Guillem Sanchis: Simulation of calcium release units in cardiomyocytes to study pulsus alternans

Title:

Simulation of  calcium release units in cardiomyocytes to study pulsus alternans

Abstract:

Cardiac alternans, characterized by a beat-to-beat alternation in the strength of the heart contraction, is a phenomenon that currently drives a very active body of research due to its link to life-threatening heart conditions such as arrhythmia and fibrillation. At the moment, the mechanism through which alternans arises is not well understood. It is known to be associated by an alternation in the levels of intracellular calcium, although it has also found to be related to an instability in the electrical propagation through the tissue; these two mechanisms have been observed both separately and together in several experimental setups. In particular, the role of RyR in alternans is a current topic of debate.

In cardiac cells, the contraction is driven by the release of Ca2+ ions from the sarcoplasmic reticulum. This happens across the cell in thousands of calcium release units, which are sets of coupled protein clusters that release calcium in response to a signal in the form of an action potential, through a positivefeedback mechanism known as calcium-induced calcium release.

The objective of this work is to implement a stochastic model of a calcium release unit to compute how the probability of a calcium spark to occur depends on a variety of biophysical parameters related with the dynamics of intracellular calcium and the stochastic configuration transitions of the protein channels. Then, the obtained probability functions are used in a simplified coupled return maps model of a cardiac cell to explore the parameter ranges that allow the appearance of calcium alternans. The fact that the homeostasis is simplified in this model allows for the study of the alternans as a consequence mainly of the behavior of local units.