title: Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation.
abstract: 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.
authors: Institute of Life Sciences, National Central Univ., 300 Jhongda Road, Jhongli, Taoyuan, Taiwan 320. rsung@cvmed.stanford.edu
authors: Ruey J
authors: RJ
authors: Sung
authors: Chu-Pin
authors: CP
authors: Lo
authors: Pi Yin
authors: PY
authors: Hsiao
authors: Hui-Chun
authors: HC
authors: Tien
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000465:Algorithms; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002395:Catecholamines / Q000502:physiology*; D004558:Electric Stimulation; D017629:Gap Junctions / Q000187:drug effects / Q000235:genetics; D006168:Guinea Pigs; D007473:Ion Channels / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D009154:Mutation / Q000502:physiology; D032383:Myocytes, Cardiac / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013045:Species Specificity; D017180:Tachycardia, Ventricular / Q000503:physiopathology*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D000318:Adrenergic beta-Agonists; D000889:Anti-Arrhythmia Agents; D002395:Catecholamines; D007473:Ion Channels; D019837:Ryanodine Receptor Calcium Release Channel; D000252:Calcium-Transporting ATPases; D002118:Calcium