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A library of cyclometallated iridium (III) complexes with a strong H-bonding motif in their ancillary ligand was synthesized, characterized and their photophysical properties measured. Demonstrated herein is a general synthetic high yield procedure for these compounds. We ascribe these yields to the use of an intermediary primer ligand. This de novo strategy circumnavigates the standard synthetic issues of H-bond rich ligand precursors (self-aggregation and poor solubility in organic solvents). Alternative and greener synthetic pathways were also explored to realize the intermediate iridium primer complex.

Background. - It is known that patients with COVID-19 are at increased risk of thrombosis. Although COVID-19 infection primarily affects the lower respiratory tract system, emerging reports suggest direct and indirect cardiovascular complications. However, the key mechanisms under thrombosis development at great arterial vessels are still unclear.Case presentation. – We report the cases of 4 patients who were admitted to our hospital and suffered from arterial thrombotic complications. All of them were older than 60 years and only 1 did not have cardiovascular risk factors. It should be noted that days prior to the diagnosis of arterial thrombosis, 3 of the 4 patients were under anticoagulant treatment. It is also interesting that in contrast to already known typical microvascular locations, our patients suffered from large arterial vessels thrombosis. Furthermore, none of them would present with severe respiratory symptoms. Conclusions. – The underlying mechanism of COVID-19-associated arterial thrombosis remains unclear and might be independent of the cytokine storm that occurs in patients with COVID-19-associated venous thrombosis. Also, the role of anti-platelets agents as prophylactic treatment in high-risk patients remains unclear. Multicenter clinical trials are necessary to clarify these issues.

A alergia alimentar é uma doença crónica, cujo número de afetados na União Europeia tem crescido continuamente ao longo dos últimos anos, principalmente entre a população infantil. Os sintomas desta condição de saúde variam entre os ligeiros, como a irritação da pele, e os potencialmente fatais, como é o caso do choque anafilático. A gestão desta condição de saúde, que implica necessariamente a evicção dos alimentos que contém os ingredientes provocadores da alergia, traduz-se muitas vezes num enorme impacto no dia-a-dia da pessoa afetada e respetivos familiares próximos, dada a ubiquidade de alguns dos alérgenos mais comuns. O presente projeto de investigação no âmbito do design centrado no humano, tem como objetivo o desenho, prototipagem e avaliação de uma aplicação móvel para a facilitação da identificação de alérgenos em produtos alimentares no contexto da sua compra. Esta investigação, integrada num projeto doutoral, pretende obter um protótipo funcional de uma aplicação para smartphone, que será testado por pessoas interessadas e que se disponibilizaram para tal, com o objetivo de satisfazer as necessidades e as expetativas dos utilizadores com alergias alimentares, de forma a simplificar a sua experiência na compra de produtos para o seu consumo diário. Esta aplicação servirá como suporte a um sistema desenvolvido num estudo à parte, possibilitando o reconhecimento de alergénios de acordo com as patologias associadas ao utilizador, facilitando a leitura e compreensão da informação existente na rotulagem desses produtos. Food Allergy is a chronic disease whose number of affected in the European Union has grown over the last few years, especially among children. Symptoms of the disease can vary between mild, such as skin irritation, and fatal, such as anaphylactic shock. Health management, which involves the eviction of food containing the allergy-inducing ingredients, often translates into a huge impact on the day-to-day life of the affected person and their close relatives, given the ubiquity of some of the most common allergenic. This research project in the scope of user-centered design aims to design, prototype, and survey a mobile application for facilitating the identification of allergens in food products in the context of their purchase. In order to meet the needs and expectations of users with food allergies, this research, integrated in a PhD research, aims to deliver a functional prototype of a smartphone application, which will be tested by interested people who took the time to do it, with the goal of meeting the needs and expectations of users with food allergies, to simplify their way of buying daily products for consumption. This app will support a system developed in another research study, allowing the recognition of allergens according to the pathologies associated with the user, facilitating the reading and understanding of the information existing in the product’s labeling. Mestrado em Design

Background Spain is the European country with the highest number of Trypanosoma cruzi infected patients. Due to the cardiac complications that these patients can develop, it is of paramount importance to evaluate the value of the different heart diagnostic tools. Method In this observational study, we describe the main characteristics and data from electrocardiogram, chest X-ray, echocardiogram and cardiac magnetic resonance imaging (MRI) of 141 patients with Chagas’ disease attended in a tertiary university hospital in Madrid from 2009 to 2018. Results A total of 50 patients (35.4%) had at least one abnormal cardiac test: 34.2% altered electrocardiogram (40/117), 24.5% altered echocardiogram (27/110) and 9.2% abnormal cardiac MRI (13/41). Of those 13 with a pathological MRI, 53.8% had normal results for any other test. The most frequent alterations observed were hypokinesia with decreased LVEF (left ventricular ejection fraction), dilatation of cavities and cardiac fibrosis. Two thirds of patients with abnormal cardiac test were asymptomatic. Altered echocardiogram was found in 43.8% of patients ≥50 years compared to 16.6% under 50 years (p = 0.003). Conclusions A transthoracic echocardiogram and a MRI of the heart added a 23.8% increment in diagnosing cardiac pathological findings.

