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

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 301; no. 4; p. H1625
• Main Authors: Sung, Ruey J, Lo, Chu-Pin, Hsiao, Pi Yin, Tien, Hui-Chun
• Format: Journal Article
• Language: English
• Published: United States 01-10-2011
• Subjects: Adrenergic beta-Agonists - pharmacology; Algorithms; Animals; Anti-Arrhythmia Agents - pharmacology; Arrhythmias, Cardiac - chemically induced; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - physiopathology; Calcium - metabolism; Calcium-Transporting ATPases - metabolism; Catecholamines - physiology; Electric Stimulation; Gap Junctions - drug effects; Gap Junctions - genetics; Guinea Pigs; Ion Channels - physiology; Membrane Potentials - physiology; Mice; Mutation - physiology; Myocytes, Cardiac - physiology; Ryanodine Receptor Calcium Release Channel - genetics; Sarcoplasmic Reticulum - metabolism; Species Specificity; Tachycardia, Ventricular - physiopathology
• ISSN: 1522-1539
• 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 β-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 Ca(2+) channel (I(Ca,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 μM 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,L) and sarcoplasmic reticulum (SR) Ca(2+) 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 Ca(2+) release channel of SR and Na-Ca exchanger up to 50% was ineffective, 30% or more reduction of either I(Ca,L) or I(UP) could totally suppress the inducibility of arrhythmia under BAS. Of note, 15% reduction of both I(Ca,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 Ca(2+) cycling and a pharmacological regimen capable of reducing I(Ca,L) could be an effective adjunctive to β-adrenergic blockers for suppressing ventricular tachyarrhythmias during CPVT.