study, n = 24,925) and analyzed their association with CAD risk in a different study (CARDIoGRAMplusC4D, n = 184,305). We validated these results by defining our genetic variables in another database (METSIM, n = 8372) and studied their relationship with CAD in the CARDIoGRAMplusC4D dataset. To estimate the effect size of the associations of interest adjusted for other lipoprotein traits and minimize potential pleiotropy, we used the Multi-trait-based Conditional & Joint analysis. Results: Genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD. HDL mean diameter (β = 0.27 [95%CI = 0.19; 0.35]), cholesterol levels in very large HDLs (β = 0.29 [95%CI = 0.17; 0.40]), and triglyceride content in very large HDLs (β = 0.14 [95%CI = 0.040; 0.25]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs (β = -0.076 [95%CI = -0.10; -0.052]) was inversely related to this risk. These results were validated in the METSIM-CARDIoGRAMplusC4D data. Conclusions: Some qualitative HDL characteristics (related to size, particle distribution, and cholesterol and triglyceride content) are related to CAD risk while HDL cholesterol levels are not. This work was supported by the Instituto de Salud Carlos III– European Regional Development Fund [grant numbers CD17/00122, IFI14/00007, PI18/00017], the Medical Research Council [grant numbers MR/K501256/1, MR/N013468/1], the Spanish Ministry of Economy and Competitiveness [grant numbers BES-2014-069718, SAF2015-71653- R], the European Union's Horizon 2020 Research and Innovation Program [grant number 796216], and the Government of Catalonia through the Agency for Management of University and Research Grants [2017 SGR 222]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CIBER Enfermedades Cardiovasculares (CIBERCV), Epidemiología y Salud Pública (CIBERESP), and Fisiopatología de la Obesidad y Nutrición (CIBEROBN) are initiatives of the Instituto de Salud Carlos III, Madrid, Spain, and financed by the European Regional Development Fund.

We present the adaptation for Spain of the updated European Cardiovascular Prevention Guidelines. In this update, greater stress is laid on the population approach, and especially on the promotion of physical activity and healthy diet through dietary, leisure and active transport policies in Spain. To estimate vascular risk, note should be made of the importance of recalibrating the tables used, by adapting them to population shifts in the prevalence of risk factors and incidence of vascular diseases, with particular attention to the role of chronic kidney disease. At an individual level, the key element is personalised support for changes in behaviour, adherence to medication in high-risk individuals and patients with vascular disease, the fostering of physical activity, and cessation of smoking habit. Furthermore, recent clinical trials with PCSK9 inhibitors are reviewed, along with the need to simplify pharmacological treatment of arterial hypertension to improve control and adherence to treatment. In the case of patients with type 2 diabetes mellitus and vascular disease or high vascular disease risk, when lifestyle changes and metformin are inadequate, the use of drugs with proven vascular benefit should be prioritised. Lastly, guidelines on peripheral arterial disease and other specific diseases are included, as is a recommendation against prescribing antiaggregants in primary prevention.Presentamos la adaptación para España de la actualización de las Guías Europeas de Prevención Vascular. En esta actualización se hace mayor énfasis en el abordaje poblacional, especialmente en la promoción de la actividad física y de una dieta saludable mediante políticas alimentarias y de ocio y transporte activo en España. Para estimar el riesgo vascular, se destaca la importancia de recalibrar las tablas que se utilicen, adaptándolas a los cambios poblaciones en la prevalencia de los factores de riesgo y en la incidencia de enfermedades vasculares, con particular atención al papel de la enfermedad renal crónica. A nivel individual resulta clave el apoyo personalizado para el cambio de conducta, la adherencia a la medicación en los individuos de alto riesgo y pacientes con enfermedad vascular, la promoción de la actividad física y el abandono del hábito tabáquico. Además, se revisan los ensayos clínicos recientes con inhibidores de PCKS9, la necesidad de simplificar el tratamiento farmacológico de la hipertensión arterial para mejorar su control y la adherencia al tratamiento. En los pacientes con diabetes mellitus 2 y enfermedad vascular o riesgo vascular alto, cuando los cambios de estilo de vida y la metformina resultan insuficientes, deben priorizarse los fármacos con demostrado beneficio vascular. Por último, se incluyen pautas sobre enfermedad arterial periférica y otras enfermedades específicas, y se recomienda no prescribir antiagregantes en prevención primaria.

