Epigenomic Assessment of Cardiovascular Disease Risk and Interactions With Traditional Risk Metrics.

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.

Validity Assessment of Low-risk SCORE Function and SCORE Function Calibrated to the Spanish Population in the FRESCO Cohorts.

INTRODUCTION AND OBJECTIVES: To assess the validity of the original low-risk SCORE function without and with high-density lipoprotein cholesterol and SCORE calibrated to the Spanish population. METHODS: Pooled analysis with individual data from 12 Spanish population-based cohort studies. We included 30 919 individuals aged 40 to 64 years with no history of cardiovascular disease at baseline, who were followed up for 10 years for the causes of death included in the SCORE project. The validity of the risk functions was analyzed with the area under the ROC curve (discrimination) and the Hosmer-Lemeshow test (calibration), respectively. RESULTS: Follow-up comprised 286 105 persons/y. Ten-year cardiovascular mortality was 0.6%. The ratio between estimated/observed cases ranged from 9.1, 6.5, and 9.1 in men and 3.3, 1.3, and 1.9 in women with original low-risk SCORE risk function without and with high-density lipoprotein cholesterol and calibrated SCORE, respectively; differences were statistically significant with the Hosmer-Lemeshow test between predicted and observed mortality with SCORE (P < .001 in both sexes and with all functions). The area under the ROC curve with the original SCORE was 0.68 in men and 0.69 in women. CONCLUSIONS: All versions of the SCORE functions available in Spain significantly overestimate the cardiovascular mortality observed in the Spanish population. Despite the acceptable discrimination capacity, prediction of the number of fatal cardiovascular events (calibration) was significantly inaccurate.

[Spanish adaptation of the 2016 European Guidelines on cardiovascular disease prevention in clinical practice]. / Adaptación española de las guías europeas de 2016 sobre prevención de la enfermedad cardiovascular en la práctica clínica.

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 <10 years of evolution, without other risk factors or complications, or type 1 diabetes of short evolution without complications. The decision to start pharmacological treatment of arterial hypertension will depend on the blood pressure level and the cardiovascular risk, taking into account the lesion of target organs. The guidelines don't recommend antiplatelet drugs in primary prevention because of the increased bleeding risk. The low adherence to the medication requires simplified therapeutic regimes and to identify and combat its causes. The guidelines highlight the responsibility of health professionals to take an active role in advocating evidence-based interventions at the population level, and propose effective interventions, at individual and population level, to promote a healthy diet, the practice of physical activity, the cessation of smoking and the protection against alcohol abuse.

Role of renal function in cardiovascular risk assessment: A retrospective cohort study in a population with low incidence of coronary heart disease.

BACKGROUND: Early-stage chronic kidney disease (CKD), a marker of cardiovascular risk, is susceptible to therapeutic intervention but need further study in populations with low incidence of coronary heart disease (CHD). Incorporating glomerular filtration rate (GFR) could improve cardiovascular risk prediction in these patients. OBJECTIVE: To determine if decreased GFR is associated with increased risk of cardiovascular morbidity and all-cause mortality and to analyse GFR effect on cardiovascular risk prediction in a population with low CHD incidence. METHODS: Retrospective, observational, population-based study of 1,081,865 adults (35-74years old). Main exposure variable: GFR. OUTCOMES: CHD, cerebrovascular disease, cardiovascular diseases, all-cause mortality. Association between GFR categories of CKD (G1-G5) and outcomes was tested with Cox survival models. G1 was defined as the reference category. Predictive value of GFR was evaluated by integrated discrimination improvement (IDI) and net reclassification improvement (NRI) indices. RESULTS: Beginning at stage-3a CKD, increased risk was observed for coronary (HR 1.27 (95%CI 1.14-1.43)), cerebrovascular (HR 1.19 (95%CI 1.06-1.34)), cardiovascular (HR 1.23 (95%CI 1.13-1.34)) and all-cause mortality risk (HR 1.17 (95%CI 1.07-1.27)). GFR did not increase discrimination and reclassification indices significantly for any outcome. CONCLUSION: In general population with low CHD incidence and stage-3 CKD, impaired GFR was associated with increased risk of all cardiovascular diseases studied and all-cause mortality, but adding GFR values did not improve cardiovascular risk calculation. Despite a four-fold higher rate of CHD incidence at GFR G3a compared to G1, this represents moderate cardiovascular risk in our context.

