Blood DNA methylation signature of diet quality and association with cardiometabolic traits.

AIMS: Diet quality might influence cardiometabolic health through epigenetic changes, but this has been little investigated in adults. Our aims were to identify cytosine-phosphate-guanine (CpG) dinucleotides associated with diet quality by conducting an epigenome-wide association study (EWAS) based on blood DNA methylation (DNAm) and to assess how diet-related CpGs associate with inherited susceptibility to cardiometabolic traits: body mass index (BMI), systolic blood pressure (SBP), triglycerides, type 2 diabetes (T2D), and coronary heart disease (CHD). METHODS AND RESULTS: Meta-EWAS including 5274 participants in four cohorts from Spain, the USA, and the UK. We derived three dietary scores (exposures) to measure adherence to a Mediterranean diet, to a healthy plant-based diet, and to the Dietary Approaches to Stop Hypertension. Blood DNAm (outcome) was assessed with the Infinium arrays Human Methylation 450K BeadChip and MethylationEPIC BeadChip. For each diet score, we performed linear EWAS adjusted for age, sex, blood cells, smoking and technical variables, and BMI in a second set of models. We also conducted Mendelian randomization analyses to assess the potential causal relationship between diet-related CpGs and cardiometabolic traits. We found 18 differentially methylated CpGs associated with dietary scores (P < 1.08 × 10-7; Bonferroni correction), of which 12 were previously associated with cardiometabolic traits. Enrichment analysis revealed overrepresentation of diet-associated genes in pathways involved in inflammation and cardiovascular disease. Mendelian randomization analyses suggested that genetically determined methylation levels corresponding to lower diet quality at cg02079413 (SNORA54), cg02107842 (MAST4), and cg23761815 (SLC29A3) were causally associated with higher BMI and at cg05399785 (WDR8) with greater SBP, and methylation levels associated with higher diet quality at cg00711496 (PRMT1) with lower BMI, T2D risk, and CHD risk and at cg0557921 (AHRR) with lower CHD risk. CONCLUSION: Diet quality in adults was related to differential methylation in blood at 18 CpGs, some of which related to cardiometabolic health.

We conducted a study to investigate the connection between diet quality, epigenetic changes, and cardiovascular health in adults. The study included 5274 participants from Spain, the USA, and the UK, combining data from four different cohorts. We assessed adherence to different healthy diets: Mediterranean style diet, plant-based diet, and Dietary Approaches to Stop Hypertension diet. We used advanced technology to analyse blood DNA methylation, which refers to chemical modifications in the DNA that can affect gene activity.We discovered 18 CpGs that showed differential methylation patterns related to the dietary scores. Importantly, 12 of these CpGs had previously been associated with cardiovascular disease or risk factors, suggesting a potential link between diet, epigenetic changes, and heart health. Some of the diet-related CpGs mapped to genes involved in pathways associated with cardiovascular disease. Moreover, using a method called Mendelian randomization, we found that several CpGs may have a causal association with body mass index, systolic blood pressure, and risk of type 2 diabetes and coronary heart disease.

Association of depression phenotypes and antidepressant treatment with mortality due to cancer and other causes: a community-based cohort study.

