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Danışman: DR. ÖĞR. ÜYESİ SELVA ZEREN Yer Bilgisi: İstanbul Gelişim Üniversitesi / Lisansüstü Eğitim Enstitüsü / Odyoloji Ana Bilim Dalı / Odyoloji Bilim Dalı Konu: Göğüs Kalp ve Damar Cerrahisi = Thoracic and Cardiovascular Surgery ; Kulak Burun ve Boğaz = Otorhinolaryngology (Ear-Nose-Throat) Dizin: Kalp hastalıkları = Heart diseases ; Kardiyopulmoner bypass = Cardiopulmonary bypass ; Koklea = Cochlea ; Koroner hastalık = Coronary disease ; Otoakustik emisyonlar = Otoacoustic emissions, Koroner hastalıklarda revaskülarizasyon ihtiyacına gereksinim duyulan hastalarda kardiyopulmoner bypass cerrahisi uygulanmaktadır. Bu çalışmanın amacı kardiyopulmoner bypass cerrahisi uygulanan hastaların medial-olivokoklear refleks (MOC) cevaplarının cerrahi öncesi ve sonrası karşılaştırılarak etkilenme düzeylerinin belirlenmesidir. Bu çalışmaya 40'ı koroner arter bypass (KAB) ameliyatı olan, 40'ı herhangi bir kalp damar hastalığı olmayan birey katılmıştır. KAB ameliyatı olan hastalara ameliyat öncesinde ve sonrasında timpanometri, safses odyometrisi, transient otoakustik emisyon (TEOAE), ve supresyonda emisyon testleri yapılmıştır. Cerrahi öncesi ve sonrası sonuçlar istatistiksel olarak analiz edilmiştir. Koroner bypass grubu olguların cerrahi öncesi TEOAE değerleri, kontrol grubu olgulara göre istatistiksel olarak anlamlı düzeyde düşük saptanmıştır (p=0,001; p, Cardiopulmonary bypass surgery is performed in patients who need revascularization in coronary diseases. The aim of this study is to compare the medial-olivocochlear reflex (MOC) responses of patients who underwent cardiopulmonary bypass surgery before and after surgery and to determine their level of influence. In this study, 40 individuals who had coronary artery bypass (CAB) surgery and 40 did not have any cardiovascular disease participated in this study. Preoperative and postoperative tympanometry, pure tone audiometry, transient otoacoustic emission (TEOAE), and emission tests in suppression were performed on patients who had CAB surgery. The results before and after surgery were statistically analyzed. Preoperative TEOAE values of the patients in the coronary bypass group were found to be statistically significantly lower than those in the control group (p=0.001; p

[spa] INTRODUCCIÓN: El envejecimiento de la población está provocando un aumento del número de pacientes ancianos con Infarto Agudo de Miocardio (IAM). Estos pacientes tienen mayor carga de comorbilidades, fragilidad, mayor riesgo de complicaciones y una mala adherencia a la medicación, lo que a su vez se asocia con un mayor gasto en recursos sanitarios. Los programas de enfermería pueden ayudar a mejorar la adherencia en estos pacientes complejos. OBJETIVO PRINCIPAL: Comparar el grado de adherencia al tratamiento al año en pacientes mayores de 75 años tras un IAM que han participado en un programa de educación sanitaria enfermero, respecto a otro grupo control. OBJETIVOS ESPECÍFICOS: (1) Conocer la prevalencia de fragilidad, deterioro cognitivo y funcional y su impacto en la evolución de los pacientes mayores de 75 años con IAM; (2) Analizar si hay variación en la calidad de vida del paciente antes y 12 meses después del IAM; (3) Analizar la posible asociación entre los diferentes componentes de la valoración geriátrica y la adherencia terapéutica en estos pacientes. METODOLOGÍA: Este proyecto de tesis está compuesto por 2 bloques. En el primero se analizan las características de los pacientes en cuanto a fragilidad, deterioro cognitivo y funcional y otras variables vinculadas al envejecimiento y su posible impacto en la evolución del paciente anciano tras un IAM. Para ello se realizó un estudio observacional prospectivo. Se incluyó de forma consecutiva pacientes mayores de 75 años ingresados en la Unidad Coronaria del Hospital Universitario de Bellvitge con el diagnóstico de SCA con elevación de segmento ST (SCAEST), sometido a angioplastia percutánea coronaria entre enero de 2013 y noviembre de 2016. Se registraron datos clínicos, así como una valoración geriátrica durante el ingreso, incluyendo fragilidad (FRAIL), deterioro cognitivo (test de Pfeiffer), dependencia para las actividades básicas (Barthel) e instrumentales (test de Lawton Broody) de la vida diaria, riesgo nutricional (MNA Short Form), comorbilidad (índice de Charlson) y calidad de vida (Seattle Angina Questionnaire). Esta valoración geriátrica se refirió a la situación previa al ingreso. El segundo gran bloque de este proyecto va destinado a analizar el posible impacto de una intervención de enfermería en la adherencia terapéutico al año en ancianos tras un SCAEST. Para ello se realizó un estudio experimental, no probabilístico con asignación aleatoria de los grupos de estudio. El periodo de inclusión y seguimiento de pacientes fue de abril de 2016 a diciembre de 2019. Se realizó valoración geriátrica durante el ingreso. En los pacientes incluidos en el grupo experimental se realizó a los 3 meses un “Programa de educación sanitaria enfermero” (PESE), haciendo hincapié en la valoración y aplicación de intervenciones para mejorar la adherencia terapéutica. Al año, se evaluó la adherencia terapéutica mediante la combinación de 4 métodos: cuestionario de Morisky-Green (4- items), test de Haynes-Sackett, registro de dispensación de farmacia y asistencia a citas programadas, considerándose “adherente” aquel paciente adherente en los 4 métodos. Esta valoración se realizó por personal que no conocía el grupo de asignación de los pacientes. También a los 12 meses se repitió la valoración geriátrica, en ambos grupos. El análisis de datos se realizó con el paquete estadístico SPSS. RESULTADOS: En el primer estudio se analizó una muestra de 259 pacientes con una edad media de 82.6 ± 6 años, 57,9% de los cuales eran hombres. Un 19,7% de los pacientes eran frágiles, un 10% presentaba discapacidad moderada o grave y un 31,7% tenía riesgo de desnutrición. La fragilidad se asoció con una mayor prevalencia de diabetes, hipertensión y accidente cerebrovascular previo, y una mayor mortalidad (21,6% frente a 3,4%; P, [eng] INTRODUCTION: The aging of the population is causing an increase in the number of elderly patients with Acute Myocardial Infarction (AMI). These patients have a higher burden of comorbidities, frailty, higher risk of complications, and poor adherence to medication, which in turn is associated with higher spending on healthcare resources. Nursing programs can help improve adherence in these complex patients. MAIN OBJECTIVE: To compare the degree of adherence to treatment in one year in patients older than 75 years after an AMI who have participated in a nursing health education program, compared to another control group. SPECIFIC OBJECTIVES: (1) To know the prevalence of frailty, cognitive and functional impairment, and its impact on the evolution of patients older than 75 years with AMI; (2) To analyze whether there is variation in the patient's quality of life before and 12 months after AMI; (3) To analyze the possible association between the different components of geriatric assessment and therapeutic adherence in these patients. METHODOLOGY: This thesis project is divided in 2 blocks. The first analyzes the characteristics of the patients in terms of frailty, cognitive and functional impairment and other variables related to aging and their possible impact on the evolution of the elderly patient after an AMI. For this, a prospective observational study was carried out. Patients older than 75 years admitted to the Coronary Unit of the Bellvitge University Hospital with the diagnosis of acute coronary syndrome with ST segment elevation, who underwent percutaneous coronary angioplasty between January 2013 and November 2016, were consecutively included. Clinical data were recorded, as well as a geriatric assessment during admission, including frailty (FRAIL), cognitive impairment (Pfeiffer test), dependence for basic (Barthel) and instrumental activities (Lawton Broody test) of daily life, nutritional risk (MNA Short Form), comorbidity (Charlson index) and quality of life (Seattle Angina Questionnaire). This geriatric assessment referred to the situation prior to admission. The second large block of this project is intended to analyze the possible impact of a nursing intervention on therapeutic adherence at one year in elderly patients after Acute Coronary Syndrome with ST segment elevation. For this, an experimental, non-probabilistic study was carried out with random assignment of the study groups. The period of inclusion and follow-up of patients was from April 2016 to December 2019. A geriatric assessment was performed during admission. In the patients included in the experimental group, a “Nursing Health Education Program” (PESE) was carried out at 3 months, emphasizing the assessment and application of interventions to improve therapeutic adherence. At one-year, therapeutic adherence was evaluated by a combination of 4 methods: Morisky-Green questionnaire (4-items), Haynes-Sackett test, pharmacy dispensing record and attendance at scheduled appointments, with the adherent patient being considered "adherent" in all 4 methods. This assessment was carried out by nurses who were unaware of the patient assignment group. Moreover, at 12 months the geriatric assessment was repeated in both groups. Data analysis was performed with the SPSS statistical package. RESULTS: In the first study, a sample of 259 patients with a mean age of 82.6 ± 6 years was analyzed, 57.9% of whom were men. 19.7% of the patients were frail, 10% had moderate or severe disability, and 31.7% were at risk of malnutrition. Frailty was associated with a higher prevalence of diabetes, hypertension, and prior stroke, and higher mortality (21.6% vs 3.4%; P

