Efectos electrofisiológicos miocárdicos intrínsecos producidos por la inhibición del sistema de intercambio sodio-protón, en condiciones de normoxia, y tras la isquemia miocárdica regional. Estudio experimental.

RESUMEN Hemos investigado: 1) los efectos protectores del intercambiador sodio-protón (NHE), con el 5-(N-etil-N-isopropil) amiloride (EIPA), a concentración 0.4 M, sobre la inducibilidad de la fibrilación ventricular (FV), y sobre la refractariedad miocárdica ventricular, tras la oclusión arterial coronaria; 2) los efectos electrofisiológicos intrínsecos producidos por la inhibición del NHE, administrando EIPA 0.4 y 1 M, en condiciones de normal oxigenación, sobre el automatismo sinusal, la conducción sinoauricular y auriculoventricular (AV), y sobre la refractariedad auricular, ventricular, y del sistema de conducción AV; y 3) los efectos electrofisiológicos miocárdicos intrínsecos producidos por la inhibición del NHE, con EIPA 0.4 y 1 M, sobre la frecuencia dominante (FD) de la FV inducida, en condiciones de normoxia, como característica electrofisiológica estrechamente relacionada con la refractariedad ventricular. Todos los experimentos se realizaron en corazón aislado y perfundido de conejo (preparación tipo Langendorff). Para conseguir el primer objetivo aplicamos el test del extraestímulo (TEE) ventricular con uno, dos, y tres extraestímulos, para tratar de inducir la FV. La aplicación del primer extraestímulo sirvió además para establecer el periodo refractario objeto de investigación. Las determinaciones se realizaron previamente y tras la oclusión arterial coronaria circunfleja, en dos grupos de experimentos: control y tratados con EIPA 0.4 M. Para cumplimentar el segundo objetivo analizamos: a) periodos refractarios efectivo y funcional auricular y del sistema de conducción AV mediante el TEE auricular, periodos refractarios efectivo y funcional ventricular mediante el TEE ventricular; b) automatismo sinusal mediante la determinación de la longitud del ciclo sinusal y del tiempo de recuperación del nodo sinusal; y c) tiempo de conducción sinoauricular con el test de Narula, conducción AV y conducción ventriculoauricular retrógrada, mediante la medición de la longitud del ciclo de Wenckebach y la longitud del ciclo de Wenckebach retrógrado respectivamente. Finalmente, para acometer el tercer objetivo analizamos, por el método de Welch, la FD media, máxima y mínima de la FV inducida por estimulación a frecuencias crecientes. Los parámetros citados se estudiaron en situación control e inhibiendo el NHE, con EIPA. Utilizamos dos concentraciones de dicho inhibidor: 0.4 y 1 M; la primera se halla en el rango de la IC50 para el NHE y la segunda es la concentración más comúnmente usada en los estudios de protección miocárdica. La inhibición del NHE con EIPA 0.4 M protegió al miocardio isquémico, al dificultar la inducibilidad de la FV. Este efecto protector, probablemente está relacionado, al menos en parte, con el mantenimiento de la refractariedad ventricular en el miocardio isquémico, lo cual ha sido también observado en el presente trabajo. Excepto para el caso del periodo refractario efectivo del sistema de conducción AV, que aumentó ligeramente con EIPA 1 M, la inhibición del NHE con EIPA 0.4 y 1 M en condiciones de normal oxigenación, no modificó la refractariedad intrínseca ventricular, auricular, ni del sistema de conducción AV, así como tampoco la FD de la FV inducida, mientras que deprimió ligeramente el cronotropismo sinusal y la conducción AV, si bien estos últimos podrían ser efectos secundarios, relacionados con la capacidad depresora del automatismo sinusal y la conducción AV que ejerce el amiloride, precursor del EIPA. El hecho de que la inhibición del NHE, manifestara efectos electrofisiológicos antiarrítmicos intrínsecos sobre el miocardio isquémico, impidiendo la caída de la refractariedad, y no ejerciera ninguna modificación electrofisiológica, en condiciones de normal oxigenación, sobre la refractariedad y la FD de la FV, propiedades ligadas a la aparición de arritmias por reentrada, coincide con lo relatado por diversos investigadores acerca del escaso, sino nulo, papel del NHE en situación fisiológica y su importancia en circunstancias fisiopatológicas como la isquemia. __________________________________________________________________________________________________We have investigated the protective effects of the sodium-proton exchanger (NHE) inhibition using 5-(N-ethyl-N-isopropyl) amiloride (EIPA) 0.4 M, on the incidence of induced ventricular fibrillation (VF), and on intrinsic ventricular refractoriness, after circumflex coronary artery occlusion. Experiments were performed on isolated rabbit heart. To induce VF extrastimulus test with one, two and three extrastimuli, was used; the first extrastimulus application also served to determine refractory periods. Parameters were determined previously and after coronary occlusion, in both control and EIPA 0.4 M treated groups. In order to investigate whether the NHE inhibition produces some myocardial intrinsic electrophysiological effect, we have also investigated using EIPA, 0.4 and 1 M, in normoxic condition: a) the sinus cycle length and sinus node recovery time, as an automatism index; b) the sinoatrial conduction (Narulas test), and atrioventricular (AV) and ventricleatrial conduction, by anterograde and retrograde Wenckebach cycle length determination respectively; c) atrial, ventricular, and AV conduction system, effective and functional refractory periods using the extrastimulus test; and d) mean, minimum and maximum dominant frequency (DF) of VF by the Welchs method, which are properties closely related with ventricular refractoriness. NHE inhibition with 0.4 M protected the ischemic myocardium, decreasing VF inducibility, at least in part, by the maintenance of ischemic myocardium refractoriness, observed in this study. No modification on refractoriness was observed, in normoxic conditions, except an AV conduction system effective refractory period increase, with EIPA 1 M. The DF of VF was either not modified. EIPA 0.4 and 1 M also slightly depressed sinus chronotropism and AV conduction

