Loading...
|
Please use this identifier to cite or link to this item:
http://ir.lib.ncu.edu.tw/handle/987654321/50851
|
| Title: | Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation |
| Authors: | Sung,RJ;Lo,CP;Hsiao,PY;Tien,HC |
| Contributors: | 生命科學系 |
| Keywords: | CARDIAC RYANODINE RECEPTOR;IN MOUSE MODEL;SARCOPLASMIC-RETICULUM;CELLULAR MECHANISM;TRIGGERED ACTIVITY;RELEASE CHANNELS;ARRHYTHMIAS;CALSEQUESTRIN;THERAPY;MICE |
| Date: | 2011 |
| Issue Date: | 2012-03-27 18:11:25 (UTC+8) |
| Publisher: | 國立中央大學 |
| Abstract: | 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 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 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,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 beta-adrenergic blockers for suppressing ventricular tachyarrhythmias during CPVT. |
| Relation: | AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY |
| Appears in Collections: | [Department of Life Science] journal & Dissertation
|
Files in This Item:
| File |
Description |
Size | Format | |
|---|
| index.html | | 0Kb | HTML | 675 | View/Open |
|
All items in NCUIR are protected by copyright, with all rights reserved.
|
