Estudio de los mecanismos básicos y el diagnóstico del daño microvascular tras un infarto agudo de miocardio. Exploración de nuevas oportunidades terapéuticas

El infarto agudo de miocardio (IAM) constituye una de las principales causas de morbilidad y mortalidad en las sociedades occidentales. A pesar de que se han hecho grandes avances en el tratamiento gracias a la reperfusión coronaria por métodos percutáneos, entre el 30-50% de los pacientes presentan un daño severo en la microcirculación conocido como obstrucción microvascular (OMV). Este fenómeno ejerce efectos negativos en cuanto a la estructura y pronóstico de los pacientes con IAM con elevación del segmento ST (IAMEST). Por ello, el principal objetivo de la presente Tesis Doctoral es avanzar en el entendimiento de los mecanismos y el diagnóstico del daño microvascular tras un IAMEST así como explorar nuevas oportunidades terapéuticas. En el primer artículo, se evaluaron los cambios dinámicos en la estructura de la pared de las arterias epicárdicas debido al daño por isquemia-reperfusión. Para este objetivo, se empleó un modelo controlado porcino de IAM realizado de forma percutánea. Se utilizaron cerdos jóvenes que se agruparon en un grupo control y cuatro grupos de 90 minutos de isquemia: uno sin reperfusión y tres más seguidos de 1 minuto, 1 semana o 1 mes de reperfusión. Se aisló la arteria descendente anterior (ADA, arteria responsable del infarto) en su porción proximal y distal al punto de colocación del balón de angioplastia y la arteria coronaria derecha (arteria no responsable del infarto). En todas las muestras, se realizaron tinciones histológicas, de inmunohistoquímica y se prepararon para microscopía electrónica. A continuación, las muestras fueron fotografiadas y analizadas mediante técnicas morfométricas. Aunque el daño en la túnica íntima comienza durante la isquemia, es durante la fase de reperfusión cuando se observa una ausencia casi completa de células CD31+ (marcador específico de células endoteliales) y roturas patológicas en la lámina elástica interna. En la túnica media, se detectó un ligero aumento del grosor durante la isquemia, mientras que en las muestras aisladas tras la reperfusión observamos un aumento significativo del grosor de la capa media, una desorganización de las células musculares y la formación de edema entre las mismas. Este patrón se manifestó de forma más pronunciada en la porción distal de la ADA en comparación con la proximal. En la túnica adventicia, la densidad de los vasa vasorum disminuyó en el grupo sin reperfusión, se mantuvo reducida después de 1 minuto y 1 semana de reperfusión y se restableció después de 1 mes de reperfusión. Esta dinámica se observó en ambas regiones de la ADA. Tras la reperfusión, comenzó la adhesión de leucocitos a la túnica íntima de la ADA, principalmente en la región proximal al balón de angioplastia. Tras una semana de reperfusión, se detectó la presencia de células CD45+ (marcador específico de leucocitos) tanto en la túnica íntima como en la media. En consecuencia, el daño por isquemia-reperfusión indujo cambios en la estructura de la pared epicárdica durante la isquemia y éstos se incrementaron durante la reperfusión. Estas alteraciones fueron más acusadas en la zona distal al punto de colocación del balón de angioplastia. En el segundo artículo, se exploró la relación entre los niveles circulantes de epithelial cell adhesion molecule (EpCAM) determinados 24 horas después de la angioplastia percutánea y la presencia de la OMV determinada mediante resonancia magnética cardiaca (RMC), así como con la función sistólica en los primeros 6 meses después del IAMEST. Se incluyó prospectivamente a 106 pacientes con un primer IAMEST tratados con angioplastia primaria. La concentración sérica de EpCAM se determinó 24 horas después de la reperfusión coronaria. Se sometió a todos los pacientes a un estudio de RMC a la semana y otro a los 6 meses del IAMEST. Se evidenció que los pacientes que tenían valores más bajos de EpCAM presentaban una mayor extensión de la OMV y un mayor tamaño de infarto en los estudios de RMC realizados 1 semana después del evento cardiovascular. La concentración de EpCAM se asoció significativamente con la presencia de OMV tanto en el análisis univariable como en el multivariable tras ajustarse por las variables clínicas y angiográficas. A pesar de que la OMV tiende a resolverse espontáneamente en las fase crónica, unos valores más bajos de EpCAM se correlacionaron con una peor función sistólica: una fracción de eyección del ventrículo izquierdo (FEVI) más deprimida y un volumen telesistólico del ventrículo izquierdo más bajo. En conclusión, los valores de EpCAM circulante tras un IAMEST reperfundido se relacionaron con la OMV determinada mediante RMC en las fases agudas y con un remodelado ventricular adverso a largo plazo. En el tercero de los artículos, el primer objetivo fue describir el papel de la isoforma anti-angiogénica vascular endothelial growth factor (VEGF)-A165b en dos modelos murinos de IAM así como evaluar el impacto que tiene su bloqueo sobre la densidad microvascular, el tamaño de infarto y la función sistólica. Se realizaron dos modelos murinos de IAM: a) ligadura permanente de la arteria coronaria (IAM no reperfundido) y b) oclusión transitoria durante 45 minutos de la arteria coronaria seguida de reperfusión (IAM reperfundido); en ambos modelos, se realizó a los animales una ecocardiografía previa a la eutanasia el día 21 post-IAM. En los dos grupos experimentales de IAM, los niveles séricos y tisulares de VEGF-A165b habían aumentado a los 21 días de la inducción del IAM. Además, existía una correlación negativa entre los valores circulantes de VEGF-A165b y la función sistólica evaluada mediante ecocardiografía. El bloqueo in vivo de VEGF-A165b utilizando anticuerpos específicos se relacionó con una mayor densidad microvascular, menor tamaño de infarto y mejor función sistólica en el modelo de IAM reperfundido, pero no en el modelo de IAM no reperfundido. El segundo objetivo de este tercer manuscrito fue demostrar la relación entre los niveles de VEGF-A165b circulantes con la