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.
This proposal seeks to understand why patients living with heart failure have a drastically increased risk of dying from sudden cardiac death and heart rhythm disorders. Heart failure causes many changes to the cells of the heart including remodeling of the ion channels and subcellular structural disruption. This study seeks to understand how these factors conspire to make heart failure patients so much more susceptible to dying from heart rhythm disorders or arrhythmias to devise future strategies for the prevention of sudden cardiac death.
| Song, Zhen; Liu, Michael B; Qu, Zhilin (2018) Transverse tubular network structures in the genesis of intracellular calcium alternans and triggered activity in cardiac cells. J Mol Cell Cardiol 114:288-299 |
| Ko, Christopher Y; Liu, Michael B; Song, Zhen et al. (2017) Multiscale Determinants of Delayed Afterdepolarization Amplitude in Cardiac Tissue. Biophys J 112:1949-1961 |
| Liu, Michael B; Ko, Christopher Y; Song, Zhen et al. (2016) A Dynamical Threshold for Cardiac Delayed Afterdepolarization-Mediated Triggered Activity. Biophys J 111:2523-2533 |