BACKGROUND: Familial hypercholesterolemia (FH) confers an increased risk of premature atherosclerotic disease. Coronary computed tomographic angiography (CTA) can assess preclinical coronary atherosclerosis. OBJECTIVES: To describe coronary CTA findings in asymptomatic molecularly defined FH individuals, to identify those factors related to its presence and extension, and to assess the impact of these results in patients' care and estimated risk. METHODS: Four hundred and forty individuals with FH, without clinical cardiovascular disease, were consecutively enrolled and underwent a coronary CTA that was used to analyze coronary atherosclerosis based on coronary calcium score (CCS), sum of stenosis severity, and plaque composition sum (PCS). For FH patients, cardiovascular risk was estimated using the specific SAFEHEART risk equation. Follow-up was performed using a standardized protocol. RESULTS: Mean age was 46.4 years (231 women, 52%). Coronary calcium was present in 55%, mean CCS was 130.9, 46% had a plaque with lumen involvement, and mean PCS was 1.1. During follow-up, there were 17 (4%) nonfatal events and 2 (1%) fatal events. CCS was independently associated to the estimated risk and low-density lipoprotein-cholesterol life-years, sum of stenosis severity to the estimated risk, and PCS to the estimated risk and low-density lipoprotein-cholesterol life-years. CTA findings induced a positive change in patients' care and in their estimated risk. CONCLUSION: Coronary artery atherosclerosis is highly prevalent in asymptomatic patients with FH and it is independently associated to cardiovascular risk. More advanced disease on CTA was associated with subsequent intensification of therapy and reduction of estimated risk. Further longitudinal studies are required to know if these findings might improve the risk stratification in patients with FH. (C) 2018 National Lipid Association. All rights reserved.

AIM To determine whether circulating antibodies against oxidized low-density lipoprotein (LDL; OLAB) levels are associated with acute myocardial infarction (AMI) in individuals without classical cardiovascular risk factors. METHODS A case-control study including 34 first AMI patients without classical risk factors (smoking, dyslipidemia, hypertension or diabetes) and 45 population-based healthy controls. RESULTS There were no differences in anthropometric variables between cases and controls. Oxidized LDL levels were similar in both groups. Total cholesterol, LDL cholesterol, apolipoprotein B and physical activity were lower in cases than in controls. OLAB levels were also lower in cases than controls (128 versus 447 U/l, P < 0.001). After adjusting for age, oxidized LDL and physical activity, participants with OLAB levels of 165 U/l or less had a higher risk of AMI (odds ratio, OR = 7.48, 95% confidence interval: 1.57-35.66). When the model was fitted with OLAB as a continuous variable, the natural logarithm (LnOLAB) levels were independently associated with AMI with an OR of 0.40 (95% confidence interval: 0.19-0.86). After adjusting the model by Framingham-risk-adapted score and oxidized LDL, the LnOLAB levels maintained their independent association (OR of 0.43, 95% confidence interval: 0.23-0.79). CONCLUSION First AMI patients without classical risk factors had lower levels of OLAB compared with healthy controls. It is likely that the immunological reaction due to oxidized LDL participates as a preventive factor in the physiopathology of atherosclerosis.

A 42-year-old man without a past cardiovascular history arrived in the emergency department reporting progressive chest pain, abdominal discomfort, dyspnea at rest, and orthopnea of 4 days duration. An abdominal ultrasound revealed significant pericardial and bilateral pleural effusion, with hepatomegaly and ascites of a probable congestive nature. A transthoracic echocardiogram showed severe pericardial effusion with data of hemodynamic compromise, and a right retroauricular mass anchored to the posterior atrial wall (Figures 1A and 2; Movies I and II in the online-only Data Supplement). Figure 1. A , Apical 4-chamber view transthoracic echocardiogram showing concentric severe pericardial effusion (PE), right (RV) and left (LV) ventricle, and tumor (arrow). B , CT scan showing tumor mass (arrow) attached to the right atrium (RA). C , Apical 4-chamber view with color flow Doppler demonstrating in the right chambers flow acceleration (arrow) secondary to extrinsic tumor compression. D , CT scan …

Introduction:Decreased plasma vitamin D (VD) levels are linked to cardiovascular damage. However, clinical trials have not demonstrated a benefit of VD supplements on left ventricular (LV) remodelling. Anterior ST-elevation acute myocardial infarction (STEMI) is the best human model to study the effect of treatments on LV remodelling. We present a proof-of-concept study that aims to investigate whether VD improves LV remodelling in patients with anterior STEMI. Methods and analysis:The VITamin D in Acute Myocardial Infarction (VITDAMI) trial is a multicentre, randomised, double-blind, placebo-controlled trial. 144 patients with anterior STEMI will be assigned to receive calcifediol 0.266 mg capsules (Hidroferol SGC)/15 days or placebo on a 2:1 basis during 12 months. Primary objective:to evaluate the effect of calcifediol on LV remodelling defined as an increase in LV end-diastolic volume >= 10\% (MRI). Secondary objectives:change in LV end-diastolic and end-systolic volumes, ejection fraction, LV mass, diastolic function, sphericity index and size of fibrotic area; endothelial function; plasma levels of aminoterminal fragment of B-type natriuretic peptide, galectin-3 and monocyte chemoattractant protein-1; levels of calcidiol (VD metabolite) and other components of mineral metabolism (fibroblast growth factor-23 (FGF-23), the soluble form of its receptor klotho, parathormone and phosphate). Differences in the effect of VD will be investigated according to the plasma levels of FGF-23 and klotho. Treatment safety and tolerability will be assessed. This is the first study to evaluate the effect of VD on cardiac remodelling in patients with STEMI. Ethics and dissemination: This trial has been approved by the corresponding Institutional Review Board (IRB) and National Competent Authority (Agencia Espanola de Medicamentos y Productos Sanitarios (AEMPS)). It will be conducted in accordance with good clinical practice (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use-Good Clinical Practice (ICH-GCP)) requirements, ethical principles of the Declaration of Helsinki and national laws. The results will be submitted to indexed medical journals and national and international meetings. The VITDAMI trial is an investigator initiated study, sponsored by the Instituto de Investigacion Sanitaria Fundacion Jimenez Diaz (IIS-FJD). Funding has been obtained from Fondo de Investigaciones Sanitarias (PI14/01567; http://www.isciii.es/) and Spanish Society of Cardiology (http://secardiologia.es/). In addition, the study medication has been provided freely by the pharmaceutical Company FAES FARMA S.A. (Leioa, Vizcaya, Spain; http://faesfarma.com/). This company was the only funder who collaborated in study design (IG-H). Sí