estructura cardiaca resultante, evaluada a los 6 meses mediante RMC, y con la aparición de episodios cardiacos adversos (muerte, re-infarto o insuficiencia cardiaca) durante el seguimiento en una cohorte prospectiva de 104 pacientes con IAMEST. Aquellos pacientes con unos niveles séricos elevados de VEGF-A165b presentaron una FEVI más deprimida al sexto mes del evento cardiovascular y una mayor tasa de eventos adversos. Con todo ello, podemos concluir que el VEFG-A165b estaba considerablemente elevado en modelos animales experimentales de IAM. Su neutralización in vivo fomentó la angiogénesis, redujo el tamaño del infarto y aumentó la función sistólica siempre que se permita la reperfusión. En pacientes con IAMEST, la mayor concentración de esta isoforna se correlacionó con peor función sistólica y con mayor incidencia de eventos adversos durante el seguimiento.Myocardial infarction (MI) is one of the main causes of morbidity and mortality in western societies. Although great advances have been made in the treatment of coronary reperfusion by percutaneous revascularization, 30 to 50% of patients suffer significant damage in the microcirculation known as microvascular obstruction (MVO). This phenomenon is considered to play a pivotal role in the development of adverse remodeling and occurrence of major adverse cardiac events after MI. Therefore, the main objective of the present PhD Thesis is to advance in the understanding of the basic mechanisms and the diagnosis of microvascular injury after ST-segment elevation MI (STEMI) as well as to explore novel therapeutic opportunities. In the first article, we evaluated the dynamic structural alterations in the wall of the epicardial arteries throught the ischemia-reperfusion process. For this objective, we employed a controlled swine model of reperfused MI. Juvenile animals were divided into one control and four reperfused MI groups: 90-min ischemia without reperfusion, or followed by 1-minute, 1-week or 1-month reperfusion. Left anterior descending coronary artery (LAD, infarct-related artery) and control right coronary artery (non-infarct-related artery) were isolated. Taking the balloon inflation region as a reference, we isolated the proximal and distal LAD areas. In all samples, we performed histological, immunohistochemical, and electron microscopy techniques. Afterwards, samples were photographed and morphometrically analysed. Although mild changes in tunica intima were observed during ischemia, an almost complete absence of endothelium, and abnormal breaks in the internal elastic layer were found post-revascularization. In tunica media, increased thickness was detected soon after coronary reperfusion, whereas larger thickness, disorganized muscle cell distribution, and edema were found one week after reperfusion. This damage was more pronounced in distal than proximal LAD. In the tunica adventitia, vasa vasorum density decayed during ischemia in both regions, but was restored after one month. Leukocyte adhesion began after revascularization, developing into a massive presence one week after reperfusion. As a consequence, ischemia-reperfusion injury induced abnormalities in epicardial coronary artery wall started during ischemia and increased after reperfusion, becoming more pronounced in the region distal to balloon inflation. In the second manuscript, we explored the association of circulating epithelial cell adhesion molecule (EpCAM) with cardiac magnetic resonance (CMR)-derived MVO at acute phase, and also with systolic function within the first six months after STEMI. We prospectively included 106 patients with a first STEMI treated with percutaneous coronary intervention and serum levels of EpCAM were determined 24 hours post-reperfusion. All patients underwent CMR imaging 1 week and 6 months post-STEMI. At 1-week CMR, EpCAM levels lower than median value (4.48 pg/ml) were related to extensive MVO, larger intramyocardial haemorrhage, and greater infarct size. At presentation, EpCAM values were significantly associated with the presence of MVO in univariate and multivariate logistic regression models. Although MVO tends to resolve at chronic phases, decreased EpCAM was associated with worse systolic function: depressed left ventricular ejection fraction (LVEF) and higher left ventricular end-systolic volume. Hence, circulating EpCAM values after reperfused STEMI were associated with CMR-derived MVO at acute phases and compromised systolic function at chronic phases. In the third article, our first objective was to describe the role of the anti-angiogenic vascular endothelial growth factor (VEGF)-A165b isoform in two murine models of MI as well as to scrutinize the beneficial impact of its blockage in vivo in terms of microvessel density, infarct size, and systolic function. Two mice MI models were formed: 1) permanent coronary ligation (non-reperfused MI), and 2) transient 45-min coronary occlusion followed by reperfusion (reperfused MI). In both models, animals underwent echocardiography before euthanasia at day 21 after MI induction. In the two MI models, circulating and myocardial VEGF-A165b presence was increased 21 days after MI induction. Serum VEGF-A165b levels inversely correlated with systolic function evaluated by echocardiography. VEGF-A165b neutralization with anti-VEGF-A165b antibody increased capillary density, reduced infarct size, and enhanced left ventricular function in reperfused, but not in non-reperfused MI experiments. As a second objective, we scrutinized the association between serum levels of VEGF-A165b with long-term systolic function and the occurrence of adverse events (defined as death, heart failure, or re-infarction) in a cohort of 104 STEMI patients. Elevated circulating VEGF-A165b levels correlated with lower CMR-derived LVEF at 6-months and with the occurrence of adverse events during follow-up. Therefore, in experimental and clinical studies, higher serum VEGF-A165b levels were related with worse systolic function. Its blockage enhanced neoangiogenesis, reduced infarct size, and increased systolic function in reperfused, but not in non-reperfused, murine MI models