The aim of this study was to determine whether genetic variants in FADS1/FADS2 and ELOVL2 are associated with overweight–obesity and body mass index (BMI) and to assess the association between these genetic variants and lipid profile and fatty acid levels. A total of 259 overweight–obese patients were compared to 369 healthy controls. FADS1, FADS2, and ELOVL2 genes were associated with BMI and overweight–obesity ( P ≤ .001). In an additive model, the C allele in each of these variants was associated with a lower BMI: −1.18, −0.90, and −1.23 units, respectively. Higher amounts of total cholesterol, low-density lipoprotein cholesterol, total saturated fatty acids (lauric [12:0], myristic [C14:0], palmitic [C16:0], stearic [C18:0], arachidic [20:0], lignoceric [24:0]), monounsaturated fatty acids (myristoleic [C14:1], erucic [C22:1 n-9]), and polyunsaturated fatty acids (α-linolenic [ALA, 18:3 n-3], docosahexaenoic [DHA, C22:6 n-3], eicosapentaenoic acid [EPA, C20:5n-3], arachidonic acid [AA, 20:4n-6], and conjugated linolenic acids [CLA1 and CLA2]) were shown in patients. A significant increase in D6D activities presented by 20:4n-6/18:2n-6 and 18:3n-6/18:2n-6, Δ9 desaturase (D9D) activity, estimated by the ratio 18:1n-9/18:0 and elongase activities (AE), and estimated by the ratio of docosatetraenoic/AA and DPA/EPA in patients. The C minor allele of FADS1 had significantly lower DHA. A significant decrease in stearic acid, EPA, and AE activity (docosatetraenoic/AA) was revealed in patients with the minor allele carriers of FADS2. The C minor allele of ELOVL2 had significantly lower ALA, EPA, DPA, and D6D activity (C20:4 n-6/C18:2n-6). These data suggest that variations in FADS1, FADS2, and ELOVL2 affect the risk of overweight–obesity and the level of circulating fatty acids and could point to a key molecular pathway of metabolic syndrome and its related comorbidities.

DNA methylation is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. The leading genetic variants at stroke risk loci identified to date explain roughly 1–2% of stroke heritability. Most of these single nucleotide polymorphisms are situated within a regulatory sequence marked by DNase I hypersensitivity sites, which would indicate involvement of an epigenetic mechanism. To detect epigenetic variants associated with stroke occurrence and stroke subtypes. A two-stage case–control epigenome-wide association study was designed. The discovery sample with 401 samples included 218 ischaemic stroke (IS) patients, assessed at Hospital del Mar (Barcelona, Spain) and 183 controls from the REGICOR cohort. In two independent samples (N = 226 and N = 166), we replicated 22 CpG sites differentially methylated in IS in 21 loci, including 2 CpGs in locus ZFHX3, which includes known genetic variants associated with stroke. The pathways associated with these loci are inflammation and angiogenesis. The meta-analysis identified 384 differentially methylated CpGs, including loci of known stroke and vascular risk genetic variants, enriched by loci involved in lipid metabolism, adipogenesis, circadian clock, and glycolysis pathways. We identified a set of 22 CpGs in 21 loci associated with IS. Our analysis suggests that DNA methylation changes may contribute to orchestrating gene expression that contributes to IS.

Aims Advanced interatrial block (IAB), is an unrecognized surrogate of atrial dysfunction and a trigger of atrial dysrhythmias, mainly atrial fibrillation (AF). Our aim was to prospectively assess whether advanced IAB in sinus rhythm is associated with AF and stroke in elderly outpatients with structural heart disease, a group not previously studied. Methods and results Prospective observational registry that included outpatients aged ≥70 years with structural heart disease and no previous diagnosis of AF. Patients were divided into three groups: normal P-wave duration ( Conclusions The presence of advanced IAB in sinus rhythm is independently associated with AF and stroke in an elderly population with structural heart disease and no previous diagnosis of AF. P-wave duration was also associated with all-cause mortality.

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10−11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10−43), alkaline phosphatase (-0.025 SD, 1.2*10−37), total cholesterol (-0.030 SD, p = 1.9*10−36) and LDL cholesterol (-0.027 SD, p = 5.1*10−30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis., Author summary Cirrhosis is a leading cause of death worldwide. However, the genetic underpinnings of cirrhosis remain poorly understood. In this study, we analyze twelve thousand individuals with cirrhosis and identify a common missense variant in a gene called MARC1 that protects against cirrhosis. Carriers of this missense variant also have lower blood cholesterol levels, lower liver enzyme levels and reduced liver fat. We identify an additional two low-frequency coding variants in MARC1 that are also associated with lower cholesterol levels, lower liver enzyme levels and protection from cirrhosis. Finally, we identify an individual homozygous for a predicted loss-of-function variant in MARC1 who exhibits very low blood LDL cholesterol levels. These genetic findings suggest that MARC1 deficiency may lower blood cholesterol levels and protect against cirrhosis, pointing to MARC1 as a potential therapeutic target for liver disease.