A 74-year-old woman was admitted to the intensive care unit with acute pulmonary edema requiring endotracheal intubation. The presence of an unknown critical aortic stenosis was revealed with markedly calcified mitral annulus and preserved left ventricular ejection fraction. Because the patient

Background and aims We aimed to assess whether elevated PCSK9 and lipoprotein (a) [Lp(a)] levels associate with coronary artery calcification (CAC), a good marker of atherosclerosis burden, in asymptomatic familial hypercholesterolemia. Methods We selected 161 molecularly defined FH patients treated with stable doses of statins for more than a year. CAC was measured using the Agatston method and quantified as categorical variable. Fasting plasma samples were collected and analyzed for lipids and lipoproteins. PCSK9 was measured by ELISA, Lp(a) and apolipoprotein (a) concentrations by inmunoturbidimetry and LC-MS/MS, respectively. Results Circulating PCSK9 levels were significantly reduced in patients without CAC (n = 63), compared to those with CAC (n = 99). Patients with the highest CAC scores (above 100) had the highest levels of circulating PCSK9 and Lp(a). In multivariable regression analyses, the main predictors for a positive CAC score was age and sex followed by circulating PCSK9 and Lp(a) levels. Conclusions In statin treated asymptomatic FH patients, elevated PCSK9 and Lp(a) levels are independently associated with the presence and severity of CAC, a good predictor of coronary artery disease.

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

summary Background & aim: Oxidized LDL (oxLDL) is a highly immunogenic particle that plays a key role in the development of atherosclerosis. Some data suggest a protective role of OxLDL autoantibodies (OLAB) in atherosclerosis. Our aim was to assess the effect of olive oil polyphenols on the immunogenicity of oxLDL to autoantibody generation. Methods: In a crossover, controlled trial, 200 healthy men were randomly assigned to 3-week sequences of 25 mL/day of 3 olive oils with high (366 mg/kg), medium (164 mg/kg), and low (2.7 mg/kg) phenolic content. Results: Plasma OLAB concentration was inversely associated with oxLDL (p < 0.001). Olive oil phenolic content increased OLAB generation, with the effect being stronger at higher concentrations of oxLDL (p ¼ 0.020 for interaction). A direct relationship was observed between OLAB and the total olive oil phenol content in LDL (r ¼ 0.209; p ¼ 0.014). OLAB concentrations, adjusted for oxLDL, increased directly in a dose-dependent manner with the polyphenol content of the olive oil administered (p ¼ 0.023). Conclusion: Olive oil polyphenols promote OLAB generation. This effect is stronger at higher concentrations of lipid oxidative damage.

Aims To perform a meta-analysis of the association between CYP2C19 loss- and gain-of-function variants and cardiovascular outcomes and bleeding in patients with coronary artery disease treated with clopidogrel, and to explore the causes of heterogeneity between studies. Methods A comprehensive literature search was conducted. A random-effects model was used to summarise the results. In the presence of between-study heterogeneity, a meta-regression analysis was performed to identify study characteristics explaining this heterogeneity. Results Patients who carried a loss-of-function allele, mainly CYP2C19*2, did not present an increased risk of a cardiovascular event, HR ¼1.23 (95% CI 0.97 to 1.55). Substantial heterogeneity was observed between studies (I 2 ¼35.6), which was partially explained by the study sample size: the pooled HR was higher among studies with a sample size

