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Introduction Lipoprotein(a) [Lp(a)] is an LDL-like molecule composed of a part of apolipoprotein(a) bounding covalently to apolipoprotein B-100. High plasma Lp(a) levels were associated with MACE in stable CAD patients. Recent research shows contradictory results in stable CAD patients with high Lp(a) plasmatic levels and impaired glucose metabolism in MACE occurrence. Purpose Investigate whether high Lp(a) levels were associated with MACE in CAD patients with impaired glucose metabolism, at an extended follow-up. Methods A prospective cohort of 1,127 CAD patients with impaired glucose metabolism (pre-diabetes and diabetes) was observed during 4.9±3.4 years. Pre-diabetes was considered when fasting plasma glucose ranged from 5.6 to 6.9 mmol/L, or hemoglobin A1c levels ranging from 5.7 to 6.4%. Lp(a) levels ≥30 mg/dL were considered high. Bivariate and multivariate Cox regression analysis evaluated the risk of Lp(a) ≥30 mg/dL for MACE occurrence. Kaplan-Meier curves estimated the survival probability for high and low Lp(a) levels. Results Of the patients with Lp(a) levels ≥30, 44.4% presented MACE and 32.0% had no MACE (p Conclusion Our study demonstrated that high Lp(a) levels were an independent predictor of MACE and cardiovascular mortality in a CAD population with impaired glucose metabolism. Lp(a) measurement may help further risk stratification for diabetes and pre-diabetes patients suffering CAD. With the recent development of drugs that selectively lower Lp(a) levels, this marker can become a clinical target for reducing CVD risk. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

Introduction Coronary artery disease (CAD) is a dynamic inflammatory disease caused by atherosclerosis. GWAS showed that ZNF259 rs964184 encoding zinc finger protein (ZPR1) was associated with dyslipidemia and CAD. Recent research found that ZPR1 transcription is up-regulated in the brain of mice fed a high-fat diet, influencing the cell cycle, apoptosis, and RNA metabolism in neurons. This process at the heart vessels may increase oxidative stress and CAD. Purpose Study the association between the ZNF259 rs964184 C>G polymorphism with dyslipidemia and CAD susceptibility in a Portuguese population. Methods A case-control study was performed with 3,160 individuals, namely 1,723 CAD patients (mean age 53.3±7.9; 78.7% male) and 1,437 controls (mean age 52.8±7.8; 76.3% male). Participants were stratified into two age groups (55 years). ZNF259 rs964184 C>G was genotyped and analysed using the dominant model (CG+GG vs CC). Multivariate logistic regression was performed in both age groups to investigate whether rs964184 polymorphism was associated with dyslipidemia and CAD susceptibility. Results The dominant model of ZNF259 was associated with dyslipidemia (OR=1.85; 95% CI: 1.22–2.79; p=0.003) and CAD (OR=1.46; 95% CI: 1.02–2.09; p=0.036) in the younger population under 45 years. In the >55 years group, this model was associated with dyslipidemia (OR 1.46; 95% CI: 1.06–2.01; p=0.020) but not with CAD. After multivariate logistic regression, the CG+GG remained an independent risk factor for CAD susceptibility only in the population Conclusion ZNF259 rs964184 is a risk factor for dyslipidemia in the whole population. Dyslipidemia may up-regulate ZPR1 transcription, enhancing the vulnerability of coronary endothelial cells to both oxidative stress and inflammatory response, increasing CAD susceptibility. This mechanism seems more relevant at the cellular level in young patients representing a possible prophylactic and therapeutic target, especially in this age group. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

Introduction The European Systematic Coronary Risk Evaluation (SCORE) has predicted a 10-year risk of CVD since 1986. It included only fatal CVD outcomes, underestimating the total CVD burden, especially for younger people. To counteract this issue, a new score was created (SCORE2) to estimate 10-year fatal and non-fatal CVD risk in Europeans without previous CVD or diabetes aged 40–69 years. Purpose Establish a comparison between SCORE and SCORE2 in terms of CV outcomes in a moderate-risk population. Methods A population of 1,178 individuals without CVD (mean age 53.3±6.9 years; 73.9 male) was stratified into three risk categories for SCORE and SCORE2: low, moderate and high-risk. Using t-test and Chi-square, we compared the two scores in terms of means and risk categories. Kaplan-Meier estimator evaluated MACE occurrence for each category of the two scores during an extended follow-up (mean of 5.2±3.4 years). MACE discriminative capacity of SCORE and SCORE2 was evaluated through C-index methodology. Results The means of the two scores were significantly different (p Conclusion SCORE2 enhanced the identification of individuals at higher risk of developing CVD and better discriminated MACE occurrence relatively to SCORE. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

Genome-wide association studies have identified several loci linked to coronary artery disease, and coronary atherosclerosis progression. However, the impact of the genetic contribution to MACE occurrence in sub-clinical atherosclerosis is unknown. Purpose This study intended to assess the relationship between a set of single nucleotide popymorphism (SNP) associated with CAD by GWAS and the MACE occurrence in an asymptomatic population. After that evaluate whether a wGRS englobing these variants is useful to estimate the prognostic. Methods Prospective study performed in an asymptomatic cohort from GENEMACOR population-based sample of 1114 subjects aged 51.7±8.3, 74.2 male, without prior coronary artery disease. Coronary Artery Calcium (CAC) score was assessed by coronary computed tomography (Agatston method), and two categories were considered 1–99 and >100. 33 SNP were evaluate to assess the significantly associated with prognostic. A weighted (wGRS) was constructed as the sum of the risk alleles weighted by the corresponding effect size (HR). Cox regression analysis adjusted for the main risk factors, calcium score (CAC) and wGRS to assess the risk of MACE during follow-up. Kaplan Meier assessed the survival. Results Of the studied 33 SNPs previously associated with CAD (GWAS), only 4 presented the significant association with MACE occurrence: CDKN2B-AS1 rs4977574, HNF4A rs1884613, APOE rs7412/rs429358A and GJA4A rs 618675. After Cox regression analysis the wGRS remained in the equation (HR=2.834); p=0.012, together with CAC score (HR 3.35); p=0.012; diabetes (HR=2.398); p=0.032 and age (HR=1.056; p=0.049. WGRS above the median presented a worst survival rate (p=0.006). Conclusion The wGRS englobing: CDKN2B-AS1 rs4977574, HNF4A rs1884613, APOE rs7412/rs429358A and GJA4A rs 618675 is independently associated with cardiovascular events in an asymptomatic population. CDKN2B-AS1 rs4977574 gene expression modulates the progression and severity of vascular calcification in vascular smooth muscle cells (VSMCs), HNF1α-AS1 is an important regulatory molecule in cancer biology and cardiovascular disease (its expression may regulate VSMCs, and high expression promotes atheroprotection). More research is crucial for understand prognosis in asymptomatic population. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPE

