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Background High white blood cells (WBC) count is a well-recognized indicator of inflammation. Previous research has considered it a risk factor for coronary artery disease (CAD). Other new inflammatory risk markers are expensive to test, are not readily available, lack standardization and have not been confirmed as risk markers by multiple prospective studies. We aim to investigate whether elevated WBC count representsan independent risk factor for CAD in our Portuguese population. Material and methods A case-control study with 3,160 individuals (mean age 53.1 ± 7.8; 77.6% male), namely 1,723 coronary patients and 1,437 controls, was performed. Together with WBC, the following CAD risk factors were analyzed: smoking, hypertension, diabetes, dyslipidemia and obesity through bivariate analysis. Multivariate logistic regression evaluated the independent risk factors for CAD. Results and conclusions Comparing cases with controls, 47.2% were smokers vs. 23.8% (P < 0.0001); 71.0% were hypertensive individuals vs. 52.3% (P < 0.0001); 89.0% had dyslipidemiavs 70.4% (P < 0.0001); 33.8% had diabetes vs. 13.2% (P < 0.0001) and 34.2% were obese patients vs. 28.9% (P = 0.001). After multivariate regression, smoking (OR = 3.14, P < 0.0001), diabetes (OR = 2.89, P < 0.0001), dyslipidemia (OR = 2.72, P < 0.0001), hypertension (OR = 1.95, P < 0.0001) and WBC (OR = 1.05, P = 0.035) remained as independent risk factors for CAD. Elevated white blood counts are associated with CAD risk in our population. This marker is inexpensive, widely available and may further predict inflammation and coronaryartery disease risk.

Background White blood count (WBC) and C-reactive protein (CRP) elevation are well-recognized inflammation indicators and considered risk factors for coronary heart disease (CHD). Most of the other newly introduced inflammatory risk markers are expensive to test, are not readily available, lack standardization, and have not been confirmed by multiple prospective studies. Whether these classic inflammatory markers may predict majoradverse coronary events (MACE) in CHD patients is controversial. We aimed to evaluate whether high WBC and CRP are independent risk factors for MACE occurrence in CHD patients with an extended follow-up. Material and methods A cohort of 1,713 CHD patients (mean age 54.0 ± 7.5 years, 78.6% male) was prospectively followed during an extended time of 4.9 ± 3.4 years (range 1 to 17 years). Bivariate and multivariate Cox regression with WBC, CRP and traditional risk factors (age,gender, smoking, family history, dyslipidemia, diabetesand BMI) analyzed those significantlyassociated with MACE. Results and conclusions MACE group presented a higher percentage of non-smokers (P = 0.006); hypertension (P = 0.003); dyslipidemia (P = 0.025) and diabetes (P < 0.0001). WBC (P = 0.048) and CRP (P < 0.0001) were also significantly higher in patients with MACE relatively to non-MACE patients. After multivariate Cox analysis, WBC and CRP remained significant risk factors for MACE, with diabetes and hypertension presenting as strong statistical value. As a conclution, the inflammatory CRP and WBC factors are accurate to predict MACE in secondary prevention. These biomarkersare easily accessed, providing helpful information in the prognosis of cardiovascular patients.

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

The Publisher regrets that this article is an accidental duplication of an article that has already been published, 10.1016/j.repc.2022.10.005. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

The inclusion of a genetic risk score (GRS) can modify the risk prediction of coronary artery disease (CAD), providing an advantage over the use of traditional models. The predictive value of the genetic information on the recurrence of major adverse cardiovascular events (MACE) remains controversial. A total of 33 genetic variants previously associated with CAD were genotyped in 1587 CAD patients from the GENEMACOR study. Of these, 18 variants presented an hazard ratio >1, so they were selected to construct a weighted GRS (wGRS). MACE discrimination and reclassification were evaluated by C-Statistic, Net Reclassification Index and Integrated Discrimination Improvement methodologies. After the addition of wGRS to traditional predictors, the C-index increased from 0.566 to 0.572 (p=0.0003). Subsequently, adding wGRS to traditional plus clinical risk factors, this model slightly improved from 0.620 to 0.622 but with statistical significance (p=0.004). NRI showed that 17.9% of the cohort was better reclassified when the primary model was associated with wGRS. The Kaplan-Meier estimator showed that, at 15-year follow-up, the group with a higher number of risk alleles had a significantly higher MACE occurrence (p=0.011). In CAD patients, wGRS improved MACE risk prediction, discrimination and reclassification over the conventional factors, providing better cost-effective therapeutic strategies. info:eu-repo/semantics/publishedVersion

