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Comparación De Las Corrientes Iónicas Implicadas En La Repolarización De

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Comparación De Las Corrientes Iónicas Implicadas En La Repolarización De UNIVERSIDAD COMPLUTENSE DE MADRID FACULTAD DE MEDICINA DEPARTAMENTO DE FARMACOLOGÍA COMPARACIÓN DE LAS CORRIENTES IÓNICAS IMPLICADAS EN LA REPOLARIZACIÓN DE LAS AURÍCULAS DERECHA E IZQUIERDA HUMANAS EN PACIENTES CON RITMO SINUSUAL Y CON FIBRILACIÓN AURICULAR TESIS DOCTORAL DE: MARTA GONZÁLEZ DE LA FUENTE BAJO LA DIRECCIÓN DE: JUAN TAMARGO MENÉNDEZ EVA DELPÓN MOSQUERA RICARDO CABALLERO COLLADO Madrid, 2013 ©Marta González de la Fuente, 2013 UNIVERSIDAD COMPLUTENSE DE MADRID FACULTAD DE MEDICINA DEPARTAMENTO DE FARMACOLOGÍA COMPARACIÓN DE LAS CORRIENTES IÓNICAS IMPLICADAS EN LA REPOLARIZACIÓN DE LAS AURÍCULAS DERECHA E IZQUIERDA HUMANAS EN PACIENTES EN RITMO SINUSAL Y CON FIBRILACIÓN AURICULAR TESIS DOCTORAL Marta González de la Fuente DIRECTORES Prof. Juan Tamargo Menéndez Prof. Eva Delpón Mosquera Prof. Ricardo Caballero Collado Madrid, 2013 A mis padres. A Jaime. A las miocitas. Esta Tesis es vuestra también. AGRADECIMIENTOS “Descifrar lo que está delante de nuestros ojos requiere una lucha constante”. Orwell Son muchas las personas a las que tengo que agradecer haber llegado hasta aquí. En primer lugar, a mis directores de Tesis, los profesores Juan Tamargo Menéndez, Eva Delpón Mosquera y Ricardo Caballero Collado. Al Profesor Juan Tamargo Menéndez, por acogerme en su grupo de investigación y por depositar su confianza en mí. Ha sido un honor poder trabajar en un equipo como éste. Y ha sido muy divertido compartir charlas y pitis contigo. Eres un gran maestro y una gran persona, Juan, muchas gracias por todo. A la Profesora Eva Delpón Mosquera, por enseñarme que el esfuerzo al final tiene su recompensa, por ser un ejemplo de constancia y dedicación al trabajo. Te deseo todo lo mejor, jefa. Gracias por confiar en mí durante estos tres años. Al Profesor Ricardo Caballero Collado, por todo lo que me ha enseñado. Aunque las “nuevas generaciones” no sepamos “compensar” y a veces “no echemos la fleca” cuando deberíamos, creo que has sido un estupendo maestro. Gracias. Sin duda, si a alguien debo estar agradecida es a mis compañeros de laboratorio. En primer lugar a mis miocitas, la Doctora Irene Amorós García y la casi-casi Doctora Adriana Barana Muñoz. Porque sin vuestro trabajo esto habría sido imposible, esta Tesis también es vuestra. Debería incluir un apartado en “Material y métodos” con las risas, las lágrimas, los pitis al sol, las cañas en el Hoces y las copas en el gallego, han sido totalmente necesarios. Porque he aprendido casi todo de vosotras, porque aunque a veces fuera un poco pesadita con mis preguntas, siempre habéis estado ahí para enseñar y ayudar a la becaria cigoto. Porque no sólo sois mis compañeras, también mis amigas. GRACIAS. Al Licenciado Pablo Dolz Gaitón, por todos los momentos compartidos. Porque entrar a la vez une, por haber sido mi hermano en esto, por los buenos momentos que hemos pasado dentro y fuera del labo, por tu comprensión. Gracias. A los dos, Adri y Pablo, muchísimo ánimo con vuestras tesis, ¡ya no os queda nada! Y a ti Ire, ahora que ya eres Doctora… ¡sólo me queda decirte que estoy segura de que vas a ser una mamá estupenda! A Sandra Sacristán García, pequeña crack de la disociación de miocitos. Por los buenos ratos juntas, porque siempre llenas de alegría el laboratorio. Por tu constancia y dedicación al trabajo. Ha sido un placer enseñarte lo poco que sé… Gracias a ti también. Al Doctor Ricardo Gómez García, porque siempre estaba ahí para arreglarme los desastres en mi equipo, porque durante el tiempo en el que hemos coincidido en el labo he aprendido muchísimo de él. Espero que todo vaya genial en tu nuevo grupo de investigación. A Paloma Vaquero, por tu ayuda con todos los papeleos y tus enseñanzas informáticas. Nunca dejas de sorprenderme. Por los buenos ratos que pasamos contigo y tus historias (la hora del café no es lo mismo cuando no estás tú), por preocuparte siempre de si estamos bien, por los guiños de cómplice. Gracias. A las nuevas incorporaciones del laboratorio, Martita, Marcos y Mercedes. Trabajad duro, seréis unos grandes “pinchauvas”, estoy segura. A Jaime. Porque sin ti nada de esto tendría sentido. Porque me ayudas tanto, por entenderlo todo, aunque no sepas nada de “pinchar”, de miocitos y de células “pochas”. Por saber tranquilizarme siempre, por tu paciencia, por ponerme los pies en el suelo cuando yo no sé cómo hacerlo, por ponerle siempre el punto positivo a las cosas cuando yo no lo encuentro. Porque tus abrazos me transmiten toda la paz que necesito. Por todo lo que comparto contigo. Por estar siempre cerca, a pesar de estar lejos. GRACIAS. Es tu Tesis también, no habría podido sin ti. A mi familia. Papá y mamá, gracias por permitirme llegar hasta aquí. Por vuestro apoyo siempre, aunque tenga mucho genio y sea un poquito insoportable a veces. Porque sois un ejemplo de