Introduction Coronary artery calcium (CAC) score has emerged as the most predictive cardiovascular risk marker in asymptomatic individuals, capable of adding prognostic information beyond the traditional risk factors (TRF). Genetic risk score (GRS) significantly improves cardiovascular genetic risk assessment at the individual level providing a more personalized measure of disease risk. Purpose We intend to evaluate which tool, added to TRF, is more valuable in predicting and discriminating cardiovascular events and death (MACE) - GRS or CAC score? Methods We performed a prospective study with 1153 participants without CAD history at baseline (74.2% male, age 51.7±8.3 years) during a mean follow-up of 5.4±3.4 years. We selected 14 SNPs previously associated with CAD presenting a risk (HR) for cardiovascular events ≥1. A weighted GRS was calculated, as the sum of these 14 risk alleles weighted by the corresponding effect size in prognostic (HR), and subsequently, subdivided into tertiles. CAC (Agatson) score was calculated in all participants and categorized into: low CAC (0≤CAC75). Two models were created with TRF baseline (hypertension, smoking, body mass index, dyslipidemia, diabetes, chronic kidney disease, physical inactivity): 1) plus wGRS and 2) plus CAC score categories. Cox Regression Analyses and C-statistic assessed the predictive and discriminative capacity of both models. Results For model 1, Cox regression presented an HR of 4.292 for TRF (p=0.007) and 2.713 for 3rd tertile of wGRS (0.036). A modest but statistically significant improvement in MACE discriminative capacity was verified by adding wGRS to TRF, increasing the C-statistic from 0.617 to 0.687 (ΔC=0.070; p=0.013). On the other hand, model 2 better discriminated MACE when the CAC score (C-statistic = 0.765) was added to TRF (ΔC=0.148; p=0.001). Cox regression displayed an HR of 4.42 for TRF (p=0.015) and an HR of 4.55 for high-risk CAC score (p=0.001). Conclusion Our results suggest that adding a polygenic risk score to conventional risk factors provides a modest improvement in the discrimination of first-onset MACE. However, the CAC score added to the traditional model allows better discrimination of MACE compared to wGRS. CAC score could be helpful for MACE prediction, at least in individuals belonging to the higher genetic risk group. However, further investigation is required before clinical implementation. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

Introduction The new SCORE2 provides risk estimates for the combined outcome of fatal and non-fatal cardiovascular disease (CVD) events, in contrast with SCORE's use for CVD mortality only. Genetic predisposition to CVD is not considered in SCORE2 for prevention and treatment. Purpose Evaluate the impact of adding a Genetic Risk Score (GRS) to the new European SCORE2 in MACE prediction and estimate the additional value in cardiovascular risk stratification in an asymptomatic Portuguese population. Methods A prospective study was performed in a population-based cohort of 1,100 individuals without known CVD and diabetes (mean age 53.3±6.9 years). For all included participants, SCORE2 was calculated and three risk categories were considered: low-, moderate- and high-risk. A 33-SNP GRS was constructed and two groups were analyzed: lower and higher than the GRS median. Kaplan-Meier survival curves were created and a Cox regression model was performed with the two scores to assess MACE risk. C-statistic methodology compared the model between SCORE2 solely and SCORE2 plus GRS. Results After Kaplan-Meier analysis for MACE occurrence, the high categories of SCORE 2 and GRS showed worst survival when compared to the lower categories (p Conclusions In this work, combining SCORE2 with multiple genetic loci gathered into a GRS, improved the identification of patients with the worst prognosis. This new tool may be of great utility in risk stratification in primary prevention. 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

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≤CAC75). 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

Primary biliary cholangitis is an autoimmune disease that mostly affects women. It is uncommon in women of childbearing age and the diagnosis during pregnancy is rare and can be challenging. Described here is a case of primary biliary cholangitis first manifesting during pregnancy, with the onset of pruritus, jaundice, biochemical liver abnormalities and positive antimitochondrial antibodies. Although treatment with ursodeoxycholic acid was started at the time of diagnosis, there was a progressive worsening of cholestatic biochemical markers throughout pregnancy. In addition, fasting hyperglycemia with polyhydramnios was diagnosed, consistent with gestational diabetes. She had a spontaneous preterm delivery at 31 weeks of gestation, of a newborn who was admitted to the neonatal intensive care unit but who subsequently had no long-term sequelae of preterm delivery. A maternal postpartum flare occurred. Treatment with ursodeoxycholic acid was well tolerated during pregnancy and lactation. info:eu-repo/semantics/publishedVersion

Introduction Coronary Heart Disease (CAD) is a multifactorial disease, including environmental and genetic risk factors. Current smoking, dyslipidemia and diabetes have a significant impact in long- term mortality and morbidity. However, several genetic variants associated with CAD but not with traditional risk factors (TRFs) has been reported to improve prediction of events and extended mortality, in younger CAD people. Aim To evaluate the clinical utility of a GRS composed by variants from GWAS associated to CAD but not with TRF to predict life-long residual risk in patients under 55 years old and a low level of TRFs. Methods We conducted a prospective study with 573 consecutive patients aged 150 mg/ml). We analysed several biochemical markers and performed a GRS with variants not associated with TRFs (TCF21 rs12190287, CDKN2B-AS1 rs1333049, CDKN2B rs4977574, PHACTR1 rs1332844, MIA3 rs17465637, ADAMTS7 rs3825807, ZC3HC1 rs11556924, SMAD3 rs17228212 and GJA4 rs618675). We studied the GRS association with a primary composite endpoint of all-cause vascular morbidity and mortality including recurrent acute coronary syndrome (myocardial infarct and unstable angina), coronary revascularization (coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI), re-hospitalization for heart failure, ischemic stroke and cardiovascular dead. Results A total of 573 patients were studied and followed up for a mean of 4.7±4.0 years. There were 169 recurrent cardiovascular events. The GRS was sub-divided into terciles, verifying that patients in the third tercile (high risk) had a higher number of risk alleles. Compared with the low-risk GRS tercile, the multivariate-adjusted HR for recurrences was 1.520 (95% CI 1.011–2.286); p=0.044 for the intermediate-risk group and was 2.051 (95% CI 1.382–3.044); p Conclusions A multilocus GRS may identify young coronary disease patients with a low level of TRFs but at significant risk of long-term events recurrence. The genetic information may improve prediction discrimination, and reclassification over the conventional risk factors alone, providing better cost-effective therapeutic strategies. Funding Acknowledgement Type of funding sources: None. Figure 1