espanolEste articulo se refiere al trabajo de los estudiantes del Master en Ensenanza del Ingles en Educacion Primaria de la Universidad del Algarve. Se presentara el plan de estudios del grado enfocandose en los componentes relacionados con la observacion en las escuelas y las practicas, es decir, los cursos de Introduccion a la Practica Profesional, en el primer ano de la licenciatura y el Practicum en el primer semestre del segundo ano. Se recomienda un enfoque basado en tareas en los principales documentos rectores, tanto en la ensenanza del ingles en general, como en el contexto de la Educacion Primaria, (Marco Comun Europeo de Referencia para las Lenguas, 2001; Cameron, 2001; Thomas & Reinders, (eds.), 2010; Richards y Rodgers, (3a. ed.), 2014; Bygate, M. (2015). Sin embargo, la mayoria de los libros utilizados en las escuelas ofrecen algunas sugerencias de tareas y se centran en actividades mas tradicionales para la ensenanza de las lenguas. Como resultado, los profesores tienen un papel muy importante en la aplicacion del enfoque basado en tareas. Son responsables por decidir como planificar las clases y pensar en como hacer los cambios y adaptaciones necesarios para trabajar en una perspectiva basada en tareas. EnglishThis paper refers to the work of the students doing the Master’s in Teaching English in Primary Education, taught at the University of Algarve. The study plan of the degree will be presented focusing on the components regarding observation in schools and the teaching practice, namely the courses Introduction to the Professional Practice, in the first year of the degree, and the Practicum in the first semester of the second year. A task-based approach is recommended in the main guiding documents, on both the teaching of English in general, and the Primary Education context, (Common European Framework of Reference for Languages, 2001; Cameron, 2001; Thomas & Reinders, (eds.), 2010; Richards & Rodgers, (3rd. ed.), 2014; Bygate, M. (2015). Nevertheless, most of the textbooks used in the schools offer few suggestions of tasks and focus on more traditional language activities. As a result, the teachers have a very important role in the implementation of a task-based approach. They are responsible for deciding on how to plan the lessons and how to think of the necessary changes and adaptations, in order to be able to work from a task-based perspective.

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.

Introduction Our group has recently validated and published a new score - KAsH score. KAsH consists of a continuous, multiplicative score based on 4 simple clinical variables available at first medical contact, proven to be a robust predictor of in-hospital mortality and all-cause mortality at 1 year follow-up in patients with myocardial infarction, putting it next to other well established risk scores. However, the role of KAsH in patients with myocardial injury (Mi), a largely uncharacterized group in the literature, remains unknown. Purpose We aim to assess the predictive power of KAsH in patients with myocardial injury (Mi), regarding in-hospital mortality and at 1 year follow-up. Methods Prospective registry of 250 patients admitted consecutively through the emergency department from January 2018 onward, with higher than P99th high-sensitive troponin assay. The kit used was Roche's Elecsys hsSTAT, and the P99th appointed by the manufacturer was 14 ng/L. All patients with chronic kidney disease ClCr KAsH = (Killip Kimbal × Age × Heart Rate) / Systolic BP We used a simplified Killip classification: without heart failure (1 point), with heart failure (2 points) and in shock (3 points). We assessed the score's association to mortality and its predictive value through ROC curves and their respective area under the curve (AUC). Results Both Killip and KAsH had a significant and positive association with in-hospital mortality (KK: p=0.02; KAsH: p0.1). Conclusions KAsH seems to maintain its in-hospital predictive value even in patients with Mi. To our knowledge, this is the first study that tries to apply risk scores and stratification tools to such a heterogeneous group of patients. By comprising hemodynamic variables, KAsH may actually be a better risk stratification tool than just the severity of heart failure on admission. However, unlike previously proven in myocardial infarction (MI), KAsH score and its hemodynamic variables do not seem to justify the high mortality on the long run behind these patients. More studies will be needed to address the complex causes behind long-term mortality of Mi patients. KASH table graph Funding Acknowledgement Type of funding source: None