Impact of quality of life related to foot problems : a case-control study

[Abstract] Foot problems are highly prevalent conditions, being a frequent reason for medical and podiatric consultation. The aim of this study was to compare the differences of quality of life (QoL) related to foot health in people with and without the presence of foot problems. A case-control study was carried out in an outpatient centre, where a clinician recorded data related to sociodemographic and clinical characteristics. In addition, self-reported data on foot health-related quality of life were recorded using the Spanish version of the Foot Health Status Questionnaire. The sample consisted of 498 participants (249 cases and 249 controls), with a median age of 30 years and an interquartile range of 23 years. The differences between the groups were statistically significant for gender, age, footwear, general health, foot health, and physical activity. Cases showed lower scores for the domain of footwear, physical activity and vitality compared to controls. Foot pathologies have a negative impact on quality of life related to foot health, and the domains of footwear, general health and physical activity seem to be the factors that are associated with the presence of alterations and foot deformities

Role of PCSK9 in the course of ejection fraction change after ST-segment elevation myocardial infarction : a pilot study

Altres ajuts: Conselleria d'Educació, Investigació, Cultura i Esport GV/2018/116Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for reducing plasma low-density lipoprotein cholesterol. Beyond lipid control, recent findings suggest a deleterious effect of this protein in the pathogenesis of postmyocardial infarction left ventricle remodelling and heart failure-related complications. The aim of this study was to assess the relationship between circulating PCSK9 and 6 month cardiac magnetic resonance imaging-derived left ventricular ejection fraction (LVEF) after a first ST-segment elevation myocardial infarction (STEMI). We prospectively evaluated 40 patients with a first STEMI, LVEF < 50% and treated with primary percutaneous coronary intervention in which PCSK9 was measured 24 h postreperfusion. All patients underwent cardiac magnetic resonance imaging 1 week and 6 months after STEMI. Baseline characteristics were compared across median values of PCSK9. The association between PCSK9 levels and LVEF at 6 months was evaluated by analysis of covariance. The mean age of the sample was 60 ± 12 years and 33 (82.5%) were male patients. The infarct location was anterior in 27 patients (67.5%), and 9 patients (22.5%) were Killip class ≥ II. The mean 1 week and 6 month LVEF were 41 ± 7% and 48 ± 10%, respectively. The mean PCSK9 was 1.93 ± 0.38 U/mL. Testing the association between serum PCSK9 and 6 month LVEF with analysis of covariance revealed an inverse relationship (r = −0.35, P = 0.028). After multivariate adjustment, circulating PCSK9 remained significant and inversely associated with 6 month LVEF (P = 0.002). In patients with a first STEMI with reduced ejection fraction at index admission and treated with primary percutaneous coronary intervention, circulating PCSK9 was associated with lower LVEF at 6 months