Introduction Epicardial adipose tissue (EAT) volume can be noninvasively detected by CT and has been suggested to predict major adverse cardiovascular events (MACE). Framingham Risk Score is one of a number of scoring systems used to determine an individual's chances of developing cardiovascular disease, hence identifying who is most likely to benefit from prevention. Objectives The purpose of this study was to determine net reclassification improvement (NRI) and improved risk prediction based on EAT volume, in comparison to a traditionally known cardiovascular risk score, such as the Framingham. Methods 895 asymptomatic volunteers were prospectively enrolled in a single Portuguese center (mean age 51.9±7.7, 78.5% male) and underwent a median follow-up time of 3.7 years (IQR 5.0). EAT volume was measured by Cardiac Computed Tomography (CCT) using a modified simplified method. For NRI assessment, EAT volume as a continuous variable was added to the Framingham Risk Score. Results After 3.7 median years of follow-up, 27 patients developed a MACE. Using NRI, the net proportion of events (netNRIe) that assigned a higher risk was 33.3% (better reclassified), and the net ratio of non-events (netNRIne) was 24.7%, resulting in a net reclassification index (netNRI) of 58.0%. When the new marker was included in the model, 58.0% of patients were better reclassified. In our work, a total of 33.3% of patients who suffered events (n=27) were correctly reclassified and assigned a higher risk. Conclusion EAT volume results in a high reclassification rate in an asymptomatic, low-risk population, demonstrating the benefit of this marker beyond traditional risk assessment models. Our study supports its application, especially in carefully selected individuals. Funding Acknowledgement Type of funding sources: None. Figure 1

Introduction Epicardial adipose tissue (EAT) is an emerging cardiovascular risk marker. It has been suggested to be an inflammatory mediator with a role in subclinical atherosclerosis and coronary artery disease. However, its prognostic relevance in hard clinical outcomes remains thoroughly unexplored in the literature. Purpose Evaluate the prognostic relevance of EAT, regarding the occurrence of major adverse cardiovascular events (MACE) in an asymptomatic population. Methods 895 asymptomatic volunteers were prospectively enrolled in a single Portuguese center (mean age 51.9±7.7, 78.5% male) and underwent a median follow-up time of 3.7 years (IQR 5.0). EAT volume was measured by Cardiac Computed Tomography (CCT) using a modified simplified method. Participants were distributed into two groups, above and below the EAT-volume median. We compared both groups regarding the occurrence of MACE through univariate analysis, Kaplan-Meier Survival curves and log-rank test. Association to subclinical atherosclerosis was addressed using correlation between EAT volume and calcium score (Agatson). Results There is a strong correlation between EAT volume and calcium score (r=0.205, p Conclusion In an asymptomatic population, EAT volume seems to be related to subclinical atherosclerosis and to the occurrence of adverse cardiovascular events on long-term follow-up. Our study addresses some unanswered questions, such as the prognostic relevance of EAT as an emerging cardiovascular risk marker. Funding Acknowledgement Type of funding sources: None.

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. Funding Acknowledgement Type of funding sources: None.

Background Metabolic syndrome (MetS) is a clinical condition composed of metabolic and cardiovascular risk factors, such as abdominal obesity, hyperglycemia, dyslipidemia and hypertension. Many patients with MetS suffer major adverse cardiovascular events (MACE) that are not adequately identified by traditional risk assessment, suggesting the need for early detection of subclinical coronary heart disease to identify those at high-risk. Coronary artery calcification (CAC) screening has added utility in categorizing patients with low, intermediate and high cardiovascular risk. Purpose Evaluate the prognostic role of CAC score in asymptomatic population patients with metabolic syndrome in cardiovascular events risk prediction. Methods A total of 1,122 asymptomatic individuals without known coronary heart disease, enrolled from GENEMACOR study, were followed for a mean of 5.3±3.4 years for the primary endpoint of all-cause of cardiovascular events. All were referred for computed tomography for the CAC scoring assessment. According to the Hoff's nomogram, 3 categories were created: low CAC (0≤CAC75). In a subgroup of 507 individuals with MetS and 615 controls, CAC values were compared by T-student and association of CAC severity with events occurrence was evaluated. Finally, a logistic regression model adjusted for CAC severity was performed in patients with MetS. Results Among our population, the extent of CAC differs significantly between men and women in the same age group. Patients with Mets (23.2%, n=115) had higher CAC scores than controls (219.0±486.0 vs 115.8±370.8, p Conclusion Our results point to the importance of the inclusion of CAC screening in patients with MetS to further stratify those patients that, despite tight control of cardiovascular risk factors, may benefit from more intensive therapies. This tool is a useful and straightforward method that could have a significant impact on the prognosis of future cardiovascular disease in patients with MetS. Funding Acknowledgement Type of funding sources: None.

Introduction TCF21 is expressed in cells that migrate into the developing plaque facilitating the repair of the vessel wall. However, the rs12190287 risk allele (C) of TCF21 can lead to reduced TCF21 expression being a risk factor for CAD. Purpose Investigate whether the variant rs12190287 G>C of TCF21 gene represents a risk factor for CAD in a Southern European population. Methods Case-control with 3139 individuals, 1723 CAD patients and 1416 controls, adjusted for age and gender. Genotyping of TCF21 rs12190287 G>C was performed by TaqMan Real-Time PCR. CAD association of each genetic model was evaluated. Multivariate logistic regression analysis adjusted for confound variables: smoking status, dyslipidemia, diabetes, physical inactivity, and hypertension, was made. Results TCF21 rs12190287 G>C has shown significant genotypic differences between cases and controls: GG 9.5% vs 11.9%; GC 43.2% vs 46.5% and CC 47.3% vs 41.6%. CAD risk was significant in all models: dominant (OR 1.28; 95% CI: 1.02–1.61; p=0.033); recessive (OR 1.26; 95% CI: 1.09–1.45; p=0.001); additive (OR 1.20; 95% CI: 1.08–1.34; p=0.001). After multivariate analysis, TCF21 variant was independently associated with CAD. Conclusion TCF21 variant rs12190287 G>C may be a risk factor for CAD. It is plausible that TCF21 loci exert its protective effect by promoting infiltration of fibromyocytes in the coronary wall lesion and fibrous layer and loss of TCF21 expression can result in fewer fibromyocytes to fibrous cap increasing vulnerability of the plaque. Funding Acknowledgement Type of funding sources: None. Variables associated with CAD risk