Framework: Although gestation marks some of the most important moments in a woman’s life, it becomes complex when associated with the problems, limitations, and risks inherent in heart disease. Objective: to comprehend the meanings women with heart disease attribute to their high-risk pregnancy and to identify their perception of the risks to the mother-child binomial. Methodology: A quantiqualitative study involving 39 pregnant women with heart disease from a public university of an inland city of São Paulo, Brazil, was conducted. Data were collected through interviews with patients and analyzed using the Discourse of the Collective Subject. Results: This study showed high-risk gestation is a process linked to personal satisfaction and fulfillment of a dream, often associated with a lack of planning, uncertainties and fears. Some participants anchored in religion/spirituality to overcome difficulties, while others used self-reliance as a support. The risks are poorly understood and often underestimated. Conclusion: High-risk gestation is a process associated with personal satisfaction, fulfillment of a dream and even a common experience, often permeated by negative feelings about the inevitable risks to the mother-child binomial. Resumen: Marco contextual: Aunque la gestación marca algunos de los momentos más importantes en la vida de una mujer, se vuelve compleja cuando se asocia con los problemas, las limitaciones y los riesgos inherentes a la enfermedad cardíaca. Objetivo: entender los significados que las mujeres con enfermedad cardíaca atribuyen a embarazos de alto riesgo e identificar su percepción de los riesgos para el binomio madre-hijo. Metodología: Fue desarrollado un estudio cuanti-cualitativo con 39 embarazadas cardíacas en una universidad pública en el interior de São Paulo, Brazil. Los datos fueron recolectados mediante entrevistas con pacientes y analizados mediante el Discurso del Sujeto Colectivo. Resultados: Este estudio reveló que el embarazo de alto riesgo es un proceso vinculado a satisfacción personal y cumplimiento de un sueño, muchas veces asociado con una falta de planificación, incertidumbres y miedos. Algunas participantes se apoyaron en la religión/espiritualidad para superar dificultades, mientras otras utilizaron la autoconfianza como apoyo. Hay poca comprensión y muchas veces subestimación de los riesgos. Conclusión: El embarazo de alto riesgo es un proceso asociado con satisfacción personal, cumplimiento de un sueño e incluso con una experiencia común, muchas veces permeada por sentimientos negativos sobre los riesgos inevitables para el binomio madre-hijo. Resumo: Marco contextual: Embora a gestação marque alguns dos momentos mais importantes na vida de uma mulher, ela se torna complexa quando associada aos problemas, limitações e riscos inerentes às doenças cardíacas. Objetivo: compreender os significados que mulheres cardiopatas atribuem à gravidez de alto risco e identificar sua percepção sobre os riscos para o binômio mãe-filho. Metodologia: Foi realizado um estudo quantitativo com 39 gestantes cardiopatas de uma universidade pública de uma cidade do interior de São Paulo, Brasil. Os dados foram coletados por meio de entrevista com os pacientes e analisados por meio do Discurso do Sujeito Coletivo. Resultados: Este estudo mostrou que a gestação de alto risco é um processo atrelado à satisfação pessoal e realização de um sonho, muitas vezes associado à falta de planejamento, incertezas e medos. Alguns participantes se ancoraram na religião / espiritualidade para superar as dificuldades, enquanto outros usaram a autossuficiência como suporte. Os riscos são mal compreendidos e frequentemente subestimados. Conclusão: A gestação de alto risco é um processo associado à satisfação pessoal, realização de um sonho e até mesmo uma experiência comum, muitas vezes permeada por sentimentos negativos sobre os riscos inevitáveis para o binômio mãe-filho.

Background Coronary disease and Hypertension are highly prevalent health problems worldwide, with the latter being one of the most common diseases in patients visiting dental clinics. Local anesthetics (LAs) with vasoconstrictor agents (VC) are known to be commonly used in dental practice. For the above-mentioned reasons, dentists should know how to adapt and treat patients with these hazardous conditions. Objective The aim of this study was to find out if the use of local anesthetics (LAs) in combination with vasoconstrictor (VC) agents in dental treatment presents a risk in patient with a known history of Hypertension and/or Coronary disease. Materials and methods This systematic review was conducted in accordance with The PRISMA guidelines and registered on the PROSPERO database (CRD42020187369). The search strategy was based on Mesh terms, Boolean operator AND, and the PICO model. It was designed to identify all the randomized clinical trials (RCTs) published in the last 30 years, which assessed whether the use of LA with VC agents in dental treatment produces a significant increase/decrease in hemodynamics in patients with known history of Hypertension and/or Coronary disease. The Cochrane Collaboration's tool was used to assess risk of bias of the included RCTs. Results An initial electronic search resulted in 87 papers; however only 9 RCTs met the inclusion criteria. There was a total of 482 subjects (N = 482), of which 412 had a known history of Hypertension or Coronary disease. Conclusions According to the literature reviewed, the use of 1 to 2 cartridges of local anesthetics with 1:80,000, 1:100,000 or 1:200,000 epinephrine in patients with controlled Hypertension and/ or Coronary disease is safe. Randomized clinical trials are essential in determining the safety or risks associated with the use of LAs with VC agents in patients with poorly controlled Hypertension and Coronary disease.

Cardiovascular mortality increases with decreasing renal function although the cause is yet unknown. Here, we have investigated whether low chronic inflammation in chronic kidney diseases (CKD) could contribute to increased risk for coronary artery diseases (CAD). Thus, a prospective case&ndash, control study was conducted in patients with CAD and CKD undergoing coronary artery bypass graft surgery with the aim of detecting differences in cardiovascular outcomes, epicardial adipose tissue volume, and inflammatory marker activity associated with renal dysfunction. Expression of membrane CD14 and CD16, inflammatory cytokines and chemokines, mitogen-activated protein (MAP) kinases and hsa-miR-30a-5p were analyzed in peripheral blood mononuclear cells (PBMCs). Epicardial fat volume and tissue inflammation in perivascular adipose tissue and in the aorta were also studied. In the present study, 151 patients were included, 110 with CAD (51 with CKD) and 41 nonCAD controls (15 with CKD). CKD increased the risk of cardiac surgery&ndash, associated acute kidney injury (CSA-AKI) as well as the 30-day mortality after cardiac surgery. Higher counts of CD14++CD16+ monocytes were associated with vascular inflammation, with an increased expression of IL1&beta, and with CKD in CAD patients. Expression of hsa-miR-30a-5p was correlated with hypertension. We conclude that CKD patients show an increased risk of CSA-AKI and mortality after cardiovascular surgery, associated with the expansion of the CD14++CD16+ subset of proinflammatory monocytes and with IL1&beta, expression. We propose that inflammation associated with CKD may contribute to atherosclerosis (ATH) pathogenesis.

Direct oral anticoagulants (DOACs) have been demonstrated to be more effective and safer than vitamin-K antagonist (VKA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF). This meta-analysis aims to assess the effect of DOACS vs. VKA in patients ≥ 80 and AF. Primary endpoints were stroke or systemic embolism and all-cause death. Secondary endpoints included major bleeding, intracranial bleeding, and gastrointestinal bleeding. A random-effects model was selected due to significant heterogeneity. A total of 147,067 patients from 16 studies were included, 71,913 (48.90%) treated with DOACs and 75,154 with VKA (51.10%). The stroke rate was significantly lower in DOACs group compared with warfarin group (Relative risk (RR): 0.72; 95% confidence interval (CI): 0.63–0.82; p < 0.001). All-cause mortality was significantly lower in DOACs group compared with warfarin group (RR: 0.82; 95% CI: 0.70–0.96; p = 0.012). Compared to warfarin, DOACs were not associated with reductions in major bleeding (RR: 0.85, 95% CI 0.69–1.04; p = 0.108) or gastrointestinal bleeding risk (RR: 1.08, 95% CI 0.76–1.53; p = 0.678) but a 43% reduction of intracranial bleeding (RR: 0.47, IC 95% 0.36–0.60; p < 0.001) was observed. Our meta-analysis demonstrates that DOACs are effective and safe with statistical superiority when compared with warfarin in octogenarians with AF.

Introduction and objective: Anemia is a common comorbidity in patients with acute coronary syndromes (ACS), and is associated with higher risk for both bleeding and ischemic complications. We aimed to assess the predictive ability of bleeding risk scores (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines [CRUSADE], Mehran and Acute Coronary Treatment and Intervention Outcomes Network [ACTION]) in ACS patients with anemia. Methods: All consecutive ACS patients were prospectively included. The primary outcome was in-hospital major bleeding according to the CRUSADE, Mehran and ACTION definitions. Anemia was defined as hemoglobin

Dual antiplatelet therapy; ST-elevation myocardial infarction; Percutaneous coronary intervention Teràpia antiagregant plaquetària; Infart de miocardi amb elevació ST; Intervenció coronària percutània Terapia antiagregante plaquetaria; Infarto de miocardio con elevación ST; Intervención coronaria percutánea Objectives: Guidelines recommending 12-month dual antiplatelet therapy (DAPT) in patients with ST-elevation acute coronary syndrome (STEACS) undergoing percutaneous coronary intervention (PCI) were published in year 2012. We aimed to describe the influence of guideline implementation on the trend in 12-month persistence with DAPT between 2010 and 2015 and to evaluate its relationship with DAPT duration regimens recommended at discharge from PCI hospitals. Design: Observational study based on region-wide registry data linked to pharmacy billing data for DAPT follow-up. Setting: All PCI hospitals (10) belonging to the acute myocardial infarction (AMI) code network in Catalonia (Spain). Participants. 10 711 STEACS patients undergoing PCI between 2010 and 2015 were followed up. Primary and secondary outcome measures: Primary outcome was 12-month persistence with DAPT. Calendar year quarter, publication of guidelines, DAPT duration regimen recommended in the hospital discharge report, baseline patient characteristics and significant interactions were included in mixed-effects logistic regression based interrupted time-series models. Results: The proportion of patients on-DAPT at 12 months increased from 58% (56–60) in 2010 to 73% (71–75) in 2015. The rate of 12-month persistence with DAPT significantly increased after the publication of clinical guidelines with a time lag of 1 year (OR=1.20; 95% CI 1.11 to 1.30). A higher risk profile, more extensive and complex coronary disease, use of drug-eluting stents (OR=1.90; 95% CI 1.50 to 2.40) and a 12-month DAPT regimen recommendation at discharge from the PCI hospital (OR=5.76; 95% CI 3.26 to 10.2) were associated with 12-month persistence. Conclusion: Persistence with 12-month DAPT has increased since publication of clinical guidelines. Even though most patients were discharged on DAPT, only 73% with potential indication were on-DAPT 12 months after PCI. A guideline-based recommendation at PCI hospital discharge was highly associated with full persistence with DAPT. Establishing evidence-based, common prescribing criteria across hospitals in the AMI-network would favour adherence and reduce variability. The study was supported by Instituto de Salud Carlos III grand number PI13/00399 and the Fundacio la Marato de TV3 grand number 430/U/2015.

