The heart function requires a tight excitation-contraction-metabolism (ECM) coupling. Altering these processes and their interactions may cause cardiac diseases. In clinical settings, an aberration of one of these processes may not be symptomatic, but a combination of two or more may interact synergistically to trigger lethal events. For example, the propensity of a congenital heart failure or long QT patient to arrhythmias may be greatly increased under even moderate metabolic stress. However, the interactions between excitation, calcium (Ca) cycling, metabolism, and contraction are extremely complex, and the dynamics are spatiotemporal and irregular. To systematically explore the dynamics and the underlying mechanisms by experiments is costly and limited. This project aims to use a systems biological approach by combining multi-scale modeling with nonlinear dynamics and statistical physics, computer simulations, and ventricular myocyte experiments to study this complex problem. We first develop a spatially-distributed ECM coupling model that is a three- dimensional network of coupled Ca release units, mitochondria, and myofilaments, in which the L-type Ca channels, the ryanodine receptors, and the mitochondrial ion channels are modeled stochastically using Markov models. Models at different scales of complexity are also developed for mechanistic understanding and effective computation. We then use the ECM models to study the Ca cycling and action potential dynamics in ventricular myocytes under metabolic stresses. We hypothesize that metabolic stress, whose effects are extremely complex, may synergistically interact with other changes to cause Ca alternans and waves and oscillations, which can be unified by our theories of 3R's (Randomness, Recruitment, and Refractoriness) and self-organized criticality. We also investigate the effects of altered myofilament Ca sensitivity and cooperatively on Ca cycling dynamics. We hypothesize that these changes may cause Ca alternans and waves via the following scenarios: 1) altering Ca buffering to cause Ca alternans and waves via the 3R theory and criticality;2) altering Ca-myofilament binding kinetics to cause mechanical alternans, which in turn causes Ca alternans and waves. The later scenario establishes a mechanistic link between mechanical alternans and arrhythmias. The predictions from the models will be validated in ventricular myocyte experiments and the models will be further refined based the on the experimental information. The findings in this project will bring in a holistic understanding o ECM coupling in the development of cardiac diseases.
Cardiac excitation, contraction, metabolism are tightly coupled to perform normal cardiac functions, and failure of one or more of them can cause cell death and arrhythmias leading to sudden cardiac death, therefore, understanding their interactions and underlying mechanisms has major implications for the health care mission of the NIH/NHLBI and for society as a whole. To facilitate this understanding, this project will develop mathematical and computer models of excitation-contraction-metabolism coupling and to study how metabolic stress and contractile abnormalities lead to cardiac diseases. These insights may suggest novel therapies for prevention of arrhythmias and contractile dysfunction, the leading cause of death in the U.S.
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