Alvarez waves are local rhythmic contractions of the myometrium with high frequency and low intensity. They can be detected using internal or external tocography and electrohysterography. Some researchers correlate these small contractions with the initiation of labor, since they have been described as a pattern representing the uterine response to prostaglandin production. Other authors either do not validate a causality relation between Alvarez waves and labor or suggest that they have low predictive value for preterm labor. Alvarez waves' research has become a multidisciplinary subject with inputs ranging from medical science, biomedical engineering, and related areas. A comprehensive review is herein conducted to summarize the state of the art regarding Alvarez waves and their role in the initiation of labor, namely in preterm birth. The results show that a large number of studies have analyzed and characterized Alvarez waves without necessarily digging into their relationship with labor. Publications were categorized in three groups: (A) reports about morphology and characterization of Alvarez waves; (B) publications reporting a positive causality relation between Alvarez waves and labor; and (C) publications reporting an absence of causality regarding the previous hypothesis. Studies in group B outnumbered those in group C. A critical analysis is presented. info:eu-repo/semantics/publishedVersion

Funding Acknowledgements Type of funding sources: None. OnBehalf GENEMACOR Introduction After the diagnosis of coronary artery disease (CAD), traditional risk factors such as diabetes mellitus, dyslipidemia, hypertension and smoking have been used to assess the risk of major cardiovascular adverse events (MACE). However, despite reduction of these factors, presence of MACE remains high. It is necessary to identify other causal risk factors for MACE in coronary patients and increased plasma Homocysteine (Hcy) level seems to be a likely candidate. However, the influence of Hcy levels in the prognosis of coronary patients presents a limited knowledge. Objective To evaluate the influence of high level of Hcy in MACE (defined as a composite endpoint of cardiovascular death, acute myocardial infarction, stroke, admission for heart failure and need to revascularization) of coronary artery patients. Materials and Methods Study analyses of 1687 patients selected from GENEMACOR study population, with at least one > 75% coronary stenosis by angiography. That population was divided in three terciles according to the Hcy level and the population of the 2nd tercil (Hcy 11.1-13.6mmol/L) was excluded. The end population of 1118 patients was a median age of 53.1 ± 7.9 years and 77.6% were men. We compared patients in the 1st (Hcy < 11.1mmol/L) and 3rd tercil (Hcy > 13.6mmol/L) during a mean follow up of 5.0 ± 4.8 years. Results 560 (50.1%) patients were included in the 1st tercil group (median age 51.6 ± 3 years, 72.0% men) and 558 (49.9%) patients were in the 3rd tercil group (median age 54.6 ± 3 years, 83.3% men). In our population, high levels of Hcy were associated with MACE (OR 1.43, 95% CI: 1.12-1.83, p 0.004). Conclusion In our population a higher level of Hcy was associated with adverse prognosis and increased occurrence of MACE. Knowing that elevated homocysteine levels are associated with increased risk of MACE, in these patients is essential to have a more intensive therapeutic strategy.

Funding Acknowledgements Type of funding sources: None. Introduction Coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide. We know that plasma level of LDL cholesterol (LDL-C) is strongly associated with atherosclerosis, and its reduction with statins has led to a decrease in the incidence and complications of CAD. According to the 2019 ESC guidelines, in high-risk patient the aim is to achieve an absolute LDL-C treatment goal of Objective To evaluate the degree of LDL-C control in coronary artery disease patients according to ESC guidelines. Materials and Methods Study analyses of 1687 patients selected from GENEMACOR study population, with at least one > 75% coronary stenosis by angiography (median age 53.3 ± 3 years and 54.8% men). LDL-C was determined by chemical methods and all patients were statin treated. The population was divided in four groups according to LDL-C levels: inferior to 55mg/dL, inferior to 70mg/dL, inferior to 115mg/dL and superior to 115mg/dL. Results LDL-C mean value was 108.7mg/dL, median 105.1mg/dL (P25 83.0 and P75 127.4mg/dL). 150 (8.9%) patients had LDL-C < 55mg/dL vs 1537 (91.1%) with LDL-C ≥ 55 mg/dl. 275 (16.3%) patients had LDL-C < 70 mg/dL vs 1412 (83.7%) with LDL-C ≥ 70 mg/dL. 1084 (64.3%%) patients had LDL < 115 mg/dL vs 603 (35.7%) with LDL-C ≥ 115 mg/dL. Conclusion In our population LDL-C control levels was low, with 91.1% patients with LDL-C ≥ 55mg/dL and 83.7% patients with LDL ≥ 70 mg/dL. It is interesting to note that most of our patients have LDL-C levels above the recommend by the newest and, surprisingly, the 2016 dyslipidemia guidelines. It is therefore important to implement a more intensive treatment strategy of dyslipidemia in coronary patients.

Cardiovascular diseases are the main cause of mortality worldwide, and childhood excess weight/obesity are strong correlators of accumulated risk in later life. A relationship between maternal preeclampsia and offspring’s childhood obesity is recognized, but most studies fail to control for strong confounders. Our goal is to analyze the association between preeclampsia and childhood excess weight/obesity, after accounting for important confounders. We recruited 5133 women with singleton pregnancies during admission for delivery. Sixty-seven pregnancies were complicated by preeclampsia. Maternal and children outcomes were assessed at 10 years of age. We analyzed the association between preeclampsia and childhood excess weight/obesity by fitting a linear regression model (using offspring body mass index (BMI) z-score at 10 years of age) and a logistic regression model (using excess weight/obesity status). We then controlled both models for known confounders, namely maternal prepregnancy BMI, parity, and smoking during pregnancy. At 10 years of age, offspring of preeclamptic mothers had a higher BMI z-score and were more likely classified as overweight/obese, but these differences were not statistically significant. After controlling for maternal prepregnancy BMI, parity, and smoking during pregnancy, there was a high magnitude change in the beta coefficient of preeclampsia in the linear (0.175; −0.014) and the logistic regression models (1.48; 1.23) suggesting that the association between preeclampsia and childhood excess weigh/obesity is significantly confounded by these variables. These confounders also showed a significant association with childhood obesity. This finding suggests that in utero exposure to preeclampsia seems to have less impact in childhood obesity than the previously described confounders. This work was funded by Programa Operacional de Saúde – Saúde XXI, Quadro Comunitário de Apoio III and Administração Regional de Saúde Norte (Regional Department of Ministry of Health); FEDER through the Operational Programme Competitiveness and Internationalization and national funding from the Foundation for Science and Technology – FCT (Portuguese Ministry of Science, Technology and Higher Education) (POCI- 01- 0145-FEDER-016837), under the project “PathMOB.: Risco cardiometabólico na infância: desde o início da vida ao fim da infância” (Ref. FCT PTDC/DTP-EPI/3306/2014); Unidade de Investigação em Epidemiologia -Instituto de Saúde Pública da Universidade do Porto (EPIUnit) (POCI-01-0145-FEDER-006862; Ref. info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID/DTP/04750/2013/PT).

Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease associated with major obstetrical complications such as gestational loss, preterm delivery, fetal growth restriction (FGR) and preeclampsia. Published literature is not consensual regarding the main risk factors for each of these outcomes. Our goal with this study was to determine the most important predictors for each of the main adverse pregnancy outcomes in this population. We conducted a retrospective cohort study of unifetal pregnancies of women with the diagnosis of SLE followed in our unit between January 1994 and December 2016. We excluded elective terminations of pregnancy and cases lost to follow-up and we analyzed 157 pregnancies (128 women). Multiple logistic regression models for the outcomes gestational loss, preterm delivery, fetal growth restriction, and preeclampsia were built. Two-sided p-values of

Background Despite being a controversial subject, multiple guidelines mention the use of Coronary Artery Calcification (CAC) scoring in the cardiovascular risk prediction, in asymptomatic population. The inclusion of CAC scoring in traditional risk models may help in decision-make providing better cardiovascular risk stratification. Purpose The aim of our study is to estimate the impact of CAC scoring in cardiovascular events risk prediction in a model based on traditional risk factors (TRFs). Methods and results The study consisted of 1052 asymptomatic individuals free of known coronary heart disease, enrolled from GENEMACOR study and referred for computed tomography for the CAC scoring assessment. A cohort of 952 was followed for a mean of 5.2±3.2 years for the primary endpoint of all-cause of cardiovascular events. The following traditional risk factors were considered: (1) current cigarette smoking, (2) dyslipidemia, (3) diabetes mellitus, (4) hypertension and (5) family history of coronary heart disease. Among this population, the extent of CAC differs significantly between men and women in the same age group. Therefore, the distribution of CAC score by age and gender was done by using the Hoff's nomogram (a). According to this nomogram, 3 categories were created: low CAC (0≤CAC75). Two Cox regression models were created, the first only with TRFs and the second adding the CAC severity categories. When including CAC categories to the TRFs, the higher severity level presented a significant risk of MACE occurrence with an HR of 4.39 (95% CI 1.83–10.52; p=0.001). Conclusion Our results point to the importance of the inclusion of CAC in both primary and secondary prevention to an improved risk stratification. Larger prospective multicentre cohorts with longer follow-up should reproduce and validate these findings. Funding Acknowledgement Type of funding source: None

Background TCF21 gene, encodes a basic-helix- loop- helix transcription factor, playing a critical action in the development of epicardial progenitor cells that give rise to coronary artery smooth muscle cells (SMC) and cardiac fibroblasts. Recent data suggest that TCF21 may play a role in the state of differentiation of SMC precursor cells that migrate to vascular lesions and contribute to fibrous cap. Purpose Investigate the association of TCF21 rs12190287G>C variant with coronary artery disease (CAD) in a Portuguese population and its role on the prognosis. Methods Case-control study with 3120 participants, 1687 coronary patients with at least 75% obstruction of a major coronary artery and 1433 controls. Genotyping used the TaqMan technique (Applied Biosystems) and then a univariate and multivariate logistic regression analysis were performed. After a mean follow-up of 5.01±4.2 years (interquartile range 1.96–7.57), the occurrence of the combined Major Adverse Cardiovascular Events (MACE) (Cardiovascular Mortality, non-fatal Myocardial Infarction, new Revascularization, Cerebrovascular Disease and Peripheric Vascular Disease) were registered and analysed by Cox regression. Finally, Kaplan-Meier survival estimate was performed. Results In the total population, GC+CC genotype was found to be associated with CAD with an OR of 1.285; CI: 1.022–1.614; p=0.031. After multivariate logistic regression, adjusted to traditional risk factors, the association with CAD remained significant for this genotype (OR=1.340; CI: 1.042–1.723; p=0.022).After Cox regression adjusted for confounding variables (age and sex, hypertension, diabetes, smoking, dyslipidemia, eGFR, Ejection fraction Conclusion The mutated TCF21 variant can provide a new marker to identify patients at high cardiovascular risk and may representa potential target for gene therapy in future. Figure 1 Funding Acknowledgement Type of funding source: None

Introduction Coronary artery disease (CAD) is the leading cause of death worldwide, placing a major economic and resource burden on health and public health systems, so efforts are being made to accurately predict risk for major adverse cardiac events (MACE). The field of risk prediction and CAD prevention continues to evolve with the identification of novel risk factors and biomarkers, such as lipoprotein a [Lp)a]. Almost 20% of the population has elevated circulating levels of Lp(a), which is recognized as an independent risk factor for CAD, stroke, peripheral arterial disease, and aortic stenosis. Importantly, studies showed that this was particularly true for women. Objective To evaluate if the elevation of Lp(a) is associated with MACE in female, male or both. Materials and methods Case control study of 3050 subjects from the GENEMACOR study population. In female population (n=676): cases were 341 patients with at least one >75% coronary stenosis (median age 55.7±7.2) and 335 normal controls (median age 55.8±6) adjusted by age with cases. In male population (n=2374): 1278 patients with at least one >75% coronary stenosis (median age 52.7±8) and 1096 controls (median age 51.9±8) also adjusted by age. χ2 and T student tests were used to analyze the demographic, laboratorial, angiographic and anthropometric characteristics of the population. Lipoprotein (a) was determined by immunoturbidimetry. High Lp(a) level was considered if superior to 30 mg/dl. Logistic regression was used to evaluate Lp(a) as a risk factor for CAD in total, female and male populations. Results In female population 44.0% patients vs 21.2% controls (p30mg/dl. In male population 39.4% patients vs 23.8% controls (p30mg/dl. In total population Lp(a)>30mg/dl was a predictor for CAD (OR 2.24, 95% CI: 1.91–2.62, p30mg/dl was also a predictor for CAD either in male (OR 2.08, 95% CI: 1.74–2.5, p Conclusions As opposed to other studies, in our population elevated Lp(a) levels (>30mg/dl) were associated with elevated CAD risk, in both men and women. We conclude that Lp(a) can be considered an independent risk factor for CAD disease in our population, and further strategies for Lp(a) reduction may indeed translate in improved outcomes in CAD disease.

