抄録
Dysfunctions in the gating of ryanodine-receptors (RyR) and intracellular Ca2+ handling play critical roles to evoke lethal arrhythmias not only in inherited arrhythmgenic syndromes such as CPVT, but also in more common cases including heart failure. To develop a human ventricular action model which allows analyses of the effects of altered RyR properties on arrhythmogenesis, we incorporated a calcium release system with 4-state Markovian RyR gating (Stern, J.Gen.Physiol.1999) into a simplified human action potential model (TenTusscher, Am.J.Physiol.2004). Introduction of Ca concentration-dependence on RyR opening rate was a first step to model Ca-induced Ca-release. To obtain reasonable RyR gating in the control, it was necessary to add a new Ca compartment (cleft), where Ca concentration increased and decayed much faster than cytosolic Ca transient. Under these settings, augmented sensitivity of RyR on cleft Ca easily evoked spontaneous oscillatory Ca releases during the decay phase of Ca transient. Induction of DADs leading to triggered activity, however, could not be reproduced straightforwardly in spite of further inclusion of SR Ca-load dependence of RyR gating. Generation of triggered action potential after repolarization required additional manipulation of sarcolemmal current systems including a reduction of IK1, a situation found in patients with terminal heart failure. Our model provides basis to elucidate mechanisms of Ca-mediated arrhythmias, and further to find out RyR-targeted anti-arrhythmic therapy. [J Physiol Sci. 2006;56 Suppl:S126]
