Multiscale Modeling of Cardiac Calcium Dynamics;How Ryanodine Receptors can induce Arrhythmias Project Summary: Cardiac calcium (Ca) dynamics will be investigated to elucidate molecular and ionic mechanisms of delayed afterdepolarizations (DADs), early afterdepolarizations (EADs) due to spontaneous Ca releases from the sarcoplasmic reticulum (SR), triggered activities, and thus ventricular fibrillation (VF) t the tissue level to provide theoretical bases for novel therapeutic strategies. We recently showed how EADs due to reactivation of the L-type Ca current can result in large gradients of refractoriness in tissue, creating a substrate for reentry. EADs are also initiated by spontaneous Ca releases. DADs are normally initiated by spontaneous Ca releases. To understand how EADs and DADs are caused at the ryanodine receptor (RyR) level and induce triggered activities at the tissue level, we use computer simulation and mathematical analysis of physiologically detailed models of Ca cycling and the action potential (AP). In this study we consider five scales 1) single RyR 2) Ca release unit (multiple channels) 3) subcell (array of Ca release units) 4) whole cell 5) tissue. The first half of this research is to establish link betwee single RyR channel properties and subcellular Ca dynamics. Recently, Zima et al showed that Ca release from the SR can be via Ca spark or leak depending on SR Ca load. We will show how RyR channel opening and closing rates, which are regulated by cytosolic and luminal Ca, change the probability to form a Ca spark or leak. We also know Ca waves occur more often when the Ca is overloaded. We will investigate how a single spontaneous Ca spark recruits neighboring Ca release units to initiate a Ca wave, how clusters of Ca sparks propagate or terminate. The second half of this research is to establish the link between subcellular Ca dynamics and tissue AP dynamics. First, we will address how subcellular Ca waves interact with AP to induce DADs and EADs. Then we will address how DADs and EADs interact with tissue properties to induce a triggered activity. Key questions we will address are 1) what is the critica size of a group of cells of DADs or EADs to overcome electrotonic source-sink mismatch to become a triggered activity under different physiological conditions and tissue geometry. 2) how an EAD or DAD from a single cell can cause a group of cells to simultaneously generate EADs or DADs to exceed the critical size required for propagation. 3) how susceptibility of triggered activity in tissue can be estimated from the RyR properties.

Public Health Relevance

We will study molecular and ionic mechanisms of sudden cardiac death, which is the major cause of death in the United States, using large-scale computer simulations. Understanding of mechanisms of sudden cardiac death will provide novel insights for antiarrhythmic drug development and therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Career Transition Award (K99)
Project #
5K99HL111334-02
Application #
8534809
Study Section
Special Emphasis Panel (ZHL1-CSR-P (O2))
Program Officer
Carlson, Drew E
Project Start
2012-08-21
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$97,128
Indirect Cost
$5,935
Name
University of California Davis
Department
Pharmacology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Xie, Yuanfang; Grandi, Eleonora; Bers, Donald M et al. (2014) How does ?-adrenergic signalling affect the transitions from ventricular tachycardia to ventricular fibrillation? Europace 16:452-7
Sato, Daisuke; Bartos, Daniel C; Ginsburg, Kenneth S et al. (2014) Depolarization of cardiac membrane potential synchronizes calcium sparks and waves in tissue. Biophys J 107:1313-7
Xie, Yuanfang; Izu, Leighton T; Bers, Donald M et al. (2014) Arrhythmogenic transient dynamics in cardiac myocytes. Biophys J 106:1391-7
Xie, Yuanfang; Grandi, Eleonora; Puglisi, Jose L et al. (2013) *-adrenergic stimulation activates early afterdepolarizations transiently via kinetic mismatch of PKA targets. J Mol Cell Cardiol 58:153-61
Izu, Leighton T; Xie, Yuanfang; Sato, Daisuke et al. (2013) Caýýýýý waves in the heart. J Mol Cell Cardiol 58:118-24