Aims The TRPC4 non-selective cation channel is widely expressed in the endothelium, where it generates Ca2+ signals that participate in the endothelium-mediated vasodilatory response. This study sought to identify single-nucleotide polymorphisms (SNPs) in the TRPC4 gene that are associated with myocardial infarction (MI). Methods and results Our candidate-gene association studies identified a missense SNP ( TRPC4-I957V ) associated with a reduced risk of MI in diabetic patients [odds ratio (OR) = 0.61; confidence interval (CI), 0.40–0.95, P = 0.02]. TRPC4 was also associated with MI in the Wellcome Trust Case–Control Consortium's genome-wide data: an intronic SNP (rs7319926) within the same linkage disequilibrium block as TRPC4-I957V showed an OR of 0.86 (CI, 0.81–0.94; P = 10−4). Functional studies of the missense SNP were carried out in HEK293 and CHO cells expressing wild-type or mutant channels. Patch-clamp studies and measurement of intracellular [Ca2+] in response to muscarinic agonists and direct G-protein activation showed increased channel activity in TRPC4-I957V-transfected cells compared with TRPC4-WT. Site-directed mutagenesis and molecular modelling of TRPC4-I957V suggested that the gain of function was due to the presence of a less bulky Val-957. This permits a firmer interaction between the TRPC4 and the catalytic site of the tyrosine kinase that phosphorylates TRPC4 at Tyr-959 and facilitates channel insertion into the plasma membrane. Conclusion We provide evidence for the association of a TRPC4 SNP with MI in population-based genetic studies. The higher Ca2+ signals generated by TRPC4-I957V may ultimately facilitate the generation of endothelium- and nitric oxide-dependent vasorelaxation, thereby explaining its protective effect at the vasculature.

Objective: Prior studies investigating the association between APOE alleles epsilon 2/epsilon 4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods: We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for epsilon 2 and epsilon 4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. Results: Alleles epsilon 2 and epsilon 4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50-2.23, p = 6.6 x 10(-10); and OR = 2.20, 95%CI = 1.85-2.63, p = 2.4 x 10(-11), respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele epsilon 4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08-1.36, p = 2.6 x 10(-4)). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation: APOE epsilon 2 and epsilon 4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE epsilon 4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied. ANN NEUROL 2010;68:934-943

Introduccion y objetivos. La cardiopatia isquemica (CI) tiene un componente genetico significativo y en los ultimos anos se han identificado variantes geneticas asociadas con ella. El objetivo de este estudio fue evaluar la magnitud de la asociacion entre una puntuacion individual de riesgo genetico, basada en el numero de alelos de riesgo acumulados en un conjunto de variantes geneticas de interes, y la presencia de CI. Metodos. Estudio de los datos in silico del consorcio de casos y controles del Wellcome Trust. Se incluyo a 1.988 pacientes con CI y 5.380 controles. Se analizo la asociacion entre una puntuacion de riesgo genetica y CI mediante regresion logistica. Resultados. Se seleccionaron nueve variantes geneticas asociadas con CI de forma independiente de los factores de riesgo. Existe una asociacion lineal entre el numero de alelos de riesgo y el riesgo de sufrir CI: odds ratio (OR) por incremento de alelo = 1,18 (intervalo de confianza [IC] del 95%, 1,15-1,22; p = 2 x 10-16). La OR de CI del ultimo quintil del numero de alelos de riesgo acumulados respecto al primero fue 2,21 (IC del 95%, 1,87-2,61; p = 5 x 10-21). Conclusiones. Las nueve variantes geneticas asociadas con CI independientemente de los factores de riesgo cardiovascular permiten crear una puntuacion de riesgo genetico de CI que se asocia con la presencia de la enfermedad. Es necesario realizar estudios de cohorte que analicen si esta puntuacion genetica puede mejorar la capacidad predictiva o la reclasificacion de las funciones de riesgo clasicas.

Ofrecemos una visión detallada de la situación actual del patrimonio paleontológico en la región aragonesa. Como podremos ver, éste es enormemente importante por todos los campos que abarca aunque no siempre se encuentre reconocido como debiera.

Objective The large conductance Ca2+ -dependent potassium channel plays a critical role in the control of vascular tone, coupling local increases in intracellular Ca2+ to membrane hyperpolarization and vascular relaxation. It also impacts blood pressure by modulating the renin-angiotensin-aldosterone system. Previous studies have shown that a polymorphism in the beta1 regulatory subunit of the Ca2+ -dependent potassium channel modulates the risk of diastolic hypertension in humans. Methods We have studied polymorphisms in the pore-forming alpha subunit gene (KCNMA1) and their association to hypertension and myocardial infarction. Results Sequencing of the KCNMA1 gene revealed two genetic variants (polymorphisms C864T and IVS17) in population-based epidemiological studies (4786 participants). We detected a significant increase in the frequency of the IVS17+37T>C polymorphism with severe systolic hypertension (48.3% for normotensive vs. 69% for severe systolic hypertension, P=0.03) and with severe general hypertension (48.7 vs. 65.8%, P=0.04), although the adjusted odd ratios did not reach statistical significance. Four C864T/IVS17 haplotypes were identified. Haplotype 4 (encompassing the C allele of the IVS17 polymorphism and the T allele of the C864T polymorphism) was related with increased severity of systolic and general hypertension as well as increased risk of myocardial infarction. Conclusion Our study provides genetic evidence that highlights the relevance of the Ca2+ -dependent potassium channel in the control of human blood pressure and its impact on cardiovascular disease.