Prognostic value of cardiac magnetic resonance early after ST-segment elevation myocardial infarction in older patients

[EN] Background older patients with ST-segment elevation myocardial infarction (STEMI) represent a very high-risk population. Data on the prognostic value of cardiac magnetic resonance (CMR) in this scenario are scarce. Methods the registry comprised 247 STEMI patients over 70 years of age treated with percutaneous intervention and included in a multicenter registry. Baseline characteristics, echocardiographic parameters and CMR-derived left ventricular ejection fraction (LVEF, %), infarct size (% of left ventricular mass) and microvascular obstruction (MVO, number of segments) were prospectively collected. The additional prognostic power of CMR was assessed using adjusted C-statistic, net reclassification index (NRI) and integrated discrimination improvement index (IDI). Results during a 4.8-year mean follow-up, the number of first major adverse cardiac events (MACE) was 66 (26.7%): 27 all-cause deaths and 39 re-admissions for acute heart failure. Predictors of MACE were GRACE score (HR 1.03 [1.02-1.04], P 155, LVEF = 2 segments. A simple score (0, 1, 2, 3) based on the number of altered factors accurately predicted the MACE per 100 person-years: 0.78, 5.53, 11.51 and 78.79, respectively (P < 0.001). Conclusions CMR data contribute valuable prognostic information in older patients submitted to undergo CMR soon after STEMI. The Older-STEMI-CMR score should be externally validated.This work was supported by Instituto de Salud Carlos III and Fondos Europeos de Desarrollo Regional FEDER (grant numbers PI20/00637, PI15/00531, and CIBERCV16/11/00486,CIBERCV16/11/00420, CIBERCV16/11/00479), apostgraduate contract FI18/00320 to C.R.-N., CM21/00175 to V.M.-G. and JR21/00041 to C.B., Fundacio La MaratoTV3 (grant 20153030-31-32), La Caixa Banking Foundation (HR17-00527), by Conselleria de Educacion-Generalitat Valenciana (PROMETEO/2021/008) and by Sociedad Espanola de Cardiologia (grant SEC/FEC-INV-CLI 21/024). J.G. acknowledges financial support from the Agencia Estatal de Investigacion (grant FJC2020-043981-I/AEI/10.13039/501100011033). D.M. acknowledges financial support from the Conselleria d'Educacio,Investigacio, Cultura i Esport, Generalitat Valenciana (grants AEST/2019/037, AEST/2020/029).Gabaldón-Pérez A; Marcos-Garcés, V.; Gavara-Doñate, J.; López-Lereu, MP.; Monmeneu, JV.; Pérez, N.; Ríos-Navarro, C.... (2022). Prognostic value of cardiac magnetic resonance early after ST-segment elevation myocardial infarction in older patients. Age and Ageing. 51(11):1-11. https://doi.org/10.1093/ageing/afac248111511

Pivotal Role of Adenosine Neurotransmission in Restless Legs Syndrome

The symptomatology of Restless Legs Syndrome (RLS) includes periodic leg movements during sleep (PLMS), dysesthesias, and hyperarousal. Alterations in the dopaminergic system, a presynaptic hyperdopaminergic state, seem to be involved in PLMS, while alterations in glutamatergic neurotransmission, a presynaptic hyperglutamatergic state, seem to be involved in hyperarousal and also PLMS. Brain iron deficiency (BID) is well-recognized as a main initial pathophysiological mechanism of RLS. BID in rodents have provided a pathogenetic model of RLS that recapitulates the biochemical alterations of the dopaminergic system of RLS, although without PLMS-like motor abnormalities. On the other hand, BID in rodents reproduces the circadian sleep architecture of RLS, indicating the model could provide clues for the hyperglutamatergic state in RLS. We recently showed that BID in rodents is associated with changes in adenosinergic transmission, with downregulation of adenosine A1 receptors (A1R) as the most sensitive biochemical finding. It was hypothesized that A1R downregulation leads to hypersensitive striatal glutamatergic terminals and facilitation of striatal dopamine release. Hypersensitivity of striatal glutamatergic terminals was demonstrated by an optogenetic-microdialysis approach in the rodent with BID, indicating that it could represent a main pathogenetic factor that leads to PLMS in RLS. In fact, the dopaminergic agonists pramipexole and ropinirole and the α2δ ligand gabapentin, used in the initial symptomatic treatment of RLS, completely counteracted optogenetically-induced glutamate release from both normal and BID-induced hypersensitive corticostriatal glutamatergic terminals. It is a main tenet of this essay that, in RLS, a single alteration in the adenosinergic system, downregulation of A1R, disrupts the adenosine-dopamine-glutamate balance uniquely controlled by adenosine and dopamine receptor heteromers in the striatum and also the A1R-mediated inhibitory control of glutamatergic neurotransmission in the cortex and other non-striatal brain areas, which altogether determine both PLMS and hyperarousal. Since A1R agonists would be associated with severe cardiovascular effects, it was hypothesized that inhibitors of nucleoside equilibrative transporters, such as dipyridamole, by increasing the tonic A1R activation mediated by endogenous adenosine, could represent a new alternative therapeutic strategy for RLS. In fact, preliminary clinical data indicate that dipyridamole can significantly improve the symptomatology of RLS