Podeu consultar la versió en castellà a http://hdl.handle.net/2445/166994, Objectives: Information on criteria for admitting elderly patients with acute coronary syndrome (ACS) to intensive care units (ICUs) is scarce. We aimed to describe factors associated with ICU admission in unselected older patients with ACS in Spain. Material and methods: The prospective LONGEVO-SCA registry (Impact of Frailty and Other Geriatric Syndromes on the Management of and Mortality in Elderly Patients With Non-ST-segment Elevation Acute Coronary Syndrome) included unselected patients over the age of 80 years with non-ST-segment elevation SCA. A geriatric assessment of each patient was done in the hospital. Clinical outcomes at 6 months were analyzed. Bivariate logistic regression analysis was applied to identify ICU admission criteria. Results: Of 508 patients with a mean age of 84.3 years, 150 (29.5%) were admitted to the ICU. The admitted patients were younger and more often had acute heart failure, elevated troponin levels, and poor left ventricular function. They also scored higher on the Acute Coronary Treatment and Intervention Outcomes Network-ICU (ACTION-ICU) and Global Registry of Acute Coronary Events (GRACE) risk scales. These patients had higher functional status scores and a lower prevalence of frailty and had more often undergone coronary angiography (P < .001). No differences in hospital mortality or outcomes at 6 months were detected between patients admitted or not admitted to ICUs. The following variables were independent predictors of ICU admission: no history of a previous episode of heart failure, an elevated troponin level on arrival, left ventricular dysfunction, high GRACE score and high Charlson Comorbidity Index, and absence of frailty. Conclusion: Around a third of elderly patients with non-ST-segment elevation ACS are admitted to an ICU. Admitted patients have a higher risk profile on arrival and a lower prevalence of geriatric syndromes.

[spa] El envejecimiento poblacional ha conducido a que los pacientes ancianos representen un gran porcentaje de los ingresos por síndrome coronario agudo en la actualidad, éstos a su vez, presentan un mayor riesgo de complicaciones en forma de eventos isquémicos y hemorrágicos, pese a ello, los ancianos se encuentran escasamente representados en los ensayos clínicos en los que se basan las recomendaciones de las guías de práctica clínica. La predicción del riesgo hemorrágico durante el ingreso en este escenario clínico es de gran relevancia, pero las herramientas pronósticas recomendadas actualmente muestran un rendimiento subóptimo en los pacientes de edad avanzada. Los componentes de la valoración geriátrica integral (comorbilidad, discapacidad, fragilidad, desnutrición) se han relacionado con un peor pronóstico en este entorno y podrían resultar útiles en la evaluación del riesgo hemorrágico en estos pacientes. Según los resultados de nuestro estudio la valoración de la comorbilidad mejoraría la capacidad predictiva de las escalas de valoración del riesgo hemorrágico durante el ingreso por un infarto en estos pacientes. Asimismo, la anemia, que es una comorbilidad frecuente en pacientes ancianos con síndrome coronario agudo, se ha asociado en estudios previos de forma consistente con el sangrado y la mortalidad en los pacientes con síndrome coronario agudo, los recientemente comercializados antiagregantes más potentes (ticagrelor y prasugrel) disminuyen la tasa de eventos trombóticos, pero lo hacen a expensas de un aumento del riesgo hemorrágico. La información sobre el perfil clínico y pronóstico de los pacientes con anemia tratados con estos antiagregantes más potentes es inexistente. Los datos hallados durante nuestro estudio apoyan el uso cuidadoso de inhibidores plaquetarios más potentes en los pacientes con elevado riesgo isquémico, a pesar de la presencia de anemia. Por otro lado, las escalas de riesgo hemorrágico al alta recomendadas en los pacientes con síndrome coronario agudo se desarrollaron a partir de ensayos clínicos que contaban con una baja representación de pacientes mayores. Esta es, probablemente, una de las principales razones que justifican una menor capacidad predictiva de estas escalas en pacientes ancianos. El análisis de los datos de nuestro registro sugieren que el punto de corte de una de las escalas recomendadas (PRECISE-DAPT) podría no ser el enfoque más óptimo en personas de edad avanzada, más aún teniendo en cuenta su mayor riesgo trombótico habitual (mayor prevalencia de diabetes, vasculopatía periférica, coronariopatía extensa o afectación de tronco común), por lo que la utilización de otros puntos de corte en el paciente anciano podría probablemente ser un enfoque más racional para predecir el riesgo hemorrágico al alta en este escenario clínico., [eng] Elderly patients represent a large percentage of admissions for acute coronary syndromes, and present an increased risk of ischemic and hemorrhagic events, despite this, the elderly are poorly represented in clinical trials. Hemorrhagic risk prediction during admission in this scenario is of great clinical relevance and the recommended prognostic tools currently show suboptimal performance in elderly patients. The components of comprehensive geriatric assessment (comorbidity, disability, fragility) have been associated with a worse prognosis and may be useful in the evaluation of hemorrhagic risk in these patients. According to the results of our study the comorbidity assessment would improve the predictive abilty of the scales of assessment of bleeding risk during admission for a acute coronary syndromes. Anemia is a frequent comorbidity in elderly patients with acute coronary syndrome, and is consistently associated with bleeding and mortality. The recently commercialized more potent antiplatelet agents (ticagrelor and prasugrel) decrease the rate of thrombotic events at the expense of an increased risk hemorrhagic. Information on the clinical profile and prognosis of patients with anemia treated with these potent antiplatelet agents is poor. The data found during our study supports the careful use of platelet inhibitors more powerful in patients with high ischemic risk, despite the presence of anemia. On the other hand, the hemorrhagic risk scales at discharge recommended in patients with acute coronary syndrome were developed from clinical trials who had a low representation of elderly patients. This is probably one of the main reasons that justify a lower predictive capacity of these scales in elderly patients. The analysis of our registry data suggests that the cut-off point of one of the recommended scales (PRECISE-DAPT) may not be the more optimal approach in the elderly, even more so considering its higher usual thrombotic risk (higher prevalence of diabetes, peripheral vascular disease, extensive coronary disease or main left disease). The use of others cut-off points in the elderly patient could probably be a more rational approach to predict bleeding risk at discharge in this scenario.

Podeu consultar al versió en anglès a http://hdl.handle.net/2445/186642, Objetivo: la información sobre los condicionantes de ingreso en unidades de críticos (UC) de pacientes ancianos con síndrome coronario agudo (SCA) es escasa. El objetivo de este estudio fue describir los factores asociados al ingreso en UC en una serie de ancianos no seleccionados con SCA en España. Métodos: el registro LONGEVO-SCA incluyó prospectivamente pacientes 80 años con SCA sin elevación del segmento ST (SCASEST), realizándose una valoración geriátrica intrahospitalaria y analizándose la evolución clínica a los 6 meses. Se analizaron los condicionantes de ingreso en UC mediante regresión logística binaria. Resultados: de un total de 508 pacientes (edad media 84,3 años), 150 (29,5%) fueron ingresados en UC. Los pacientes ingresados en UC presentaban menor edad, mayor proporción de insuficiencia cardíaca aguda, troponina positiva y peor función ventricular izquierda, así como puntuaciones superiores en las escalas de riesgo GRACE y ACTION-ICU. Estos pacientes presentaban, asimismo, una mejor situación funcional y una menor prevalencia de fragilidad, y fueron sometidos a coronariografía con mayor frecuencia (p < 0,001). No se apreciaron diferencias en mortalidad hospitalaria ni evolución a los 6 meses entre ambos grupos. Los predictores independientes de ingreso en UC fueron la ausencia de insuficiencia cardíaca previa, troponina positiva al ingreso, disfunción ventricular izquierda, valores elevados en la escala GRACE y en el índice de Charlson, y ausencia de fragilidad. Conclusiones: alrededor de un tercio de los ancianos con SCASEST son ingresados en UC. Los pacientes ingresados en UC presentan mayor perfil de riesgo al ingreso y menor prevalencia de síndromes geriátricos.