Background: Environmental and genetic factors contribute to the development of complex diseases such as myocardial infarction (MI), the leading cause of death in men and women. Women develop MI approximately 10 years later than men, a difference that could be explained by the genes coding for the estrogen receptors. Single nucleotide polymorphisms (SNPs) in the ESR2 gene may affect susceptibility for MI in a sex-dependent manner. Methods: A nested case-control design was used to analyze 3 polymorphisms of the ESR2 gene and their associated haplotypes in 710 myocardial infarction cases from the REGICOR (Registre Gironí del Corazón) study and 2379 controls randomly selected in a representative population of a Spanish cross-sectional study. Results: The rs1271572 T allele was significantly more common in patients who developed MI (P < 0.001). No association was observed for rs1256049 or rs4986938. Assuming a dominant model of inheritance, the association, as determined by logistic multivariate regression after adjustment for conventional cardiac risk factors, remained statistically significant in men [odds ratio (OR) 1.65, 95% CI 1.18–2.30; P = 0.003) but not in women (P = 0.754). A very common haplotype encompassing the rs1271572 variant was also associated with the risk of MI in the overall population (OR 1.41, 95% CI 1.06–1.87; P = 0.020) and in men (OR 1.57, 95% CI 1.12–2.21; P = 0.009). Conclusions: The rs1271572 SNP T variant was associated with increased risk of MI in a Spanish population, and this association was found to be limited to men only. Sex differences in the genetic risk merit further investigation.

Introduccion y objetivos La paraoxonasa 1 (PON1) y la paraoxonasa 2 (PON2) son enzimas antioxidantes cuyos polimorfismos PON1-192 y PON2-311 se han relacionado con el riesgo de infarto agudo de miocardio, con resultados discordantes. El objetivo de este estudio es determinar la asociacion con el riesgo de infarto agudo de miocardio (IAM) de los polimorfismos PON1-192 y PON2-311 y su interaccion. Metodos Se realizo un estudio de casos y controles en el que se recluto a 746 pacientes consecutivos con IAM y 1.796 controles libres de enfermedad cardiovascular seleccionados al azar de la misma poblacion de la que provenian los casos, en 4 comunidades autonomas espanolas entre 1999 y 2000. Se determinaron los polimorfismos PON1-192 y PON2-311, ademas de los factores clasicos de riesgo cardiovascular. Se estimaron modelos de regresion logistica para los analisis multivaribles. Resultados Las odds ratio (OR) del genotipo QQ del polimorfismo PON1-192 y el SS del PON2-311 (presen-tes en el 50 y el 66% de la poblacion, respectivamente) de presentar un IAM fueron 1,26 (intervalo de confianza [IC] del 95%, 1,02-1,55) y 1,25 (IC del 95%, 1,04-1,50), respectivamente, en comparacion con los portadores de los alelos R y C. Ademas, para los sujetos que presentan ambos genotipos QQ y SS, la OR ajustada de tener un IAM se incremento hasta 1,41 (IC del 95%, 1,13-1,76). Conclusiones Nuestros resultados indican que los polimorfismos PON1-192 y PON2-311 son factores de riesgo de IAM independientes en nuestra poblacion.

The one disease associated with the greatest morbidity and mortality in industrialized countries is coronary heart disease (CHD). High density lipoprotein (HDL) is one of the most important independent protective factors for the arteriosclerosis which underlies CHD. Paraoxonase1 (PON1) is an enzyme that confers antioxidant properties to HDL. In vitro, PON1 hydrolyzes a large variety of endogenous or exogenous substrates, some of which are clearly involved in the progression of arteriosclerosis. A close relationship between PON1 deficiency and accelerated progression of arteriosclerosis has been found in animal models. Moreover, PON1 activity is reduced in high oxidative stress diseases such as CHD, dyslipoproteinemias, inflammatory processes, diabetes and certain neuropathies. Reduced PON1 enzyme activity is associated with several arteriosclerosis-related diseases. The most thoroughly studied genetic variant of PON1 is PON1-192, in which the R allele is associated with elevated paraoxonase activity. This allele, present in 24.8% of the Italian population, is found in up to 78.9% of the population of Ecuadorian Cayapa Indians. A metaanalysis of studies on the relationship between CHD and the R allele showed the latter to be an independent risk factor for this disease, with an odds ratio of 1.18 (95% confidence interval, 1.101.27). The PON1 enzyme is a potentially useful new qualitative indicator in addition to the well known reverse cholesterol transport capacity associated with high plasma levels of HDL.

Fundamento y objetivo: La practica de ejercicio fisico regular se asocia a un aumento del colesterol ligado a las lipoproteinas de alta densidad (cHDL), cuyo efecto antioxidante y protector frente a la enfermedad coronaria es bien conocido. La paraoxonasa 1 (PON1) es una enzima relacionada con la actividad antioxidante de la HDL. Se han descrito varios polimorfismos en el gen PON1, uno de ellos situado en el locus 192 (PON1-192) y que comprende los alelos Q (baja actividad de PON1) y R (alta actividad de PON1). El objetivo de este estudio ha sido determinar si existe un efecto de la actividad fisica en el perfil lipidico distinto en funcion del genotipo PON1-192 en mujeres. Pacientes y metodo: Formaron parte de este estudio de cohorte retrospectiva 651 mujeres participantes en un estudio transversal de factores de riesgo. Se analizaron las caracteristicas antropometricas, lipidos y lipoproteinas sericos, presion arterial, genotipos del polimorfismo PON1-192, menopausia, y se utilizo el cuestionario de la actividad fisica en el tiempo libre de Minnesota para valorar la cantidad de ejercicio fisico realizado diariamente durante el ultimo ano. Resultados: Las participantes en el estudio se clasificaron en 3 categorias correspondientes a los terciles de la cantidad de ejercicio fisico realizado. Si bien no se hallaron diferencias de los parametros lipidicos en la muestra global del estudio, se observo una tendencia lineal creciente de los valores de cHDL y decreciente para el cociente log trigliceridos/cHDL al aumentar la actividad fisica en mujeres homocigotas RR. Un analisis posterior en subgrupos revelo que las asociaciones de un incremento del cHDL y de un decremento del cociente log trigliceridos/cHDL con una mayor practica de actividad fisica eran exclusivas de mujeres no menopausicas y homocigotas RR. Conclusiones: Este hallazgo indica que el polimorfismo 192 de la PON1 podria modular el efecto de la actividad fisica en la concentracion de cHDL y el catabolismo de las particulas ricas en trigliceridos en mujeres en edad fertil.