Background Epigenome-wide association studies for cardiometabolic risk factors have discovered multiple loci associated with incident cardiovascular disease (CVD). However, few studies have sought to directly optimize a predictor of CVD risk. Furthermore, it is challenging to train multivariate models across multiple studies in the presence of study- or batch effects. Methods and Results Here, we analyzed existing DNA methylation data collected using the Illumina HumanMethylation450 microarray to create a predictor of CVD risk across 3 cohorts: Women's Health Initiative, Framingham Heart Study Offspring Cohort, and Lothian Birth Cohorts. We trained Cox proportional hazards-based elastic net regressions for incident CVD separately in each cohort and used a recently introduced cross-study learning approach to integrate these individual scores into an ensemble predictor. The methylation-based risk score was associated with CVD time-to-event in a held-out fraction of the Framingham data set (hazard ratio per SD=1.28, 95% CI, 1.10-1.50) and predicted myocardial infarction status in the independent REGICOR (Girona Heart Registry) data set (odds ratio per SD=2.14, 95% CI, 1.58-2.89). These associations remained after adjustment for traditional cardiovascular risk factors and were similar to those from elastic net models trained on a directly merged data set. Additionally, we investigated interactions between the methylation-based risk score and both genetic and biochemical CVD risk, showing preliminary evidence of an enhanced performance in those with less traditional risk factor elevation. Conclusions This investigation provides proof-of-concept for a genome-wide, CVD-specific epigenomic risk score and suggests that DNA methylation data may enable the discovery of high-risk individuals who would be missed by alternative risk metrics. This work was supported by the US Department of Agriculture, Agriculture Research Service (8050–51000-098-00D). Dr. Westerman was additionally supported by National Institutes of Health predoctoral training grant 5T32HL069772-14. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. This article was prepared in collaboration with investigators of the WHI but has not been reviewed by the WHI and does not necessarily reflect the opinions of the WHI investigators or the National Heart, Lung, and Blood Institute. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with Boston University (Contract No. N01-HC-25195 and HHSN268201500001I). This article was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or National Heart, Lung, and Blood Institute. The LBC 1936 is supported by Age UK (Disconnected Mind program) and the Medical Research Council (MR/M01311/1). Methylation typing in LBC 1936 was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. LBC 1936 work was conducted in the Centre for Cognitive Ageing and Cognitive Epidemiology, which supported Dr. Deary and is supported by the medical Research Council and Biotechnology and Biological Sciences Research Council (MR/K026992/1). Sí

Bayes syndrome is a new clinical entity, characterized by the association of advanced interatrial block (IAB) on surface electrocardiogram with atrial fibrillation (AF) and other atrial arrhythmias. This syndrome is associated with an increased risk of stroke, dementia, and mortality. Advanced IAB is diagnosed by the presence of a P-wave >= 120 ms with biphasic morphology (+/-) in inferior leads. The cause of IAB is complete Bachmann bundle blockade, leading to retrograde depolarization of the left atrium from areas near the atrioventricular junction. The anatomic substrate of advanced IAB is fibrotic atrial cardiomyopathy. Dyssynchrony induced by advanced IAB is a trigger and maintenance mechanism of AF. This alteration of the atrial architecture produces atrial remodeling, blood stasis and hypercoagulability, triggering the thrombogenic cascade. The presence of advanced IAB, even in patients without documented atrial arrhythmias, has also been associated with AF, stroke, dementia, and mortality. However, in these patients, there is no evidence to support the use of anticoagulation. Therefore, in patients with advanced IAB, a proactive search for AF is recommended. (C) 2020 Sociedad Espanola de Cardiologia. Published by Elsevier Espana, S.L.U. All rights reserved.

Introduction and objectives New biomarkers could improve the predictive capacity of classic risk functions. The aims of this study were to determine the association between circulating levels of apolipoprotein A1 (apoA1), apolipoprotein B (apoB), albumin , and 25-OH-vitamin D and coronary events and to analyze whether these biomarkers improve the predictive capacity of the Framingham-REGICOR risk function. Methods A case-cohort study was designed. From an initial cohort of 5404 individuals aged 35 to 74 years with a 5-year follow-up, all the participants who had a coronary event (n = 117) and a random group of the cohort (subcohort; n = 667) were selected. Finally, 105 cases and 651 individuals representative of the cohort with an available biological sample were included. The events of interest were angina , fatal and nonfatal myocardial infarction and coronary deaths. Results Case participants were older, had a higher proportion of men and cardiovascular risk factors, and showed higher levels of apoB and lower levels of apoA1, apoA1/apoB ratio, 25-OH-vitamin D and albumin than the subcohort. In multivariate analyses, plasma albumin concentration was the only biomarker independently associated with coronary events (HR, 0.73; P = . 002). The inclusion of albumin in the risk function properly reclassified a significant proportion of individuals, especially in the intermediate risk group (net reclassification improvement, 32.3; P = .048). Conclusions Plasma albumin levels are inversely associated with coronary risk and improve the predictive capacity of classic risk functions.

Introduction and objectives Our aims were to determine acute myocardial infarction (AMI) incidence and mortality rates, and population and in-hospital case-fatality in the population older than 74 years; variability in clinical characteristics and AMI management of hospitalized patients, and changes in the incidence and mortality rates, case-fatality, and management by age groups from 1996 to 1997 and 2007 to 2008. Methods A population-based AMI registry in Girona (Catalonia, Spain) including individuals with suspected AMI older than 34 years. Results The incidence rate increased with age from 169 and 28 cases/100 000 per year in the group aged 35 to 64 years to 2306 and 1384 cases/100 000 per year in the group aged 85 to 94 years, in men and women, respectively. Population case-fatality also increased with age, from 19% in the group aged 35 to 64 years to 84% in the group aged 85 to 94 years. A lower population case-fatality was observed in the second period, mainly explained by a lower in-hospital case-fatality. The use of invasive procedures and effective drugs decreased with age but increased in the second period in all ages up to 84 years. Conclusions Acute myocardial infarction incidence, mortality, and case-fatality increased exponentially with age. There is still a gap in the use of invasive procedures and effective drugs between younger and older patients.