Association of increased monetary cost of dietary intake, diet quality and weight management in Spanish adults.

Higher monetary diet cost is associated with healthier food choices and better weight management. How changes in diet cost affect changes in diet quality and weight remains unknown. The aim of this study was to assess the impact of changes in individual monetary diet cost on changes in diet quality, measured by the modified Mediterranean diet score recommendations (MDS-rec) and by energy density (ED), as well as changes in weight and BMI. We conducted a prospective, population-based study of 2181 male and female Spaniards aged between 25 and 74 years, who were followed up to the 2009-2010 academic year. We measured weight and height and recorded dietary data using a validated FFQ. Average food cost was calculated from official Spanish government data. We fitted multivariate linear and logistic regression models. The average daily diet cost increased from 3·68(SD0.0·89)€/8·36 MJ to 4·97(SD1·16)€/8·36 MJ during the study period. This increase was significantly associated with improvement in diet quality (Δ ED and Δ MDS-rec; P<0·0001). Each 1€ increase in monetary diet cost per 8·36 MJ was associated with a decrease of 0·3 kg in body weight (P=0·02) and 0·1 kg/m(2) in BMI (P=0·04). These associations were attenuated after adjusting for changes in diet quality indicators. An improvement in diet quality and better weight management were both associated with an increase in diet cost; this could be considered in food policy decisions.

Multilocus genetic risk scores for venous thromboembolism risk assessment.

BACKGROUND: Genetics plays an important role in venous thromboembolism (VTE). Factor V Leiden (FVL or rs6025) and prothrombin gene G20210A (PT or rs1799963) are the genetic variants currently tested for VTE risk assessment. We hypothesized that primary VTE risk assessment can be improved by using genetic risk scores with more genetic markers than just FVL-rs6025 and prothrombin gene PT-rs1799963. To this end, we have designed a new genetic risk score called Thrombo inCode (TiC). METHODS AND RESULTS: TiC was evaluated in terms of discrimination (Δ of the area under the receiver operating characteristic curve) and reclassification (integrated discrimination improvement and net reclassification improvement). This evaluation was performed using 2 age- and sex-matched case-control populations: SANTPAU (248 cases, 249 controls) and the Marseille Thrombosis Association study (MARTHA; 477 cases, 477 controls). TiC was compared with other literature-based genetic risk scores. TiC including F5 rs6025/rs118203906/rs118203905, F2 rs1799963, F12 rs1801020, F13 rs5985, SERPINC1 rs121909548, and SERPINA10 rs2232698 plus the A1 blood group (rs8176719, rs7853989, rs8176743, rs8176750) improved the area under the curve compared with a model based only on F5-rs6025 and F2-rs1799963 in SANTPAU (0.677 versus 0.575, P<0.001) and MARTHA (0.605 versus 0.576, P=0.008). TiC showed good integrated discrimination improvement of 5.49 (P<0.001) for SANTPAU and 0.96 (P=0.045) for MARTHA. Among the genetic risk scores evaluated, the proportion of VTE risk variance explained by TiC was the highest. CONCLUSIONS: We conclude that TiC greatly improves prediction of VTE risk compared with other genetic risk scores. TiC should improve prevention, diagnosis, and treatment of VTE.

[Statement of the Spanish Interdisciplinary Cardiovascular Prevention Committee (CEIPC) on the 2012 European Cardiovascular Prevention Guidelines]. / Comentarios del Comité Español Interdisciplinario de Prevención Cardiovascular (CEIPC) a las guías europeas de prevención cardiovascular 2012.