Objective: This study aimed to assess the association of somatic depressive symptoms (SDS), cognitive/emotional depressive symptoms (C-EDS), and antidepressant treatment on mortality due to cancer and other causes in a community cohort. Methods: A community-based sample recruited in 1995, 2000, and 2005 aged between 35 and 75 years was examined in two waves and followed for a median of 6.7 years. SDS and C-EDS phenotypes were assessed using the Patient Health Questionnaire-9. Medication used by participants was collected. Deaths and their causes were registered during follow-up. Cox proportional hazard models stratified by sex were performed to determine the association between depressive phenotypes and mortality. Results: The cohort consisted of 5,646 individuals (53.9% women) with a mean age of 64 years (SD = 11.89). During the follow-up, 392 deaths were recorded, of which 27.8% were due to cancer. C-EDS phenotype was associated with an increased risk of cancer mortality in both men (HR = 2.23; 95% CI = 1.11-4.44) and women (HR = 3.69; 95% CI = 1.69-8.09), and SDS was significantly associated with non-cancer mortality in men (HR = 2.16; 95 CI % = 1.46-3.18). Selective serotonin reuptake inhibitors (SSRIs) were significantly associated with both cancer (HR = 2.78; 95% CI = 1.10-6.98) and non-cancer mortality (HR = 2.94; 95% CI = 1.76-4.90) only in the male population. Conclusion: C-EDS phenotype was related to an increased risk of cancer mortality at 6 years. In addition, the use of SSRIs in the male population was associated with cancer and all-cause mortality.

Five-Year Changes in Inflammatory, Metabolic, and Oxidative Biomarkers and 10-Year Cardiovascular Disease Incidence: The REGICOR Cohort Study.

Ischemic cardiovascular diseases (CVD) originate from an imbalance between atherosclerotic plaque formation, instability, and endothelial healing dynamics. Our aim was to examine the relationship between 5-year changes in inflammatory, metabolic, and oxidative biomarkers and 10-year CVD incidence in a population without previous CVD. This was a prospective cohort study of individuals aged 35-74 years (n = 419) randomly selected from 5263 REGICOR participants without CVD recruited in 2005. Biomarkers were measured at baseline and in 2010. Participants were followed up until 2020 for a composite CVD endpoint including coronary artery disease, stroke, and peripheral artery disease. We used Cox regression to analyze the effect of biomarker levels on the occurrence of the composite endpoint, adjusted for traditional CVD risk factors and baseline levels of each biomarker. Individuals with elevated IL-6 or insulin after 5 years had a higher independent risk of CVD at 10 years, compared to those with lower levels. Each rise of 1 pg/mL of IL-6 or 10 pg/mL of insulin increased the 10-year risk of a CVD event by 32% and 2%, respectively. Compared to a model with traditional CVD risk factors only, the inclusion of IL-6 and insulin improved continuous reclassification by 51%. Elevated serum levels of IL-6 and insulin were associated with a higher risk of CVD at 10 years, independently of traditional CVD risk factors.

The natural history of QTc interval and its clinical impact in coronavirus disease 2019 survivors after 1 year.

Background and objective: Prolonged QTc interval on admission and a higher risk of death in SARS-CoV-2 patients have been reported. The long-term clinical impact of prolonged QTc interval is unknown. This study examined the relationship in COVID-19 survivors of a prolonged QTc on admission with long-term adverse events, changes in QTc duration and its impact on 1-year prognosis, and factors associated with a prolonged QTc at follow-up. Methods: We conducted a single-center prospective cohort study of 523 SARS-CoV-2-positive patients who were alive on discharge. An electrocardiogram was taken on these patients within the first 48 h after diagnosis and before the administration of any medication with a known effect on QT interval and repeated in 421 patients 7 months after discharge. Mortality, hospital readmission, and new arrhythmia rates 1 year after discharge were reviewed. Results: Thirty-one (6.3%) survivors had a baseline prolonged QTc. They were older, had more cardiovascular risk factors, cardiac disease, and comorbidities, and higher levels of terminal pro-brain natriuretic peptide. There was no relationship between prolonged QTc on admission and the 1-year endpoint (9.8% vs. 5.5%, p = 0.212). In 84% of survivors with prolonged baseline QTc, it normalized at 7.9 ± 2.2 months. Of the survivors, 2.4% had prolonged QTc at follow-up, and this was independently associated with obesity, ischemic cardiomyopathy, chronic obstructive pulmonary disease, and cancer. Prolonged baseline QTc was not independently associated with the composite adverse event at 1 year. Conclusions: Prolonged QTc in the acute phase normalized in most COVID-19 survivors and had no clinical long-term impact. Prolonged QTc at follow-up was related to the presence of obesity and previously acquired chronic diseases and was not related to 1-year prognosis.