Advanced interatrial block (A-IAB) has been associated to atrial fibrillation (AF) and ischemic stroke, raising the question as to whether such patients, even when still in sinus rhythm without documented AF, could benefit from oral anticoagulation. AF and A-IAB are both markers of stroke. The anatomical substrate in both is fibrotic atrial cardiomyopathy, resulting in atrial electromechanical dyssynchrony, dysfunction, and left atrial remodelling, that favour blood stasis and hypercoagulation. Under these conditions thrombogenic cascade may be triggered, resulting in systemic embolization. Before proposing oral anticoagulation in the management of selected patients with A-IAB, as is currently recommended in patients with AF and high CHA2DS2-Vasc score, a randomized clinical trial will have to demonstrate efficacy and safety of anticoagulation in this setting. In the meantime, an individualized approach may be considered based on the recognition of those patients at a higher risk of stroke. These may be elderly patients with A-IAB and several risk factors and, thus, with a high CHA2DS2-Vasc score and the presence of environmental arrhythmias. Sin financiación 2.778 JCR (2020) Q3, 81/142 Cardiac & Cardiovascular Systems 1.394 SJR (2020) Q1, 64/349 Cardiology and Cardiovascular Medicine No data IDR 2020 UEM

Objective— The objectives of this study were to decipher whether age-independent cardiovascular risk is associated with DNA methylation at 5′-cytosine-phosphate-guanine-3′ (CpG) level and to determine whether these differential methylation signatures are associated with the incidence of cardiovascular events. Approach and Results— We designed a 2-stage, cross-sectional, epigenome-wide association study. Age-independent cardiovascular risk calculation was based on vascular age and on the residuals of the relationship between age and cardiovascular risk. Blood DNA methylomes from 2 independent populations were profiled using the Infinium HumanMethylation450 BeadChip. The discovery stage of these studies was performed in the REGICOR cohort (REgistre GIroní del COR; n=645). Next, we validated the initial findings in the Framingham Offspring Study (n=2542). Eight CpGs located in 4 genes ( AHRR , CPT1A , PPIF , and SBNO2 ) and 3 intergenic regions showed differential methylation in association with age-independent cardiovascular risk ( P ≤1.17×10 −7 ). These CpGs explained 12.01% to 15.16% of the variability of age-independent cardiovascular risk in REGICOR and 7.51% to 8.53% in Framingham Offspring Study. Four of them were only related to smoking, 3 were related to smoking and body mass index, and 1 to diabetes mellitus, triglycerides levels, and body mass index ( P ≤7.81×10 −4 ). In addition, we developed methylation risk scores based on these CpGs and observed an association between these scores and cardiovascular disease incidence (hazard ratio=1.32; 95% confidence interval: 1.16–1.51). Conclusions— Age-independent cardiovascular risk was related to different DNA methylation profiles, with 8 CpGs showing differential methylation patterns. Most of these CpGs were associated with smoking, and 3 of them were also related to body mass index. Risk scores based on these differential methylation patterns were associated with cardiovascular events and could be useful predictive indices.

The purpose was to analyze statin effectiveness in a general population with differing levels of coronary heart disease (CHD) risk. Patients (35-74 years) without previous cardiovascular disease were included and stratified according to 10-year CHD risk (

Background: Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacological stimulation of the nitric oxide pathway as a therapeutic strategy. Methods: We analyzed the association of common and rare genetic variants in 2 genes that mediate nitric oxide signaling (Nitric Oxide Synthase 3 [ NOS3 ] and Guanylate Cyclase 1, Soluble, Alpha 3 [ GUCY1A3 ]) with a range of human phenotypes. We selected 2 common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3 ) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335 464 participants in the UK Biobank and summary association results from 7 large-scale genome-wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27 815). Results: A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease (odds ratio, 0.37; 95% confidence interval [CI], 0.31-0.45; P =5.5*10 –26 ], peripheral arterial disease (odds ratio 0.42; 95% CI, 0.26-0.68; P =0.0005), and stroke (odds ratio, 0.53; 95% CI, 0.37-0.76; P =0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm Hg higher systolic blood pressure (95% CI, 12-34; P =5.6*10 –5 ) and a 3-fold higher risk of coronary heart disease (odds ratio, 3.03; 95% CI, 1.29-7.12; P =0.01). Conclusions: A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease, and stroke. Pharmacological stimulation of nitric oxide signaling may prove useful in the prevention or treatment of cardiovascular disease.