Background Metabolic syndrome (MetS), characterized by a cluster of cardiovascular risk factors, is considered to be the major health hazard of modern world and a 21st century epidemic. Recent GWAS have identified several susceptibility regions involved in lipid metabolism and oxidation, also associated with MetS. Genetic risk score (GRS) is an emerging method that attempts to establish correlation between SNPs and clinical phenotypes. Aim Evaluate the value of a GRS encompassing SNPs involved in lipidic metabolism and oxidation pathways, in predicting CAD outcome (MACEs and long-term cardiovascular Mortality) in a coronary population with MetS. Methods 1101 coronary patients and MetS, were selected from the GENEMACOR study. Genotyping was performed by TaqMan allelic discrimination assay. A Multiplicative score (mGRS) was constructed according to the multiplicative model with variants belonging to the lipid and oxidative axes (PSRC1, PCSK9, KIF6, ZNF259, LPA, APO E, PON192, PON108, PON55, MTHFR677, MTHFR1298, MTHFD1L). This GRS was categorized using the mean (higher vs lower than mean). Cumulate Mortality Hazards Model (Cox regression) adjusted for age, gender, smoking, hypertension, dyslipidaemia, diabetes, hsCRP, eGFR, Ejection fraction (EF), and multivessel disease) was used to find independent predictors of cardiovascular outcome. We performed Kaplan-Meier Survival curves for both groups (higher vs lower than mean GRS) and log-rank test to compare survival distributions in both groups. Results The following variables have emerged independently associated with time to MACE occurrence: mGRS (HR=1.31 95% CI (1.07; 1.59); p=0.008), male gender, EF and multivessel disease. Concerning cardiovascular mortality, mGRS also remained an independent predictor (HR=1.44 (1.04–1.99); p=0.028) alongside age, smoking, diabetes and EF. The Log-Rank test showed significant differences between the two curves related to MACE occurrence and cardiovascular mortality (p=0.001 and 0.002, respectively). The Kaplan-Meier survival showed that as mGRS increases, patient survival decreases. Conclusion In patients with MetS, a GRS comprising variants in lipidic and oxidative pathways, proved to be a useful stratification tool, identifying patients likely to have a worst prognosis over time. Our data further underlines the additive potential and clinical utility of genetic information in shaping secondary prevention. Figure 1 Funding Acknowledgement Type of funding source: None

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

Background: Genetic risk score can quantify individual’s predisposition to coronary artery disease; however, its usefulness as an independent risk predictor remains inconclusive. Objective: To evaluate the incremental predictive value of a genetic risk score to traditional risk factors associated with coronary disease. Methods: Thirty-three genetic variants previously associated with coronary disease were analyzed in a case-control population with 2,888 individuals. A multiplicative genetic risk score was calculated and then divided into quartiles, with the 1st quartile as the reference class. Coronary risk was determined by logistic regression analysis. Then, a second logistic regression was performed with traditional risk factors and the last quartile of the genetic risk score. Based on this model, two ROC curves were constructed with and without the genetic score and compared by the Delong test. Statistical significance was considered when p values were less than 0.05. Results: The last quartile of the multiplicative genetic risk score revealed a significant increase in coronary artery disease risk (OR = 2.588; 95% CI: 2.090-3.204; p < 0.0001). The ROC curve based on traditional risk factors estimated an AUC of 0.72, which increased to 0.74 when the genetic risk score was added, revealing a better fit of the model (p < 0.0001). Conclusions: In conclusion, a multilocus genetic risk score was associated with an increased risk for coronary disease in our population. The usual model of traditional risk factors can be improved by incorporating genetic data. Resumo Fundamento: O escore de risco genético pode quantificar a predisposição do indivíduo em desenvolver doença arterial coronariana; no entanto, sua utilidade como preditor de risco independente permanece inconclusiva. Objetivo: Avaliar o incremento no valor preditivo de um escore de risco genético aos fatores de risco tradicionais associados à doença arterial coronariana. Métodos: Trinta e três variantes genéticas previamente associadas à doença arterial coronariana foram analisadas em uma população caso-controle com 2888 indivíduos. Um escore de risco genético multiplicativo foi calculado e dividido em quartis, com o 1º quartil como a classe de referência. O risco coronário foi determinado por análise de regressão logística. Uma segunda regressão logística foi realizada com fatores de risco tradicionais e o último quartil do escore de risco genético. Com base nesse modelo, duas curvas ROC foram construídas com e sem o escore de risco e comparadas pelo teste de DeLong. A significância estatística foi considerada quando os valores de p eram inferiores a 0,05. Resultados: O último quartil do score de risco genético multiplicativo revelou um aumento significativo no risco de doença arterial coronariana (OR = 2,588; IC 95%: 2,090-3,204; p < 0,0001). A curva ROC baseada nos fatores de risco tradicionais estimou uma AUC de 0,72, que aumentou para 0,74 quando o score de risco genético foi adicionado, revelando um ajuste melhor do modelo (p < 0,0001). Conclusões: Em conclusão, um escore de risco genético com múltiplos loci foi associado a um risco aumentado de doença coronariana na nossa população. O modelo usual de fatores de risco tradicionais pode ser melhorado pela incorporação de dados genéticos.

