CCBM: NHLBI SCOR

Project 1: Experimentally validated computational models of molecularly-defined K channels I to1 ; I Kr ; I Ks ; and I K1 will be developed. They will be incorporated into models of single canine and human normal and HF myocytes, and the role of each current on integrative properties of the action potential, such as AP duration and morphology, will be quantified. Modeling results will be used to aid in interpreting data from experiments on isolated cells in which Kv4, HERG, KvLQT1/minK, and Kir2 gene products are overexpressed or suppressed. The possible benefits of somatic gene transfer as a method of correcting cardiac repolarization abnormalities will be investigated by studying the ways in which the degree of electrotonic coupling, expression or suppression levels and rates (defined as the percentage of cells in which expression or suppression is achieved) interact to determine AP recovery properties in two- and three-dimensional tissue models.

Project 2: Aim 1 of Project 2 will further characterize properties of voltage-dependent L-type Ca channel inactivation. This voltage-dependence will be incorporated into the Ca 2+ channel, and single canine cell model. Aim 5 of Project 2 will establish a functional profile of L-type Ca 2+ channel properties in human and canine HF. Any intrinsic changes in channel gating revealed in the course of these studies (for example, voltage-dependent inactivation, calcium inactivation, or altered open probability) will be incorporated into single canine and human normal and HF myocyte models, and effects of altered L-type Ca 2+ current properties on AP morphology and duration, and Ca 2+ transients will be investigated.

Project 3: Experimental data on frequency dependent SR Ca 2+ loading will be used to refine the existing model of Ca 2+ cyclingHF canine myocytes. The hypothesis that SR Ca 2+ load controls AP duration via changes in the magnitude of Ca 2+ -mediated inactivation of the Ca 2+ current will be tested in a combined experimental and modeling study. Models of Ca 2+ regulation of I K conductance will be developed, and possible modulatory effects on AP duration will be analyzed. An experimentally validated model of Na-Ca exchange will be developed, and its role in AP morphology analyzed. Data on spatial variation of K current, SERCA2, and NCX density throughout normal and HF myocardium will be used to formulate computational models of endocardial, midmyocardial, and epicardial cells, and will be incorporated into the 3D heart model. The hypothesis that action potential duration variability (APDV) observed in isolated failing cells is produced by beat-to-beat fluctuations in SR Ca 2+ load, and therefore beat-to-beat fluctuation of L-type Ca 2+ current inactivation, will be tested in combined experimental and modeling studies. The hypothesis that regional APDV within the myocardium produces QT interval variability (QTV) observed at the whole heart and ECG level will be investigated by varying the mass of tissue within which there is APDV in the 3D model, and calculating the resulting variability in the simulated QT interval. Influence of region size and electrotonic coupling on model QTV will be simulated.

Project 4: An objective of Modeling Core E is to develop an experimentally validated model of the human HF myocyte, and if data availability permits, the normal HF mycocyte. Particpants in Modeling Core E will work with each of the Project researchers, as well as members of Human Cell Core C, to achieve this goal.

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