Obesity is associated with increased risk of several diseases and has become epidemic. Obesity is highly heritable but the genetic variants identified by genome-wide association studies explain only limited variability. Epigenetics could contribute to explain the missing variability. The study aim was to discover differential methylation patterns related to obesity. We designed an epigenome-wide association study with a discovery phase in a subsample of 641 REGICOR study participants, validated by analysis of 2,515 participants in the Framingham Offspring Study. Blood DNA methylation was assessed using Illumina HumanMethylation450 BeadChip. Next, we meta-analyzed the data using the fixed effects method and performed a functional and pathway analysis using the Ingenuity Pathway Analysis software. We were able to validate 94 CpGs associated with body mass index (BMI) and 49 CpGs associated with waist circumference, located in 95 loci. In addition, we newly discovered 70 CpGs associated with BMI and 33 CpGs related to waist circumference. These CpGs explained 25.94% and 29.22% of the variability of BMI and waist circumference, respectively, in the REGICOR sample. We also evaluated 65 of the 95 validated loci in the GIANT genome-wide association data; 10 of them had Tag SNPs associated with BMI. The top-ranked diseases and functions identified in the functional and pathway analysis were neurologic, psychological, endocrine, and metabolic.

Background and aims The main aim of this study is to describe the differences in the cardio-ankle vascular index (CAVI) in individuals with metabolic cardiovascular risk factors or a previous history of vascular diseases (WCVRF) compared to healthy individuals (free of risk factors and previous history of vascular diseases; FCVRF) in a general Mediterranean population. The secondary aim is to describe the proportion of CAVI≥9 depending on the cardiovascular risk category in both CVRF groups by sex. Methods The study is a descriptive analysis of 2613 participants randomly selected in the Girona province (Catalonia, Spain). Results CAVI mean differences between sexes and age categories in both CVRF groups followed the same pattern, the FCVRF group (men 25.2%; women 14.4%) in turn had a lower prevalence of CAVI≥9 than the WCVRF group (men 57.9%; women 51.8%). The percentage of men and women with CAVI≥9 with low risk was 13.9% and 11.3% in the FCVRF group, and 31.8% and 42.0% in the WCVRF group; with moderate risk, it was 55.8% and 10.0% in the FCVRF group and 60.3% and 49.0% in the WCVRF group. Conclusions In both sexes, FCVRF groups had a lower prevalence of CAVI≥9 as well as lower mean CAVI scores, across all 10 year-age categories from 40 to 69 years, than WCVRF groups. Moreover, CAVI≥9 was frequent in individuals with low and moderate coronary risk in the WCVRF group but also in the FCVRF group. These results suggest that CAVI assessment to detect asymptomatic arteriosclerosis could be a useful tool to improve cardiovascular risk stratification.

The clinical significance of a high ankle brachial index (ABI) and its relationship to cardiovascular disease (CVD) and mortality is controversial. The aim of this study was to estimate the association between abnormally high ABI ≥ 1.4 and coronary heart disease (CHD), cerebrovascular disease, and all-cause mortality in a Mediterranean population without CVD.A prospective population based cohort study of 6352 subjects was followed up for a median 6.2 years. Subjects under 35 years, with a history of CVD or an ABI0.9 were excluded. All CHD events (angina, myocardial infarction, coronary revascularisation), cerebrovascular events (stroke, transient ischaemic attack), and all-cause mortality were recorded.A total of 5679 subjects fulfilled the inclusion criteria, of which 5517 (97.1%) had a normal ABI whereas 162 (2.9%) had an ABI ≥ 1.4. The profile of individuals with abnormally high ABI revealed as independent related factors age (OR = 1.0; p = .045), female sex (OR = 0.4; p .01), diabetes (OR = 1.9; p = .02), and lower diastolic blood pressure (OR = 0.9; p .001). During follow-up 309 (5.4%) participants presented with a CV event and 286 (5.0%) died. An ABI ≥ 1.4 was associated with a higher incidence of CV events in the univariate (HR = 1.7) but not in the multivariate survival Cox regression analysis. An ABI ≥ 1.4 was independently associated with all-cause mortality (HR = 2.0; IC 95% 1.32-2.92) and cardiovascular mortality (HR = 3.1; IC 95% 1.52-6.48).In subjects without CVD, those with abnormally high ABI do not have a greater CV event rate than those with a normal ABI. However, there seems to be a trend towards higher mortality risk, supporting the guidelines that consider this subgroup to be a high risk population.

Resumen: Las VI Guías Europeas de Prevención Cardiovascular recomiendan combinar las estrategias poblacional y de alto riesgo, con los cambios de estilo de vida como piedra angular de la prevención, y proponen la función SCORE para cuantificar el riesgo cardiovascular. Esta guía hace más hincapié en las intervenciones específicas de las enfermedades y las condiciones propias de las mujeres, las personas jóvenes y las minorías étnicas. No se recomienda el cribado de aterosclerosis subclínica con técnicas de imagen no invasivas. La guía establece cuatro niveles de riesgo (muy alto, alto, moderado y bajo), con objetivos terapéuticos de control lipídico según el riesgo. La diabetes mellitus confiere un riesgo alto, excepto en sujetos con diabetes tipo 2 con menos de 10 años de evolución, sin otros factores de riesgo ni complicaciones, o con diabetes tipo 1 de corta evolución sin complicaciones. La decisión de iniciar el tratamiento farmacológico de la hipertensión arterial dependerá del nivel de presión arterial y del riesgo cardiovascular, teniendo en cuenta la lesión de órganos diana. Siguen sin recomendarse los fármacos antiplaquetarios en prevención primaria por el riesgo de sangrado. La baja adherencia al tratamiento exige simplificar el régimen terapéutico e identificar y combatir sus causas. La guía destaca que los profesionales de la salud pueden ejercer un papel importante en la promoción de intervenciones poblacionales y propone medidas eficaces, tanto a nivel individual como poblacional, para promover una dieta saludable, la práctica de actividad física, el abandono del tabaquismo y la protección contra el abuso de alcohol. Abstract: The VI European Guidelines for Cardiovascular Prevention recommend combining population and high-risk strategies with lifestyle changes as a cornerstone of prevention, and propose the SCORE function to quantify cardiovascular risk. The guidelines highlight disease specific interventions, and conditions as women, young people and ethnic minorities. Screening for subclinical atherosclerosis with noninvasive imaging techniques is not recommended. The guidelines distinguish four risk levels (very high, high, moderate and low) with therapeutic objectives for lipid control according to risk. Diabetes mellitus confers a high risk, except for subjects with type 2 diabetes with less than

