Aplicaciones de la Fisiología Coronaria en escenarios clínicos y angiográficos complejos

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Medicina, leída el 15/02/2021. Tesis formato europeo (compendio de artículos)Cronary angiography was, for many years, the only available tool to diagnose and assess the consequences of coronary atherosclerosis, becoming the standard reference in the study of ischemic heart disease allowing to routinely describe the severity of coronary stenosis or the severity of the disease based on the number of vessels affected. Subsequently, the introduction of invasive methods to assess coronary physiology allowed to obtain a precise assessment regarding the physiological impact of epicardial coronary stenoses, while demonstrating the poor diagnostic performance of angiography to assess the functional impact these stenoses. Among the coronary physiology techniques, the fractional flow reserve (FFR) and the instantaneous wave-free ratio (iFR) are the most used and are currently recommended in clinical practice to decide whether coronary revascularization is indicated. Both techniques received the highest grade of recommendation in the latest European guidelines for myocardial revascularization in the context of intermediate or doubtful stenosis in patients with stable ischemic heart disease (SIHD). However, despite a growing body of evidence supporting the value of physiology in detecting ischemia, the large-scale adoption of this technique is still limited. It has been pointed out that one of the causes underlying the underuse of FFR is that it requires the induction of pharmacological stress through the use of vasodilator drugs such as adenosine, which potentially causes side effects and an additional cost, especially in a case of need of multiple interrogation in the same coronary tree. Besides, this is certainly due to the fact that the FFR validation was carried out mainly in specific clinical and anatomical subgroups, such as stenoses of intermediate severity and SIHD. The safety of revascularization deferral on the ground of FFR or other physiological indices is also limited in other common clinical settings, such as acute coronary syndromes (ACS), left main coronary artery (LMCA) disease or diabetic patients. Lastly, it should be noted that intracoronary pressure indices share an important limitation with coronary angiography: they do not provide information on the state of the coronary microcirculation. This obstacle not only prevents the diagnosis of non-obstructive causes of myocardial ischemia, but also hinders the advancement of knowledge of specific pharmacological treatments that can provide clinical benefit through the modification of this important domain of the coronary circulation...Durante años, la angiografía coronaria constituyó la única herramienta para poder diagnosticar y valorar las consecuencias de la aterosclerosis coronaria, constituyéndose como la referencia estándar en el estudio de la cardiopatía isquémica y dando origen a una terminología que todavía utilizamos de forma rutinaria para describir la severidad de las estenosis coronarias o la gravedad de la enfermedad en base al número de vasos afectados. Posteriormente, la introducción de métodos invasivos para valorar la fisiología coronaria permitió obtener una evaluación precisa respecto a la repercusión fisiológica de las estenosis coronarias epicárdicas, al tiempo que demostró el bajo rendimiento diagnóstico de la angiografía para valorar la repercusión funcional de las estenosis coronarias. Entre las técnicas de fisiología coronaria, la reserva fraccional de flujo coronario (FFR) y el cociente instantáneo libre de ondas (iFR) son las dos más utilizadas en la actualidad y actualmente son recomendadas en la práctica clínica para decidir si la revascularización coronaria esta indicada. Ambas técnicas recibieron el grado máximo de recomendación en las últimas guías europeas de revascularización miocárdica en el contexto de estenosis de grado moderado o de severidad dudosa en pacientes con cardiopatía isquémica estable. Sin embargo, pese a su demostrado valor clínico, la adopción a gran escala de estas técnicas de fisiología es todavía limitado. Se ha señalado que una de las causas que subyacen a la infrautilización de del FFR es que precisa la inducción de estrés farmacológico mediante el uso de fármacos vasodilatadores como la adenosina, que provoca efectos secundarios y conlleva un coste económico añadido, especialmente en un escenario muy frecuente como el de la enfermedad multivaso. Pero sin duda ello obedece también al hecho de que la validación del FFR se realizó fundamentalmente en subgrupos clínicos y anatómicos específicos, como las estenosis de severidad intermedia y la enfermedad coronaria estable. Ello limita la aplicabilidad del FFR y otros índices fisiológicos en otros escenarios muy frecuentes, como los síndromes coronarios agudos o la enfermedad del tronco común izquierdo, o los pacientes diabéticos. Por último, es de reseñar que los índices de presión intracoronaria comparten con la angiografía coronaria una importante limitación: no proporcionar información sobre el estado de la microcirculación coronaria. Este obstáculo impide no sólo el diagnóstico de causas no obstructivas de isquemia miocárdica, sino que también obstaculiza el avance del conocimiento de tratamientos farmacológicos específicos que puedan aportar un beneficio clínico a través de la modificación de este importante dominio de la circulación coronaria...Fac. de MedicinaTRUEunpu

Nitrogen-Doped Zinc Oxide for Photo-Driven Molecular Hydrogen Production

Due to its thermal stability, conductivity, high exciton binding energy and high electron mobility, zinc oxide is one of the most studied semiconductors in the field of photocatalysis. However, the wide bandgap requires the use of UV photons to harness its potential. A convenient way to appease such a limitation is the doping of the lattice with foreign atoms which, in turn, introduce localized states (defects) within the bandgap. Such localized states make the material optically active in the visible range and reduce the energy required to initiate photo-driven charge separation events. In this work, we employed a green synthetic procedure to achieve a high level of doping and have demonstrated how the thermal treatment during synthesis is crucial to select specific the microscopic (molecular) nature of the defect and, ultimately, the type of chemistry (reduction versus oxidation) that the material is able to perform. We found that low-temperature treatments produce material with higher efficiency in the water photosplitting reaction. This constitutes a further step in the establishment of N-doped ZnO as a photocatalyst for artificial photosynthesis