Physical activity has been identified as a protective factor against the occurrence and progression of coronary heart disease. The lipoprotein lipase (LPL) HindIII polymorphism has been associated with changes in triglyceride and high density lipoprotein (HDL)-cholesterol levels. We have investigated whether the association between the LPL HindIII genetic polymorphism and lipid levels is modified by physical activity. We have also tested the hypothesis that physical activity may interact with smoking and the LPL HindIII polymorphism to determine an individual's plasma lipid concentrations. A total of 520 men were selected from a representative sample used in a population study conducted in Gerona, Spain. The median value (291 kcal/day) of energy expenditure in leisure-time physical activity of the studied sample was selected as a cut-off to define sedentary or active subjects. Serum HDL-cholesterol was positively and significantly associated with the amount of daily energy expenditure in physical activity, whereas inverse associations were seen between physical activity and triglyceride concentration and with the triglyceride to HDL-cholesterol ratio. These effects were consistent across LPL HindIII genotypes. There was a statistically significant interaction between LPL genotype and smoking on lipid concentrations. No statistically significant differences were observed in lipid levels of active or sedentary non-smokers between H- carriers and H+H+ homozygotes for the LPL HindIII polymorphism. In smokers, sedentary H+H+ homozygotes showed significantly higher triglyceride and lower HDL-cholesterol concentrations than sedentary H- carriers. These differences were smaller and not statistically significant when lipid values of active H+H+ homozygotes were compared with active H- carriers. Among all subgroups, sedentary smokers with the H+H+ genotype had the most adverse lipid profile, which was considerably less adverse in H+H+ smokers who were physically active. These findings suggest that the presence of the H+H+ genotype has a deleterious effect on lipid profile in an adverse environment such as smoking, and that the expenditure of more than 291 kcal/day in physical activity attenuates this effect.

Aims There is increasing evidence that paraoxonase, an HDL-linked enzyme, exerts its effect by removing lipid-peroxidation products. We have conducted a case-control study in Gerona, Spain, to find out whether paraoxonase1 polymorphism at codon 192 (Q and R alleles) is associated with increased risk of coronary heart disease, and how diabetes mellitus, associated with high oxidative risk, influences such an association. Methods and Results One hundred and fifty six consecutive myocardial infarction patients and 310 age- and sex-matched control subjects were studied. There were no differences in the distribution of genotype and allele frequencies between patients and controls. The odds ratios for diabetes and dyslipaemia in control and patients stratified by genotype group were compared. Whereas dyslipaemic status was significantly related to myocardial infarction in QQ homozygotes and R carriers, diabetes mellitus was significantly associated with myocardial infarction only in R-carrier subjects. In logistic regression analysis, diabetic R carriers demonstrated a more than two and a half-fold increase in myocardial infarction risk compared with non-diabetic R carriers (OR: 2·65, P

Coronary artery disease (CAD) has a substantial genetic component and, in recent years, a number of genetic variants associated with the disease have been identified. The objective of this study was to evaluate the magnitude of the association between a genetic risk score, which is based on the accumulated number of risk alleles in all genetic variants of interest, and the presence of CAD.The study involved in silico data from the Wellcome Trust Case-Control Consortium on 1988 patients with CAD and 5380 controls. The association between the genetic risk score and CAD was assessed using logistic regression analysis.Nine genetic variants independently associated with CAD irrespective of other cardiovascular risk factors were selected. There was a linear association between the number of risk alleles and the risk of presenting with CAD (odds ratio [OR] for an increase of one allele=1.18; 95% confidence interval [CI], 1.15-1.22; P=2 x 10-16). The OR for CAD for the last quintile of the accumulated number of risk alleles relative to the first was 2.21 (95%CI, 1.87-2.61; P=5 x 10-21).A genetic risk score based on nine genetic variants independently associated with CAD irrespective of other cardiovascular risk factors was associated with the presence of the disease. Cohort studies are needed to determine whether this genetic risk score can improve the predictive capacity or the risk classification of classical risk functions.