Background and purpose Epilepsy has been associated with cardiovascular comorbidity. Risk prediction equations are the standard tools in primary prevention of cardiovascular disease. Our aim was to compare the prevalence of cardiovascular risk factors (CVRFs), cardiovascular risk and statin use in people with epilepsy (PWE) and the general population. Methods The CVRFs and cardiovascular risk score were compared between 815 PWE from an outpatient register and 5336 participants from a general population cohort. Results People with epilepsy had less hypertension (43.3% vs. 50.4%), less diabetes (15.8% vs. 19.2%), more dyslipidemia (40.2% vs. 34.6%) and lower cardiovascular risk than the general population (P < 0.01). No etiology was associated with a worse CVRF profile or higher cardiovascular risk. Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) had more dyslipidemia than the general population (41.6% vs. 34.6%) but similar cardiovascular risk. Independently of risk or CVRFs, PWE had 60% more probability of receiving statins than the general population. Conclusions People with epilepsy had more dyslipidemia, related to EIAEDs, and lower cardiovascular risk but still took more statins than the general population. Physicians should use clinical judgement to decide on further treatment of CVRFs in PWE who are below the recommended risk threshold for treatment and should consider lipid abnormalities a potential side-effect of EIAEDs. Other therapy options may need to be evaluated before starting lipid-lowering treatment.

Introduction and objectives Regular leisure-time physical activity (LTPA) has been consistently recognized as a protective factor for cardiovascular diseases (CVD) and all-cause mortality. However, the pattern of this relationship is still not clear. The aim of this study was to assess the relationship of LTPA with incident CVD and mortality in a Spanish population. Methods A prospective population-based cohort of 11 158 randomly selected inhabitants from the general population. LTPA was assessed by a validated questionnaire. Mortality and CVD outcomes were registered during the follow-up (median: 7.24 years). The association between LTPA and outcomes of interest (all-cause mortality and cardiovascular disease) was explored using a generalized additive model with penalized smoothing splines and multivariate Cox proportional hazard models. Results We observed a significant nonlinear association between LTPA and all-cause and CVD mortality, and fatal and nonfatal CVD. Moderate-vigorous intensity LTPA, but not light-intensity LTPA, were associated with beneficial effects. The smoothing splines identified a cutoff at 400 MET-min/d. Below this threshold, each increase of 100 MET-min/d in moderate-vigorous LTPA contributed with a 16% risk reduction in all-cause mortality (HR, 0.84; 95%CI, 0.77-0.91), a 27% risk reduction in CVD mortality (HR, 0.73; 95%CI, 0.61-0.87), and a 12% risk reduction in incident CVD (HR, 0.88; 95%CI, 0.79-0.99). No further benefits were observed beyond 400 MET-min/d. Conclusions Our results support a nonlinear inverse relationship between moderate-vigorous LTPA and CVD and mortality. Benefits of PA are already observed with low levels of activity, with a maximum benefit around 3 to 5 times the current recommendations.