A recent GWAS study found a significant association between the BUD13-ZNF259 rs964184 polymorphism, dyslipidemia and the onset of coronary disease (CAD). This variant encoding zinc finger protein (ZPR1) interacts with the receptor tyrosine kinase at cellular level, increasing oxidative stress, inflammatory response and atherogenesis. There are no studies of the effect of this variant on the Portuguese population. Objective Investigate the association of BUD13-ZNF259 rs964184 with dyslipidemia and its impact on CAD risk. Evaluate its impact in different age groups of our population. Methods A case-control study was performed with 3050 subjects (1619 coronary patients with 53.3±8 years; 78.9% male and 1431 controls with 52.8±8 years; 76.6% male) from the GENEMACOR study population. Traditional risk factors (smoking, dyslipidemia, diabetes, family history, hypertension, body mass index, alcohol consumption, physical inactivity) and others considered new, such as creatinine clearance, pulse wave velocity, homocysteine, fibrinogen, lipoprotein (a), APOB and PCR (hs) were investigated. BUD13-ZNF259 variant was genotyped and analyzed using the dominant model (CG + GG vs. CC). Bivariate and multivariate analyzes (logistic regression) were used to estimate the ORs and 95% CI, after adjusting for potential confounding factors, in 3 different age groups (55). Results BUD13-ZNF259 polymorphism presented an independent and significant risk of CAD (OR=1.58; 95% CI: 1.07–2.32; p=0.019) only in the group of young coronary patients Conclusion BUD13-ZNF259 rs964184 variant showed a significant risk for the onset of CAD in the young population (

Introduction The complex interaction between genes and environmental factors contribute to individual-level risk of coronary artery disease (CAD), often resulting in premature CAD. The role for genetic risk scores in premature CAD is still controversial. Objective To evaluate the importance of conventional risk factors and of a genetic risk score in younger and older patients with coronary artery disease Methods From a group of 1619 pts with angiographic documented CAD from the GENEMACOR study, we selected 1276 pts admitted for ACS and analysed them in 2 groups (group A: ≤50 years, n=491 pts, 87.2% male, mean age 44±4.9 and group B: >50 years, n=785 pts, 75.2% male, mean age 57±4.2). Univariate analysis was used to characterize the traits of each group and we used ROC curves and respective AUCs to evaluate the power of genetics in the prediction of CAD, through a Genetic Risk Score (GRS). Results 99.3% of the young patients had at least one modifiable risk factor, 18.4% had 2 modifiable risk factors and 75.2% had 3 or more modifiable risk factors. The pattern of risk factors contributing to CAD were different among groups: family history (A: 27.5%, B: 21.4%, p=0.015) and smoking habits (A: 64.8%, B: 42.9%, p0.805, p=0.0178 and 0.748->0.761, p=0.0007 in patients under and over 50, respectively). Conclusion Coronary artery disease is not all the same, as premature CAD shares a unique and specific pattern of risk factors, clinical presentation, angiographic severity and prognosis. Genetics should not be used as an excuse to justify premature CAD, as there is frequently more than one potentially reversible risk factor present even in young patients and the additive predictive value of GRS is modest.

Type 2 Diabetes (T2D) is a risk factor for dysregulation of glomerular filtration rate (GFR) and albuminuria. However, it remains unclear whether this association is only causal. Genetic variants are inherited independent of potential confounding factors and represent a lifetime exposure. Aim Investigate whether the reduction of GFR is a direct consequence of T2D or there are other genetic mechanisms involved in the pathophysiology of the evolution to chronic kidney disease. Methods Cross-sectional study with a total of 2579 individuals was performed, of which 735 patients had T2D. Subjects were classified as `'diabetic” if they were taking oral anti-diabetic medication or insulin or if their fasting plasma glucose was higher than 7.0 mmol/l or 126 mg/dl. Within the diabetic group, we considered those with (n=63) and without (n=627) decreased GFR. GFR was calculated through the Cockcroft and Gault formula and decreased GFR was defined as GFR120 mg/ml, dyslipidemia, alcohol consumption, CAD diagnosis). A logistic regression was performed firstly with the risk factors solely; and secondly adding the genetic variants in order to evaluate the independent predictors of progression to renal failure in T2D. Results After the first multivariate logistic regression with all the risk factors for decreased GFR, only CAD remained in the equation, showing to be an independent risk factor for progression to renal failure, in T2D (OR=4.17; 95% CI: 1.64–10.59; p=0.003). In the second logistic regression, including risk factors and the genetic variants, only ZNF259 rs964184 showed an independent and significant association with the risk of decreased GFR (OR=3.03; 95% CI: 1.06–8.70; p=0.039). Conclusion This study shows that the variant ZNF259 rs964184 is associated with decreased kidney function, independently of other risk factors. This finding needs further investigation to clarify the genetic mechanism behind the association of rs964184 with decreased GFR, in Type 2 diabetes.

Introduction Coronary artery disease (CAD) is a multifactorial process with substantial genetic contribution. However, genetic predisposition among patients with a different number of lifestyle factors and premature CAD, remains a complex and thoroughly unexplored topic. Objective To evaluate, in a young population, the importance of conventional risk factors as well as of a genetic risk score in the appearance of CAD. Methods A case-control study was conducted with 1075 patients from the GENEMACOR study population, under 50 years-old (555 cases, 86.8% male, mean age 44.1±4.9 years and 520 controls, 86.2% male, mean age 44.3±4.8 years). Univariate analysis addressed the association of different modifiable risk factors with premature CAD. Genetic risk score (GRS) was computed comprising 33 genetic risk variants in a multiplicative method. GRS was evaluated according to the number of traditional risk factors and risk for premature CAD was estimated and its independent predictive value estimated by logistic regression. Results 72.6% of patients had ≥3 risk factors vs 31.2% of controls (p Conclusion In our population, GRS was an independent predictor for premature CAD. In young patients with ≥3 risk factors, genetics play a less decisive role in the development of CAD. Even in young patients, modifiable risk factors should be addressed aggressively as they may represent a higher burden than genetic predisposition itself.

Uterine contractions’ monitoring has been pointed out as an important tool that may be useful in the preterm risk assessment, term birth estimation and uterine physiology investigation. The multichannel EHG provides a mapping of the myometrium electrical activity projection on the selected channels, providing a wealth of information, including pacemaker regions, signal propagation and contraction amplitude and spectral characteristics. The EHG multichannel data representation, regarding contractile activity, presents an interpretation challenge, given the presence of the multiple contractions of, possibly, different types, in the respective acquisition channels, for different recording sessions and gestational ages of one or multiple pregnant subjects. Typically, an EHG dataset contains data from various subjects, for which multiple recording sessions could be performed, possibly leading to hundreds of recordings. The post-processing step of this data for contraction retrieval may result in multidimensional datasets, requiring interpretation in multiple research scenarios. In this work, a novel representation method is introduced, the Contractiongram, an intuitive graphical tool to facilitate the interpretation of the EHG contractile data for a subject or a whole dataset, throughout the pregnancy, including multisession acquisition scenarios. An application example is presented for a widely used open access EHG database. A contraction detection and classification were a result of a previous research work and used as a data pool for this study. The graphical representation obtained in the current study is a suitable tool for the identification of uterine contraction patterns in selected channels corresponding to different myometrial regions, in designated gestational ages.