Women with familial hypercholesterolemia phenotype are undertreated and poorly controlled compared to men.

Familial hypercholesterolemia (FH) is an autosomal dominant disease that has a prevalence of approximately 1/250 inhabitants and is the most frequent cause of early coronary heart disease (CHD). We included 1.343.973 women and 1.210.671 men with at least one LDL-c measurement from the Catalan primary care database. We identified 14.699 subjects with Familial hypercholesterolemia-Phenotype (FH-P) based on LDL-c cut-off points by age (7.033 and 919 women, and 5.088 and 1659 men in primary and secondary prevention, respectively). Lipid lower therapy (LLT), medication possession ratio (MPR) as an indicator of adherence, and number of patients that reached their goal on lipid levels were compared by sex. In primary and secondary prevention, 69% and 54% of women (P = 0.001) and 64% and 51% of men (P = 0.001) were on low-to-moderate-potency LLT. Adherence to LLT was reduced in women older than 55 years, especially in secondary prevention (P = 0.03), where the percentage of women and men with LDL-c > 1.81 mmol/L were 99.9% and 98.9%, respectively (P = 0.001). Women with FH-P are less often treated with high-intensity LLT, less adherent to LLT, and have a lower probability of meeting their LDL-c goals than men, especially in secondary prevention.

Cholesterol and Hypertension Treatment Improve Coronary Risk Prediction but Not Time-Dependent Covariates or Competing Risks.

Background and Aims: Cardiovascular (CV) risk functions are the recommended tool to identify high-risk individuals. However, their discrimination ability is not optimal. While the effect of biomarkers in CV risk prediction has been extensively studied, there are no data on CV risk functions including time-dependent covariates together with other variables. Our aim was to examine the effect of including time-dependent covariates, competing risks, and treatments in coronary risk prediction. Methods: Participants from the REGICOR population cohorts (North-Eastern Spain) aged 35-74 years without previous history of cardiovascular disease were included (n = 8470). Coronary and stroke events and mortality due to other CV causes or to cancer were recorded during follow-up (median = 12.6 years). A multi-state Markov model was constructed to include competing risks and time-dependent classical risk factors and treatments (2 measurements). This model was compared to Cox models with basal measurement of classical risk factors, treatments, or competing risks. Models were cross-validated and compared for discrimination (area under ROC curve), calibration (Hosmer-Lemeshow test), and reclassification (categorical net reclassification index). Results: Cancer mortality was the highest cumulative-incidence event. Adding cholesterol and hypertension treatment to classical risk factors improved discrimination of coronary events by 2% and reclassification by 7-9%. The inclusion of competing risks and/or 2 measurements of risk factors provided similar coronary event prediction, compared to a single measurement of risk factors. Conclusion: Coronary risk prediction improves when cholesterol and hypertension treatment are included in risk functions. Coronary risk prediction does not improve with 2 measurements of covariates or inclusion of competing risks.

High cardiovascular risk in older patients with opioid use disorder: Differences with the general population.