Resumo: Introdução: A hipertensão arterial é um problema de Saúde Pública, afeta 25% da população adulta mundial. Fatores genéticos e ambientais contribuem para a sua patogénese. O polimorfismo C825T da subunidade β3 da Proteína G (rs5443) favorece a produção de uma variante alternativa, truncada, que facilita a sinalização intracelular, pode interferir na regulação da pressão arterial. Essa variante genética tem sido descrita como um fator de risco para a hipertensão arterial, com resultados controversos. Objetivo: Avaliar a associação do polimorfismo C825T do gene GNβ3 com o aparecimento de hipertensão arterial, numa população portuguesa do Arquipélago da Madeira. Métodos: Com uma amostra de 1641 indivíduos (média de 50,6 ± 8,1 anos), fizemos um estudo caso‐controlo com 848 indivíduos com hipertensão arterial e 793 controlos, ajustados para o sexo e a idade. Todos os participantes colheram sangue para análises bioquímicas e foram genotipados para o polimorfismo C825T. Foi feita uma regressão logística para ver quais as variáveis que se relacionam com a hipertensão arterial. A análise dos dados foi feita com o software estatístico SPSS, versão 19.0. Usamos como limiar de significância o valor de p < 0,05. Resultados: Encontramos uma associação significativa entre o polimorfismo C825T e o aparecimento de hipertensão arterial (odds ratio = 1,275; IC 95% (1,042–1,559); p = 0,018) no modelo dominante, após análise multivariada. Conclusão: O polimorfismo C825T da subnidade β3 da Proteína G está associado, de forma significativa e independente, com o aparecimento hipertensão arterial na nossa população. Abstract: Introduction: Hypertension is an important public health problem, affecting about 25% of the adult population worldwide.1 Genetic and environmental factors contribute to its pathogenesis. The T allele of the C825T polymorphism of the beta 3 subunit of G protein (rs5443) leads to the production of a truncated variant that enhances intracellular signaling and may interfere with the regulation of blood pressure. This genetic variant has been described as a risk factor for hypertension, although study results are controversial. Objective: The objective of this study was to analyze the association of the C825T polymorphism of the GNB3 gene with the occurrence of hypertension in a Portuguese population from the Madeira archipelago. Methods: A case‐control study was performed with 1641 Caucasian individuals (mean age 50.6±8.1 years), 848 with hypertension and 793 controls. Blood was collected from all participants for biochemical and genetic analysis, including genotyping of the C825T polymorphism. Logistic regression analysis was performed to determine which variables were significantly associated with the onset of hypertension. Statistical analyses were performed using IBM SPSS version 19.0 and p‐values

