Local control of calcium release and its implications for cardiac myocyte properties

The studies presented in this dissertation develop experimentally-based models of the canine ventricular myocyte and apply these models to better understand the role of the interaction between intracellular Ca2+ dynamics and membrane currents in determining AP configuration in both healthy and diseased states.; To help resolve the role of the transient outward current (I_to1 ) in modulating AP duration (APD), Markov state models of the human/canine Kv4.3- and Kv1.4-encoded currents are developed based on experimental measurements. A model of canine I_to1 is formulated as the combination of the Kv4.3 and Kv1.4 currents, and is incorporated into a canine ventricular myocyte model. Simulations demonstrate strong coupling between L-type Ca2+ current and I_Kv4.3, and predict a bimodal relationship between I_Kv4.3 density and APD, whereby perturbations in I _Kv4.3 density may produce either prolongation or shortening of APD depending on baseline I_to1 current level.; The canine ventricular myocyte model is reformulated to conform to local control theory, which asserts that L-type Ca2+ current tightly controls Ca2+ release from the sarcoplasmic reticulum (SR) via local interaction of closely apposed L-type Ca2+ channels (LCCs) and ryanodine receptors (RyRs). The model formulation incorporates details of microscopic excitation-contraction (EC) coupling properties in the form of Ca2+ release units (CaRUs) in which individual sarcolemmal LCCs interact in a stochastic manner with nearby RyRs. The CaRUs are embedded within and interact with the global systems of the myocyte. The model can reproduce both the detailed properties of EC coupling, such as variable gain and graded SR Ca2+ release, and whole-cell phenomena, such as modulation of AP duration by SR Ca2+ release.; The local control myocyte model is applied to the scenarios of β-adrenergic stimulation and heart failure. Incorporation of phosphorylation dependent effects on model membrane currents and Ca2+-cycling proteins yields altered AP configuration consistent with APs measured experimentally in the presence of β-adrenergic agonists. Moreover, discrete effects of β-adrenergic stimulation on LCCs and RyRs are correlated with specific changes in the voltage dependence of EC coupling gain which have been observed in experiments. Heart failure associated alterations in expression level of K+ membrane currents and Ca2+-handling proteins yield defective EC coupling and profound prolongation of model APD. Additional analyses suggest that SR Ca2+ load plays a more significant role in heart failure related AP prolongation than altered LCC availability and kinetics.