Calsequestrin mutation and catecholaminergic polymorphic ventricular tachycardia: a simulation study of cellular mechanism.
OBJECTIVE
Patients with a missense mutation of the calsequestrin 2 gene (CASQ2) are at risk for catecholaminergic polymorphic ventricular tachycardia. This mutation (CASQ2(D307H)) 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 CASQ2(D307H) 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 Ca(V)1.2 (the L-type Ca2+ current, I(Ca(L))) and other targets of beta-adrenergic stimulation.


RESULTS
ISO increases I(Ca(L)), prolonging action potential (AP) duration (Control: 172 ms, +ISO: 207 ms, at cycle length of 1500 ms) and increasing CaT (Control: 0.79 microM, +ISO: 1.61 microM). ISO increases I(Ca(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. CASQ2(D307H) reduces SR storage capacity, thereby reducing the magnitude of CaT (Control: 0.79 microM, CASQ2(D307H): 0.52 microM, at cycle length of 1500 ms). The combined effect of CASQ2(D307H) 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 I(Na) and I(Ca(L)) activation, generating a triggered arrhythmogenic AP.


CONCLUSIONS
The CASQ2(D307H) 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 beta-adrenergic stimulation.
Faber
Gregory M
GM
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106-7207, USA.
Rudy
Yoram
Y
D000200:Action Potentials / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002155:Calsequestrin / Q000235:genetics* / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D006168:Guinea Pigs; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D023421:Models, Animal; D020125:Mutation, Missense; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D020746:Calcium Channels, L-Type; D002155:Calsequestrin; D007545:Isoproterenol; D002118:Calcium