The uterine electromyogram, also named Electrohysterogram (EHG), is a non-invasive technique that has been used for pregnancy and labour monitoring as well as for research work on uterine physiology. This technique is well established in this field. There is however a vast unexplored potential in the EHG that is currently the subject of interdisciplinary research work involving different scientific fields such as medicine, engineering, physics and mathematics. In this paper, an unsupervised clustering method is applied to a previously obtained set of frequency spectral representations of the respective EHG signal contractions that were previously automatically detected and delineated. An innovative approach using the complete spectrum projection is described, rather than a set of relevant points. The feasibility of the method is established despite the concerns of possible computational burden incurred by the processing of the whole spectrum. Given the unsupervised nature of this classification, a validation procedure was performed whereas the obtained clusters were labelled through the correlation with the common knowledge about the most relevant uterine contraction types, as described in the literature. As a result of this study, a spectral description of the Alvarez contractions was obtained where it was possible to breakdown these important events in two different types according to their spectrum. Spectral estimates of Braxton-Hicks contractions were also obtained and associated to one of the clusters. This led to a full spectral characterization of these uterine events.

The progression of hypertensive heart disease leads to the left ventricular diastolic dysfunction (LVDD), which is associated with increased cardiovascular morbidity and mortality. The purpose of this analysis is to explore the determinants for LVDD in patients with hypertension.This is a secondary analysis of data of Impedance Cardiography in the Evaluation of Left Ventricular Diastolic Dysfunction in Patients with Arterial Hypertension (IMPEDDANS) Study. Mann-Whitney and Chi-square tests were used for univariable analysis. Multiple logistic regression was used to model for LVDD occurrence and discriminative capacity of the model assessed by the value of the area under the curve given by the receiver-operating characteristic curve.Older age (65 vs. 58 years, p0.001), longer duration of hypertension (160 vs. 48 months, p0.001), uncontrolled hypertension (59.8 vs. 15.9%, p0.001), tobacco smoking (17.8 vs. 3.8%, p=0.016), higher systolic blood pressure (133 vs. 124mmHg, p=0.001) and slower heart rate (62 vs. 66bpm, p=0.023) were associated with LVDD. Multivariate model identified uncontrolled hypertension (AdjOR 36.90; 95% CI 7.94-171.58; p0.001), smoking (AdjOR 6.66; 95% CI 1.63-27.26; p=0.008), eccentric hypertrophy (AdjOR 3.59; 95% CI 0.89-14.39; p=0.072), duration of hypertension (AdjOR 1.03; 95% CI 1.02-1.05; p0.001) and concentric remodeling (AdjOR 0.19; 95% CI 0.04-0.93; p=0.041) as the more determinant for occurrence of LVDD. The discriminative capacity of the model was AUC=0.95 (95% CI 0.91-0.98).The occurrence of LVDD in hypertensive patients was strongly associated to long-lasting, uncontrolled hypertension, tobacco smoking, concentric remodeling and eccentric hypertrophy.

The prevalence of malnutrition in ambulatory patients with heart failure is difficult to determine, depending on the timing and methodology.To determine the nutritional status of outpatients with systolic heart failure with the Mini Nutritional Assessment (MNA) full and short-form versions, and evaluate its relationship with the short-term prognosis, biomarkers and quality of life.Fifty consecutive (70% male), geriatric (74.3+ 6.2years old) stable outpatient with heart failure (NYHA class II 68%, III 32%) and left ventricular ejection fraction of 26.7 +11.5% were included and followed during 12 months. At a routine visit to the heart failure clinic, the MNA, the Minnesota Living with Heart Failure questionnaire (MLHFQ) were applied. According to the MNA screening score the nutritional status was classified using the MNA full (MNA-F) and the short-form (MNA-F) versions of the questionnaire. The recorded events were death and hospitalization.The survival and hospitalizations curves were evaluated with the Log-Rank test and Cox Regression analysis. The association between parameters was analyzed with the Pearson and Spearmann correlation coefficient.(1) The mortality and hospitalization rates were 12% and 42%, respectively. (2) With the MNA-SF 7.6% of the patients had malnutrition and 20% were at risk of malnutrition. There was a good agreement (90%) between the MNA-SF and the MNA-F classifications. (3) There was a significant relationship between the MNA screening score and the MLHFQ (rs= -0.592 p0.001), Nt-ProBNP (rs= -0.49 p0.001) and total plasma protein (r= 0.672 p=0.006); (3) The MNA-SF nutritional classification was associated with the 12 months survival (Log-Rank p=0.044) and hospitalization (Log-Rank p=0.005) curves. (4) Those patients with malnutrition by the MNA-SF were at greater risk of death (HR= 8.0 p=0.059) and hospitalization (HR 8.1 p=0.008).The MNA is useful for the evaluation of the nutritional status of elderly outpatients with systolic heart failure. It is a good predictor of the short-term outcome and is also associated with the quality of life and Nt-ProBNP.

Funding: This study was supported by the European Regional Development Fund’s Operational Programme for the Enhancement of Economic Potential and Territorial Cohesion for the Autonomous Region of Madeira (INTERVIR ). Recent genetic studies have revealed an association between polymorphisms at the ADAMTS7 gene locus and coronary artery disease (CAD) risk. Functional studies have shown that a CAD-associated polymorphism (rs3825807) affects ADAMTS7 maturation and vascular smooth muscular cell (VSMC) migration. Here, we tested whether ADAMTS7 (A/G) SNP is associated with cardiovascular (CV) survival in patients with established CAD. A cohort of 1,128 patients with angiographic proven CAD, who were followed up prospectively for a mean follow- up period of 63 (range 6-182) mo, were genotyped for rs3825807 A/G. Survival statistics (Cox regression) compared heterozygous (AG) and wild-type (AA) with the reference homozygous GG. Kaplan- Meier (K-M) survival curves were performed according to ADAMTS7 genotypes for CV mortality. Results showed that 47.3% of patients were heterozygous (AG), 36.5% were homozygous for the wild-type allele (AA) and only 16.2% were homozygous for the GG genotype. During the follow-up period, 109 (9.7%) patients died, 77 (6.8%) of CV causes. Survival analysis showed that AA genotype was an independent risk factor for CV mortality compared with reference genotype GG (HR = 2.7, P = 0.025). At the end of follow-up, the estimated survival probability (K-M) was 89.8% for GG genotype, 82.2% for AG and 72.3% for AA genotype (P = 0.039). Carriage of the mutant G allele of the ADAMTS7 gene was associated with improved CV survival in patients with documented CAD. The native overfunctional ADAMTS7 allele (A) may accelerate VSMC migration and lead to neointimal thickening, atherosclerosis progression and acute plaque events. ADAMTS7 gene should be further explored in CAD for risk prediction, mechanistic and therapeutic goals. publishersversion published