Background: Coronary heart disease (CHD) is the leading cause of mortality worldwide. CHD clusters in families but this familial aggregation remains largely unexplained. ESR1 is a candidate gene for CHD although recent meta-analyses of the rs2234693 variant reported inconsistent evidence for association with myocardial infarction (MI) in men. The objectives of this study were to perform a qualitative and a quantitative assessment of all evidence to date regarding this association. Methods: We performed structured literature searches for studies addressing the association between the ESR1 rs2234693 and CHD. We assessed the quality of these studies collectively and individually according to recently published guidelines on the reporting and interpretation of genetic association studies. We also performed a meta-analysis of all studies to date, including a sample of MI cases and controls from our region. Results: The qualitative assessment indicated that many studies met a low proportion of the criteria proposed by the current guidelines. No significant association between ESR1 rs2234693 and MI was observed in our sample or in the meta-analysis (16 studies; N ∼ 32,000; OR ∼ 1). Strong between-study heterogeneity was largely explained by a quality score based on the quality criteria. Studies that reported significant associations were generally of poorer quality. Conclusion: We confirm the lack of association between the ESR1 rs223469 and CHD, and show that inconsistencies between previous studies is explained by differences in their quality. © 2009 Elsevier Ireland Ltd. All rights reserved.

Two particular polymorphisms, namely PON1-192 and PON2-311, in the genes encoding the antioxidant enzymes paraoxonase-1 (PON1) and paraoxonase-2 (PON2) have been associated with an increased risk of acute myocardial infarction (AMI). However, previous findings have been contradictory. The aim of this study was to investigate the association between the PON1-192 and PON2-311 polymorphisms and their interaction on AMI risk.This case-control study involved 746 consecutive AMI patients and 1796 control subjects without cardiovascular disease, who were randomly selected from the same population from which the patients came. All participants were recruited between 1999 and 2000 from four Spanish autonomous regions. All were assessed for the presence of PON1-192 and PON2-311 and for classical cardiovascular risk factors. Multivariate analysis was carried out using logistic regression modeling.The odds ratios (OR) of AMI for patients with the PON1-192 QQ and PON2-311 SS genotypes (who comprised 50% and 66% of the population, respectively) were 1.26 (95% confidence interval [CI], 1.02-1.55) and 1.25 (95% CI, 1.04-1.50), respectively, compared with R and C allele carriers. Moreover, in patients with both QQ and SS genotypes, the adjusted OR of AMI increased to 1.41 (95% CI, 1.13-1.76).Our results indicate that the PON1-192 and PON2-311 polymorphisms were independent risk factors of AMI in our population.

The E65K polymorphism in the β 1 -subunit of the large-conductance, Ca 2+ -dependent K + (BK) channel, a key element in the control of arterial tone, has recently been associated with low prevalence of diastolic hypertension. We now report the modulatory effect of sex and age on the association of the E65K polymorphism with low prevalence of diastolic hypertension and the protective role of E65K polymorphism against cardiovascular disease. We analyzed the genotype frequency of the E65K polymorphism in 3924 participants selected randomly in two cross-sectional studies. A five-year follow-up of the cohort was performed to determine whether cardiovascular events had occurred since inclusion. Estrogen modulation of wild-type and mutant ion channel activity was assessed after heterologous expression and electrophysiological studies. Multivariate regression analyses showed that increasing age upmodulates the protective effect of the K allele against moderate-to-severe diastolic hypertension in the overall group of participants (odds ratio [OR], 0.35; P =0.006). The results remained significant when analyses were restricted to women (OR, 0.18; P =0.02) but not men (OR, 0.46; P =0.09). This effect was independent of the reported acute modulation of BK channels by estrogen. A five-year follow-up study also demonstrated a reduced age- and sex-adjusted hazard ratio of 0.11, 95% CI, 0.01 to 0.79 of K-carriers for “combined cardiovascular disease” (myocardial infarction and stroke) compared with EE homozygotes. Our study provides the first genetic evidence for the different impact of the BK channel in the control of human blood pressure in men and women, with particular relevance in aging women, and highlights the E65K polymorphism as one of the strongest genetic factors associated thus far to protection against myocardial infarction and stroke.

Regular physical activity is associated with an increase in high-density lipoprotein cholesterol (HDL-C), whose antioxidant and protective effect for coronary artery disease is well known. Paraoxonase-1 (PON1) is an enzyme related with the antioxidant activity of HDL. The PON1 gene has several genetic polymorphisms; one of them locates in codon 192, whose alleles Q and R are associated with low and high PON1-activity, respectively. The objective of this study was to determine whether physical activity has different effects on the lipid profile in women depending on the PON1-192 genotype.Six hundred and fifty-one women from a cross-sectional risk-factor study were included in this retrospective cohort study. We analyzed anthropometrical characteristics, serum lipids and lipoproteins, blood pressure, PON1-192 genotypes and menopause. We used the Minnesota Leisure Time Physical Activity Questionnaire to assess the daily physical activity in the previous year.Women included in the study were classified into three categories by tertiles of daily physical activity. Although no differences in the lipidic parameters were found, we observed an increasing trend in HDL-C concentration and a decreasing trend in log-triglyceride-to-HDL-cholesterol ratio with increasing physical activity in RR homozygous women. In subgroup analyses, we observed that the association of high physical activity and increased HDL-C concentration or decreased log-triglyceride-to-HDL-cholesterol ratio were exclusive for RR homozygous non-menopausal women.The results of this study suggest that PON1-192 polymorphism could modulate the effect of physical activity on HDL-C concentration and on triglyceride-rich lipoprotein catabolism in non-menopausal women.