Introduction Previous midterm follow-up reports after implantation of the Absorb™ everolimus-eluting bioresorbable scaffold (BRS; Abbott Vascular, Santa Clara, CA, USA) in stable coronary artery disease and acute coronary syndrome have shown an increase of scaffold thrombosis leading to an excess of the device-oriented composite endpoint (DOCE: a composite of cardiac death, target vessel myocardial infarction [TVMI], and clinically driven target lesion revascularisation [CD-TLR])1. In contrast, in the six-month primary report of ABSORB STEMI: the TROFI II Study (NCT01986803)2, which randomised patients with ST-elevation myocardial infarction (STEMI) to receive either the Absorb BRS or the XIENCE metallic everolimus-eluting stent (EES; Abbott Vascular), optical frequency domain imaging (OFDI)-derived healing score was comparable between the BRS arm and the EES arm. The aim of this report was to present the three-year clinical outcome results of the BRS and the metallic EES at the time when full resorption of the scaffold device can be expected. Methods The trial design and methods, as well as the study population, have been described in previous reports2. Follow-up information at three years was available in 100% of the study population (Figure 1). All clinical events were adjudicated by an independent clinical events adjudication committee. Time-to-event variables were compared by log-rank test. Results Clinical outcomes at three years are tabulated in Table 1. At three years, the rates of DOCE were 5.3% (5/95) in the BRS arm and 3.1% (3/96) in the EES arm without a statistically significant difference (p=0.465). There were two cardiac deaths (2.1%) in the BRS arm: one was adjudicated as cardiac death on day 280 since no information was available as the patient died overseas. The autopsy of the second patient who died on day 999 revealed no evidence of scaffold thrombosis. There were no cardiac deaths in the EES arm. Discussion Three years after implantation of BRS or EES, in the setting of primary PCI, the rates of DOCE and ST were low and not significantly different between both arms. It is of note that there were no cases of ST after two years, while most of the patients in both arms discontinued dual antiplatelet therapy between one and two years (Supplementary Table 1). The three-year clinical results are in line with the comparable OFDI-derived healing scores2 and neointimal quality3 at six months. In addition, the recent report in the subpopulation of the current cohort showed a better vasomotion in BRS than in EES and similar microcirculatory function as well as healing score at three years4. Although routine thrombectomy is not recommended in the recent guidelines, in treating STEMI patients with BRS, thrombectomy could facilitate better scaffold sizing to achieve better long-term outcome. In the substudy of the present trial4, intraluminal dismantling was observed by OCT in 26.3%. However, the fact that the substudy only included event-free patients precludes the understanding of the clinical implication of intraluminal dismantling. Limitations The trial was not powered to evaluate clinical endpoints. The implantation technique reflects the state of the art at the time of enrolment in 2014 and did not take into account the more recent findings on BRS usage in terms of size selection, lesion preparation and deployment technique. It remains to be elucidated whether the comparative clinical outcomes in this study performed in STEMI patients will be maintained after three years. Conclusions Three years after implantation of BRS or EES, in the setting of primary PCI, the rates of DOCE and ST were low and not significantly different between both arms. The three-year clinical results are in line with the comparable healing scores observed at six months. However, the study was not powered to assess clinical endpoints.

Atherosclerosis (ATH) and coronary artery disease (CAD) are chronic inflammatory diseases with an important genetic background; they derive from the cumulative effect of multiple common risk alleles, most of which are located in genomic noncoding regions. These complex diseases behave as nonlinear dynamical systems that show a high dependence on their initial conditions; thus, long-term predictions of disease progression are unreliable. One likely possibility is that the nonlinear nature of ATH could be dependent on nonlinear correlations in the structure of the human genome. In this review, we show how chaos theory analysis has highlighted genomic regions that have shared specific structural constraints, which could have a role in ATH progression. These regions were shown to be enriched with repetitive sequences of the Alu family, genomic parasites that have colonized the human genome, which show a particular secondary structure and are involved in the regulation of gene expression. Here, we show the impact of Alu elements on the mechanisms that regulate gene expression, especially highlighting the molecular mechanisms via which the Alu elements alter the inflammatory response. We devote special attention to their relationship with the long noncoding RNA (lncRNA); antisense noncoding RNA in the INK4 locus (ANRIL), a risk factor for ATH; their role as microRNA (miRNA) sponges; and their ability to interfere with the regulatory circuitry of the (nuclear factor kappa B) NF-κB response. We aim to characterize ATH as a nonlinear dynamic system, in which small initial alterations in the expression of a number of repetitive elements are somehow amplified to reach phenotypic significance.

ANTECEDENTES DEL TEMA: La disfunción circulatoria es una alteración característica de los pacientes con cirrosis hepática. Se caracteriza por una vasodilatación arterial esplácnica secundaria a la hipertensión portal. En los últimos años se ha avanzado en el conocimiento de su patogenia y la alteración de la función cardíaca es un factor que también se ha implicado en la fisiopatología de la disfunción circulatoria en la cirrosis hepática. HIPÓTESIS: La disfunción circulatoria en la cirrosis hepática es el resultado de la progresión de la vasodilatación arterial esplácnica secundaria a la hipertensión portal. Se sugiere que en la cirrosis hepática existe una alteración en la función cardiaca que también está implicada en el desarrollo y/o empeoramiento de la disfunción circulatoria. OBJETIVOS: Caracterizar las anormalidades de la función cardiaca en la cirrosis hepática y evaluar su papel en la patogénesis de la disfunción circulatoria y renal. MÉTODOS: Se examinaron 152 pacientes (34 sin ascitis, 95 con ascitis sin insuficiencia renal y 21 con síndrome hepatorrenal) mediante ecocardiografía Doppler. En 102 pacientes, se analizó la función diastólica midiendo parámetros relacionados con la velocidad del llenado ventricular izquierdo, la velocidad de la válvula mitral y las dimensiones de la aurícula izquierda. En un subgrupo de 54 pacientes, además se midieron las presiones cardiopulmonares por cateterismo cardíaco. En 50 pacientes se estudió la función sistólica mediante la determinación de la deformidad del miocardio del ventrÍculo izquierdo (“strain miocárdico”), que estima la contractilidad miocárdica y la función sistólica. RESULTADOS: La disfunción diastólica de grados 1 y 2 se presentó en 42% y 16% de los pacientes, respectivamente. La disfunción diastólica grado 2 se asoció con presiones cardiopulmonares más elevadas, aunque los valores de estas presiones estaban dentro de los límites de normalidad en todos los casos. La disfunción diastólica tuvo una correlación directa con la insuficiencia hepática, pero no con el grado de alteración de las funciones circulatoria y renal. El porcentaje de pacientes sin o con disfunción diastólica de grado 1 o 2 fue semejante entre los casos con cirrosis compensada, cirrosis con ascitis sin insuficiencia renal o pacientes con síndrome hepatorrenal, a pesar de las diferencias en el grado de disfunción circulatoria entre estos grupos, medida por la actividad de la renina y de la concentración de noradrenalina en el plasma. La frecuencia cardíaca y la función sistólica fueron normales en todos los casos. CONCLUSIONES: Aunque la prevalencia de disfunción diastólica es relativamente elevada en la cirrosis (58%), en la mayoría de los casos es de poca gravedad. La disfunción circulatoria en la cirrosis es el resultado del desarrollo simultáneo de vasodilatación arterial esplácnica y las funciones cardiacas cronotrópica e inotrópica alteradas.

Background: Patients with coronary artery disease with left ventricular dysfunction present higher mortality and are the major beneficiaries of a myocardial revascularization procedure. A previous study showed that left ventricular ejection fraction (LVEF) is a negative determinant for cardiac catheterization (CAT) after myocardial perfusion scintigraphy (MPS). Objective: To determine clinical and scintigraphic factors associated with cardiac catheterization (CAT) indication in patients undergoing myocardial perfusion SPECT (MPS).Population: Patients consecutively submitted to PMC in the period from March 2008 to December 2012. Methods: All patients undergoing MPS during the study were recorded in a data bank, where epidemiological, clinical and scintigraphic data (perfusion scores and LVEF) were recorded. Patients or their attending physicians were contacted by phone semiannually for follow-up. For statistical analysis, univariate analyzes were performed and variables were selected for inclusion in a logistic regression model. Results: 5536 patients were submitted to MPS, of which 643 performed CAT after the examination. This group presents a higher prevalence of males, hypertensive, dyslipidemic and previously revascularized. Patients undergoing CAT have angina more frequently, more extensive ischemia scores and lower LVEF. Only presence of angina (IC 95% 1.2 - 1.7, p < 0.001) and extent of ischemia (95% CI 1.2 - 1.3, p < 0.001) were independent variables for CAT indication. Conclusion: The presence of angina and the extent of ischemia were the main predictors for CAT post-MPS indication while lower LVEF was not an independent predictor. Resumo Fundamentos: Pacientes coronariopatas portadores de disfunção ventricular esquerda apresentam maior mortalidade e por isso são os maiores beneficiados de procedimento de revascularização miocárdica. Estudo anterior demonstrou que a fração de ejeção do ventrículo esquerdo (FEVE) é um determinante negativo para realização de cateterismo cardíaco (CAT) após a realização de cintilografia miocárdica de perfusão (CMP). Objetivo: Determinar os fatores clínicos e cintilográficos associados à indicação de cateterismo cardíaco em pacientes submetidos a CMP. População: Pacientes consecutivamente submetidos a CMP no período de março de 2008 a dezembro de 2012. Metodologia: Todos os pacientes submetidos a CMP durante o estudo foram cadastrados num banco de dados, onde foram registrados os dados epidemiológicos, clínicos e cintilográficos (escores de perfusão e FEVE). Pacientes ou seus médicos assistentes foram contatados semestralmente por telefone para acompanhamento. Para análise estatística, foram realizadas análise univariada e selecionadas as variáveis para a inclusão em um modelo de regressão logística. Resultados: Foram submetidos a CMP 5536 pacientes, dos quais 643 realizaram CAT após o exame. Este grupo apresenta maior prevalência do sexo masculino, hipertensos, dislipidêmicos e revascularizados previamente. Os pacientes submetidos ao CAT têm angina com mais frequência, escores de isquemia mais extensos e menor FEVE. Apenas a presença de angina (IC 95% 1,2 - 1,7; p < 0,001) e a extensão de isquemia (IC 95% 1,2 - 1,3; p < 0,001) se mostraram variáveis independentes para indicação de CAT. Conclusão: A presença de angina e a extensão de isquemia foram os principais preditores para indicação de CAT pós-CMP enquanto a FEVE menor não foi um preditor independente.

Critical to the detection of vulnerable plaque (VPs) rupture is quantification of their anisotropic mechanical properties (Finet et al. 2004, Nayak et al. 2017). A number of biomechanical studies h...