INTRODUCTION: Cardiovascular disease is a health concern in ageing population with opioid use disorders (OUD). The study aims to analyse the cardiovascular risk factors in individuals with OUD. METHODS: An observational study was carried out to compare cardiovascular risk factors of adults >50 years with OUD on methadone therapy from public outpatient drug treatment centres, with that of an age- and gender-matched sample (ratio of 1:5) of subjects from a sample of the Spanish population (REGICOR cohort). High cardiovascular risk (HCVR) at 10 years was defined according to Framingham-REGICOR and SCORE risk functions. RESULTS: The individuals studied included 94 people with OUD and 495 from the general population; the mean age was 55.7 ± 4.8 years and 432 (72.7%) were men. Obesity (21.2% vs. 35.2%), hypertension (26.3% vs. 42.1%), total cholesterol (30.3% vs. 65.4%) and LDL-cholesterol ≥130 mg/dL (27.2% vs. 59.3%) were significantly more prevalent in the general population group, while tobacco smoking (96.0% vs. 25.9%), low HDL-cholesterol (46.5% vs. 21.2%), hypertriglyceridaemia (39.4% vs. 18.8%) and atherogenic dyslipidaemia (30.3% vs. 10.5%) were significantly higher in individuals with OUD. Differences in abdominal obesity (62.6% vs. 65.3%) were not significant. HCVR was more prevalent in patients with OUD: 15.2% versus 5.8% (Framingham-REGICOR function) and 21.2% versus 11.3% (SCORE function). DISCUSSION AND CONCLUSIONS: Older adults with OUD on methadone therapy have a different prevalence of cardiovascular risk factors and HCVR than the general population. Preventive measures, particularly tobacco smoking cessation and weight control, should be included in the routine care of individuals with OUD.

Standardized Comparison of Cardiovascular Risk Factors Prevalence in Spanish Women and Men Living with HIV and in the General Population.

People living with HIV (PLWH) have an increased risk of cardiovascular (CV) disease, likely due to a higher prevalence of CV risk factors. We compared the age-standardized prevalence and management of CV risk factors in PLWH to that of the general population in Spain. Blood pressure, lipid, glucose, and anthropometric profiles were cross-sectionally compared along with the treatment of hypertension, dyslipidemia, and diabetes in a general population cohort and a PLWH cohort. Prevalence rates were standardized by the direct method by 10-year age groups in European standard populations and stratified by gender. We included 47,593 individuals aged 35 to 74 years, 28,360 from the general population cohort and 19,233 from the PLWH cohort. Compared to the general population, PLWH had a higher concentration of triglycerides (>35 mg/dL in women and >26 mg/dL in men) and a higher prevalence of smoking (>23% and >17%) and diabetes (>9.9% and >8.5%). The prevalence of treated diabetes, hypertension, and dyslipidemia were up to three-fold lower in both women and men living with HIV. There was a significant difference in PLWH compared to the general population in the lipid, glucose, and anthropometric profile. In addition, PLWH were less often treated for diagnosed diabetes, hypertension, and dyslipidemia.

DNA methylation biomarkers of myocardial infarction and cardiovascular disease.

BACKGROUND: The epigenetic landscape underlying cardiovascular disease (CVD) is not completely understood and the clinical value of the identified biomarkers is still limited. We aimed to identify differentially methylated loci associated with acute myocardial infarction (AMI) and assess their validity as predictive and causal biomarkers. RESULTS: We designed a case-control, two-stage, epigenome-wide association study on AMI (ndiscovery = 391, nvalidation = 204). DNA methylation was assessed using the Infinium MethylationEPIC BeadChip. We performed a fixed-effects meta-analysis of the two samples. 34 CpGs were associated with AMI. Only 12 of them were available in two independent cohort studies (n ~ 1800 and n ~ 2500) with incident coronary and cardiovascular disease (CHD and CVD, respectively). The Infinium HumanMethylation450 BeadChip was used in those two studies. Four of the 12 CpGs were validated in association with incident CHD: AHRR-mapping cg05575921, PTCD2-mapping cg25769469, intergenic cg21566642 and MPO-mapping cg04988978. We then assessed whether methylation risk scores based on those CpGs improved the predictive capacity of the Framingham risk function, but they did not. Finally, we aimed to study the causality of those associations using a Mendelian randomization approach but only one of the CpGs had a genetic influence and therefore the results were not conclusive. CONCLUSIONS: We have identified 34 CpGs related to AMI. These loci highlight the relevance of smoking, lipid metabolism, and inflammation in the biological mechanisms related to AMI. Four were additionally associated with incident CHD and CVD but did not provide additional predictive information.

Cardiovascular risk in mild to moderately decreased glomerular filtration rate, diabetes and coronary heart disease in a southern European region.

