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The Dynamical Emergence of Calcium-Mediated Arrhythmias from the Subcellular Calcium Release Unit Network

  • Author(s): Ko, Christopher Young
  • Advisor(s): Weiss, James N.
  • et al.
Abstract

Abnormal calcium (Ca) cycling conditions in cardiac myocytes have been identified as a major contributor to lethal cardiac arrhythmias that lead to sudden cardiac death. Under these conditions, Ca waves can emerge spontaneously from within the subcellular Ca release unit (CRU) network in Ca overloaded myocytes and facilitate the formation of delayed afterdepolarization (DAD) and early afterdepolarization (EAD) arrhythmia triggers at the cellular scale. Whether DADs and EADs can overcome the electronic sink effect of resting neighboring myocytes to propagate and disrupt the normal conduction of action potentials in cardiac tissue highly depends upon the timing and spatial organization of myocytes exhibiting spontaneous Ca waves. The exact mechanisms that govern these events are still under much debate and not fully understood. The goal of our studies in this body of work is two-fold. The first is to understand how a broad spectrum of spontaneous Ca release events, including Ca waves, are able to emerge collectively from within the CRU network. The second is to understand how the effects of subcellular Ca release events traverse scales to influence the morphology of DADs and EADs at the cellular scale and promote arrhythmias at the tissue scale. In order to achieve these ends, we have utilized a multidisciplinary approach that draws upon and integrates ideas, concepts, and techniques largely from experimental electrophysiology, nonlinear dynamics, and mathematical modeling. This approach has allowed tremendous versatility in the way arrhythmias can be conceptualized, quantitatively assessed, and logically predicted. As such, we have discovered a universal mechanism of criticality that governs the transition from stochastic Ca sparks to deterministic Ca waves, a general theory for Ca wave entrainment that can explain subcellular pacemaker site emergence, novel complex EAD morphologies that emerge due to the interaction between the stochastic effects of subcellular Ca release and the deterministic relationships among voltage-gated ion channels, that the distribution of latencies to the onset of Ca waves among myocytes is the most important factor promoting DADs in cardiac tissue, and that DADs and EADs can promote arrhythmias not only by generating triggers but by enhancing tissue substrate vulnerability.

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