Triggered arrhythmias induced by heart failure remodeling: A multi-scale computational approach

University Of California Los Angeles, Los Angeles CA

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Abstract

? DESCRIPTION (provided by applicant): Sudden cardiac death in the form of lethal arrhythmias is a major cause of death in patients in heart failure (HF). However, it is still not wll understood how the individual ionic and structural changes of HF remodeling promote delayed after-depolarizations (DADs) in single myocytes which can lead to triggered arrhythmias in tissue. Arrhythmias are fundamentally a tissue and organ level phenomenon which necessitates a multi-scale approach to fully understand how subcellular changes can affect the heart's function as a whole. Computational modeling of calcium (Ca) dynamics has given us insight into how calcium sparks in the sarcoplasmic reticulum (SR) can give rise to DADs that can act as arrhythmogenic triggers. Despite these advances, current action potential models have either been too simple or too computationally intensive to both incorporate the effects of subcellular remodeling while still accurately representing arrhythmias in tissue. Our lab has developed complex spatial myocyte models incorporating the subcellular Ca release unit network that can simulate spontaneous Ca sparks and waves and thus DADs. The goal of this study is to determine the underlying mechanisms of DAD-mediated triggered arrhythmias in HF using models at the subcellular, cellular, and tissue scales. Specific Aim 1 will focus on how subcellular and cellular HF remodeling promotes DADs and triggered activity in single myocytes. Each individual HF remodeling change will be simulated in a systematic manner to isolate the key mechanisms that are globally influential for Ca spark synchronization and DAD formation. This will not only improve our understanding of DAD-genesis in HF, but also provide insight into DAD prevention strategies. Specific Aim 2 will focus on elucidating the mechanisms of DAD-mediated triggered arrhythmias in the remodeled tissue of HF. Myocyte and gap junctional remodeling can generate DADs that combine to form both arrhythmogenic triggers and substrates. Coupled myocytes incorporating the subcellular and cellular remodeling will be simulated in a cable to identify the effects of HF remodeling and voltage-Ca feedback on triggered activity initiation and propagation in tissue. These proposed studies will not only lead to improved understanding of arrhythmogenic mechanisms in HF, but also would provide ideal training in the multi-scale approaches required to understand complex biological systems.