Development and Long-Term Follow-Up of an Experimental Model of Myocardial Infarction in Rabbits

[EN] A chronic model of acute myocardial infarction was developed to study the mechanisms involved in adverse postinfarction ventricular remodeling. In an acute myocardial infarction (AMI), the left circumflex coronary artery of New Zealand White rabbits (n = 9) was occluded by ligature for 1 h, followed by reperfusion. A specific care protocol was applied before, during, and after the intervention, and the results were compared with those of a sham operated group (n = 7). After 5 weeks, programmed stimulation and high-resolution mapping were performed on isolated and perfused hearts using the Langendorff technique. The infarct size determined by 2,3,5-triphenyltetrazolium chloride inside of the area at risk (thioflavin-S) was then determined. The area at risk was similar in both groups (54.33% (experimental infarct group) vs. 58.59% (sham group), ns). The infarct size was 73.16% as a percentage of the risk area. The experimental infarct group had a higher inducibility of ventricular arrhythmias (100% vs. 43% in the sham group, p = 0.009). A reproducible chronic experimental model of myocardial infarction is presented in which the extent and characteristics of the lesions enable the study of the vulnerability to develop ventricular arrhythmias because of the remodeling process that occurs during cardiac tissue repair.This research was funded by Generalitat Valenciana (PROMETEO/2018/078), Instituto de Salud Carlos III (CB16/11/00486; PI15/01408; PIE15/0001 3and PI18/01620) to F.J.C.Genovés, P.; Arias-Mutis, ÓJ.; Parra, G.; Such-Miquel, L.; Zarzoso, M.; Del Canto, I.; Soler, C.... (2020). Development and Long-Term Follow-Up of an Experimental Model of Myocardial Infarction in Rabbits. Animals. 10(9). https://doi.org/10.3390/ani1009157610

The training-induced changes on automatism, conduction and myocardial refractoriness are not mediated by parasympathetic postganglionic neurons activity