INTRODUCTION AND OBJECTIVES: Individuals with mild to moderately decreased estimated glomerular filtration rate (eGFR=30-59 mL/min/1.73 m2) are considered at high risk of cardiovascular disease (CVD). No studies have compared this risk in eGFR=30-59, diabetes mellitus (DM), and coronary heart disease (CHD) in regions with a low incidence of CHD. METHODS: We performed a retrospective cohort study of 122 443 individuals aged 60-84 years from a region with a low CHD incidence with creatinine measured between January 1, 2010 and December 31, 2011. We identified hospital admissions due to CHD (myocardial infarction, angina) or CVD (CHD, stroke, or transient ischemic attack) from electronic medical records up to December 31, 2013. We estimated incidence rates and Cox regression adjusted subdistribution hazard ratio (sHR) including competing risks in patients with eGFR=30-59, DM and CHD, or combinations, compared with individuals without these diseases. RESULTS: The median follow-up was 38.3 [IQR, 33.8-42.7] months. Adjusted sHR for CHD in individuals with eGFR=30-59, DM, eGFR=30-59 plus DM, previous CHD, CHD plus DM, and CHD plus eGFR=30-59 plus DM, were 1.34 (95%CI, 1.04-1.74), 1.61 (95%CI, 1.36-1.90), 1.96 (95%CI, 1.42-2.70), 4.33 (95%CI, 3.58-5.25), 7.05 (5.80-8.58) and 7.72 (5.72-10.41), respectively. The corresponding sHR for CVD were 1.25 (95%CI, 1.06-1.46), 1.56 (95%CI, 1.41-1.74), 1.83 (95%CI, 1.50-2.23), 2.86 (95%CI, 2.48-3.29), 4.54 (95%CI, 3.93-5.24), and 5.33 (95%CI, 4.31-6.60). CONCLUSIONS: In 60- to 84-year-olds with eGFR=30-59, similarly to DM, the likelihood of being admitted to hospital for CHD and CVD was about half that of individuals with established CHD. Thus, eGFR=30-59 does not appear to be a coronary-risk equivalent. Individuals with CHD and DM, or eGFR=30-59 plus DM, should be prioritized for more intensive risk management.

Physical Activity and Genome-wide DNA Methylation: The REgistre GIroní del COR Study.

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 REgistre GIroní del COR cohort. Next, we validated the CpG suggestively associated with PA (P < 10) in two independent populations (n = 1735 and 190, respectively). Physical activity was assessed with validated questionnaires and classified as light PA (LPA), moderate PA, vigorous PA, moderate-vigorous PA (MVPA) and total PA. We examined linear and nonlinear associations and meta-analyzed the results in the three populations. The linear associations were meta-analyzed with a fixed-effects model and the P values of the nonlinear associations with the Stouffer and Fisher methods. We established a P value threshold that fulfilled Bonferroni criteria over the number of CpG analyzed (0.05/421,940 = 1.185 × 10). RESULTS: In the meta-analyses, two CpG sites had a statistically significant nonlinear association with MVPA. cg24155427 (P = 1.19 × 10), located in an intergenic region in chromosome 1, has been previously associated with smoking, lupus, and aging. cg09565397 (P = 1.59 × 10), located within DGAT1 in chromosome 8, which encodes an enzyme involved in triacylglycerol synthesis. CONCLUSIONS: This population-based study identified two new, differentially methylated CpG sites with a nonlinear dose-response relationship to MVPA. These associations must be additionally validated and may be considered for further research on the biological mechanisms underlying health benefits of PA.

Derivation and validation of SIDIAP-FHP score: A new risk model predicting cardiovascular disease in familial hypercholesterolemia phenotype.

BACKGROUND AND AIMS: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Early smoking-onset age and risk of cardiovascular disease and mortality.

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.