arborea representativa da Mata Atlântica, pertencente a familia Chrysobalanaceae. Para obtencao de sementes de boa qualidade, um dos aspectos que devem ser considerados e o momento de sua coleta, que pode ser determinada pelo estadio de desenvolvimento do fruto. Quanto ao armazenamento, as especies apresentam comportamento diferente e cada uma possui exigencias proprias para a manutencao da qualidade fisiologica de suas sementes. Os objetivos deste trabalho foram: avaliar a resposta germinativa do estadio de maturacao de frutos de oiti sobre o vigor das sementes; e o efeito do armazenamento de endocarpos de oiti em ambiente de laboratorio sobre a qualidade fisiologica das sementes. Esta pesquisa foi dividida em duas etapas: na primeira, foram coletados frutos em diferentes estadios de maturacao (amarelo, verde-amarelado, verde e escuro-enrugado). Na segunda etapa, os frutos amarelos (recem coletados) foram despolpados e os endocarpos armazenados por um periodo de 90 dias em ambiente de laboratorio (condicoes nao controladas). Para o primeiro ensaio, os frutos foram colocados para germinar em bandejas, contendo o substrato areia, com 10 repeticoes de 10 sementes, em viveiro. Para o segundo ensaio, a cada 30 dias e, antes do armazenamento (tempo zero), os endocarpos foram colocados para germinar nessas mesmas condicoes. Conclui-se, portanto, que frutos de oiti na coloracao amarela, podem ser recomendados como adequados para coleta, pela elevada qualidade fisiologica de suas sementes. O armazenamento de endocarpos de oiti, em ambiente nao controlado, foi favoravel ate aos 30 dias; a partir desse periodo, o armazenamento de endocarpos foi prejudicial a qualidade de suas sementes.

Over the years, pets began to be seen as members of families. Many tutors want to provide everything they can to ensure that all the needs of their animals, often called “children,” are met, which can be evidenced by maintaining demand levels in the industry, even in times of crisis. Thus, this research aimed to study the behavior of the PET market in the city of Solânea-PB, evaluating the supply and demand present in the region. Having as theoretical and bibliographic support, the definitions and theories of the study and strategic market planning, proceeded with the application of questionnaires intended for the consumer market, being tutors of at least one pet, and the offerers of the city. After analyzing the data, using a qualitative and quantitative approach, as the main results, there is a lack of variety in the offer of products / services as the main deficiency of providers reported by consumers, in addition to the demand for services such as diagnostic imaging, specialty care and hotel for dogs and cats, demonstrating business potential in the city. From the perspective of providers, the study pointed to some difficulties in the relationship with clients, especially regarding the valuation of services and the professional of Veterinary Medicine. Con el paso de los años, las mascotas comenzaron a verse como miembros de una familia. Muchos tutores quieren poner todo a su alcance para que se cubran todas las necesidades de sus animales, a menudo llamados “niños”, lo que se evidencia en el mantenimiento de los niveles de demanda en el sector, incluso en tiempos de crisis. Así, esta investigación tuvo como objetivo estudiar el comportamiento del mercado de PET en la ciudad de Solânea-PB, evaluando la oferta y demanda presente en la región. Teniendo como soporte teórico y bibliográfico, las definiciones y teorías del estudio y planificación estratégica del mercado, se procedió a la aplicación de cuestionarios destinados al mercado consumidor, siendo tutores de al menos una mascota, y a los concursantes de la ciudad. Luego de analizar los datos, utilizando un enfoque cualitativo, como principales resultados, existe una falta de variedad en la oferta de productos / servicios como la principal deficiencia de los proveedores reportada por los consumidores, además de la demanda de servicios como el diagnóstico por imagen servicio por especialidades y hotel para perros y gatos, demostrando potencial comercial en la ciudad. Desde la perspectiva de los proveedores, el estudio apuntó algunas dificultades en la relación con los clientes, especialmente en términos de valoración de servicios y profesionales en Medicina Veterinaria. Com o passar dos anos, os animais de estimação começaram a ser vistos como membros das famílias. Muitos tutores querem proporcionar tudo o que estiver ao alcance para que todas as necessidades de seus animais, muitas vezes chamados de “filhos”, sejam supridas, o que pode ser evidenciado pela manutenção nos níveis de demanda no setor, mesmo em tempos de crise. Assim, esta pesquisa teve como objetivo estudar o comportamento do mercado PET da cidade de Solânea-PB, avaliando a oferta e a demanda presente na região. Tendo como aporte teórico e bibliográfico, as definições e teorias do estudo e planejamento estratégico de mercado, procedeu-se com a aplicação de questionários destinados ao mercado consumidor, sendo tutores de pelo menos um animal de estimação, e aos ofertantes da cidade. Após análise dos dados, mediante abordagem qualiquantitativa, como principais resultados, verifica-se a carência de variedade na oferta de produtos/serviços como principal deficiência dos ofertantes relatada pelos consumidores, além da demanda por serviços como diagnóstico por imagem, atendimento por especialidades e hotel para cães e gatos, demonstrando potencialidades de negócio na cidade. Sob a ótica dos ofertantes, o estudo apontou para algumas dificuldades no relacionamento com os clientes, sobretudo no quesito valorização dos serviços e do profissional da Medicina Veterinária.