Based on the two main frameworks for evaluating scientific evidence--SEC and GRADE--European cardiovascular prevention guidelines recommend interventions across all life stages using a combination of population-based and high-risk strategies with diet as the cornerstone of prevention. The evaluation of cardiovascular risk (CVR) incorporates HDL levels and psychosocial factors, a very high risk category, and the concept of age-risk. They also recommend cognitive-behavioural methods (e.g., motivational interviewing, psychological interventions, led by health professionals and with the participation of the patient's family, to counterbalance psychosocial stress and reduce CVR through the institution of positive habits such as a healthy diet, physical activity, smoking cessation, and adherence to treatment. Additionally, public health interventions--such as smoking ban in public areas or the elimination of trans fatty acids from the food chain--are also essential. Other innovations include abandoning antiplatelet therapy in primary prevention and the recommendation of maintaining blood pressure (BP) within the 130-139/80-85 mmHg range in diabetic patients and individuals with high CVR. Finally, due to the significant impact on patient progress and medical costs, special emphasis is given to the low therapeutic adherence levels observed. In sum, improving cardiovascular prevention requires a true partnership among the political class, public administrations, scientific and professional associations, health foundations, consumer associations, patients and their families. Such partnership would promote population-based and individual strategies by taking advantage of the broad spectrum of scientific evidence available, from clinical trials to observational studies and mathematical models to evaluate population-based interventions, including cost-effectiveness analyses.

[Statement of the Spanish Interdisciplinary Cardiovascular Prevention Committee (CEIPC for its Spanish acronym) on the 2012 European Cardiovascular Prevention Guidelines]. / Comentarios del Comité Español Interdisciplinario de Prevención Cardiovascular (CEIPC) a las Guías Europeas de Prevención Cardiovascular 2012.

Based on the two main frameworks for evaluating scientific evidence (SEC and GRADE) European cardiovascular prevention guidelines recommend interventions across all life stages using a combination of population-based and high-risk strategies with diet as the cornerstone of prevention. The evaluation of cardiovascular risk (CVR) incorporates HDL levels and psychosocial factors, a very high risk category, and the concept of age-risk. They also recommend cognitive-behavioural methods (e.g., motivational interviewing, psychological interventions) led by health professionals and with the participation of the patient's family, to counterbalance psychosocial stress and reduce CVR through the institution of positive habits such as a healthy diet, physical activity, smoking cessation, and adherence to treatment. Additionally, public health interventions - such as smoking ban in public areas or the elimination of trans fatty acids from the food chain - are also essential. Other innovations include abandoning antiplatelet therapy in primary prevention and the recommendation of maintaining blood pressure within the 130-139/80-85mmHg range in diabetic patients and individuals with high CVR. Finally, due to the significant impact on patient progress and medical costs, special emphasis is given to the low therapeutic adherence levels observed. In sum, improving cardiovascular prevention requires a true partnership among the political class, public administrations, scientific and professional associations, health foundations, consumer associations, patients and their families. Such partnership would promote population-based and individual strategies by taking advantage of the broad spectrum of scientific evidence available, from clinical trials to observational studies and mathematical models to evaluate population-based interventions, including cost-effectiveness analyses.

Assessment of the value of a genetic risk score in improving the estimation of coronary risk.

BACKGROUND: The American Heart Association has established criteria for the evaluation of novel markers of cardiovascular risk. In accordance with these criteria, we assessed the association between a multi-locus genetic risk score (GRS) and incident coronary heart disease (CHD), and evaluated whether this GRS improves the predictive capacity of the Framingham risk function. METHODS AND RESULTS: Using eight genetic variants associated with CHD but not with classical cardiovascular risk factors (CVRFs), we generated a multi-locus GRS, and found it to be linearly associated with CHD in two population based cohorts: The REGICOR Study (n=2351) and The Framingham Heart Study (n=3537) (meta-analyzed HR [95%CI]: ~1.13 [1.01-1.27], per unit). Inclusion of the GRS in the Framingham risk function improved its discriminative capacity in the Framingham sample (c-statistic: 72.81 vs.72.37, p=0.042) but not in the REGICOR sample. According to both the net reclassification improvement (NRI) index and the integrated discrimination index (IDI), the GRS improved re-classification among individuals with intermediate coronary risk (meta-analysis NRI [95%CI]: 17.44 [8.04; 26.83]), but not overall. CONCLUSIONS: A multi-locus GRS based on genetic variants unrelated to CVRFs was associated with a linear increase in risk of CHD events in two distinct populations. This GRS improves risk reclassification particularly in the population at intermediate coronary risk. These results indicate the potential value of the inclusion of genetic information in classical functions for risk assessment in the intermediate risk population group.

[Trends in leisure time physical activity practice in the 1995-2005 period in Girona]. / Tendencias en la práctica de actividad física en el tiempo libre en el periodo 1995-2005 en Girona.