[spa] Actualmente, de todos los Anticoagulantes de Acción Directa (ACODs) aprobados, sólo rivaroxaban ha mostrado unos resultados satisfactorios en el Síndrome Coronario Agudo (SCA); en cambio, apixaban no lo demostró. Una de las hipótesis de que apixaban no pudiera demostrar su eficacia, sin sacrificar la seguridad, incrementado los sangrados, sería que la dosis seleccionadas en este estudio fueron demasiado altas, y se deberían haber reducido respecto a las de Fibrilación Auricular (FA). Los mecanismos de acción de apixaban apoyan su potencial uso terapéutico en la prevención de complicaciones trombóticas en el sistema vascular arterial, sin embargo los efectos de estos agentes sobre la activación y agregación plaquetaria en un modelo celular de la coagulación rico en plaquetas no se han investigado en detalle. Esta tesis ha tratado de actualizar la información disponible sobre la farmacología y los datos clínicos de apixaban en la prevención del ictus y de la embolia sistémica en pacientes con FA, y la posterior evaluación y cuantificación de los efectos inhibidores de apixaban sobre diferentes aspectos de la formación de trombos en el territorio arterial (deposición de fibrina y agregación plaquetaria a índices de cizalladura arteriales; propiedades tromboelastométricas del coágulo en formación; y generación de trombina local en un modelo celular de la coagulación enriquecido en plaquetas). Para la confirmación de las hipótesis planteadas se han utilizado distintas aproximaciones experimentales en condiciones de flujo dinámico y estático con el fin de determinar si apixaban a dosis más bajas, que a las que están indicadas para la prevención y tratamiento de complicaciones tromboembólicas, podría ser un candidato para la prevención de eventos isquémicos en el territorio arterial. Las principales conclusiones son: 1. Apixaban mostró una acción inhibidora diferencial sobre los componentes de hemostasia primaria y secundaria dependiendo de las técnicas utilizadas para su estudio. 2. Los efectos de concentraciones crecientes (10, 40 y 160 ng/mL) de apixaban inhibieron distintamente la generación de trombina local, los parámetros tromboelastométricos durante la formación del coágulo, y la deposición de plaquetas y fibrina en los vasos dañados en los estudios con la sangre circulante. 3. En los estudios en condiciones de flujo, apixaban muestra una acción antiplaquetaria notable con las concentraciones más altas (40 y 160 ng/mL). 4. La concentración más elevada de apixaban inhibe casi completamente la formación de fibrina en los estudios en condiciones de flujo arterial. 5. Concentraciones de apixaban 4 a 16 veces inferiores a la Cmax, alcanzada con la dosis antitrombótica aprobada para FA, podrían ser adecuadas para reducir la generación de trombina, la formación de agregados de plaquetas grandes y, aun así, permitir la formación de fibrina, preservando así su contribución a la hemostasia en el contexto del SCA. 6. Los estudios en los ensayos modificados de generación de trombina mediados por plaquetas podrían ser útiles para investigar la acción antiplaquetaria de otros ACODs en la prevención de complicaciones aterotrombóticas en territorios arteriales. 7. Nuestros resultados indican que los estudios experimentales en condiciones de flujo en combinación con los ensayos de la generación de trombina modificados podrían facilitar la selección de la concentración de ACOD, la cual prevendría el reclutamiento de plaquetas relacionadas con la trombina en los trombos patológicos arteriales, reduciendo el riesgo de interferir con la formación de fibrina necesario para la consolidación de la hemostasia. Estos datos deben permitir el desarrollo de estudios posteriores en los que se pueda establecer el efecto antitrombótico de las asociaciones de apixaban a bajas dosis, que a las que están indicadas para la prevención y tratamiento de complicaciones tromboembólicas, con los agentes antiplaquetarios utilizados en la prevención secundaria de eventos aterotrombóticos., [eng] Currently, of all approved Direct Oral Anticoagulants (DOACs), only rivaroxaban has shown satisfactory results in Acute Coronary Syndrome (ACS); On the other hand, apixaban did not demonstrate it. One of the hypotheses that apixaban was not successful could be that the selected doses in this study were too high, and should have been reduced compared to prevention of stroke in patients with atrial fibrillation (SPAF) dose. This thesis has updated the available apixaban data in SPAF, and has evaluated and quantified of its inhibitory effects on different aspects of thrombi formation in the arterial territory with different experimental approaches, in order to determine if they were applied at lower doses than those indicated for the prevention and treatment of thromboembolic complications. The main conclusions are: 1. Apixaban showed a differential inhibitory action on the components of primary and secondary hemostasis depending on the techniques used for its study. 2. The effects of increasing concentrations of apixaban (10, 40 and 160 ng/mL) differentially inhibited the local thrombin generation (TG), thromboelastometric parameters during clot formation, and deposition of platelets and fibrin in vessels damaged in the studies with circulating blood. 3. In studies under flow conditions, apixaban shows a remarkable antiplatelet action with the highest concentrations (40 and 160 ng/mL). 4. The highest concentration of apixaban almost completely inhibits fibrin formation in studies under arterial flow conditions. 5. Concentrations of apixaban 4 to 16 times lower than Cmax, achieved with the antithrombotic dose approved for AF, could be adequate to reduce the TG, the formation of large platelet aggregates and, nevertheless, allow the formation of fibrin, thus preserving its contribution to hemostasis in the ACS context. 6. Studies in modified platelet-mediated TG assays may be useful in investigating the antiplatelet action of other DOACs in the prevention of atherothrombotic complications in arterial territories. 7. Our results indicate that experimental studies under flow conditions in combination with modified TG assays could facilitate [DOAC] selection, which would prevent recruitment of thrombin-related platelets in pathological arterial thrombi, reducing the risk of interfering with the formation of fibrin necessary for the consolidation of hemostasis.

Despite increased awareness, poor adherence to treatments for chronic diseases remains a global problem. Adherence issues are common in patients taking antihypertensive therapy and associated with increased risks of coronary and cerebrovascular events. Whilst there has been a gradual trend toward improved control of hypertension, the number of patients with blood pressure values above goal has remained constant. This has both personal and economic consequences. Medication adherence is a multifaceted issue and consists of three components: initiation, implementation, and persistence. A combination of methods is recommended to measure adherence, with electronic monitoring and drug measurement being the most accurate. Pill burden, resulting from free combinations of blood pressure lowering treatments, makes the daily routine of medication taking complex, which can be a barrier to optimal adherence. Single-pill fixed-dose combinations simplify the habit of medication taking and improve medication adherence. Re-packing of medication is also being utilized as a method of improving adherence. This paper presents the outcomes of discussions by a European group of experts on the current situation of medication adherence in hypertension.

INTRODUCTION Postprandial lipemia (PPL) influences the development of atherosclerosis. However, there are still significant gaps to fully understanding of postprandial metabolism and its regulating factors. OBJECTIVES Main objective: To determine whether metabolic syndrome (MetS) traits influence the PPL of coronary patients, and whether this influence depends on the number of MetS criteria. Secondary objectives: 1) To investigate whether the number of criteria of metabolic syndrome may predict the degree of postprandial response in patients with normal fasting triglycerides (TGs); 2) To determine the exact contribution of the presence of MetS to age-associated enlarged PPL; 3) To explore the phenotypic flexibility of high risk patients, measured with an oral fat tolerance test (OFTT), according to different cardio-metabolic abnormalities and body mass index (BMI). METHODS We developed two independent studies: A first one where we compared the PPL response to a rich fatty meal of 88 healthy young men ( 40; and 20 healthy people > 65) (all ApoE3/E3), at fasting state and at 2nd and 4th postprandial hours; and a second one where 1002 coronary artery disease patients from the CORDIOPREV study were submitted at the beginning of the study to an OFTT with 0.7 g fat/kg body weight and serial blood test analyzing lipid fractions were drawn at 0, 1, 2, 3 and 4 hours during the postprandial state. Patients were classified according to the presence of MetS and the number of its traits. We also explored in that cohort the dynamic response according to six body size phenotypes: (i) normal weight, metabolically healthy; (ii) normal weight, metabolically abnormal; (iii) overweight, metabolically healthy; (iv) overweight, metabolically abnormal; (v) obese, metabolically healthy; and (vi) obese, metabolically abnormal. RESULTS In the first study, we didn’t find differences between the healthy young men and the healthy elderly. MetS patients displayed a higher postprandial TG area below the curve than the other two cohorts p < 0.001. In the CORDIOPREV study, PPL response was directly related to the presence of MetS. We found a positive association between the number of MetS criteria and the response of postprandial plasma TGs (p= 0.001), area under the curve (AUC) of TGs (p= 0.001) and incremental AUC of TGs (p= 0.001). However, the influence of them on postprandial TGs remained statistically significant only in those patients without basal hypertriglyceridemia. Only fasting TGs, fasting glucose and waist circumference appeared as significant independent contributors (p < 0.05). Metabolically healthy patients displayed lower PPL compared with those metabolically abnormal, independently whether or not they were obese (p < 0.001 and p < 0.01, respectively). CONCLUSIONS MetS may account for the differences in PPL that have been attributed to age. Fasting TGs are the major contributors to the postprandial TGs levels. MetS influences the PPL in patients with coronary heart disease, particularly in non-hypertriglyceridemic patients. Finally, our findings showed that certain types of the metabolic phenotypes of obesity are more favorable modulating their response to a fat load test. To identify these phenotypes may be the best strategy for personalized treatment of obesity. INTRODUCCIÓN La lipemia postprandial (LPP) influye en el desarrollo de arteriosclerosis. Sin embargo, existen importantes áreas de incertidumbre para comprender completamente el metabolismo energético postprandial y sus factores reguladores. OBJETIVOS Objetivo principal: Determinar si los rasgos de síndrome metabólico (SMet) influyen en la LPP en pacientes coronarios, y si esta influencia depende del número de criterios presentes de SMet. Objetivos secundarios: 1) investigar si el número de criterios de SMet puede predecir el grado de respuesta postprandial en pacientes con triglicéridos (TGs) plasmáticos en ayunas normales; 2) determinar la contribución exacta de la presencia de SMet en la respuesta anormal de LPP asociada a la edad; y 3) explorar la flexibilidad fenotípica de pacientes de alto riesgo, medida a través de un test de sobrecarga oral de grasa (TSOG), de acuerdo a diferentes anormalidades cardiometabólicas y al índice de masa corporal (IMC). MÉTODOS Se han desarrollado dos estudios independientes: un primer estudio comparando la respuesta en la LPP a una comida rica en grasa en 88 hombres jóvenes sanos (40 años, y 20 sanos >65 años) (todos ApoE3/E3), en ayunas y a las 2 y 4 horas tras la sobrecarga; y un segundo estudio donde 1002 pacientes con enfermedad coronaria pertenecientes al estudio CORDIOPREV completaron al inicio del mismo un TSOG con 0.7 g de grasa/kg, con extracciones sanguíneas a las 0, 1, 2, 3 y 4 horas durante el estado postprandial. Los pacientes fueron clasificados según la presencia de SMet y el número de sus criterios. También se exploró en esta cohorte de pacientes coronarios su respuesta dinámica de acuerdo a seis fenotipos diferentes corporales: (i) normopeso, metabólicamente sano; (ii) normopeso, metabólicamente enfermo; (iii) sobrepeso, metabólicamente sano; (iv) sobrepeso, metabólicamente enfermo; (v) obeso, metabólicamente sano; y (vi) obeso, metabólicamente enfermo. RESULTADOS En nuestro primer estudio, no encontramos diferencias entre los varones sanos jóvenes y los mayores sanos. Los pacientes con SMet mostraron mayor magnitud en la respuesta de TGs postprandiales que los otros dos grupos (p < 0.001). En el estudio CORDIOPREV, la magnitud en la respuesta de la LPP se relacionó directamente con la presencia de SMet. Encontramos una asociación positiva entre el número de criterios de SMet y la respuesta de TGs plasmáticos postprandiales (p= 0.0001), ABC de TGs (p= 0.0001) y el incremento del area bajo la curva (AUC) de TGs plasmáticos (p= 0.001). La influencia de estos criterios sobre los TGs postprandiales sólo se mantuvo significativa en aquellos pacientes sin hipertrigliceridemia basal. Tan sólo la cifras de TGs y glucosa en ayunas, así como el perímetro de cintura se mantuvieron como predictores independientes significativos de LPP (p < 0.05). Los pacientes metabólicamente sanos mostraron menor LPP comparados con aquellos metabólicamente enfermos, independientemente de si eran obesos o no (p< 0.001). CONCLUSIONES La presencia de SMet puede modular las diferencias en LPP que han sido atribuidas a la edad. Las cifras de TG en ayunas son el factor que más influye en el grado de respuesta de TGs plasmáticos postprandiales. El SMet influye en la magnitud de la LPP de pacientes coronarios, especialmente en aquellos sin hipertrigliceridemia basal. Finalmente, nuestros hallazgos muestran que ciertos fenotipos metabólicos de obesidad son más favorables modulando su respuesta a un TSOG. Identificar estos fenotipos podría constituir la mejor estrategia para un tratamiento personalizado de la obesidad.