Essential hypertension (EH) is a disease in which both environment and genes have an important role. This study was designed to identify the interaction model between genetic variants and environmental risk factors that most highly potentiates EH development.We performed a case-control study with 1641 participants (mean age 50.6 ± 8.1 years), specifically 848 patients with EH and 793 controls, adjusted for gender and age. Traditional risk factors, biochemical and genetic parameters, including the genotypic discrimination of 14 genetic variants previously associated with EH, were investigated. Multifactorial dimensionality reduction (MDR) software was used to analyze gene-environment interactions. Validation was performed using logistic regression analysis with environmental risk factors, significant genetic variants, and the best MDR model.The best model indicates that the interactions among the ADD1 rs4961 640T allele, diabetes, and obesity (body mass index ≥30) increase approximately four-fold the risk of EH (odds ratio = 3.725; 95% confidence interval: 2.945-4.711; p 0.0001).This work showed that the interaction between the ADD1 rs4961 variant, obesity, and the presence of diabetes increased the susceptibility to EH four-fold. In these circumstances, lifestyle adjustment and diabetes control should be intensified in patients who carry the ADD1 variant.

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.

Introdução: A hipertensão arterial é uma doença complexa, multifatorial, controlada por fatores genéticos e ambientais. Objetivo: Avaliar a susceptibilidade genética no aparecimento de hipertensão arterial e sua associação com os fatores de risco tradicionais na eclosão desta patologia. Material e Métodos: Estudo caso-controlo com 1712 indivíduos, idade média de 51,0 ± 7,9 anos (860 hipertensos e 852 controlos). Avaliaram-se os fatores tradicionais, bioquímicos e as variantes genéticas: ACE I/D rs4340, ACE A2350G rs4343, AGT T174M rs4762, AGT M235T rs699 AGTR1 A1166C rs5186, CYP11B2 -344 C/T rs1799998, ADRB1 R389G rs1801253, ADRB2 R16G rs1042713, ADD1 G460W rs4961, SCNN1G G173A rs5718, GNB3 C825T rs5443, ATP2B1 A/G rs2681472, CYP17A1 T/C rs11191548, SLC4A2 C/T rs2303934. Calculámos o risco de cada gene para a hipertensão, pelos modelos dominante, recessivo, co-dominante e multiplicativo. Através da regressão logística, avaliámos as variáveis associadas à hipertensão. Elaboraram-se curvas ROC com os fatores tradicionais e posteriormente adicionando as variantes genéticas associadas com hipertensão. Analisámos os dados através do SPSS for Windows 19.0 e MedCalc v. 13.3.3.0. Resultados: As variantes genéticas ADD1 G460W, GNB3 C825T, ACE I/D e ACE A2350G associaram-se à hipertensão. A curva ROC com os factores de risco tradicionais e estas variantes mostrou um incremento na capacidade preditiva de hipertensão (p = 0,018). Discussão: Segundo os resultados do nosso estudo as variantes genéticas que após análise univariada se associaram à hipertensão arterial foram a ACE I/D rs4340, ACE A2350G rs4343, ADD1 G460W rs4961, GNB3 C825T rs5443. As duas primeiras variantes relacionam-se com a hipertensão arterial por interferirem no sistema renina-angiotensina-aldosterona, que tem um importante papel na regulação da pressão arterial. Salienta-se o facto dos genes que codificam os componentes do sistema renina-angiotensinaaldosterona serem candidatos naturais ao desenvolvimento e progressão da hipertensão arterial. Também na nossa população os polimorfismos da alfa-aducina (ADD1 G460W rs4961), associaram-se à hipertensão arterial. Nesta população portuguesa, conhecida por ter elevado consumo de sal, faz sentido que estes polimorfismos, sejam relevantes na gestão do sal e da água e consequentemente, no aparecimento de hipertensão arterial. A variante genética GNB3 C825T rs5443 que interfere na sinalização intracelular também constituiu uma forte candidata à hipertensão arterial. Com a elaboração da curva ROC e cálculo das AUC inicialmente só com os fatores de risco tradicionais e posteriormente adicionando as variantes ADD1 G460W, GNB3 C825T, ACE I/D e ACE A2350G aos fatores de risco tradicionais, verificámos ter havido um incremento no risco preditivo de hipertensão arterial, relativamente ao existente só com os fatores de risco tradicionais, com significado estatístico (p = 0,018). Isto sugere que a hipertensão arterial é uma doença multifatorial, que resulta da interação de fatores