Hypertension is the most prevalent risk factor for cardiovascular diseases, present in almost 30% of adults. A key element in the control of vascular tone is the large-conductance, Ca(2+)-dependent K(+) (BK) channel. The BK channel in vascular smooth muscle is formed by an ion-conducting alpha subunit and a regulatory beta(1) subunit, which couples local increases in intracellular Ca(2+) to augmented channel activity and vascular relaxation. Our large population-based genetic epidemiological study has identified a new single-nucleotide substitution (G352A) in the beta(1) gene (KCNMB1), corresponding to an E65K mutation in the protein. This mutation results in a gain of function of the channel and is associated with low prevalence of moderate and severe diastolic hypertension. BK-beta(1E65K) channels showed increased Ca(2+) sensitivity, compared with wild-type channels, without changes in channel kinetics. In conclusion, the BK-beta(1E65K) channel might offer a more efficient negative-feedback effect on vascular smooth muscle contractility, consistent with a protective effect of the K allele against the severity of diastolic hypertension. This work was supported by the Human Frontiers Science Organization, the Ministerio de Ciencia y Tecnología (Spain), Red HERACLES (Fondo de Investigaciones Sanitarias, Spain), Comissió Interdepartamental de Recerca i Innovació Tecnològica, de la Generalitat de Catalunya per a la Promoció de la Recerca Universitaria, and Fondo Nacional de Investigaciones Científicas y Tecnológicas (Chile)

Paraoxonase (PON1) is an antioxidant enzyme closely associated with high-density lipoproteins. Low PON1 has been shown in oxidative stress-associated processes such as dyslipidemia, diabetes mellitus, advancing age, and smoking. Indeed, oxidative stress is related to the degree of insulin resistance, a key component of the metabolic syndrome. Therefore, the possible relationship between PON1 activity and the metabolic syndrome was investigated. From 1364 randomly recruited subjects, 285 were found to have the metabolic syndrome, according to the guidelines published by the National Cholesterol Education Program, Adult Treatment Panel III. PON1 activity, lipid peroxides, and PON1 codon 192 genotypes, which strongly modulate PON1 activity, were determined. Serum PON1 activity levels were found to be significantly lower, and lipid peroxide concentrations significantly higher, in subjects with the metabolic syndrome compared with unaffected subjects (P = 0.033 and0.001, respectively). Study subjects showed a significant decreasing trend in PON1 activity levels and a significant increasing trend in lipid peroxide concentrations, with the increase in the number of metabolic disturbances. No differences in the prevalence of PON1 codon 192 genotypes were found among the categories of metabolic abnormalities. In conclusion, a greater degree of severity of the metabolic syndrome is associated with a progressively worse antioxidant/oxidant balance, which is consistent with increased oxidative stress and lower antioxidant PON1 enzymatic capacity.

Methods: We determined the effect of smoking on PON1 activity levels in a population-based sample of 1380 subjects and examined the possibility of regular physical activity modulating the effect of cigarette smoking on PON1 activity levels at a population level. Results: Mean PON1 activity was significantly lower in smokers than in non- or ex-smokers (237.6±8.4 vs. 276.7±5.3 U/l, mean±S.E.M.; P = 0.001). PON1 activity levels were significantly higher in physically active subjects than in those who were inactive (296.1±10.4 vs. 260.1±9.2 U/l; P =0.002). Inactive smokers showed significantly lower PON1 activity levels than inactive nonsmokers ( P =0.002). These differences disappeared when active nonsmokers were compared with active smokers. Serum PON1 activity levels were found to be significantly increased in active smokers compared to those in inactive smokers. A statistically significant interaction ( P =0.003) between smoking and physical activity on PON1 activity was observed. Conclusion: Smoking appears to have a deleterious effect on PON1 activity levels. Being physically active clearly attenuates this effect.

Oxidized low density lipoprotein (oxLDL) plays a pivotal role in the development of atherosclerosis. The aim of the study was to investigate the relationship between oxLDL and other oxidative stress biomarkers with stable coronary heart disease (CHD). We compared the degree of oxidative stress in patients with CHD and sex-matched healthy control subjects in a case-control study. The study included 64 male subjects: 32 patients with stable CHD and 32 normal control subjects. Levels of circulating oxLDL were measured by a monoclonal antibody 4E6-based competition ELISA. Comparison of oxidative stress marker levels between cases and controls, adjusted for age, revealed significantly higher plasma oxLDL levels (63.329 /25.49 vs. 37.739 /20.58 U/l, P/0.001), lower serum levels of autoantibodies against oxLDL (341.539 /350.46 vs. 796.459 /1034.2 mU/ml, P/0.021), higher activities of the antioxidant enzymes superoxide dismutase in erythrocytes (9519 /70.2 vs. 771.69 /191.2 U/g, P/0.032) and glutathione peroxidase in whole blood (GSH-Px: 10 714.49 /3705.4 vs. 5512.29 /1498.1 U/l, P B/0.001). The risk of having CHD was 20.6-fold greater (95% CI, 1.86/228.44, P/0.014) in the highest tertile of the oxLDL distribution than in the lowest, determined by logistic regression analysis on the combined study population after adjustment for age and other potential confounding factors. When the risk associated with GSH-Px levels was calculated, the odds ratio was 305.3 (95% CI, 5.07/18369.95, P/0.006) in the highest tertile compared with the lowest. Our results showed that an oxidative stress occurs in patients with CHD despite being clinically stable and under medical treatment. The combination of oxLDL levels and GSH-Px activity may be useful for the identification of patients with stable CHD. # 2003 Elsevier Science Ireland Ltd. All rights reserved.