Civil Liability of Regional Health Services: The Case of the Piedmont Region

Civil liability represents one of the main responsibilities for healthcare facilities; it is the legal responsibility of paying money for damage to a person’s health. Even though this responsibility plays a key role in the economic sustainability of healthcare facilities, the literature does not enough investigate this responsibility in regional health services. The paper aims to define the evolution of compensation models for health civil liability adopted by regional health services. Through a longitudinal case study, the paper investigates the compensation model by a leading regional health service. The finding highlights the evolution of the compensation model for health civil liability adopted by a leading Regional Health Service from 1990 to 2021. It describes a transition from an insurance model to a mixed model based on self-coverage up to a set economic level, an insurance policy with self-insurance retention and deductible for all claims. The research contributes to the literature and practice throughout the definition of a compensation model for damages based on self-insurance of regional health service and insurance policies. The research promotes a compensation model used by a leading regional health service

An International Survey on Taking Up a Career in Cardiovascular Research: Opportunities and Biases toward Would-Be Physician-Scientists

Background Cardiovascular research is the main shaper of clinical evidence underpinning decision making, with its cyclic progression of junior researchers to mature faculty members. Despite efforts at improving cardiovascular research training, several unmet needs persist. We aimed to appraise current perceptions on cardiovascular research training with an international survey. Methods and Results We administered a 20-closed-question survey to mentors and mentees belonging to different international institutions. A total of 247 (12%) surveys were available (out of 2,000 invitations). Overall, mentees and mentors were reasonably satisfied with the educational and research resources. Significant differences were found analyzing results according to gender, geographic area, training and full-time researcher status. Specifically, women proved significantly less satisfied than men, disclosed access to fewer resources and less support from mentors (all P Conclusions Several potential biases appear to be present in the way training in cardiovascular research is provided worldwide, including one against women. If confirmed, these data require proactive measures to decrease discriminations and improve the cardiovascular research training quality

Acute coronary syndromes in human immunodeficiency virus patients: a meta-analysis investigating adverse event rates and the role of antiretroviral therapy

Aims Highly active antiretroviral therapy (HAART) dramatically reduces human immunodeficiency virus (HIV)-associated morbidity and mortality, but adverse effects of HAART are becoming an increasing challenge, especially in the setting of acute coronary syndromes (ACS). We thus performed a comprehensive review of studies focusing on ACS in HIV patients. Methods and results MEDLINE/PubMed was systematically screened for studies reporting on ACS in HIV patients. Baseline, treatment, and outcome data were appraised and pooled with random-effect methods computing summary estimates [95% confidence intervals (CIs)]. A total of 11 studies including 2442 patients were identified, with a notably low prevalence of diabetes [10.86 (4.11, 17.60); 95% CI]. Rates of in-hospital death were 8.00% (2.8, 12.5; 95% CI), ascribable to cardiovascular events for 7.90% (2.43, 13.37; 95% CI), with 2.31% (0.60, 4.01; 95% CI) developing cardiogenic shock. At a median follow-up of 25.50 months (11.25, 42; 95% CI), no deaths were recorded, with an incidence of 9.42% of acute myocardial infarction (2.68, 16.17; 95% CI) and of 20.18% (9.84, 30.51; 95% CI) of percutaneous coronary revascularization. Moreover, pooled analysis of the studies reporting incidence of acute myocardial infarction in patients exposed to protease inhibitors showed an overall significant risk of 2.68 (odds ratio 1.89, 3.89; 95% CI). Conclusion Human immunodeficiency virus patients admitted for ACS face a substantial short-term risk of death and a significant long-term risk of coronary revascularization and myocardial infarction, especially if receiving protease inhibitors

Chromatin and DNA methylation dynamics during retinoic acid-induced RET gene transcriptional activation in neuroblastoma cells.

Although it is well known that RET gene is strongly activated by retinoic acid (RA) in neuroblastoma cells, the mechanisms underlying such activation are still poorly understood. Here we show that a complex series of molecular events, that include modifications of both chromatin and DNA methylation state, accompany RA-mediated RET activation. Our results indicate that the primary epigenetic determinants of RA-induced RET activation differ between enhancer and promoter regions. At promoter region, the main mark of RET activation was the increase of H3K4me3 levels while no significant changes of the methylation state of H3K27 and H3K9 were observed. At RET enhancer region a bipartite chromatin domain was detected in unstimulated cells and a prompt demethylation of H3K27me3 marked RET gene activation upon RA exposure. Moreover, ChIP experiments demonstrated that EZH2 and MeCP2 repressor complexes were associated to the heavily methylated enhancer region in the absence of RA while both complexes were displaced during RA stimulation. Finally, our data show that a demethylation of a specific CpG site at the enhancer region could favor the displacement of MeCP2 from the heavily methylated RET enhancer region providing a novel potential mechanism for transcriptional regulation of methylated RA-regulated loci