Los autores de este trabajo forman parte de PREDIMED study investigators. Son los siguientes: Principales: Xavier Pintó, Marta Fanlo-Maresma, Emili Corbella, Xavier Corbella, M Teresa Mitjavila, Juan J Moreno, Rosa Casas, Ramon Estruch, Dolores Corella, Mònica Bulló, Miguel Ruiz-Canela, Olga Castañer, J Alfredo Martinez, Emilio Ros, PREDIMED Study Investigators. PREDIMED Study investigators: Estruch R, Martínez-González MA, Corella D, Fitó M, Ros E, Salas-Salvadó J, Arós F, Aldamiz-Echevarría M, Alonso-Gómez AM, Berjón J, Forga L, Gállego J, García-Layana A, Larrauri A, Portu-Zapirain J, Timiraos J, Ros E, Covas MI, Martínez-González MA, Salas-Salvadó J, Pérez-Heras A, Serra-Mir M, Pi-Sunyer X, González CA, Hu FB, Sabaté J, de la Cruz E, Galera A, Gimenez-Garcia M, Lafuente H, Rodríguez-Sanchez MA, Trias F, Sarasa I, Figueras R, Liceran M, Pallarols C, Esteve V, Storniolo C, Serra-Mir M, Pérez-Heras A, Sala-Vila A, Valls-Pedret C, Viñas C, Casas R, Medina-Remón A, Romero S, Baena JM, García M, Oller M, Amat J, Duaso I, García Y, Iglesias C, Simón C, Quinzavos L, Parra L, Liroz M, Benavent J, Clos J, Pla I, Amorós M, Bonet MT, Martín MT, Sánchez MS, Altirriba J, Manzano E, Altés A, Cofán M, Doménech M, Freitas-Simoes TM, Roth I, Amor AJ, Ortega E, Laguna JC, Alegret M, Gilabert R, Bargalló N, Martínez-González MA, Buil-Cosiales P, Toledo E, García-Arellano A, Cenoz-Osinaga JC, Lecea-Juárez O, Razquin C, Sánchez-Tainta A, Sanjulián B, Díez-Espino J, Zazpe I, Basterra-Gortari FJ, Eguaras S, Goñi E, Vazquez Z, Bes-Rastrollo M, Gea A, Martín-Calvo N, Berrade N, Marti A, Alfredo Martínez J, Martínez-Lapiscina EH, García-López M, Cervantes S, Barcena Amigo F, Oreja Arrayago C, Lasanta Saez MJ, Quintana Pedraza L, Cia Lecumberri P, Elcarte Lopez T, Forcen Alonso T, Alvárez-Alvárez I, Salas-Salvadó J, Guasch-Ferré M, González R, Molina C, Márquez F, Babio N, García Roselló J, Diaz-López A, Martin F, Tort R, Isach A, Becerra N, Ferreira C, Cabré JJ, Fernández-Ballart J, Ibarrola-Jurado N, Mestres G, Rosique-Esteban N, Alegret C, Martínez P, Millán S, Piñol JL, Basora T, Salas-Huetos A, Hernández JM, Carrasco P, Ortega-Azorín C, Asensio EM, Osma R, Barragán R, Francés F, Guillén M, González JI, Sáiz C, Portolés O, Giménez FJ, Coltell O, Fernández-Carrión R, Guillem-Sáiz P, González-Monje I, Quiles L, Pascual V, Riera C, Pages MA, Godoy D, Carratalá-Calvo A, Sánchez-Navarro S, Valero-Barceló C, Fitó M, Vila J, Subirana I, Tello S, de la Torre R, Muñoz-Aguayo D, Elosua R, Marrugat J, Schröder H, Molina N, Maestre E, Rovira A, Farré M, Arós F, Timiraos J, Salaverría I, Rekondo J, Belló MC, Del Hierro T, Algorta J, Francisco S, Alonso A, San Vicente J, Sanz E, Felipe I, Alonso Gómez A, Loma-Osorio A, Gómez-Gracia E, Fernández-Crehuet J, Gutiérrez-Bedmar M, Benítez Pont R, Bianchi Alba M, Wärnberg J, Gómez-Huelgas R, Martínez-González J, Velasco García V, de Diego Salas J, Baca Osorio A, Gil Zarzosa J, Sánchez Luque JJ, Vargas López E, Romaguera D, García-Valdueza M, Moñino M, Yáñez A, Proenza A, Prieto R, Munuera S, Vivó M, Bestard F, Munar JA, Coll L, Fiol F, Ginard M, Jover A, García J, Leal M, Martínez E, Santos-Lozano JM, Ortega-Calvo M, Román P, José García F, Iglesias P, Corchado Y, Mellado L, Miró-Moriano L, Lozano-Rodríguez JM, Domínguez-Espinaco C, Vaquero-Díaz S, López-Sabater MC, Castellote-Bargalló AI, Quifer-Rada P, Palmas L, Álvarez-Pérez J, Díaz-Benítez EM, Sánchez-Villegas A, Casañas-Quintana LT, Pérez-Cabrera J, Ruano-Rodríguez C, Bautista-Castaño I, Sarmiento de la Fe F, García Pastor JA, Díaz-González BV, Castillo Anzalas JM, Sosa-Also RE, Medina-Ponce J, Cabezas C, Vinyoles E, Rovira MA, García L, Flores G, Verdú JM, Baby P, Ramos A, Mengual L, Roura P, Yuste MC, Guarner A, Rovira A, Santamaría MI, Mata M, de Juan C, Brau A, Ruiz-Gutiérrez V, Sánchez Perona J, Montero Romero E, García-García M, Jurado-Ruiz E, Portillo MP, Sáez G, Tur J., Background Adherence to a Mediterranean diet (MedDiet) is thought to reduce liver steatosis. Objectives To explore the associations with liver steatosis of 3 different diets: a MedDiet + extra-virgin olive oil (EVOO), MedDiet + nuts, or a control diet. Methods This was a subgroup analysis nested within a multicenter, randomized, parallel-group clinical trial, PREvención con DIeta MEDiterránea (PREDIMED trial: ISRCTN35739639), aimed at assessing the effect of a MedDiet on the primary prevention of cardiovascular disease. One hundred men and women (mean age: 64 ± 6 y), at high cardiovascular risk (62% with type 2 diabetes) from the Bellvitge-PREDIMED center were randomly assigned to a MedDiet supplemented with EVOO, a MedDiet supplemented with mixed nuts, or a control diet (advice to reduce all dietary fat). No recommendations to lose weight or increase physical activity were given. Main measurements were the percentage of liver fat and the diagnosis of steatosis, which were determined by NMR imaging. The association of diet with liver fat content was analyzed by bivariate analysis after a median follow-up of 3 y. Results Baseline adiposity and cardiometabolic risk factors were similar among the 3 treatment arms. At 3 y after the intervention hepatic steatosis was present in 3 (8.8%), 12 (33.3%), and 10 (33.3%) of the participants in the MedDiet + EVOO, MedDiet + nuts, and control diet groups, respectively (P = 0.027). Respective mean values of liver fat content were 1.2%, 2.7%, and 4.1% (P = 0.07). A tendency toward significance was observed for the MedDiet + EVOO group compared with the control group. Median values of urinary 12(S)-hydroxyeicosatetraenoic acid/creatinine concentrations were significantly (P = 0.001) lower in the MedDiet + EVOO (2.3 ng/mg) than in the MedDiet + nuts (5.0 ng/mg) and control (3.9 ng/mg) groups. No differences in adiposity or glycemic control changes were seen between groups. Conclusions An energy-unrestricted MedDiet supplemented with EVOO, a food with potent antioxidant and anti-inflammatory properties, is associated with a reduced prevalence of hepatic steatosis in older individuals at high cardiovascular risk.

