Abstract
The relationship between alternans and arrhythmogenicity was studied in genetically modified murine hearts modeling catecholaminergic polymorphic ventricular tachycardia (CPVT) during Langendorff perfusion, before and after treatment with catecholamines and a β-adrenergic antagonist. Heterozygous (RyR2p/s) and homozygous (RyR2s/s) RyR2-P2328S hearts, and wild-type (WT) controls, were studied before and after treatment with epinephrine (100 nM and 1 μM) and propranolol (100 nM). Monophasic action potential recordings demonstrated significantly greater incidences of arrhythmia in RyR2p/s and RyR2s/s hearts as compared to WTs. Arrhythmogenicity in RyR2s/s hearts was associated with alternans, particularly at short baseline cycle lengths. Both phenomena were significantly accentuated by treatment with epinephrine and significantly diminished by treatment with propranolol, in full agreement with clinical expectations. These changes took place, however, despite an absence of changes in mean action potential durations, ventricular effective refractory periods or restitution curve characteristics. Furthermore pooled data from all hearts in which arrhythmia occurred demonstrated significantly greater alternans magnitudes, but similar restitution curve slopes, to hearts that did not demonstrate arrhythmia. These findings thus further validate the RyR2-P2328S murine heart as a model for human CPVT, confirming an alternans phenotype in common with murine genetic models of the Brugada syndrome and the congenital long-QT syndrome type 3. In contrast to these latter similarities, however, this report demonstrates the dissociation of alternans from changes in the properties of restitution curves for the first time in a murine model of a human arrhythmic syndrome.
Highlights
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a hereditary arrhythmic disorder characterized by ventricular tachyarrhythmias precipitated by exercise, stress or catecholamine infusion (Wehrens et al, 2003)
The present study extends correlations between alternans and arrhythmia (Weiss et al, 2006) to genetically modified hearts carrying the P2328S mutation and representing a true genetic model of CPVT (Goddard et al, 2008)
There were no significant differences in incidence of arrhythmia between groups treated with propranolol
Summary
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a hereditary arrhythmic disorder characterized by ventricular tachyarrhythmias precipitated by exercise, stress or catecholamine infusion (Wehrens et al, 2003). Such arrhythmias may potentially lead to ventricular fibrillation, resulting in syncope and sudden cardiac death (Priori et al, 2001). Six distinct RyR2 mutations, occurring in the absence of structural abnormalities, echocardiographic evidence of cardiac failure or QT prolongation, have been reported to result in CPVT (Laitinen et al, 2001; Priori et al, 2001). A hereditary P2328S mutation has been shown to alter
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