ambientais, genéticos e estilos de vida que interagem entre si e levam ao aparecimento desta importante patologia. Conclusão: No nosso estudo os polimorfismos associados à hipertensão, estão ligados ao eixo renina-angiotensina-aldosterona (ACE I/D, ACE A2350G), bem como à gestão de sal e água (ADD1 G460W, GNB3 C825T). Através de uma análise multivariada, concluiuse que estas duas últimas variantes genéticas conjuntamente com quatro dos fatores tradicionais (tabagismo, hábitos alcoólicos, obesidade e diabetes) se associam de forma significativa e independente à hipertensão arterial essencial. Num modelo preditivo de hipertensão arterial, a introdução das variantes genéticas aumenta ligeiramente o valor preditivo do modelo. Introduction: Arterial hypertension is a complex, multifactorial disease, controlled by genetic and environmental factors. Objective: Evaluate the genetic susceptibility for developing arterial hypertension and its association with the traditional risk factors in the outbreak of this pathology. Material and Methods: Case-control study with 1712 individuals, mean age of 51.0 ± 7.9 years (860 hypertensive patients and 852 controls). Biochemical and traditional risk factors, and genetic variants were evaluated: ACE I/D rs4340, ACE A2350G rs4343, AGT T174M rs4762, AGT M235T rs699 AGTR1 A1166C rs5186, CYP11B2 -344 C/T rs1799998, ADRB1 R389G rs1801253, ADRB2 R16G rs1042713, ADD1 G460W rs4961, SCNN1G G173A rs5718, GNB3 C825T rs5443, ATP2B1 A/G rs2681472, CYP17A1 T/C rs11191548, SLC4A2 C/T rs2303934. The risk of each gene for hypertension was estimated by the dominant, recessive, co-dominant and multiplicative models. By logistic regression, variables associated with hypertension were evaluated. ROC curves were first performed with traditional risk factors and then adding the genetic variants associated with hypertension. Data were analyzed by SPSS for Windows 19.0 and MedCalc v. 13.3.3.0. Results: The genetic variants ADD1 G460W, GNB3 C825T, ACE I/D, ACE A2350G were associated with hypertension. ROC curve with traditional risk factors and these variants showed an increase in the predictive capacity of hypertension (p = 0.018). Discussion: According to the results of our study, the genetic variants found to be associated with hypertension were: ACE I/D rs4340, ACE A2350G rs4343, ADD1 G460W rs4961 and GNB3 C825T rs5443. The first two variants are associated with hypertension by interfering with the renin-angiotensin-aldosterone system, which plays an important role in regulating blood pressure. It should be noted that genes encoding the components of renin-angiotensin-aldosterone system are natural candidates for the development and progression of hypertension. In our population alpha-aducin polymorphism (ADD1 G460W rs4961) was also associated with hypertension. In a Portuguese population, known to have high salt intake, it makes sense that this polymorphism which is relevant in salt and water management may consequently be relevant in the onset of hypertension. The genetic variant GNB3 C825T rs5443 that affects intracellular signalling was also found to be a strong risk candidate for hypertension. Initially, with the elaboration of the ROC curve and calculation of the AUC using only with traditional risk factors and later by adding the variants ADD1 G460W, GNB3 C825T, ACE I/D and ACE A2350G to the traditional risk factors, we verified that genetic polymorphisms increased the predictive risk of hypertension, when compared to the risk given only by traditional risk factors, with statistical significance (p = 0.018). This suggests that hypertension is a multifactorial disease that results from the interaction of environmental, genetic and lifestyle factors that interact with each other and lead to the advent of this important pathology. Conclusion: In our study, the hypertension-associated polymorphisms are linked to the renin-angiotensin-aldosterone axis (ACE I/D, ACE A2350G), as well as to salt and water management (ADD1 G460W, GNB3 C825T). Through a multivariate analysis, it was concluded that these two last genetic variants together with four of the traditional risk factors (smoking, alcohol consumption, obesity and diabetes) are associated in a significant and independent way with essential hypertension. In a predictive model of hypertension, the introduction of genetic variants slightly increases the predictive value of the model. info:eu-repo/semantics/publishedVersion