INTRODUCTION Postprandial lipemia (PPL) influences the development of atherosclerosis. However, there are still significant gaps to fully understanding of postprandial metabolism and its regulating factors. OBJECTIVES Main objective: To determine whether metabolic syndrome (MetS) traits influence the PPL of coronary patients, and whether this influence depends on the number of MetS criteria. Secondary objectives: 1) To investigate whether the number of criteria of metabolic syndrome may predict the degree of postprandial response in patients with normal fasting triglycerides (TGs); 2) To determine the exact contribution of the presence of MetS to age-associated enlarged PPL; 3) To explore the phenotypic flexibility of high risk patients, measured with an oral fat tolerance test (OFTT), according to different cardio-metabolic abnormalities and body mass index (BMI). METHODS We developed two independent studies: A first one where we compared the PPL response to a rich fatty meal of 88 healthy young men ( 40; and 20 healthy people > 65) (all ApoE3/E3), at fasting state and at 2nd and 4th postprandial hours; and a second one where 1002 coronary artery disease patients from the CORDIOPREV study were submitted at the beginning of the study to an OFTT with 0.7 g fat/kg body weight and serial blood test analyzing lipid fractions were drawn at 0, 1, 2, 3 and 4 hours during the postprandial state. Patients were classified according to the presence of MetS and the number of its traits. We also explored in that cohort the dynamic response according to six body size phenotypes: (i) normal weight, metabolically healthy; (ii) normal weight, metabolically abnormal; (iii) overweight, metabolically healthy; (iv) overweight, metabolically abnormal; (v) obese, metabolically healthy; and (vi) obese, metabolically abnormal. RESULTS In the first study, we didn’t find differences between the healthy young men and the healthy elderly. MetS patients displayed a higher postprandial TG area below the curve than the other two cohorts p < 0.001. In the CORDIOPREV study, PPL response was directly related to the presence of MetS. We found a positive association between the number of MetS criteria and the response of postprandial plasma TGs (p= 0.001), area under the curve (AUC) of TGs (p= 0.001) and incremental AUC of TGs (p= 0.001). However, the influence of them on postprandial TGs remained statistically significant only in those patients without basal hypertriglyceridemia. Only fasting TGs, fasting glucose and waist circumference appeared as significant independent contributors (p < 0.05). Metabolically healthy patients displayed lower PPL compared with those metabolically abnormal, independently whether or not they were obese (p < 0.001 and p < 0.01, respectively). CONCLUSIONS MetS may account for the differences in PPL that have been attributed to age. Fasting TGs are the major contributors to the postprandial TGs levels. MetS influences the PPL in patients with coronary heart disease, particularly in non-hypertriglyceridemic patients. Finally, our findings showed that certain types of the metabolic phenotypes of obesity are more favorable modulating their response to a fat load test. To identify these phenotypes may be the best strategy for personalized treatment of obesity. INTRODUCCIÓN La lipemia postprandial (LPP) influye en el desarrollo de arteriosclerosis. Sin embargo, existen importantes áreas de incertidumbre para comprender completamente el metabolismo energético postprandial y sus factores reguladores. OBJETIVOS Objetivo principal: Determinar si los rasgos de síndrome metabólico (SMet) influyen en la LPP en pacientes coronarios, y si esta influencia depende del número de criterios presentes de SMet. Objetivos secundarios: 1) investigar si el número de criterios de SMet puede predecir el grado de respuesta postprandial en pacientes con triglicéridos (TGs) plasmáticos en ayunas normales; 2) determinar la contribución exacta de la presencia de SMet en la respuesta anormal de LPP asociada a la edad; y 3) explorar la flexibilidad fenotípica de pacientes de alto riesgo, medida a través de un test de sobrecarga oral de grasa (TSOG), de acuerdo a diferentes anormalidades cardiometabólicas y al índice de masa corporal (IMC). MÉTODOS Se han desarrollado dos estudios independientes: un primer estudio comparando la respuesta en la LPP a una comida rica en grasa en 88 hombres jóvenes sanos (40 años, y 20 sanos >65 años) (todos ApoE3/E3), en ayunas y a las 2 y 4 horas tras la sobrecarga; y un segundo estudio donde 1002 pacientes con enfermedad coronaria pertenecientes al estudio CORDIOPREV completaron al inicio del mismo un TSOG con 0.7 g de grasa/kg, con extracciones sanguíneas a las 0, 1, 2, 3 y 4 horas durante el estado postprandial. Los pacientes fueron clasificados según la presencia de SMet y el número de sus criterios. También se exploró en esta cohorte de pacientes coronarios su respuesta dinámica de acuerdo a seis fenotipos diferentes corporales: (i) normopeso, metabólicamente sano; (ii) normopeso, metabólicamente enfermo; (iii) sobrepeso, metabólicamente sano; (iv) sobrepeso, metabólicamente enfermo; (v) obeso, metabólicamente sano; y (vi) obeso, metabólicamente enfermo. RESULTADOS En nuestro primer estudio, no encontramos diferencias entre los varones sanos jóvenes y los mayores sanos. Los pacientes con SMet mostraron mayor magnitud en la respuesta de TGs postprandiales que los otros dos grupos (p < 0.001). En el estudio CORDIOPREV, la magnitud en la respuesta de la LPP se relacionó directamente con la presencia de SMet. Encontramos una asociación positiva entre el número de criterios de SMet y la respuesta de TGs plasmáticos postprandiales (p= 0.0001), ABC de TGs (p= 0.0001) y el incremento del area bajo la curva (AUC) de TGs plasmáticos (p= 0.001). La influencia de estos criterios sobre los TGs postprandiales sólo se mantuvo significativa en aquellos pacientes sin hipertrigliceridemia basal. Tan sólo la cifras de TGs y glucosa en ayunas, así como el perímetro de cintura se mantuvieron como predictores independientes significativos de LPP (p < 0.05). Los pacientes metabólicamente sanos mostraron menor LPP comparados con aquellos metabólicamente enfermos, independientemente de si eran obesos o no (p< 0.001). CONCLUSIONES La presencia de SMet puede modular las diferencias en LPP que han sido atribuidas a la edad. Las cifras de TG en ayunas son el factor que más influye en el grado de respuesta de TGs plasmáticos postprandiales. El SMet influye en la magnitud de la LPP de pacientes coronarios, especialmente en aquellos sin hipertrigliceridemia basal. Finalmente, nuestros hallazgos muestran que ciertos fenotipos metabólicos de obesidad son más favorables modulando su respuesta a un TSOG. Identificar estos fenotipos podría constituir la mejor estrategia para un tratamiento personalizado de la obesidad.

