Dilated cardiomyopathy (DCM) is the most common form of primary cardiac muscle disease, with prevalence estimated at 36.5 cases per 100,000. DCM is characterized by ventricular dilation, decreased myocardial contractility and cardiac output, and increased risk of sudden cardiac death. Ventricular myocytes isolated from failing hearts exhibit changes in expression levels of proteins involved in repolarization of the action potential (AP) and intracellular calcium (Ca2+) cycling. These changes are accompanied by reduction of junctional sarcoplasmic reticulum (JSR) Ca2+ concentration, peak intracellular Ca2+ transient amplitude, slowed diastolic Ca2+ extrusion and prolongation of AP duration. We have previously formulated a """"""""minimal"""""""" computational model of the failing canine ventricular myocyte that incorporates experimental data on down-regulation of potassium (K+) currents and the SR Ca2+-ATPase, and up-regulation of the Na+-Ca2+ exchanger. This model is able to qualitatively reconstruct changes in AP and Ca2+ transient morphology observed in failing myocytes. Model simulations predict that down- regulation of the SR Ca2+-ATPase by itself produces significant prolongation of AP duration by reducing JSR Ca2+ level, JSR Ca2+ release and the magnitude of Ca2+-dependent inactivation of L-type Ca2+ current (ICa,L). This decreased Ca2+-dependent inactivation increases ICa,L during the plateau phase, thereby increasing AP duration. These model predictions are supported by results of preliminary experiments. This has led us to hypothesize that JSR Ca2+ level through effects on JSR Ca2+ release and Ca2+-dependent inactivation of ICa.L, modulates AP duration, and that this modulation is important under a range of conditions producing changes in JSR Ca2+ level, including heart failure. The general goal of the proposed research is to test this hypothesis by means of experiments coupled with computational modeling.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL060133-04A1
Application #
6471922
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Wang, Lan-Hsiang
Project Start
1998-05-01
Project End
2006-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
4
Fiscal Year
2002
Total Cost
$276,285
Indirect Cost
Name
Johns Hopkins University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Tanskanen, Antti J; Alvarez, Luis H R (2007) Voltage noise influences action potential duration in cardiac myocytes. Math Biosci 208:125-46
Tanskanen, Antti J; Greenstein, Joseph L; Chen, Alex et al. (2007) Protein geometry and placement in the cardiac dyad influence macroscopic properties of calcium-induced calcium release. Biophys J 92:3379-96
Greenstein, Joseph L; Hinch, Robert; Winslow, Raimond L (2006) Mechanisms of excitation-contraction coupling in an integrative model of the cardiac ventricular myocyte. Biophys J 90:77-91
Hinch, R; Greenstein, J L; Winslow, R L (2006) Multi-scale models of local control of calcium induced calcium release. Prog Biophys Mol Biol 90:136-50
Winslow, Raimond L; Tanskanen, Antti; Chen, Mindao et al. (2006) Multiscale modeling of calcium signaling in the cardiac dyad. Ann N Y Acad Sci 1080:362-75
Winslow, Raimond L; Cortassa, Sonia; Greenstein, Joseph L (2005) Using models of the myocyte for functional interpretation of cardiac proteomic data. J Physiol 563:73-81
Tanskanen, Antti J; Greenstein, Joseph L; O'Rourke, Brian et al. (2005) The role of stochastic and modal gating of cardiac L-type Ca2+ channels on early after-depolarizations. Biophys J 88:85-95
Iyer, Vivek; Mazhari, Reza; Winslow, Raimond L (2004) A computational model of the human left-ventricular epicardial myocyte. Biophys J 87:1507-25
Hinch, R; Greenstein, J L; Tanskanen, A J et al. (2004) A simplified local control model of calcium-induced calcium release in cardiac ventricular myocytes. Biophys J 87:3723-36
Greenstein, Joseph L; Tanskanen, Antti J; Winslow, Raimond L (2004) Modeling the actions of beta-adrenergic signaling on excitation--contraction coupling processes. Ann N Y Acad Sci 1015:16-27

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