The purpose of this study is to test the role that parasympathetic postganglionic neurons could play on the adaptive electrophysiological changes produced by physical training on intrinsic myocardial automatism, conduction and refractoriness. Trained rabbits were submitted to aphysical training protocol on treadmill during 6 weeks. The electrophysiological study was performed in an isolated heart preparation. The investigated myocardial properties were: (a) sinus automatism, (b) atrioventricular and ventriculoatrial conduction, (c) atrial, conduction system and ventricular refractoriness. The parameters to study the refractoriness were obtained by means of extrastimulus test at four diVerent pacing cycle lengths (10% shorter than spontaneous sinus cycle length, 250, 200 and 150 ms) and (d) mean dominant frequency (DF) of the induced ventricular Wbrillation (VF), using a spectral method. The electrophysiological protocol was performed before and during continuous atropine administration (1 ¿M), in order to block cholinergic receptors. Cholinergic receptor blockade did not modify either the increase in sinus cycle length, atrioventricular conduction and refractoriness (left ventricular and atrioventricular conduction system functional refractory periods) or the decrease of DF of VF. These Wndings reveal that the myocardial electrophysiological modiWcations produced by physical training are not mediated by intrinsic cardiac parasympathetic activity.The authors thank Carmen Rams, Ana Diaz, Pilar Navarro and Cesar Avellaneda for their excellent technical assistance. This work has been supported by grants from the Spanish Ministry of Education and Science (DEP2007-73234-C03-01) and Generalitat Valenciana (PROMETEO 2010/093). M Zarzoso was supported by a research scholarship from Generalitat Valenciana (BFPI/2008/003).Zarzoso Muñoz, M.; Such Miquel, L.; Parra Giraldo, G.; Brines Ferrando, L.; Such, L.; Chorro, F.; Guerrero, J.... (2012). The training-induced changes on automatism, conduction and myocardial refractoriness are not mediated by parasympathetic postganglionic neurons activity. European Journal of Applied Physiology. 112(6):2185-2193. https://doi.org/10.1007/s00421-011-2189-4S218521931126Armour JA, Hopkins DA (1990a) Activity of in vivo canine ventricular neurons. Am J Physiol Heart Circ Physiol 258:H326–H336. doi: 10.1152/ajpregu.00183.2004Armour JA, Hopkins DA (1990b) Activity of canine in situ left atrial ganglion neurons. Am J Physiol Heart Circ Physiol 259:H1207–H1215Armour JA (2004) Cardiac neuronal hierarchy in health and disease. 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Am J Physiol Heart Circ Physiol 281:1346–1352Inoue H, Zipes DP (1987) Changes in atrial and ventricular refractoriness and atrioventricular nodal conduction produced by combinations of vagal and sympathetic stimulation that result in a constant spontaneous sinus cycle length. Circ Res 60:942–951Jew KN, Olsson MC, Mokelke EA, Palmer BM, Moore RL (2001) Endurance training alters outward K+ current characteristics in rat cardiocytes. J Appl Physiol 90:1327–1333Johnson TA, Gray AL, Lauenstein JM, Newton SS, Massari VJ (2004) Parasympathetic control of the heart I. An interventriculo-septal ganglion is the major source of the vagal intracardiac innervation of the ventricles. J Appl Physiol 96:2265–2272. doi: 10.1152/japplphysiol.00620.2003Katona PG, McLean M, Dighton DH, Guz A (1982) Sympathetic and parasympathetic cardiac control in athletes and nonathletes at rest. 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Alteration of Ventricular Fibrillation by Flecainide, Verapamil, and Sotalol