BACKGROUND AND AIM: Sulfur amino acids are recognized as potent modulators of lipid metabolism. Plasma total cysteine (tCys) is associated with fat mass, obesity and serum LDL-cholesterol and apolipoprotein (Apo)-B in large population studies. It is not known how fasting plasma concentrations of cysteine precursors and products relate to these associations in humans, given that sulfur-containing compounds (SCC) influence rodent weight gain and serum lipids. METHODS AND RESULTS: We investigated the cross-sectional associations of fasting plasma SCC (methionine, total homocysteine, cystathionine, tCys, taurine and total glutathione) with BMI and fasting serum lipids and apolipoproteins in 854 men and women with and without cardiovascular disease (CVD). In multiple linear regression analysis adjusted for age, gender, CVD and other SCC, neither methionine, taurine, nor total glutathione was associated with BMI. Plasma taurine was, however, inversely related to HDL-cholesterol (partial r = -0.12, p = 0.004) and its associated apoA1 (partial r = -0.18, p

Various studies have compared coronary artery disease (CAD) patients with controls in order to determine which polymorphisms are associated with a higher risk of disease. The results have often been contradictory. Moreover, these studies evaluated polymorphisms in isolation and not in association, which is the way they occur in nature.Our purpose was to evaluate the risk of CAD in patients with associated polymorphisms in the same gene or in differen genes.We evaluated the risk associated with ACE DD, ACE 8 CC, ACT 174MM, AGT 235TT, MTHFR 677TT, MTHFR 1298AA, PON1 192RR and PON1 55MM in 298 CAD patients and 298 healthy individuals. We then evaluated the risk of associated polymorphisms in the same gene (ACE DD + ACE 8GG; AGT 174MM + AGT 235TT; MTHFR 677TT + MTHFR 1298AA). Finally, for the isolated polymorphisms which were significant, we evaluated the risk of polymorphism associations at different functional levels (ACE + AGT; ACE + MTHFR; ACE + PON1). Multiple logistic regression was used to identify independent risk factors for CAD.Isolated polymorphisms including ACE DD(p0.0001), ACE 8 gg (p=0.023), and MTHFR 1298AA (p = 0.049) presented with a significantly higher frequency in the CAD group. An association of polymorphisms in the same gene did not have an additive or synergistic effect, nor did it increase the risk of CAD. Polymorphic associations in different genes increased the risk of CAD, compared with the isolated polymorphisms. The association of ACE DD or ACE 8 GG with PON1 192RR increased the risk of CA fourfold (1.8 to 4.2). After logistic regression analysis, current smoking, family history, fibrinogen, diabetes, and the ACE DD or ACE 8 GG + MTHFR 1298AA and ACE DD or ACE 8 GG + PON1 192RR associations remained in the, model and proved to be independent predictors of CAD.The association of polymorphisms in the same gene did not increase the risk of the isolated polymorphism. The association of polymorphisms in genes belonging to different enzyme systems was always linked to increased risk compared to the isolated polymorphisms. This study may contribute to a better understanding of overall genetic risk for CAD rather than that associated with each polymorphism in isolation.

Complex diseases such as coronary artery disease (CAD), hypertension and diabetes are usually caused by individual susceptibility to multiple genes, environmental factors, and the interaction between them. The paraoxonase 1 (PON1) enzyme has been implicated in the pathogenesis of atherosclerosis and CAD. Two common polymorphisms in the coding region of the PON1 gene, which lead to a glutamine (Q)/arginine (R) substitution at position 192 and a leucine (L)/methionine (M) substitution at position 55, influence PON1 activity. Studies have investigated the association between these polymorphisms and CAD, but with conflicting results.1) To evaluate the association between PON1 polymorphisms and CAD risk; and 2) to study the interaction between PON1 polymorphisms and others in different candidate genes.We evaluated the risk of CAD associated with PON1 Q192R and L55M polymorphisms in 298 CAD patients and 298 healthy individuals. We then evaluated the risk associated with the interaction of the PON1 polymorphisms with ACE DD, ACE 8 GG and MTHFR 1298AA. Finally, using a logistic regression model, we evaluated which variables (genetic, biochemical and environmental) were linked significantly and independently with CAD.We found that the PON1 55MM genotype was more common in the CAD population, but this did not reach statistical significance as a risk factor for CAD, while PON1 192RR presented an 80% higher relative risk compared to the population without this polymorphism. The interaction between PON1 192RR and MTHFR 1298AA, sited in different genes, increased the risk for CAD, compared with the polymorphisms in isolation (OR=2.76; 95% CI=1.20-6.47; p=0.009), as did the association of PON1 192RR with ACE DD, which presented a 337% higher risk compared to the population without this polymorphic association (OR=4.37; 95% CI=1.47-13.87; p=0.002). Similarly, the association between PON1 192RR and ACE 8 GG was linked to an even higher risk (OR=6.23; 95% CI=1.67-27.37; p0.001). After logistic regression, smoking, family history, fibrinogen, diabetes, Lp(a) and the association of PON1 192RR + ACE 8 GG remained in the regression model and proved to be significant and independent risk factors for CAD. In the regression model the latter association had OR=14.113; p=0.018.When analyzed separately, the PON1 192RR genotype presented a relative risk for CAD 80% higher than in the population without this genotype. Its association with other genetic polymorphisms sited in different genes, coding for different enzymes and belonging to different physiological systems, always increased the risk for CAD. After correction for other conventional and biochemical risk factors, the PON1 192RR + ACE 8 GG association remained a significant and independent risk factor for CAD.

Objective:Approximately 15% of patients who develop coronary artery disease (CAD) have reduced stratified cardiovascular risk by existing predictive models. It is estimated that, for CAD, the genetic variation explains 40–55% of this variability.Characterize the genetic profile of a representative s