The utility of genetic risk scores (GRS) as independent risk predictors remains inconclusive. Here, we evaluate the additive value of a multi-locus GRS to the Framingham risk score (FRS) in coronary artery disease (CAD) risk prediction. A total of 2888 individuals (1566 coronary patients and 1322 controls) were divided into three subgroups according to FRS. Multiplicative GRS was determined for 32 genetic variants associated to CAD. Logistic Regression and Area Under the Curve (AUC) were determined first, using the TRF for each FRS subgroup, and secondly, adding GRS. Different models (TRF, TRF+GRS) were used to classify the subjects into risk categories for the FRS 10-year predicted risk. The improvement offered by GRS was expressed as Net Reclassification Index and Integrated Discrimination Improvement. Multivariate analysis showed that GRS was an independent predictor for CAD (OR = 1.87; p

Essential hypertension (EH) is a complex disease in which physiological, environmental, and genetic factors are involved in its genesis. The genetic variant of the alpha-adducin gene (ADD1) has been described as a risk factor for EH, but with controversial results.The objective of this study was to evaluate the association of ADD1 (Gly460Trp) gene polymorphism with the EH risk in a population from Madeira Island.A case-control study with 1614 individuals of Caucasian origin was performed, including 817 individuals with EH and 797 controls. Cases and controls were matched for sex and age, by frequency-matching method. All participants collected blood for biochemical and genotypic analysis for the Gly460Trp polymorphism. We further investigated which variables were independently associated to EH, and, consequently, analyzed their interactions.In our study, we found a significant association between the ADD1 gene polymorphism and EH (odds ratio 2.484, P = .01). This association remained statistically significant after the multivariate analysis (odds ratio 2.548, P = .02).The ADD1 Gly460Trp gene polymorphism is significantly and independently associated with EH risk in our population. The knowledge of genetic polymorphisms associated with EH is of paramount importance because it leads to a better understanding of the etiology and pathophysiology of this pathology. info:eu-repo/semantics/publishedVersion

Several genetic risk scores (GRS) have been associated with cardiovascular disease; their role, however, in survival from proven coronary artery disease (CAD) have yielded conflicting results. Objective: The objective of this study was to evaluate long- term cardiovascular mortality according to the genetic risk score in a Southern European population with CAD. Methods: A cohort of 1464 CAD patients with angiographic proven CAD were followed up prospectively for up to 58.3 (interquartile range: 25.8- 88.1) months. Genotyping of 32 single- nucleotide polymorphisms previously associated with CAD was performed using oligonucleotides probes marked with fluorescence for each allele. GRS was constructed according to the additive model assuming codominance and categorised using the median (=26). Cox Regression analysis was performed to determine independent multivariate predictors of cardiovascular mortality. Kaplan- Meier survival curves compared high vs low GRS using log- rank test. C- index was done for our population, as a measure of discrimination in survival analysis model. Results: During a mean follow- up of 58.3 months, 156 patients (10.7%) died, 107 (7.3%) of CV causes. High GRS (≥26) was associated with reduced cardiovascular survival. Survival analysis with Cox regression model adjusted for 8 variables showed that high GRS, dyslipidemia, diabetes and 3- vessel disease were independent risk factors for cardiovascular mortality (HR=1.53, P=.037; HR=3.64, P=.012; HR=1.75, P=.004; HR=2.97, P

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