INTRODUCTION AND OBJECTIVES: The aims of the study were: to describe the distribution of physical activity practice; to determine the prevalence and trends of sedentary lifestyle in the population aged 35 to 74 years of Girona in the 1995-2005 period; and to identify the variables associated to sedentary lifestyle at the population level. METHODS: Data from three independent population-based cross-sectional studies undertaken in 1995 (n=1419), 2000 (n=2499), and 2005 (n=5628) were analyzed. Physical activity was measured using the Minnesota Leisure Time Physical Activity questionnaire. Sedentary lifestyle was defined as an energy expenditure in moderate physical activity (4-5.5 METs) <675 kcal/week or <420 kcal/week in intense PA (≥ 6 METs). Logistic regression was used to determine the variables associated with sedentary lifestyle. RESULTS: The age-standardized prevalence of sedentary lifestyle was 53.8%, 39.5%, and 32.6% in 1995, 2000, and 2005 respectively. The prevalence of sedentary lifestyle has decreased especially in women older than 50 years living in the urban areas. An increase in light and moderate physical activity practice in men older than 50 years and in light physical activity practice in women older than 50 years was observed. Female gender, age, smoking and lower educational level were associated with a higher prevalence of sedentary lifestyle. CONCLUSIONS: Prevalence of sedentary lifestyle has decreased in the 1995-2005 period in Girona, especially in women, but is still high. Health promotion programs should include physical activity practice as a key element and should take into account gender and social inequalities.

Waist circumference and impaired fasting glucose screening in a Mediterranean population.

We evaluate the merits of routine waist circumference measurements for screening of impaired fasting glucose (IFG). Waist circumference and body mass index showed a strong association with the risk of IFG. The present data indicate the need for routine anthropometric measurements in clinical practice screening for IFG.

Qualitative assessment of previous evidence and an updated meta-analysis confirms lack of association between the ESR1 rs2234693 (PvuII) variant and coronary heart disease in men and women.

BACKGROUND: Coronary heart disease (CHD) is the leading cause of mortality worldwide. CHD clusters in families but this familial aggregation remains largely unexplained. ESR1 is a candidate gene for CHD although recent meta-analyses of the rs2234693 variant reported inconsistent evidence for association with myocardial infarction (MI) in men. The objectives of this study were to perform a qualitative and a quantitative assessment of all evidence to date regarding this association. METHODS: We performed structured literature searches for studies addressing the association between the ESR1 rs2234693 and CHD. We assessed the quality of these studies collectively and individually according to recently published guidelines on the reporting and interpretation of genetic association studies. We also performed a meta-analysis of all studies to date, including a sample of MI cases and controls from our region. RESULTS: The qualitative assessment indicated that many studies met a low proportion of the criteria proposed by the current guidelines. No significant association between ESR1 rs2234693 and MI was observed in our sample or in the meta-analysis (16 studies; N approximately 32,000; OR approximately 1). Strong between-study heterogeneity was largely explained by a quality score based on the quality criteria. Studies that reported significant associations were generally of poorer quality. CONCLUSION: We confirm the lack of association between the ESR1 rs223469 and CHD, and show that inconsistencies between previous studies is explained by differences in their quality.

Acute myocardial infarction population incidence and in-hospital management factors associated to 28-day case-fatality in the 65 year and older.

BACKGROUND AND OBJECTIVES: The myocardial infarction (MI) incidence rate, prognosis and hospitalisation rate in the population 65 and over are rarely studied. We sought to determine MI hospitalisation and incidence rates, and 28-day case-fatality, in the 65 year and older population, and to analyse whether their management and prognosis differed from that of younger patients. METHODS: All residents in Gerona (Spain) older than 24 years with suspected fatal or non-fatal MI were investigated and included in a population registry. RESULTS: MI mortality, incidence, and case-fatality dramatically increased with age after 64. Smoking, thrombolysis, antiplatelet and betablocker drug use, coronary angiograms, and coronary revascularisation decreased with age. The risk of death of patients between 75 and 84 years (OR: 4.15, 95% confidence interval, CI: 1.70-10.15) and between 85 and 94 years (OR: 4.68, 95% CI: 1.62-13.52) was higher than in the 34-64 years age group, independently of any patient characteristic. CONCLUSIONS: The magnitude of the impact of MI in the elderly at population and hospital levels is substantially higher than in those younger than 65 years of age. After this age patients receive less treatments and procedures than their younger counterparts.