Efecto precoz del B-bloqueante Esmolol sobre la regresión del remodelado coroonario en ratas espontáneamente hipertensas y estudio observacional de la influencia del tratamiento crónico B-bloqueantes en la aparición de complicaciones perioperatorias en cirugía no cardiaca

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Cirugía. Fecha de lectura: 29-04-2016Esta tesis tiene embargado el acceso al texto completo hasta el 29-10-2017La hipertensión arterial produce remodelado de cavidades cardiacas y pared vascular, que conduce a la aparición de complicaciones cardíacas (insuficiencia cardiaca, infarto de miocardio, arritmias graves) con aumento secundario de la morbimortalidad. Varios fármacos antihipertensivos (ARA-II, IECAS, calcioantagonistas y β-bloqueantes) han mostrado su capacidad para revertir el anterior proceso de remodelado en un periodo de tratamiento de meses-años, mejorando así el pronóstico de estos pacientes. El esmolol es un fármaco bloqueante 1-adrenérgico (cardioselectivo) que posee ciertas ventajas farmacocinéticas respecto a otros hipotensores, junto con un efecto bradicardizante e hipotensor rápido y potente. En un estudio experimental previo, realizado en ratas espontáneamente hipertensas (SHR), nuestro grupo demostró que el esmolol reducía significativamente, en tan solo 48 horas de perfusión intravenosa, la hipertrofia ventricular izquierda, siendo el primer fármaco capaz de producir dicho efecto de manera precoz (15). En base a este hallazgo, diseñamos el presente trabajo experimental con el objetivo de investigar si el anterior tratamiento con esmolol revertía el remodelado de la arteria coronaria en la SHR. Nuestros resultados muestran que el fármaco produce dicho efecto y que lo hace a través de los siguientes mecanismos: 1º) reducción del grosor de la pared y de la capa media arterial; 2º) normalización de la reactividad vascular, favorecida por una mayor biodisponibilidad de óxido nítrico; 3º) reducción del estrés oxidativo con un aumento de actividad de la superóxido dismutasa y catalasa; y 4º) disminución de la concentración de dimetilarginina asimétrica que conduce a una mayor producción de óxido nítrico. Adicionalmente, durante una estancia de 3 meses en el hospital St George´s de Londres, hemos diseñado y realizado un estudio clínico observacional con el objetivo de analizar la eficacia del tratamiento crónico -bloqueante en la profilaxis de las complicaciones de la cirugía no cardíaca. Para ello, hemos evaluado retrospectivamente una cohorte de 80 pacientes sometidos a cirugía mayor no cardíaca, e ingresados en la Unidad de Cuidados Intensivos de este hospital. Tras un periodo de seguimiento de 2-4 semanas desde el postoperatorio inmediato hasta el alta hospitalaria/fallecimiento, los pacientes incluidos en el brazo de tratamiento -bloqueante presentaron un mayor número de factores de riesgo cardiovascular y mayor incidencia de arritmias en el postoperatorio. Sin embargo, no se encontraron diferencias en la incidencia de otros eventos cardiacos, complicaciones no cardiacas, duración de la estancia hospitalaria o tasa de mortalidad entre los pacientes tratados o sin tratar con -bloqueantes. Los resultados de este estudio sugieren que el tratamiento crónico con -bloqueantes no induce la aparición de complicaciones perioperatorias (salvo arritmias postoperatorias) en cirugía no cardíaca. No obstante, se necesitan estudios prospectivos y aleatorizados adicionales, con un tamaño muestral mayor, para dilucidar la eficacia real del tratamiento crónico con -bloqueantes en la profilaxis de complicaciones perioperatorias tras cirugía no cardíaca.Hypertension induces remodeling of the cardiac cavities and vascular wall, leading to the onset of cardiac complications (heart failure, myocardial ischemia, serious arrhythmias) and the resulting increase in morbidity and mortality. Several antihypertensive drugs (ARA-II, ACE inhibitors, calcium channel and β- adrenergic receptor blockers) have shown their ability to reverse the above remodeling process within months or years of treatment, thus improving the patients’ prognosis. Esmolol is a -adenergic blocking agent (cardioselective) that possesses certain pharmacokinetic advantages over other antihypertensive drugs, and also has fast and powerful bradycardic and hypotensive effects. In a previous experimental study in spontaneously hypertensive rats (SHRs), our group had shown that esmolol significantly reduced, after just 48 hours of intravenous infusion, left ventricular hypertrophy, being the first drug known to produce this effect in such a short period of time (15). Based on this finding, we designed the present experimental study with the objective of investigating whether the above esmolol treatment revert coronary artery remodeling in SHR. Our results show that the drug produces the above effect, and that it does so through the following mechanisms: 1st) reducing the thickness of the arterial wall and the middle layer; 2nd) normalization of vascular reactivity by increasing nitric oxide bioavailability; 3rd) reducing oxidative stress by increasing the activity of superoxide dismutase and catalase; and 4) decreasing the concentration of the asymmetric dimethylarginine, which leads to increased nitric oxide production. Additionally, during a 3 month stay at St George's Hospital in London, an observational clinical study was designed and performed with the aim of analyzing the effectiveness of chronic therapy with β- blockers in the prophylaxis of perioperative complications of major noncardiac surgery. This was done by retrospectively evaluating a cohort of 80 patients who underwent major noncardiac surgery and were transferred to the Intensive Care Unit of the hospital. After a follow-up period of 2-4 weeks after surgery until discharge/death, the patients who were included in the beta-blocker arm had a greater number of cardiovascular risk factors and a higher incidence of postoperative arrhythmias. However, no differences in relation to the incidence of other cardiac events, noncardiac complications, length of hospital stay or mortality rate were found between patients treated or untreated with β-blockers. The results of this study suggest that chronic treatment with β-blockers does not induce perioperative complications (except postoperative arrhythmias) after noncardiac surgery. However, additional prospective and randomized studies, with a larger sample size, are needed to elucidate the actual effectiveness of chronic treatment with β-blockers as prophylaxis for perioperative complications after noncardiac surgery