Background—The purpose of this study was to determine whether the myocardial electrophysiological properties are useful for predicting changes in the ventricular fibrillatory pattern. Methods and Results—Thirty-two Langendorff-perfused rabbit hearts were used to record ventricular fibrillatory activity with an epicardial multiple electrode. Under control conditions and after flecainide, verapamil, or d,l-sotalol, the dominant frequency (FrD), type of activation maps, conduction velocity, functional refractory period, and wavelength (WL) of excitation were determined during ventricular fibrillation (VF). Flecainide (1.9±0.3 versus 2.4±0.6 cm, P<0.05) and sotalol (2.1±0.3 versus 2.5±0.5 cm, P<0.05) prolonged WL and diminished FrD during VF, whereas verapamil (2.0±0.2 versus 1.7±0.2 cm, P<0.001) shortened WL and increased FrD. Simple linear regression revealed an inverse relation between FrD and the functional refractory period (r=0.66, P<0.0001), a direct relation with respect to conduction velocity (r=0.33, P<0.01), and an inverse relation with respect to WL estimated during VF (r=0.49, P<0.0001). By stepwise multiple regression, the functional refractory periods were the only predictors of FrD. Flecainide and sotalol increased the circuit size of the reentrant activations, whereas verapamil decreased it. The 3 drugs significantly reduced the percentages of more complex activation maps during VF. Conclusions—The activation frequency is inversely related to WL during VF, although a closer relation is observed with the functional refractory period. Despite the diverging effects of verapamil versus flecainide and sotalol on the activation frequency, WL, and size of the reentrant circuits, all 3 drugs reduce activation pattern complexity during VF.Chorro Gasco, Francisco Javier, [email protected] ; Guerrero Martinez, Juan Francisco, [email protected] ; Sanchis Fores, Juan, [email protected] ; Such Belenguer, Luis, [email protected]

Competitiveness and overtourism: a proposal for an early warning system in Spanish urban destinations

The tourism industry is undergoing accelerated changes that pose significant challenges for both destination and business managers as well as for researchers of the tourism phenomenon. Two of these challenges that are particularly relevant are the emergence of the sharing economy and its influence on the degree of overtourism perceived in the tourist destinations. This paper addresses the subject through the use of machine learning techniques. The findings show that machine learning techniques are especially well-suited tools for dealing with these kinds of tourism issues. The findings also show that for the Spanish case, tourism competitiveness is a key predictor of overtourism

Effect of chronic exercise on myocardial electrophysiological heterogeneity and stability. Role of intrinsic cholinergic neurons: A study in the isolated rabbit heart

