Copyright © 2007, European Society of Cardiology
Calsequestrin mutation and catecholaminergic polymorphic ventricular tachycardia: A simulation study of cellular mechanism
aDepartment of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106-7207, United States
bCardiac Bioelectricity and Arrhythmia Center and Department of Biomedical Engineering, Washington University, St. Louis, MO 63130-4899, United States
* Corresponding author. Cardiac Bioelectricity and Arrhythmia Center, 290 Whitaker Hall, Campus Box 1097, One Brookings Drive, St. Louis, MO 63130-4899, United States. Tel.: +1 314 935 8160; fax: +1 314 935 8168. rudy{at}wustl.edu
Objectives Patients with a missense mutation of the calsequestrin 2 gene (CASQ2) are at risk for catecholaminergic polymorphic ventricular tachycardia. This mutation (CASQ2D307H) results in decreased ability of CASQ2 to bind Ca2+ in the sarcoplasmic reticulum (SR). In this theoretical study, we investigate a potential mechanism by which CASQ2D307H manifests its pro-arrhythmic consequences in patients.
Methods Using simulations in a model of the guinea pig ventricular myocyte, we investigate the mutation's effect on SR Ca2+ storage, the Ca2+ transient (CaT), and its indirect effect on ionic currents and membrane potential. We model the effects of isoproterenol (ISO) on CaV1.2 (the L-type Ca2+ current, ICa(L)) and other targets of β-adrenergic stimulation.
Results ISO increases ICa(L), prolonging action potential (AP) duration (Control: 172 ms, +ISO: 207 ms, at cycle length of 1500 ms) and increasing CaT (Control: 0.79 µM, +ISO: 1.61 µM). ISO increases ICa(L) by reducing the fraction of channels which undergo voltage-dependent inactivation and increasing transitions from a non-conducting to conducting mode of channel gating. CASQ2D307H reduces SR storage capacity, thereby reducing the magnitude of CaT (Control: 0.79 µM, CASQ2D307H: 0.52 µM, at cycle length of 1500 ms). The combined effect of CASQ2D307H and ISO elevates SR free Ca2+ at a rapid rate, leading to store-overload-induced Ca2+ release and delayed afterdepolarization (DAD). If resting membrane potential is sufficiently elevated, the Na+–Ca2+ exchange-driven DAD can trigger INa and ICa(L) activation, generating a triggered arrhythmogenic AP.
Conclusions The CASQ2D307H mutation manifests its pro-arrhythmic consequences due to store-overload-induced Ca2+ release and DAD formation due to excess free SR Ca2+ following rapid pacing and β-adrenergic stimulation.
KEYWORDS Arrhythmia (mechanisms); Ca-channel; Ion channels
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  J. W.M. Bassani and R. A. Bassani Sarcoplasmic reticulum Ca2+ release channel complex and automatism: A matter of fine tuning Cardiovasc Res, July 1, 2007; 75(1): 7 - 9. [Full Text] [PDF]
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