[Background] High-density lipoprotein (HDL) functionality and low-density lipoprotein (LDL) atherogenic traits can describe the role of both particles on cardiovascular diseases more accurately than HDL- or LDL-cholesterol levels. However, it is unclear how these lipoprotein properties are particularly affected by different cardiovascular risk factors., [Objective] To determine which lipoprotein properties are associated with greater cardiovascular risk scores and each cardiovascular risk factor., [Methods] In two cross-sectional baseline samples of PREDIMED trial volunteers, we assessed the associations of HDL functionality (N = 296) and LDL atherogenicity traits (N = 210) with: 1) the 10-year predicted coronary risk (according to the Framingham-REGICOR score), and 2) classical cardiovascular risk factors., [Results] Greater cardiovascular risk scores were associated with low cholesterol efflux values; oxidized, triglyceride-rich, small HDL particles; and small LDLs with low resistance against oxidation (P-trend, [Conclusions] Dysfunctional HDL and atherogenic LDL particles are present in high cardiovascular risk patients. Dyslipidemia and male sex are predominantly linked to HDL dysfunctionality, whilst diabetes and advanced age are associated with LDL atherogenicity., This work was supported by: Agència de Gestió d’Ajuts Universitaris i de Recerca (2017 SGR 222), Fundació La Marató de TV3 (201512.31), and Instituto de Salud Carlos III (CB06/03/0028 and PI15/00047). A.H. was funded by Instituto de Salud Carlos III (CD17/00122), M.-T.S.-F. was supported by Agència de Gestió d’Ajuts Universitaris i de Recerca (2015 FI_B 01042), and M. Fitó was supported by Instituto de Salud Carlos III (CES12/025). CIBERs of Pathophysiology of Obesity and Nutrition (CIBEROBN) and Cardiovascular Diseases (CIBERCV) are initiatives of the Instituto de Salud Carlos III, Madrid, Spain.

Background: Cardiovascular guidelines do not give firm recommendations on statin therapy in patients with gout because evidence is lacking. Aim: To analyze the effectiveness of statin therapy in primary prevention of coronary heart disease (CHD), ischemic stroke (IS), and all-cause mortality in a population with gout. Methods: A retrospective cohort study (July 2006 to December 2017) based on Information System for the Development of Research in Primary Care (SIDIAPQ), a research-quality database of electronic medical records, included primary care patients (aged 35-85 years) without previous cardiovascular disease (CVD). Participants were categorized as nonusers or new users of statins (defined as receiving statins for the first time during the study period). Index date was first statin invoicing for new users and randomly assigned to nonusers. The groups were compared for the incidence of CHD, IS, and all-cause mortality, using Cox proportional hazards modeling adjusted for propensity score. Results: Between July 2006 and December 2008, 8018 individuals were included; 736 (9.1%) were new users of statins. Median follow-up was 9.8 years. Crude incidence of CHD was 8.16 (95% confidence interval [CI]: 6.25-10.65) and 6.56 (95% CI: 5.85-7.36) events per 1000 person-years in new users and nonusers, respectively. Hazard ratios were 0.84 (95% CI: 0.60-1.19) for CHD, 0.68 (0.44-1.05) for IS, and 0.87 (0.67-1.12) for all-cause mortality. Hazard for diabetes was 1.27 (0.99-1.63). Conclusions: Statin therapy was not associated with a clinically significant decrease in CHD. Despite higher risk of CVD in gout populations compared to general population, patients with gout from a primary prevention population with a low-to-intermediate incidence of CHD should be evaluated according to their cardiovascular risk assessment, lifestyle recommendations, and preferences, in line with recent European League Against Rheumatism recommendations.