Evidence points epicardial adipose tissue (EAT) as an emerging cardiovascular risk marker. Whether genetic polymorphisms linked with atherosclerosis are associated with higher EAT is still unknown. We aim to assess the role of genetic burden of atherosclerosis and its association to EAT in a cohort of asymptomatic individuals without coronary disease. A total of 996 participants were prospectively enrolled in a single Portuguese center. EAT volume was measured by Cardiac Computed Tomography and participants were distributed into 2 groups, above and below median EAT. SNPs were genotyped and linked to their respective pathophysiological axes. A multiplicative genetic risk score (mGRS) was constructed, representing the genetic burden of the studied SNPs. To evaluate the association between genetics and EAT, we compared both groups by global mGRS, mGRS by functional axes, and SNPs individually. Individuals above-median EAT were older, had a higher body mass index (BMI) and higher prevalence of hypertension, metabolic syndrome, diabetes, and dyslipidemia. They presented higher GRS, that remained an independent predictor of higher EAT volumes. The group with more EAT consistently presented higher polymorphic burden across numerous pathways. After adjustment, age, BMI, and mGRS of each functional axis emerged as independently related to higher EAT volumes. Amongst the 33 SNPs, MTHFR677 polymorphism emerged as the only significant and independent predictor of higher EAT volumes. Patients with higher polymorphism burden for atherosclerosis present higher EAT volumes. We present the first study in a Portuguese population, evaluating the genetic profile of EAT through GWAS and GRS, casting further insight into this complicated matter.

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Background Hepatocyte nuclear factor4 A (HNF4A) gene was considered by GWAS associated with atherosclerosis and CAD susceptibility. Loss-of-function mutations in human hepatocyte nuclear factor 4α (HNF4α), a transcriptor factor encoded by the HNF4A gene, are associated with maturity-onset diabetes of the young and lipid disorders. However, the mechanisms underlying the lipid disorders are poorly understood. Aim We propose identifying the genetic predisposition to atherosclerosis progression and events occurrence or regression and better prognosis, through a cohort study from GENEMACOR population. Methods We investigated a cohort of 1,712 patients who underwent coronary angiography with more than 70% stenosis of at least one main coronary vessel. 33 SNPs associated with the risk of CAD in previous GWAS were genotyped by TaqMan assays methodology. We evaluated the best genetic model associated with CAD prognosis (events) with a 95% CI in bivariate analysis. The hazard function was performed by a Cox survival regression model adjusted for age, sex, type 2 diabetes, hypertension, and hypercholesterolemia, to evaluate their relationship with the event's incidence. Finally, we constructed Kaplan–Meier cumulative-event curves for the significant genetic variants. Results Our evaluation revealed a SNP paradoxically associated with protection from atherosclerosis progression and events occurrence: rs1884613 C>G in the HNF4A gene on chromosome 20 dominant model [OR=0.653; 95% CI (0.522–0.817); p=0.0002]. Cox survival regression model showed a CAD protective effect of HNF4A with a Hazard ratio (HR) of 0.771; p=0.007. The Kaplan-Meier cumulative event analysis disclosed that the CG+GG vs CC genotype of rs1884613 HNF4α was associated with a better prognosis (Breslow test, p=0.004) at the end of the follow-up. Conclusion We identified, in this study, one SNPs paradoxically associated with a better CAD prognosis rs1884613 in HNF4A. The HNF4A gene variants could induce loss of HNF4α function, modifying and modulating hepatic lipase and lipid metabolism conferring a beneficial effect on atherosclerosis progression and events occurrence. FUNDunding Acknowledgement Type of funding sources: None.