The Beaker phenomenon and the genomic transformation of northwest Europe

From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain’s gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries

Gestión del conocimiento. Perspectiva multidisciplinaria. Volumen 10

El libro “Gestión del Conocimiento. Perspectiva Multidisciplinaria”, Volumen 10, de la Colección Unión Global, es resultado de investigaciones. Los capítulos del libro, son resultados de investigaciones desarrolladas por sus autores. El libro es una publicación internacional, seriada, continua, arbitrada de acceso abierto a todas las áreas del conocimiento, que cuenta con el esfuerzo de investigadores de varios países del mundo, orientada a contribuir con procesos de gestión del conocimiento científico, tecnológico y humanístico que consoliden la transformación del conocimiento en diferentes escenarios, tanto organizacionales como universitarios, para el desarrollo de habilidades cognitivas del quehacer diario. La gestión del conocimiento es un camino para consolidar una plataforma en las empresas públicas o privadas, entidades educativas, organizaciones no gubernamentales, ya sea generando políticas para todas las jerarquías o un modelo de gestión para la administración, donde es fundamental articular el conocimiento, los trabajadores, directivos, el espacio de trabajo, hacia la creación de ambientes propicios para el desarrollo integral de las instituciones

Precariedad, exclusión social y diversidad funcional (discapacidad): lógicas y efectos subjetivos del sufrimiento social contemporáneo (III). Innovación docente en Filosofía

El PIMCD Precariedad, exclusión social y diversidad funcional (discapacidad): lógicas y efectos subjetivos del sufrimiento social contemporáneo (III). Innovación docente en Filosofía se ocupa de conceptos que generalmente han tendido a ser eludidos en la enseñanza académica de filosofía. Se trata de la tercera edición de un PIMCD que ha venido recibiendo financiación en las últimas convocatorias PIMCD UCM, de los que se han derivado publicaciones colectivas publicadas por Ediciones Complutense y Siglo XXI

Gestión del conocimiento. Perspectiva multidisciplinaria. Volumen 17

El libro “Gestión del Conocimiento. Perspectiva Multidisciplinaria”, Volumen 17 de la Colección Unión Global, es resultado de investigaciones. Los capítulos del libro, son resultados de investigaciones desarrolladas por sus autores. El libro es una publicación internacional, seriada, continua, arbitrada, de acceso abierto a todas las áreas del conocimiento, orientada a contribuir con procesos de gestión del conocimiento científico, tecnológico y humanístico. Con esta colección, se aspira contribuir con el cultivo, la comprensión, la recopilación y la apropiación social del conocimiento en cuanto a patrimonio intangible de la humanidad, con el propósito de hacer aportes con la transformación de las relaciones socioculturales que sustentan la construcción social de los saberes y su reconocimiento como bien público

Daño microvascular tras un infarto agudo de miocardio. Foco en el laboratorio de hemodinámica

This study was funded by the Instituto de Salud Carlos III and the European Regional Development Fund (FEDER) (grants PI20/00637, CIBERCV16/11/00486 and FI18/00320), the Conselleria de Educació de la Generalitat Valenciana (PROMETEO/2021/008) and the Agencia Estatal de Investigación (grant FJC2020-043981).Ríos-Navarro, C.; Gavara-Doñate, J.; Bodí, V. (2022). Microvascular injury after acute myocardial infarction. Focus on the catheterization laboratory. Revista Española de Cardiología. 75(10):777-779. https://doi.org/10.1016/j.rec.2022.05.011777779751