In silico study of calcium handling in the human failing heart
- Autores: Mª Teresa Mora Fenoll
- Directores de la Tesis: Beatriz Ana Trenor Gomis (dir. tes.), José María Ferrero de Loma-Osorio (dir. tes.)
- Lectura: En la Universitat Politècnica de València ( España ) en 2020
- Idioma: español
- Tribunal Calificador de la Tesis: Esther Pueyo Paules (presid.), M.S. Guillem (secret.), Stefano Severi (voc.)
- Programa de doctorado: Programa de Doctorado en Tecnologías para la Salud y el Bienestar por la Universitat Politècnica de València
- Materias:
- Enlaces
- Tesis en acceso abierto en: RiuNet
- Resumen
Heart failure, a cardiomyopathy that produces mechanical dysfunction and sudden cardiac death following fatal arrhythmias, is one of the main causes of mortality worldwide that also causes elevated morbidity rates. Current clinical therapies are challenged by the complexity of this cardiac pathology, in which many factors are involved in the electrical instabilities that lead to an altered function. The electrical activity of the heart comprises a wide range of spatial and temporal scales. Ion transport across transmembrane proteins initiate the cellular depolarization that is propagated cell to cell through the myocardium depolarizing and then repolarizing the entire heart in an orchestrated manner. The electrical excitation of cardiomyocytes triggers the cellular contraction, a process in which Ca2+ ions are the main mediators. Ca2+ dynamics plays a relevant role in controlling excitation-contraction coupling and consequently, investigations have focused on Ca2+-handling proteins and the regulation of Ca2+ homeostasis to elucidate the causes of impaired contractility and pro-arrhythmic conditions in cardiac diseases.
This thesis takes advantage of the existence of mathematical models with detailed representation of the subcellular processes to perform computational simulations of cardiac electrophysiology and understand the altered mechanisms that govern heart failure, especially those related with intracellular Ca2+ cycling.
It is known that failing myocytes undergo a specific remodeling of ion channels and Ca2+-handling proteins that lead to an impaired excitation-contraction coupling. Initially, it was analyzed, in the human action potential model of ventricular myocytes selected for the whole study, the effects of modulating ionic mechanisms on the electrical activity and Ca2+ dynamics. In tissue, heart failure induces additional changes affecting cellular coupling. The development of fibroblasts and impact on myocyte electrophysiology was investigated, including the vulnerability to generate alternans, a common precursor to arrhythmogenesis. Finally, the beta-adrenergic signaling model was integrated with the action potential model because of the electrophysiological modulation exerted by the sympathetic nervous system, which is aggravated under heart failure conditions.
Results highlighted the need of studying heart failure therapies on failing cells because of the different response of ion channels and membrane proteins to drugs. Functional Ca2+ proteins were important to maintain Ca2+ homeostasis and to avoid malignant electrical consequences, being SERCA pump the most critical factor. Apart from the electrophysiological remodeling, fibroblast interaction contributed to alter Ca2+ dynamics in myocytes and, when analyzing Ca2+ alternans, spatial electrical discordances predominated in failing tissues. The inclusion of beta-adrenergic stimulation showed that the inotropic response was diminished in heart failure as well as the antiarrhythmic benefits provided by catecholamines in the normal heart.
These findings contribute to gain insight into the pathophysiology of heart failure and the development of new pharmacological agents targeted to restore Ca2+ dynamics. The control of intracellular Ca2+ cycling is crucial to ensure both the mechanical force and the electrical activity that lead to a rhythmic contraction of the heart.