Epidemiologic studies show a strong relationship between blood pressure (BP) measurements and the incidence of major cardiovascular events [(1)][1]. The primary basis for the treatment of hypertension has been the belief that reducing BP provides cardiovascular protection. This is supported by

Ca „skoring“ jest metoda kojom otkrivamo postojanje i rasprostranjenost kalcificiranih aterosklerotskih promjena na srčanim krvnim žilama, poglavito arterijama. Prisutnost kalcija u srčanim arterijama patognomična je za aterosklerozu. Bliska korelacija između aterosklerotskoga plaka i opsega koronarnoga kalcija (engl. coronary calcium, CAC) potvrđena je i od strane histopatologije i intravaskularnoga ultrazvuka. Koronarni kalcij definira se kao lezija gustoće iznad 130 Hounsfield jedinica (koje se kreću od -1.000 (zrak), preko 0 (voda), i više od 1000 (gusta kortikalna kost), s površinom od tri ili više susjednih piksela (najmanje 1 mm2). Izvornu metodu kalcij skoringa razvio je Agatston* sa suradnicima, a određen je produktom površine kalcificiranoga područja plaka i maksimalne gustoće kalcij lezije (od 1 do 4 na temelju Hounsfield jedinica). Standardizirane su kategorije za Ca „skoring“: rezultat 1 – 10 koji se smatra minimalnim, 11 – 100 blagim, 101 – 400 umjerenim, a > 400 teškim. Uz Agatston Score, postoji još i metodu Ca „skoringa“ na temelju specifičnosti lezija koja proizlazi iz CT testa za kalcifikacije koronarnih arterija. Srčanim CT-om utvrđen kalcificirani koronarni plak ima visoku osjetljivost i negativnu prediktivnu vrijednost za opstruktivni CAD, ali ograničenu specifičnost. Ca „skoring“ može pomoći kliničarima u učinkovitu „isključenju“ angiografski značajnoga CAD-a u simptomatskih bolesnika. To se može vidjeti u studiji kao što je Framinghamova studija, u kojoj su sudjelovale asimptomatske mlađe odrasle osobe (muškarci mlađi od 55 godina i žene mlađe od 65 godina), koje su bili hospitalizirane zbog prvoga akutnog infarkta miokarda. Kod Ca skoringa služi se različitim radiološkim instrumentima i uređajima kako bi se pravilno i učinkovito pronašlo postojanje i rasprostranjenost kalcificiranih aterosklerotskih promjena na srčanim krvnim žilama, poglavito arterijama. Metode mjerenja kalcija u krvnim žilama jesu fluoroskopija, intravaskularni ultrazvuk i kvantitativne metode kojima pripadaju MSCT I EBCT. Kod kvantitativnih metoda koristimo se i postprocessing softverima, koji nam omogućuju prikaz kalcificirane lezije u boji, što pojednostavljuje posao operatera, koji samo treba ocrtati „područje interesa“ (engl. region of interest, ROI) bojom kodiranoga plaka. Također, postoje automatizirana mjerenja kalcificiranih lezija. Ca 'scoring' is a method of discovering the existence and extent of calcified atherosclerotic changes in the heart blood vessels, especially arteries. The presence of calcium in the coronary arteries is pathognomonic for atherosclerosis. The close correlation between the extent of atherosclerotic plaque and coronary calcium was confirmed by histopathology and intravascular ultrasound. Coronary calcium is defined as the density of lesions above 130 Hounsfield units (ranging from -1.000 (air) through 0 (water), and more than 1000 (dense cortical bone), with an area of three or more adjacent pixels (at least 1 or 2 mm ). The original method of calcium scoring was developed by Agatston * with co-workers, and is determined by the product of the surface area of calcified plaque and a maximum density of calcium lesions (1-4 based on Hounsfield units). The standardized categories for calcium scoring are: score 1-10 which is considered minimal, score 11-100 which is considered good, score 101-400 which is considerate moderate and above 400 which is considerate heavy. Also, we have calcium scoring method based on the specifics of lesions resulting from CT test for coronary artery calcification. Cardiac CT determined calcified coronary plaque with high sensitivity and negative predictive value for obstructive CAD, but a limited specificity. Ca scoring can help clinicians in effective "exclusion" of angiographically significant CAD in symptomatic patients. This can be seen in studies such as the Framingham study, involving asymptomatic young adults (males younger than 55 and women younger than 65 years) who were hospitalized for the first acute myocardial infarction. In Ca scoring we use various radiological instruments and devices in order to properly and effectively find the existence and extent of calcified atherosclerotic changes in the heart blood vessels, especially arteries. Methods of measurement of calcium in the blood vessels are: fluoroscopy, intravascular ultrasound and quantitative methods where we have MSCT and EBCT. In quantitative methods we use postprocessing software that allow us to see the calcified lesions in color, which simplifies the job of the operator who has only to outline the area of interest color coded plaque. Also, there are automated measurement of calcified lesions.

Background: decisive information on the parameters involved in cognitive impairment in patients with chronic heart failure is as yet lacking. Our aim was to determine the functional and psychosocial variables related with cognitive impairment using the mini-mental-state examination (MMSE) with age-and education-corrected scores. Methods: a cohort study of chronic heart failure patients included in an integrated multidisciplinary hospital/primary care program. The MMSE (corrected for age and education in the Spanish population) was administered at enrolment in the program. Analyses were performed in 525 patients. Demographic and clinical variables were collected. Comprehensive assessment included depression (Yesavage), family function (family APGAR), social network (Duke), dependence (Barthel Index), frailty (Barber), and comorbidities. Univariate and multivariate logistic regression were performed to determine the predictors of cognitive impairment. Results: cognitive impairment affected 145 patients (27.6 %). Explanatory factors were gender (OR: 2.77 (1.75-4.39) p 3.5 (OR: 0.59 (0.35-0.99) p = 0.048), and beta-blocker treatment (OR: 0.36 (0.17 to 0.76, p = 0.007)). No association was found between cognitive impairment and social support or family function. Conclusion: the observed prevalence of cognitive impairment using MMSE corrected scores was 27.6 %. A global approach in the management of these patients is needed, especially focusing on women and patients with frailty, low albumin levels, and ischemic aetiology heart failure.

[spa] INTRODUCCIÓN: La doble antiagregación plaquetaria con ácido acetilsalicílico (AAS) y un inhibidor oral del receptor P2Y12 (clopidogrel, prasugrel o ticagrelor) es actualmente el tratamiento antiplaquetario de elección pacientes con un síndrome coronario agudo (SCA) o en los que se practica un intervencionismo coronario percutáneo (ICP). El principal problema de clopidogrel es su gran variabilidad interindividual de respuesta, existiendo un porcentaje elevado de pacientes que presentan una respuesta disminuida o subóptima al fármaco. La trascendencia de dicha variabilidad de respuesta se manifiesta en la asociación entre respuesta pobre o subóptima al fármaco y eventos cardiovasculares isquémicos en el seguimiento. Pese al desarrollo de nuevos fármacos (prasugrel y ticagrelor) más potentes y con una mayor eficacia clínica en los pacientes con SCA, el clopidogrel es todavía el antagonista del receptor P2Y12 más usado en nuestro medio, siendo además la primera opción en los pacientes con cardiopatía isquémica estable en los que se realiza ICP. Por tanto, la existencia en nuestro medio de una proporción importante de pacientes con SCA o en los que se realiza ICP que reciben tratamiento con clopidogrel, pudiendo estar un porcentaje de ellos en mayor riesgo de padecer eventos isquémicos por presentar una respuesta subóptima al fármaco, evidencia la vigencia del problema y el interés por profundizar en el conocimiento de los mecanismos potencialmente asociados a una respuesta subóptima a clopidogrel y cómo el uso de fármacos que consiguen un bloqueo más potente de la vía iniciada en el receptor P2Y12 puede superar el efecto de dichos mecanismos y conseguir un nivel de inhibición plaquetar adecuado. OBJETIVOS: El objetivo general de esta tesis doctoral fue profundizar en el conocimiento de varios mecanismos clínicos potencialmente asociados con una hiperreactividad plaquetar y una respuesta subóptima a clopidogrel, además de evaluar si el uso de un fármaco (cangrelor) que consigue un bloqueo más potente de la vía iniciada en el receptor P2Y12, puede superar el efecto de dichos mecanismos y conseguir un nivel de inhibición plaquetar adecuado en pacientes con un riesgo elevado de presentar respuesta subóptima a clopidogrel. MÉTODOS Y RESULTADOS: Se han incluido en la presente tesis 6 artículos originales (además de 3 artículos de revisión), cuya metodología y resultados se discuten ampliamente en el texto principal. CONCLUSIONES: Las conclusiones de los estudios farmacodinámicos realizados son: a) la administración de omeprazol reduce el efecto antiplaquetario del clopidogrel, independientemente del momento de administración de ambos fármacos; b) el uso de pantoprazol a dosis altas no modifica la eficacia antiagregante del clopidogrel, sin importar el momento de administración de ambos fármacos; c) la interacción entre clopidogrel y los inhibidores de la bomba de protones no es un efecto de clase y sería específica de los fármacos de este grupo con un mayor potencial de afectación del CYP2C19; d) el hábito tabáquico (medido objetivamente según las concentraciones de cotinina sérica) se asocia con un aumento del efecto antiagregante de clopidogrel, con relación dosis-respuesta; e) un porcentaje elevado de pacientes con infarto agudo de miocardio con elevación del segmento ST presentan al iniciar la angioplastia primaria una respuesta subóptima a clopidogrel (y en menor grado a AAS), que podría estar asociada con una menor permeabilidad inicial de la arteria responsable del infarto; f) las temperaturas en el rango de la hipotermia terapéutica producen un empeoramiento in vitro de la respuesta a clopidogrel, sin afectar la inhibición plaquetar inducida por AAS; g) la administración de cangrelor in vitro produce un bloqueo muy potente del receptor P2Y12, sin diferencias en su eficacia entre pacientes con y sin diabetes mellitus, consiguiendo unos moderados efectos inhibitorios en vías de señalización plaquetar no purinérgicas., [eng] BACKGROUND: The main downside of clopidogrel is its broad variability in response, leading to a relatively high percentage of patients with diminished or suboptimal response, which is clearly associated with adverse cardiovascular outcomes. Despite the development of more potent agents, clopidogrel is still the most used P2Y12 receptor antagonist in Spain in patients with coronary artery disease and/or undergoing percutaneous coronary intervention (PCI). This implies that a percentage of patients may be at higher risk of suffering adverse ischemic events due to suboptimal responsiveness, which underscores the relevance of deepen our knowledge of the mechanisms associated with clopidogrel variability in response and whether a potent blockade of the P2Y12 receptor can overcome these mechanisms. OBJECTIVE: To provide insights into the knowledge of several clinical factors that may be associated with platelet hyperreactivity and a suboptimal response to clopidogrel, in addition to assess whether the use of an agent that attains a very potent inhibition of the P2Y12 pathway may overcome these factors and achieve an optimal degree of platelet inhibition in patients at high risk of presenting poor responsiveness to clopidogrel. METHODS AND RESULTS: Methods and results of the 6 original articles included in this dissertation (and 3 review articles) are detailed in the main text. CONCLUSIONS: The conclusions are: a) omeprazole impairs clopidogrel- induced antiplatelet effects irrespective of timing of drug administration; b) pantoprazole does not affect clopidogrel efficacy, irrespective of timing of drug administration; c) the interaction between clopidogrel and proton-pump inhibitors is not class-specific but a drug-specific effect affecting those primarily metabolized by CYP2C19; d) cigarette smoking is associated with a dose- response augmented clopidogrel efficacy; e) a high percentage of ST-elevation myocardial infarction patients have inadequate response to clopidogrel when starting a primary PCI, which might be associated with impaired initial patency of the infarct-related artery; f) in vitro mild hypothermia is associated with impaired clopidogrel-mediated platelet inhibition, with no effect on aspirin responsiveness; g) cangrelor in vitro provides potent and dose-dependent blockade of the platelet P2Y12 receptor, with no differential effect in patients with and without diabetes mellitus, exerting moderate inhibitory effects on non- purinergic platelet signaling pathways.