Introduction The new European SCORE2 estimates the combined risk of fatal and non-fatal cardiovascular (CV) events, in contrast with SCORE's use for CV mortality only. Although controversial, several studies point out that Coronary Artery Calcification (CAC) scoring could improve CV risk stratification in primary prevention. Purpose Assess the impact of including CAC score to the new SCORE2 in MACE prediction and CV risk stratification in an asymptomatic Portuguese population. Methods The new SCORE2 was calculated in a population-based cohort of 1,014 individuals (mean age 58.6±8.5 years) without known CV disease and diabetes. Population was stratified into three SCORE2 risk categories (low-, moderate- and high-risk). According to the Hoff's nomogram, CAC score was categorized into: low CAC (0≤CAC<100 or P<50); moderate CAC (100≤CAC<400 or P50–75) and high or severe CAC (CAC≥400 or P>75). Kaplan-Meier survival curves were estimated and a multivariate regression analysis predicted the MACE risk for both scores. C-statistic methodology evaluated the ability of CAC when added to the SCORE2 model in MACE prediction. Results Kaplan-Meier curves showed that the highest categories of both scores presented a worst survival. Cox regression analysis showed that the highest categories of both CAC and SCORE2 remained in the equation with an increased MACE risk (HR) of 3.69 (p=0.008) and 9.87 (p=0.005), respectively, when compared with the lowest categories. C-statistic demonstrated that the predictive value for MACE increased from 0.668 (SCORE2 model) to 0.787 when CAC was included (p=0.012), showing a better predictive and discriminative capacity for MACE. Conclusions Our results highlight the importance of adding CAC score to SCORE2 in primary prevention to improve cardiovascular risk stratification and MACE risk prediction. Larger prospective multicenter cohorts with longer follow-up should reproduce and validate these findings. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

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Background Increasing evidence points epicardial adipose tissue (EAT) as an emerging cardiovascular risk marker. Whether genetic polymorphisms are associated with a higher EAT burden is still unknow. Genetic risk score (GRS) is an emerging method that attempts to establish correlation between single nucleotide polymorphisms (SNPs) and clinical phenotypes. Aim Evaluate the role of genetic burden and its association to EAT. Methods 996 patients (mean age 59±8, 78% male) were prospectively enrolled in a single center. EAT was measured on cardiac CT using a modified simplified method. Patients were divided into 2 groups (above vs. below the median EAT volume). We studied different polymorphisms across the following gene-regulated pathways: oxidation, renin-angiotensin system, cellular, diabetes/obesity and dyslipidemia pathways. Genotyping was performed by TaqMan allelic discrimination assay. A multiplicative genetic risk score (mGRS) was constructed and represents the genetic burden of the different polymorphisms studied. To evaluate the relation between genetics and EAT volume, we compared both groups by: global mGRS, gene cluster/axis mGRS and individual SNPs. Results Patients with above-median EAT volume were older, had higher body mass index (BMI) and higher prevalence of hypertension, diabetes and dyslipidemia (p<0.05). Patients with higher EAT volumes presented a higher global mean GRS (p<0.001), with the latter remaining an independent predictor for higher EAT volumes (OR 1.3, 95% CI 1.2–1.5), alongside age and BMI. In the analysis by gene clusters, patients with more epicardial fat consistently presented a higher polymorphism burden (translated by a higher mGRS level) across numerous pathways: oxidation, renin-angiotensin system, cellular, diabetes/obesity and dyslipidemia. After adjusting for confounders and other univariate predictors of higher fat volume, the following have emerged as independently related to higher EAT volumes: mGRS comprising the genes of different clusters, age and BMI. Amongst the 33 genes analyzed, only MTHFR677 polymorphisms (a gene with a critical role in regulating plasma homocysteine levels) emerged as significantly related to higher EAT volumes in our population (OR 1.4, 95% CI: 1.100–1.684, p=0.005). Conclusion Patients with a higher polymorphism burden in genes involved in the oxidation, renin-angiotensin, cellular, diabetes/obesity and dyslipidemia pathways present higher levels of epicardial fat. This potential association seems to be independent from the expected association between epicardial fat and cardiovascular risk factors. To our knowledge, this is the first time such genetic profiling has been done, casting further insight into this complex matter. Funding Acknowledgement Type of funding source: None