Cardiac arrhythmias are responsible for more than 300,000 deaths per year in the US alone. Despite extensive research over many decades the underlying mechanisms for these arrhythmias are not completely understood. A common mechanism, believed to underlie a wide variety of arrhythmias, is the presence of ectopic focal excitations in the heart. These ectopic foci disrupt the normal sinus rhythm, and can produce triggered excitations which can lead to reentry and/or wave fractionation in the heart. Remarkably, it is not understood what determines the timing, location, and morphology of these focal excitations. Many experimental studies have shown that abnormal calcium cycling, at the single cell level, plays an essential role in the formation of these focal excitations. These studies are corroborated by gene based studies showing that specific mutations of Ca cycling proteins are found in hearts prone to ectopic activity and fibrillation. However, the detailed mechanisms linking subcellular Ca and focal excitations at the tissue and whole heart level is not known. In this project we propose to develop a multi-scale computational framework that can be used to describe the properties of Ca mediated ectopic foci.
Our aim i s to explore how abnormal Ca cycling at the subcellular level can summate over thousands of cells to form ectopic foci in tissue. Our computer models will shed light on the underlying mechanisms by bridging the gap between ion channels, cell electrophysiology, and tissue scale electrical activity.

Public Health Relevance

In this project we apply multi-scale mathematical modeling to understand the underlying mechanisms for ectopic focal excitations in the heart. Insight into these mechanisms will help cardiac researchers develop gene based, or pharmacological treatments, of a wide variety of cardiac arrhythmias.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Modeling and Analysis of Biological Systems Study Section (MABS)
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Larkin, Jennie E
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California State University Northridge
Schools of Arts and Sciences
United States
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Walton, Richard D; Martinez, Marine E; Bishop, Martin J et al. (2014) Influence of the Purkinje-muscle junction on transmural repolarization heterogeneity. Cardiovasc Res 103:629-40
Behradfar, Elham; Nygren, Anders; Vigmond, Edward J (2014) The role of Purkinje-myocardial coupling during ventricular arrhythmia: a modeling study. PLoS One 9:e88000
Bishop, Martin J; Vigmond, Edward J; Plank, Gernot (2013) The functional role of electrophysiological heterogeneity in the rabbit ventricle during rapid pacing and arrhythmias. Am J Physiol Heart Circ Physiol 304:H1240-52
Boyle, Patrick M; Masse, Stephane; Nanthakumar, Kumaraswamy et al. (2013) Transmural IK(ATP) heterogeneity as a determinant of activation rate gradient during early ventricular fibrillation: mechanistic insights from rabbit ventricular models. Heart Rhythm 10:1710-7
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Asfaw, Mesfin; Alvarez-Lacalle, Enric; Shiferaw, Yohannes (2013) The timing statistics of spontaneous calcium release in cardiac myocytes. PLoS One 8:e62967
Bishop, Martin J; Plank, Gernot; Vigmond, Edward (2012) Investigating the role of the coronary vasculature in the mechanisms of defibrillation. Circ Arrhythm Electrophysiol 5:210-9
Campos, Fernando O; Prassl, Anton J; Seemann, Gunnar et al. (2012) Influence of ischemic core muscle fibers on surface depolarization potentials in superfused cardiac tissue preparations: a simulation study. Med Biol Eng Comput 50:461-72
Asfaw, Mesfin; Shiferaw, Yohannes (2012) Exploring the dynamics of dimer crossing over a Kramers type potential. J Chem Phys 136:025101

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