Tesis doctoral de Cristina Espinosa Molina
Atrial fibrillation (af) is the more frequent arrhythmia. Af affects 0.4 per cent of the general population and its prevalence increases with age, affecting 4-5% of the people older than 65 years and 10% older than 75 years. This arrhythmia predisposes the thrombosis and is associated with phenomena embolism, development of heart failure and ventricular function deterioration. Af also generates physiological and anatomical modifications favoring its persistence: auricular dilation, myofibril fibrosis, shortening of the atrial refractory periods and the velocity of conduction. In addition, af degrades the quality of life of the patient and causes a sustained increase in public expenditure on health. At this moment, treatment of af includes the use of antiarrhythmics that reverse back to sinus rhythm and ablative procedures that involve many risks and complications as cardiac tamponade, pulmonary veins stenosis, atrium-esophageal fistulas, thrombus-embolisms, arrhythmias that are usually accompanied by antiarrhythmics drugs. Ironically these drugs can have long-term proarrhythmic effects; resulting in af manifesting in a large number of patients. Therefore, the main objective of this doctoral thesis is to expand the knowledge of the mechanisms leading to the induction and perpetuation of af. Specifically, this thesis is focused on the role of the pathological changes in intracellular calcium regulation that contribute to af development in human atrial myocytes. our laboratory has been the first to show an association of atrial fibrillation to increased spontaneous calcium release in atrial myocytes isolated from patients with atrial arrhythmias. Moreover, we have recently shown that the activation of adenosine a2a receptors (a2ar) stimulates spontaneous calcium release in human atrial myocytes, suggesting that the level of expression and/or the activity of these receptors might intervene in atrial arrhythmogenesis. The three experimental studies of this thesis are based on these findings. despite the technical and methodological difficulties that involve studies with human cardiomyocytes, all the investigation carried out in this thesis has been done with atrial human cardiomyocytes, in order to facilitate the translation of the results. Our studies have been based on electrophysiological techniques that allow analysis of the mechanisms that regulate the intracellular calcium on a quantitative basis, specifically using the patch-clamp technique and confocal calcium imaging. in summary, the results show that the control of the a2ars activity can control the spontaneous sr calcium release in human atrial cardiomyocytes. Specifically, the a2ar inhibition reduce the high sr calcium release incidence in patients with af to the basal levels observed in the myocytes of patients without af. Moreover, the sr calcium handling (along with ica) play a main role on the beat-to-beat response stabilization in human atrial myocytes submitted to high stimulation frequencies. According with this findings, the results show that the spontaneous calcium release modulation mediated by pka regulates the stability of the beat-to-beat response. Effectively, selective pka or a2ar inhibition eliminates the basal spontaneous calcium release and favors the uniform beat-to-beat response, while a2ar activation increase the spontaneous calcium release that favors non-uniform beat-to-beat responses. then together, the results of this thesis points to a2ar as a new molecular therapeutic target in af treatment.
Datos académicos de la tesis doctoral «Calcium homeostasis in human atrial cardiomyocytes: role of a2a receptors remodeling in atrial fibrillation.«
- Título de la tesis: Calcium homeostasis in human atrial cardiomyocytes: role of a2a receptors remodeling in atrial fibrillation.
- Autor: Cristina Espinosa Molina
- Universidad: Autónoma de barcelona
- Fecha de lectura de la tesis: 18/12/2009
Dirección y tribunal
- Director de la tesis
- Leif Madsen
- Tribunal
- Presidente del tribunal: cristina Prat vidal
- josep María Padro fernandez (vocal)
- (vocal)
- (vocal)