DNA Methylation and Age-Independent Cardiovascular Risk, an Epigenome-Wide Approach: The REGICOR Study (REgistre GIroní del COR).

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.

Heart rate at admission is a predictor of in-hospital mortality in patients with acute coronary syndromes: Results from 58 European hospitals: The European Hospital Benchmarking by Outcomes in acute coronary syndrome Processes study.

AIMS: The purpose of this study was to investigate the relationship between heart rate at admission and in-hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation acute coronary syndrome (NSTE-ACS). METHODS: Consecutive ACS patients admitted in 2008-2010 across 58 hospitals in six participant countries of the European Hospital Benchmarking by Outcomes in ACS Processes (EURHOBOP) project (Finland, France, Germany, Greece, Portugal and Spain). Cardiogenic shock patients were excluded. Associations between heart rate at admission in categories of 10 beats per min (bpm) and in-hospital mortality were estimated by logistic regression in crude models and adjusting for age, sex, obesity, smoking, hypertension, diabetes, known heart failure, renal failure, previous stroke and ischaemic heart disease. In total 10,374 patients were included. RESULTS: In both STEMI and NSTE-ACS patients, a U-shaped relationship between admission heart rate and in-hospital mortality was found. The lowest risk was observed for heart rates between 70-79 bpm in STEMI and 60-69 bpm in NSTE-ACS; risk of mortality progressively increased with lower or higher heart rates. In multivariable models, the relationship persisted but was significant only for heart rates >80 bpm. A similar relationship was present in both patients with or without diabetes, above or below age 75 years, and irrespective of the presence of atrial fibrillation or use of beta-blockers. CONCLUSION: Heart rate at admission is significantly associated with in-hospital mortality in patients with both STEMI and NSTE-ACS. ACS patients with admission heart rate above 80 bpm are at highest risk of in-hospital mortality.

Interaction between cardiovascular risk factors and body mass index and 10-year incidence of cardiovascular disease, cancer death, and overall mortality.

The effect of above-normal body mass index (BMI) on health outcomes is controversial because it is difficult to distinguish from the effect due to BMI-associated cardiovascular risk factors. The objective was to analyze the impact on 10-year incidence of cardiovascular disease, cancer deaths and overall mortality of the interaction between cardiovascular risk factors and BMI. We conducted a pooled analysis of individual data from 12 Spanish population cohorts with 10-year follow-up. Participants had no previous history of cardiovascular diseases and were 35-79years old at basal examination. Body mass index was measured at baseline being the outcome measures ten-year cardiovascular disease, cancer and overall mortality. Multivariable analyses were adjusted for potential confounders, considering the significant interactions with cardiovascular risk factors. We included 54,446 individuals (46.5% with overweight and 27.8% with obesity). After considering the significant interactions, the 10-year risk of cardiovascular disease was significantly increased in women with overweight and obesity [Hazard Ratio=2.34 (95% confidence interval: 1.19-4.61) and 5.65 (1.54-20.73), respectively]. Overweight and obesity significantly increased the risk of cancer death in women [3.98 (1.53-10.37) and 11.61 (1.93-69.72)]. Finally, obese men had an increased risk of cancer death and overall mortality [1.62 (1.03-2.54) and 1.34 (1.01-1.76), respectively]. In conclusion, overweight and obesity significantly increased the risk of cancer death and of fatal and non-fatal cardiovascular disease in women; whereas obese men had a significantly higher risk of death for all causes and for cancer. Cardiovascular risk factors may act as effect modifiers in these associations.

The association between education and cardiovascular disease incidence is mediated by hypertension, diabetes, and body mass index.