Background and Purpose: Selecting an ideal antithrombotic therapy for elderly patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) can be challenging since they have a higher thromboembolic and bleeding risk than younger patients. The current study aimed to assess the efficacy and safety of triple therapy (TT: oral anticoagulation plus dual antiplate- let therapy: aspirin plus clopidogrel) in patients > 75 years of age with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). Methods: A prospective multicenter study was conducted from 2003 to 2012 at 6 Spanish teaching hospitals. A cohort study of consecutive patients with AF undergoing PCI and treated with TT or dual antiplatelet therapy (DAPT) was analyzed. All outcomes were evaluated at 1- year of follow-up. Results: Five hundred and eighty-five patients, 289 (49%) of whom were > 75 years of age (79.6 ± 3.4 years; 33% women) were identified. TT was prescribed in 55.9% of patients at discharge who had a higher thromboembolic risk (CHA 2 DS 2 VASc score: 4.23 ± 1.51 vs 3.76 ± 1.40, p = 0.007 and a higher bleeding risk (HAS-BLED > 3: 88.6% vs 79.2%, p = 0.02) than those on DAPT. Therefore, patients on TT had a lower rate of thromboembolism than those on DAPT (0.6% vs 6.9%, p = 0.004; HR 0.08, 95% CI: 0.01 - 0.70, p = 0.004). Major bleeding events occurred more frequently in patients on TT than in those on DAPT (11.7% vs 2.4%, p = 0.002; HR 5.2, 95% CI: 1.53 - 17.57, p = 0.008). The overall mortality rate was similar in both treatment groups (11.9% vs 13.9%, p = 0.38); however, after adjustment for confounding variables, TT was associated with a reduced mortality rate (HR 0.33, 95% CI: 0.12 - 0.86, p = 0.02). Conclusions In elderly patients with AF undergoing PCI, the use of TT compared to DAPT was associ- ated with reduced thromboembolism and mortality rates, although a higher rate of major bleeding.

BACKGROUND: Remote sensing (RS) is increasingly used for exposure assessment in epidemiological and burden of disease studies, including those investigating whether chronic exposure to ambient fine particulate matter (PM2.5) is associated with mortality. OBJECTIVES: To compare relative risk estimates of mortality from diseases of the circulatory system for PM2.5 modeled from RS with that for PM2.5 modeled using ground-level information. METHODS: We geocoded the baseline residence of 668,629 American Cancer Society Cancer Prevention Study II (CPS-II) cohort participants followed from 1982 to 2004 and assigned PM2.5 levels to all participants using seven different exposure models. Most of the exposure models were averaged for the years 2002-2004, while one RS estimate was for a longer, contemporaneous period. We used Cox proportional hazards regression to estimate relative risks (RR) for the association of PM2.5 with circulatory mortality and ischemic heart disease. RESULTS: Estimates of mortality risk differed among exposure models. The smallest relative risk was observed for the RS estimates that excluded ground-based monitors for circulatory deaths (RR = 1.02 (95% confidence interval (CI): 1.00-1.04 per 10 microg/m3 increment in PM2.5). The largest relative risk was observed for the land use regression model that included traffic information (RR = 1.14, 95% CI: 1.11-1.17 per 10 microg/m3 increment in PM2.5). CONCLUSIONS: We found significant associations between PM2.5 and mortality in every model; however, relative risks estimated from exposure models using ground-based information were generally larger than those estimated with RS alone.

The present thesis deals with a deep analysis of the genetic structure of extant human worldwide populations, with a special focus on the Mediterranean. Different genetic markers, 18 Alu insertions and 367 single nucleotide polymorphisms (SNPs), were analysed for the first time in general populations and Bedouins from Jordan. The same SNPs were also genotyped in a consistent set of samples from the Mediterranean Basin. Specifically, Alu markers were used to assess the genetic diversity within Jordan and to define the relationships across present-day Middle Eastern, North African, and European populations. While SNPs located in the top coronary artery disease (CAD) risk regions (1p13, 1q41, 9p21, and 10q11) were used to explore the genetic variation and the LD patterns across 19 populations from Europe, Middle East and North Africa, together with Asian and African samples from the 1000 Genomes Project. Furthermore, Tunisian and Moroccan case-control samples were used to test for the first time the applicability of European GWAS results in these four genomic regions to North African populations. Finally, simulated genomic data were used to evaluate the consistency of association results across European, Asian and Sub-Saharan African case-control samples. Neutral and CAD risk markers pointed out a low but significant geographic structure in the Mediterranean area. As a particular case in the Mediterranean context, Bedouins and general population from Jordan showed statistical differences (p=0.038). The genetic heterogeneity detected is likely related to the fact that urban areas have been subject to several external influences but Bedouins have preserved their own genetic background because of their nomadic and isolated lifestyle. The general patterns of genetic variation observed in the four CAD risk regions analysed are in agreement with the genetic structure generated by demographic processes. Despite this fact, the present work also identified potential signals of positive and balancing selection in some specific risk markers and haplotypes. Actually, potential signatures of positive selection in the 9p21 region and of balancing selection in 9p21 and 10q11 have been observed. The regions under positive or balancing selection are shared across continents but the specific markers under selection are, in some cases, continent-specific. Results from the association study in North Africa revealed significant association signals in the four genomic regions analysed in Moroccan and Tunisian samples confirming the trans-ethnic importance of these genomic regions for the risk of CAD. However, in the meta-analyses performed with the North African case-control samples, only the 9p21 and 10q11 regions showed association signals and none of the North African risk SNPs was associated with CAD in Europe. These arguments suggest the existence of continent-specific CAD risk variants in these chromosomal regions. Significant differences in the LD and in the haplotype patterns confirm the heterogeneity in the genomic structure between North Africans and Europeans. In addition, differences in the LD structure persist even across Europeans, North Africans, Asians, and Sub-Saharan Africans. Finally, the simulation study highlighted an overall consistency in effect direction across populations of different ancestry, specially between Europeans and Asians. Because simulations assumed no actual differences in genetic effect size between populations and because the rate of between-population effect size differences generated by our study was considerably lower than the rate reported from empirical studies using real data, our study supports the existence of real differences in the genetic risk architecture of complex traits between populations. In general, this study confirmed that a substantial fraction of association signals are shared across people of different ancestries. However, some discrepancies in the effect size across populations highlighted the importance of accounting for population structure in association studies., Esta tesis analiza la variación genética de muestras poblacionales europeas, africanas y asiáticas, con particular énfasis en la región mediterránea. Se usaron 18 marcadores Alu para evaluar la diversidad genética dentro de Jordania (en beduinos y en población general) y para definir la relación entre las actuales poblaciones del Mediterráneo. Por otra parte, 367 polimorfismos de un solo nucleótido (SNPs) localizados en cuatro regiones de riesgo para la enfermedad arterial coronaria (CAD) (1p13, 1q41, 9p21 y 10q11) se utilizaron para explorar la variación genética en 19 poblaciones de Europa, Oriente Medio y África del Norte, junto a las muestras asiáticas y africanas del Proyecto 1000 Genomas. Estas cuatro regiones de riesgo CAD fueron analizadas también en un conjunto de muestras de casos y controles de Marruecos y Túnez. Por último, se simularon muestras de casos y controles africanos, europeos, y asiáticos para evaluar el nivel de consistencia interpoblacional en los estudios de asociación. Como caso particular en el Mediterráneo, los beduinos y la población general de Jordania mostraron diferencias significativas (p=0,038). Los beduinos se agruparon con los norteafricanos, mientras que los jordanos generales se agruparon con las poblaciones más orientales del Mediterráneo. Los patrones generales de variación observados en las cuatro regiones de riesgo CAD mostraron una estructura genética plausiblemente modelada por procesos demográficos. A pesar de esto, el presente trabajo también detectó señales potenciales de selección natural positiva en la región 9p21 y de selección equilibradora en las regiones 9p21 y 10q11. También fueron detectadas asociaciones significativas en las cuatro regiones genómicas analizadas, previamente identificadas en europeos, en Marruecos y Túnez. Sin embargo, sólo las regiones 9p21 y 10q11 mostraron asociación en el meta-análisis realizado utilizando las muestras de casos y controles norteafricanos. El estudio de simulación destacó una alta replicabilidad de las señales de asociación entre los distintos continentes. Sin embargo, algunas discrepancias en el tamaño del efecto revelaron la posible existencia de diferencias interpoblacionales en la arquitectura del riesgo genético de caracteres complejos y destacaron la importancia de incluir la estructura poblacional en los estudios de asociación.