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Miquel Marchena defended his thesis directed by Dr. Blas Echebarria on July 23, 2020. Titled “Modeling pathological effects in intracellular calcium dynamics leading to atrial fibrillation”, the thesis presents a detailed computational model of atrial cell from which different pathological conditions that induce have been studied. atrial fibrillation.

Jul 23, 2020

Miquel Marchena defended his thesis directed by Dr. Blas Echebarria on July 23, 2020. Titled “Modeling pathological effects in intracellular calcium dynamics leading to atrial fibrillation”, the thesis presents a detailed computational model of atrial cell from which different pathological conditions that induce have been studied. atrial fibrillation.

The heartbeat occurs thanks to the synchronization of the contraction of the heart cells. Dysregulation in this mechanism can produce episodes of abnormal heart contraction. The source of these abnormalities is usually given at the subcellular level, where calcium is the most important ion that controls cell contraction. The regulation of calcium concentration is determined by rianodine receptors (RyR), the calcium channels that connect the cytosol and the sarcoplasmic reticulum. RyRs open and close randomly with a calcium-dependent probability. Local calcium release events are known as sparks and are due to the opening of one or more RyRs. Thus, it is crucial to have a deep understanding of both the spatio-temporal characteristics of calcium patterns and the role that RyRs play in understanding the transition between healthy and unhealthy cells.

The aim of the Thesis has been to understand the changes that occur at the subcellular level that, in advanced stages, induce the transition to Atrial Fibrillation (AF). In order to solve the problem, a mathematical subcellular model of atrial cells has been developed and validated that includes electro-physiological currents as well as fundamental subcellular structures. The high resolution of the model has made it possible to study the spatio-temporal characteristics of calcium in both stimulated cells and in equilibrium conditions. The simulations demonstrate the relevance of clustering RyRs into clusters that, in heterogeneous RyRs distributions, produce macro-sparks. These macro-sparks can produce ectopic contractions under pathological conditions. The incorporation of RyRs modulators into the model produces a non-uniform spatial distribution of sparks, as observed in cells with AF. In this sense, calsecuestrina (CSQ) is one of the fundamental buffers that modifies the dynamics of calcium. The absence of CSQ causes an increase in the frequency of sparks and, when there is an excess of calcium, also encourages the appearance of global calcium oscillations. Finally, the effect of the absence of membrane invaginations on the cytosol has also been characterized, as it is an effect observed in cells with AF and heart failure. However, this Thesis represents a breakthrough in understanding the mechanisms that produce AF with a computational model that, in the future, can be used to complement in vitro or in vivo studies, thus helping to find therapies for this disease.

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