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- W1994689996 abstract "Metabolic or oxidative stress can trigger the abrupt collapse or oscillation of mitochondrial membrane potential, which activates KATP current and alters the cardiac action potential. This mechanism can introduce both temporal and spatial dispersion of electrical excitability in the form of a “metabolic sink”, leading to heterogeneous conduction in the tissue, reentrant tachyarrhythmias, or fibrillation. To quantitatively study this mechanism, a 2D monodomain model of the myocardium (5×5cm2; 200 micron resolution) was developed, comprised of 63,000 nodes, each representing an integrated cellular model of cardiac excitation-contraction coupling, mitochondrial energetics, and ROS-induced ROS release (ECME-RIRR). Oxidative stress was initiated in a central circular zone of the tissue by increasing the fractional mitochondrial ROS production (shunt) during oxidative phosphorylation from 2% to 10%. Model simulations show that mitochondrial dynamics bifurcate during stimulation at 1 Hz and complete depolarization of αΨm ensues in the sink zone. Within the metabolic sink, sarcolemmal KATP currents increase, action potentials dramatically shorten, and the refractory period is abbreviated. These effects are enhanced by increasing the KATP density. In addition, fast and irregular electric activity (ventricular fibrillation) in the electrically paced tissue is observed when an S2 stimulus is introduced within or near the border of the metabolic sink, but only when the sink exceeds a critical size (r>0.4cm). Phase singularity analysis indicates that the fibrillatory activity is initiated at sites close the border zone. The results emphasize the power of integrating cellular electrophysiological, Ca2+ handling, and metabolic subsystems into a multiscale model to simulate emergent macroscopic phenomena in the heart. Moreover, the results provide a proof-of-concept of the metabolic sink hypothesis and a new tool to study its role in arrhythmogenesis and sudden cardiac death." @default.
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- W1994689996 date "2009-02-01" @default.
- W1994689996 modified "2023-10-16" @default.
- W1994689996 title "Effects Of Mitochondrial Depolarization On Cardiac Electrical Activity In An Integrated Multiscale Model Of The Myocardium" @default.
- W1994689996 doi "https://doi.org/10.1016/j.bpj.2008.12.3508" @default.
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