Education and cardiovascular disease (CVD) are inversely associated but the mediating factors have not been totally elucidated. Our aim was to analyze the mediating role of modifiable risk factors. Cohort study using the REGICOR population cohorts. Participants without previous CVD were included (n = 9226). Marginal structural models were used to analyze the association between education and CVD incidence at 6 years of follow-up. Mediation by modifiable risk factors (diabetes, dyslipidemia, hypertension, smoking, body mass index, and physical activity) was assessed using the counterfactual framework. Participants with a university degree had a CVD incidence hazard ratio (HR) of 0.51 (95% confidence interval (CI) = 0.30, 0.85), compared to those with primary or lower education. Only hypertension, BMI, and diabetes mediated the association between education and CVD incidence, accounting for 26% of the association (13.9, 6.9, and 5.2%, respectively). Sensitivity analyses showed that hypertension was the strongest mediator (average causal mediation effect [95% CI] = increase of 2170 days free of CVD events [711, 4520]). The association between education and CVD incidence is partially mediated by hypertension, BMI, and diabetes. Interventions to decrease the prevalence of these risk factors could contribute to diminish the CVD inequalities associated with educational level.

Familial hypercholesterolemia in a European Mediterranean population-Prevalence and clinical data from 2.5 million primary care patients.

BACKGROUND: Familial hypercholesterolemia (FH), the most frequent hereditary cause of premature coronary heart disease (CHD), is underdiagnosed and insufficiently treated. OBJECTIVES: The objectives of the study were to estimate the prevalence of the FH phenotype (FH-P) and to describe its clinical characteristics in a Mediterranean population. METHODS: Data were obtained from the Catalan primary care system's clinical records database (Catalan acronym: SIDIAP). Patients aged >7 years with at least 1 low-density lipoprotein cholesterol measurement recorded between 2006 and 2014 (n = 2,554,644) were included. Heterozygous FH-P and homozygous FH-P were defined by untreated low-density lipoprotein cholesterol plasma concentrations. The presence of cardiovascular diseases and risk factors was defined by coded medical records from primary care and hospital discharge databases. RESULTS: The age- and sex-standardized prevalence of heterozygous FH-P and homozygous FH-P were 1/192 individuals and 1/425,774 individuals, respectively. In the group aged 8 to 18 years, 0.46% (95% confidence interval: 0.41-0.52) had FH-P; overall prevalence was 0.58% (95% confidence interval: 0.58-0.60). Among patients with FH-P aged >18 years, cardiovascular disease prevalence was 3.5 times higher than in general population, and CHD prevalence in those aged 35 to 59 years was 4.5 times higher than in those without FH-P. Lipid-lowering therapy was lacking in 13.5% of patients with FH-P, and only 31.6% of men and 22.7 of women were receiving high or very high-intensity lipid-lowering therapy. CONCLUSION: Prevalence of FH-P was higher than expected, but underdiagnosed and suboptimally treated, especially in women. Moreover, treatment started late considering the high CHD incidence associated with this condition.

DNA Methylation and High-Density Lipoprotein Functionality-Brief Report: The REGICOR Study (Registre Gironi del Cor).

OBJECTIVE: The function of high-density lipoproteins (HDLs) may better reflect their atheroprotective role, compared with HDL-cholesterol levels. The association between DNA methylation and HDL function has not yet been established. APPROACH AND RESULTS: We designed an epigenome-wide association study including 645 individuals from the REGICOR study (Registre Gironi del Cor). We determined DNA methylation from peripheral blood cells using the HumanMethylation450 array. We analyzed HDL functionality by determining HDL cholesterol efflux capacity and HDL inflammatory index. We discovered 3 methylation sites located in HOXA3, PEX5, and PER3 related to cholesterol efflux capacity and 1 located in GABRR1 related to HDL inflammatory index. Using a candidate gene approach, we also found 2 methylation sites located in CMIP related to cholesterol efflux capacity. CONCLUSIONS: We identified 6 potential loci associated with HDL functionality in HOXA3, PEX5, PER3, CMIP, and GABRR1. Additional studies are warranted to validate these findings in other populations.

Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels.

BACKGROUND: Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation. OBJECTIVES: The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD. METHODS: We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD. RESULTS: One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk. CONCLUSIONS: Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.