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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL101196-01
Application #
7846076
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Larkin, Jennie E
Project Start
2010-07-01
Project End
2014-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$331,535
Indirect Cost
Name
California State University Northridge
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
055752331
City
Northridge
State
CA
Country
United States
Zip Code
91330
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Shiferaw, Yohannes; Aistrup, Gary L; Wasserstrom, J Andrew (2017) Mechanism for Triggered Waves in Atrial Myocytes. Biophys J 113:656-670
Vigmond, Edward J; Stuyvers, Bruno D (2016) Modeling our understanding of the His-Purkinje system. Prog Biophys Mol Biol 120:179-88
Hernandez-Hernandez, Gonzalo; Alvarez-Lacalle, Enric; Shiferaw, Yohannes (2015) Role of connectivity and fluctuations in the nucleation of calcium waves in cardiac cells. Phys Rev E Stat Nonlin Soft Matter Phys 92:052715
Behradfar, Elham; Nygren, Anders; Vigmond, Edward J (2014) The role of Purkinje-myocardial coupling during ventricular arrhythmia: a modeling study. PLoS One 9:e88000
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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
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Boyle, Patrick M; Veenhuyzen, George D; Vigmond, Edward J (2013) Fusion during entrainment of orthodromic reciprocating tachycardia is enhanced for basal pacing sites but diminished when pacing near Purkinje system end points. Heart Rhythm 10:444-51
Asfaw, Mesfin; Alvarez-Lacalle, Enric; Shiferaw, Yohannes (2013) The timing statistics of spontaneous calcium release in cardiac myocytes. PLoS One 8:e62967

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