Molecular and Electrophysiological Bases of Catecholaminergic Polymorphic Ventricular Tachycardia

Uwais Mohamed, M.B.B.S., F.R.A.C.P.; Carlo Napolitano, M.D., Ph.D.; Silvia G. Priori, M.D., Ph.D.

Disclosures

J Cardiovasc Electrophysiol. 2007;18(7):791-797. 

In This Article

Arrhythmogenesis in CPVT: Lessons Learned from a CPVT Mouse Model

Given that CPVT morphology resembled the VT of digitalis toxicity, it had been suggested that arrhythmias in CPVT could be mediated by DADs and triggered activity. The functional characterization in vitro of the mutations identified in RYR2 and CASQ2 are compatible with the hypothesis that DADs could be the final common electrophysiological abnormality that precipitates arrhythmias in CPVT. However, the demonstration that adrenergic stimulation is able to induce DADs in cardiac myocytes that carry a CPVT-linked mutation required further experiments in vitro and in vivo.

Viatchenko-Caprinsky et al. and Terentiev et al. infected rat cardiac myocytes with adenoviruses engineered to express mutant CASQ2.[45,46] The authors performed microelectrode recordings and were able to demonstrate that upon adrenergic stimulation, DADs develop in myocytes expressing mutant CASQ2. This model provided for the first time the evidence that mutant CASQ2 increases susceptibility to DADs, yet has the limitation of studying cardiac cells that express both the mutant and the endogenous wild type calsequestrin. In this respect, the development of a knock-in mouse with mutant calsequestrin would be valuable.

The proof of concept that RyR2 mutations may lead to the development of DADs and triggered activity was made possible by the development of a knock in mouse model carrier of the R4496C mutations identified in CPVT patients. Cerrone et al.[47] demonstrated in vivo that this animal model responds to caffeine administration, developing polymorphic and bidirectional VT (Fig. 4A) that closely mimics the clinical presentation of CPVT. Therefore, this knock-in mouse model could become extremely useful to investigate RyR2-related arrhythmogenesis and the pathophysiology of CPVT. Using this model, Liu et al.[48] demonstrated that DADs promptly develop upon exposure to beta adrenergic stimulation in cardiac myocytes isolated from the heart of knock in mice (Fig. 4C), but not in myocytes isolated from wild type mice (Fig. 4B). Liu et al. also demonstrated that DADs of small amplitude are already present in unstimulated RyR2 R4496C myocytes (Fig. 4C), thus confirming the observation by Jiang et al.[39] that the mutant RyR2 presents enhanced resting activity and increased single channel open probability leading to Ca2+ overload. The development of DADs and triggered activity in the absence of beta-adrenergic stimulation suggests that a preexisting abnormality of the mutant ryanodine is present and is further accentuated by beta-adrenergic stimulation. Similar data were also reported by Kannakeril et al. in a knock-in mouse model of CPVT carrier of the R176Q mutation that showed the same phenotype described in our R4496C model.[49]

Arrhythmias in the CPVT knock-in mouse model. Panel A: bidirectional ventricular tachycardia developing in RyR2 R4496C ± mouse upon exposure to caffeine and epinephrine. Lower panels depict action potentials recorded in isolated cardiac myocytes from wild type mice (panel B) and RyR2 R4496C ± knock-in mice (panel C) at baseline and during superfusion with isoproterenol. Arrows indicate paced beats. Delayed after-depolarizations are present in unstimulated condition in mutant myocytes (panel C upper trace) and triggered activity develops during adrenergic stimulation (panel C lower trace). On the contrary, only small- and long-coupled DADs develop in wild type myocyte (panel B lower trace).

The demonstration that DADs are the initiating mechanism for arrhythmogenesis in CPVT provides a two-fold rational for the use of beta blockers for the treatment of CPVT. Antiadrenergic therapy is a logical therapy to attenuate the effect of adrenergic stimulation induced by exercise of emotion. In addition to this effect, the bradycardia induced by beta blockers is likely to exert an additional antiarrhythmic action by reducing the probability for a DAD to reach the threshold for triggering premature beats.[50] Accordingly, the evidence that DADs-mediated arrhythmias are more severe at faster heart rates provides the clinician with an accessible end point to define the right dose of beta blockers in CPVT patients: the lower the heart rate achieved, the higher the probability of preventing malignant arrhythmias.

Liu et al.[48] used the knock in mouse model to test the hypothesis discussed previously in this review, that pharmacological facilitation of FKBP12.6 binding to RyR2 is able to prevent polymorphic VT and bidirectional VT. Unfortunately, when Liu et al. used compound K201 that enhances FKBP12.6 and RYR2 interaction, they showed that K201 neither abolished nor prevented DADs and triggered activity, and it was unable to prevent the bidirectional VT induced by caffeine and epinephrine in RyR2 R4496C ± mice.[48] This observation makes unlikely the hypothesis the modulation of the interaction of the two proteins may be an innovative therapeutic strategy for CPVT patients.

The availability of an animal model now provides a tool to assess different strategies to prevent the development of ventricular tachyarrhythmias in CPVT.

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