A computational model of the human left-ventricular epicardial myocyte is presented. Models of each of the major ionic currents present in these cells are formulated and validated using experimental data obtained from studies of recombinant human ion channels and/or whole-cell recording from single myocytes isolated from human left-ventricular subepicardium. Continuous-time Markov chain models for the gating of the fast Na(+) current, transient outward current, rapid component of the delayed rectifier current, and the L-type calcium current are modified to represent human data at physiological temperature. A new model for the gating of the slow component of the delayed rectifier current is formulated and validated against experimental data. Properties of calcium handling and exchanger currents are altered to appropriately represent the dynamics of intracellular ion concentrations. The model is able to both reproduce and predict a wide range of behaviors observed experimentally including action potential morphology, ionic currents, intracellular calcium transients, frequency dependence of action-potential duration, Ca(2+)-frequency relations, and extrasystolic restitution/post-extrasystolic potentiation. The model therefore serves as a useful tool for investigating mechanisms of arrhythmia and consequences of drug-channel interactions in the human left-ventricular myocyte.
Abstract-The cardiac delayed rectifier potassium current mediates repolarization of the action potential and underlies the QT interval of the ECG. Mutations in either of the two molecular components of the rapid delayed rectifier (I K,r ), HERG and KCNE2, have been linked to heritable or acquired long-QT syndrome. Mechanisms whereby mutations of KCNE2 produce fatal cardiac arrhythmias characteristic of long-QT syndrome remain unclear. In this study, we characterize functional interactions between HERG and KCNE2 with a view to defining underlying mechanisms for action potential prolongation and long-QT syndrome. Whereas coexpression of hKCNE2 with HERG alters both kinetics and density of ionic current, incorporation of these effects into a quantitative model of the action potential predicts that only changes in current density significantly affect repolarization. Thus, the primary functional consequence of hKCNE2 on action potential morphology is through modulation of I K,r density, as predicted by the model. Mutations associated with long-QT syndrome that result only in modest changes of gating kinetics may be epiphenomena or may modulate action potential repolarization via interaction with alternative pore-forming potassium channel ␣ subunits. Key Words: delayed rectifier potassium channels Ⅲ Markov chains Ⅲ action potential Ⅲ arrhythmia Ⅲ accessory proteins I t has been shown that human ether-à-go-go-related gene (HERG) 1,2 encodes the pore-forming subunit of the rapid delayed rectifier potassium channel (I K,r ). 1,3 Abbott et al 4 recently showed that channels formed by coexpression of KCNE2 (encoding minK-related peptide 1, MiRP1) and the pore-forming subunit HERG resemble native cardiac I K,r channels more closely in their gating and unitary conductance, modulation by extracellular potassium, and inhibition by class III antiarrhythmic medications (eg, E-4031). 4 More importantly, they identified mutations in hKCNE2 (eg, Q9E and M54T) that were associated with acquired long-QT syndrome and ventricular fibrillation. Various mutations in HERG have also been linked with the familial form of long-QT syndrome. 5,6 Therefore, whereas lesions in either of the two molecular components of I K,r , HERG and hKCNE2, have been linked to heritable or acquired long-QT syndrome, mechanisms whereby genetic lesions of hKCNE2 produce fatal cardiac arrhythmias remain unclear. Mutant hKCNE2, when coexpressed with HERG, can result in alterations of both current density and kinetics or of kinetics alone. 4 This raises the question of whether altered current density or channel kinetics contributes more significantly to action potential prolongation and arrhythmia in patients with these genetic lesions. Better understanding of functional interactions between these two gene products could facilitate development of superior therapeutic approaches for particular lesions in either HERG or hKCNE2.Our first objective, therefore, is to characterize the functional effects of hKCNE2 coexpression with HERG. Because ion channel gating models ...
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