Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation

Sung RJ, Lo CP, Hsiao PY, Tien HC. Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation. Am J Physiol Heart Circ Physiol 301: H1625-H1638, 2011. First published July 8, 2011; doi:10.1152/ajpheart.00696.2010.-Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant arrhythmogenic disorder linked to mutations in the cardiac ryanodine receptor (RyR2) and calsequestrin, predisposing the young to syncope and cardiac arrest. To define the role of beta-adrenergic stimulation (BAS) and to identify potential therapeutic targeted sites relating to intracellular calcium cycling, we used a Luo-Rudy dynamic ventricular myocyte model incorporated with interacting Markov models of the L-type Ca2+ channel (I-Ca,I-L) and RyR2 to simulate the heterozygous state of mouse RyR2 R4496C mutation (RyR2(R4496C+/-)) comparable with CPVT patients with RyR2 R4497C mutation. Characteristically, in simulated cells, pacing at 4 Hz or faster or pacing at 2 Hz under BAS with effects equivalent to those of isoproterenol at >= 0.1 mu M could readily induce delayed afterdepolarizations (DADs) and DAD-mediated triggered activity (TA) in RyR2(R4496C+/-) but not in the wild-type via enhancing both I-Ca,I-L and sarcoplasmic reticulum (SR) Ca2+ ATPase (I-UP). Moreover, with the use of steady state values of isolated endocardial (Endo), mid-myocardial (M), and epicardial (Epi) cells as initial data for conducting single cell and one-dimensional strand studies, the M cell was more vulnerable for developing DADs and DAD-mediated TA than Endo and Epi cells, and the gap junction coupling represented by diffusion coefficient (D) of <= 0.000766*98 cm(2)/ms was required for generating DAD-mediated TA in RyR2(R4496C+/-). Whereas individual reduction of Ca2+ release channel of SR and Na-Ca exchanger up to 50% was ineffective, 30% or more reduction of either I-Ca,I-L or I-UP could totally suppress the inducibility of arrhythmia under BAS. Of note, 15% reduction of both I-Ca,I-L and I-UP exerted a synergistic antiarrhythmic efficacy. Findings of this model study confirm that BAS facilitates induction of ventricular tachyarrhythmias via its action on intracellular Ca2+ cycling and a pharmacological regimen capable of reducing I-Ca,I-L could be an effective adjunctive to beta-adrenergic blockers for suppressing ventricular tachyarrhythmias during CPVT.