trabajo y de constancia. Porque al final, todo lo que soy, lo he aprendido de vosotros. Por vuestro cariño y ayuda. GRACIAS. A mis hermanos, a Diego, por ser un ejemplo de superación, por todo el cariño con el que me tratas siempre. Te admiro mucho, hermano mayor. A Fran y a María, gracias por escucharme y comprenderme. No dejéis de aprender nunca. Fran, ánimo con tu Tesis, estoy segura de que aunque el camino sea complicado, tu pasión por la Historia te llevará muy lejos, digan lo que digan. Marieta, mi niña no-tan-pequeña ya, mucha suerte en tu nueva vida en Alemania. Ojalá encuentres tu sitio pronto. Serás una gran trabajadora social, lo sé. Que las circunstancias actuales no te cambien, pequeña. Aguanta fuerte. A mis amigos… A los de siempre, Pollo, Tita, Emma, Isa, Tou, Pili…Por mucho que pasen los años, siempre estáis ahí. A las niñas de la uni, Cris, Isa, Lau y Evo. Por los tiempos que pasamos, por ser el principio de todo esto. Porque la botica une, y a pesar de nuestras ocupadísimas vidas siempre hay un huequito para vosotras. Gracias por confiar siempre en mí. No sabéis todo lo que valoro un “yo sé que tú puedes” viniendo de vosotras. A los nuevos amigos, escuercitos y bolardetes… Todo es más fácil cuando se está rodeada de gente como vosotros. ¡Habéis sido tan importantes para mí en estos últimos tiempos! Gracias. A mi “familia madrileña”, cada vez más desperdigada, a la pequeña Carol, a Tichu, a Rous, a Lau, a Tere, a los niños. Estos 10 años en Madrid han sido increíbles. A mi compi estos últimos meses… Seño, las penas son menos penas con una botella de Apocalipsis y el cariño de una burgalesa con un extraño acento canario. A los Dres. Almendral, Atienza, Fernández-Avilés, Pinto y demás equipo de los servicios de Cardiología y de Cirugía Cardiovascular del Hospital General Universitario Gregorio Marañón, por proporcionarnos las muestras auriculares humanas utilizadas en esta Tesis Doctoral. A María Isabel Colado Megía y a Ignacio Lizasoaín Hernández, actual y antiguo director del Departamento, y, en general, a todo el Departamento de Farmacología de la Facultad de medicina de la Universidad Complutense de Madrid, por acogerme estos tres años. Al Instituto de Salud Carlos III y a Astra-Zeneca por financiar mi estancia durante este periodo pre-doctoral. ABSTRACT Abstract INTRODUCTION AND OBJECTIVES Atrial fibrilation (AF) is the most prevalent arrhythmia and the main risk factor associated with cerebrovascular events. Nowadays, pharmacological treatment of AF is clearly suboptimal, mainly due to rapid changes (4 to 6 hours after the onset) in the electrical properties of the atria (electrical remodelling) induced by the arrhythmia itself. This electrical remodelling promotes the maintenance and recurrence of AF, and it is characterized by a marked shortening of the atrial action potential (AP) duration (APD) and refractoriness as a consequence of changes in Ca2+ and K+ channel density. At least three different types of right atrial cells have been identified on the basis of their outward K+ repolarizing currents, and, consequently, on the morphology of their AP. This fact shows the existence of intra-atrial heterogeneities in the repolarizing currents in physiological conditions. However, up to date, all studies regarding electrical remodelling produced by AF, considered the myocytes of the right atrium (RA) electrically identical, and no data were provided on whether AF-induced electrical remodelling differentially affected diverse atrial cell types. Besides the intra-atrial differences, in humans, as in other species, several data point towards the existence of interatrial dissimilarities in the repolarizing currents. Refractary period is shorter in the left atrium (LA) than in the RA, and inward rectifier K+ currents are greater in the left than in the right atrial cells. Therefore, it could be possible that chronic AF- induced electrical remodelling could differentially affect voltage-dependent K+ currents in each atrium. However, studies comparing the voltage–dependent repolarizing currents in the human RA and LA, as well as data regarding how AF-induced electrical remodelling affects each atrium, are scarce or absent. It has been proposed that β-adrenergic stimulation has profound influence in the genesis and maintenance of AF. Moreover, previous data suggest that chronic AF is associated with 2+ an enhancement of β-adrenoceptor effects on the depolarizing Ca current (ICaL). However, up to date, the effects of β-adrenoceptor stimulation on atrial repolarizing currents, as well as the effects produced by β-adrenoceptor stimulation on the characteristics of the AP have not been compared yet in myocytes from the RA and LA obtained from patients in sinus rhythm (SR) and with chronic AF. Abstract Therefore, the objectives of the present Doctoral Thesis were: 1. To compare voltage-dependent K+ currents in enzymatically dissociated myocytes obtained from the right (RAA) and the left (LAA) atrial appendages of patients in SR.
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