[EN] A study has been made of the effect of chronic exercise on myocardial electrophysiological heterogeneity and stability, as well as of the role of cholinergic neurons in these changes. Determinations in hearts from untrained and trained rabbits on a treadmill were performed. The hearts were isolated and perfused. A pacing electrode and a recording multielectrode were located in the left ventricle. The parameters determined during induced VF, before and after atropine (1 mu M), were: fibrillatory cycle length (VV), ventricular functional refractory period (FRPVF), normalized energy (NE) of the fibrillatory signal and its coefficient of variation (CV), and electrical ventricular activation complexity, as an approach to myocardial heterogeneity and stability. The VV interval was longer in the trained group than in the control group both prior to atropine (78 +/- 10 vs. 68 +/- 10 ms) and after atropine (76 +/- 8 vs. 67 +/- 10 ms). Likewise, FRPVF was longer in the trained group than in the control group both prior to and after atropine (53 +/- 8 vs. 42 +/- 7 ms and 50 +/- 6 vs. 40 +/- 6 ms, respectively), and atropine did not modify FRPVF. The CV of FRPVF was lower in the trained group than in the control group prior to atropine (12.5 +/- 1.5% vs. 15.1 +/- 3.8%) and, decreased after atropine (15.1 +/- 3.8% vs. 12.2 +/- 2.4%) in the control group. The trained group showed higher NE values before (0.40 +/- 0.04 vs. 0.36 +/- 0.05) and after atropine (0.37 +/- 0.04 vs. 0.34 +/- 0.06; p = 0.08). Training decreased the CV of NE both before (23.3 +/- 2% vs. 25.2 +/- 4%; p = 0.08) and after parasympathetic blockade (22.6 +/- 1% vs. 26.1 +/- 5%). Cholinergic blockade did not modify these parameters within the control and trained groups. Activation complexity was lower in the trained than in the control animals before atropine (34 +/- 8 vs. 41 +/- 5), and increased after atropine in the control group (41 +/- 5 vs. 48 +/- 9, respectively). Thus, training decreases the intrinsic heterogeneity of the myocardium, increases electrophysiological stability, and prevents some modifications due to muscarinic block.This research was supported by the Spanish Ministry of Education and Science, (DEP2007-73234-C03-01 to AMA), http://www.mecd.gob.es/portada-mecd/; and the Generalitat Valenciana (PROMETEO 2010/093 to FJC, and FPI/2008/003 to MZ), http://www.gva.es/va/inicio/presentacion; jsessionid=ydprbDQZTsCTz85W1Such-Miquel, L.; Brines-Ferrando, L.; Alberola, A.; Zarzoso Muñoz, M.; Chorro Gasco, FJ.; Guerrero-Martínez, JF.; Parra-Giraldo, G.... (2018). Effect of chronic exercise on myocardial electrophysiological heterogeneity and stability. Role of intrinsic cholinergic neurons: A study in the isolated rabbit heart. 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N., & Quindry, J. C. (2014). Mechanisms of Exercise-Induced Cardioprotection. Physiology, 29(1), 27-38. doi:10.1152/physiol.00030.2013Hull, S. S., Vanoli, E., Adamson, P. B., Verrier, R. L., Foreman, R. D., & Schwartz, P. J. (1994). Exercise training confers anticipatory protection from sudden death during acute myocardial ischemia. Circulation, 89(2), 548-552. doi:10.1161/01.cir.89.2.548Hajnal, Á., Nagy, O., Litvai, Á., Papp, J., Parratt, J. R., & Végh, Á. (2005). Nitric oxide involvement in the delayed antiarrhythmic effect of treadmill exercise in dogs. Life Sciences, 77(16), 1960-1971. doi:10.1016/j.lfs.2005.02.015Such, L., Alberola, A. M., Such-Miquel, L., López, L., Trapero, I., Pelechano, F., … Chorro, F. J. (2008). Effects of chronic exercise on myocardial refractoriness: a study on isolated rabbit heart. Acta Physiologica, 193(4), 331-339. doi:10.1111/j.1748-1716.2008.01851.xZarzoso, M., Such-Miquel, L., Parra, G., Brines-Ferrando, L., Such, L., Chorro, F. J., … Alberola, A. 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El presente trabajo estudia las modificaciones intrínsecas que el ejercicio físico produce en la respuesta cardíaca durante fibrilación ventricular (FV), tanto en condiciones de perfusión estable como cuando se produce isquemia en una zona del miocardio. Se estudiarán dichas modificaciones comparándolas con las producidas por el efecto de un fármaco (Glibenclamida) y con un grupo control. El análisis se realizará desde el punto de vista del dominio frecuencial, estudiando la homogeneidad espacial de la frecuencia dominante (ROIsaFD) y de la energía normalizada (ROIsaEN), en registros de cartografía cardíaca unipolar de corazón aislado de conejo. Se utilizarán tres grupos de conejos: control (GC: sin entrenamiento, N=18), entrenados (GE: N=9) y fármaco (GF: sin entrenamiento, con tratamiento, N=15). Se realizarán comparaciones intergrupos, teniendo en cuenta el hecho de que se realizan medidas repetidas en el tiempo, y se harán comparaciones intragrupos para estudiar el efecto del tiempo. Los resultados obtenidos sugieren que los efectos intrínsecos producidos por ejercicio físico sobre la homogeneidad espacial de la respuesta espectral de la FV son similares a los producidos por el tratamiento con Glibenclamida, especialmente cuando se tienen zonas isquémicas

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EL DESARROLLO DEL TURISMO EN EL PARQUE NATURAL DEL ALTO TAJO

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