Corneal regeneration using adipose-derived mesenchymal stem cells

Producción CientíficaAdipose-derived stem cells are a subtype of mesenchymal stem cell that offers the important advantage of being easily obtained (in an autologous manner) from low invasive procedures, rendering a high number of multipotent stem cells with the potential to differentiate into several cellular lineages, to show immunomodulatory properties, and to promote tissue regeneration by a paracrine action through the secretion of extracellular vesicles containing trophic factors. This secretome is currently being investigated as a potential source for a cell-free based regenerative therapy for human tissues, which would significantly reduce the involved costs, risks and law regulations, allowing for a broader application in real clinical practice. In the current article, we will review the existing preclinical and human clinical evidence regarding the use of such adipose-derived mesenchymal stem cells for the regeneration of the three main layers of the human cornea: the epithelium (derived from the surface ectoderm), the stroma (derived from the neural crest mesenchyme), and the endothelium (derived from the neural crest cells)

Maintenance over Time of the Effect Produced by Esmolol on the Structure and Function of Coronary Arteries in Hypertensive Heart Diseases

We previously observed that esmolol treatment for 48 h reduced vascular lesions in spontaneously hypertensive rats (SHRs). Therefore, we investigated whether this beneficial effect is persistent after withdrawal. Fourteen-month-old SHRs (SHR-Es) were treated with esmolol (300 μg/kg/min) or a vehicle for 48 h. Two separate groups were also given identical treatment, but they were then monitored for a further 1 week and 1 month after drug withdrawal. We analyzed the geometry and composition of the coronary artery, vascular reactivity and plasma redox status. Esmolol significantly decreased wall thickness (medial layer thickness and cell count), external diameter and cross-sectional area of the artery, and this effect persisted 1 month after drug withdrawal. Esmolol significantly improved endothelium-dependent relaxation by ACh (10−9–10−4 mol/L); this effect persisted 1 week (10−9–10−4 mol/L) and 1 month (10−6–10−4 mol/L) after withdrawal. Esmolol reduced the contraction induced by 5-HT (3 × 10−8–3 × 10−5 mol/L), and this effect persisted 1 week after withdrawal (10−6–3 × 10−5 mol/L). Esmolol increased nitrates and reduced glutathione, and it decreased malondialdehyde and carbonyls; this enhancement was maintained 1 month after withdrawal. This study shows that the effect of esmolol on coronary remodeling is persistent after treatment withdrawal in SHRs, and the improvement in plasma oxidative status can be implicated in this effect

Short-Term Esmolol Improves Coronary Artery Remodeling in Spontaneously Hypertensive Rats through Increased Nitric Oxide Bioavailability and Superoxide Dismutase Activity

The aim of this study was to assess the effects of short-term esmolol therapy on coronary artery structure and function and plasma oxidative stress in spontaneously hypertensive rats (SHR). For this purpose, 14-month-old male SHR were treated for 48 hours with esmolol (SHR-E, 300 μg/kg/min). Age-matched untreated male SHR and Wistar Kyoto rats (WKY) were used as hypertensive and normotensive controls, respectively. At the end of intervention we performed a histological study to analyze coronary artery wall width (WW), wall-to-lumen ratio (W/L), and media cross-sectional area (MCSA). Dose-response curves for acetylcholine (ACh) and sodium nitroprusside were constructed. We also assessed several plasma oxidative stress biomarkers, namely, superoxide scavenging activity (SOSA), nitrites, and total antioxidant capacity (TAC). We observed a significant reduction in WW (P<0.001), W/L (P<0.05), and MCSA (P<0.01) and improved endothelium-dependent relaxation (AUCSHR-E = 201.2±33 versus AUCSHR = 97.5±21, P<0.05) in SHR-E compared with untreated SHR; no differences were observed for WW, MCSA, and endothelium-dependent relaxation by ACh at higher concentrations (10−6 to 10−4 mol/l) for SHR-E with respect to WKY. SOSA (P<0.001) and nitrite (P<0.01) values were significantly higher in SHR-E than in untreated SHR; however, TAC did not increase after treatment with esmolol. Esmolol improves early coronary artery remodeling in SHR