The relationship between alternans and arrhythmia was examined for the first time in genetically modified murine hearts modelling catecholaminergic polymorphic ventricular tachycardia (CPVT) (Goddard et al, 2008). Homozygous (RyR2s/s) RyR2-P2328S hearts were studied during Langendorff perfusion, both before and after treatment with epinephrine (100 nmol or 1 μmol) and propranolol (100 nmol). Monophasic action potential recordings obtained during regular, extrasystolic and dynamic pacing (Sabir et al, 2008a) protocols demonstrated incidences of arrhythmia in full agreement with clinical expectations (fig 1).
Thus arrhythmic waveforms were observed in a larger proportion of RyR2s/s hearts (67%, 4/6 hearts) than wild-type (WT) controls (27%, 4/15 hearts). The addition of epinephrine to solutions increased incidences of arrhythmia to 83% (5/6 hearts) at 100 nmol and and 100% (5/5 hearts) at 1 μmol and 58% (5/12 hearts), respectively. In contrast, treatment with propranolol decreased incidences of arrhythmia. Thus arrhythmic waveforms were observed in 20% (1/5) of WT hearts, whether in the presence or absence of epinephrine at either concentration. Under such conditions arrhythmia occurred in 20% (1/5) of RyR2s/s hearts before and 40% (2/5) after exposure to epinephrine at either concentration. Arrhythmogenicity in RyR2s/s hearts was found to be associated with alternans (fig 2).
This phenomenon was accentuated by treatment with epinephrine and prevented by treatment with propranolol, again in full agreement with clinical expectations. Data obtained during the application of dynamic pacing protocol (Sabir et al, 2008a; Sabir et al, 2008b) permitted the construction of restitution curves (Nolasco and Dahlen, 1968). Increases in the maximum gradients of such curves have previously been associated with alternans and arrhythmia in a broad range of situations, including murine models of other hereditary arrhythmic syndromes, namely the Brugada syndrome and the congenital long-QT syndrome type 3. In contrast to such findings, alternans occurring in association with arrhythmia in RyR2s/s hearts was not associated with changes in the properties of such curves (fitted by the function y = y0 + A(1 − e−x/τ), fit data summarised in ⇓tables 1 and 2).
We thus associate arrhythmogenicity in a murine genetic model of CPVT with alternans for the first time, and demonstrate its independence from alterations in the slopes of restitution curves.