Introduction: Transgenic mice expressing a dominant negative form of the neuron-restrictive silencer factor (dnNRSF), which facilitates reactivation of fetal cardiac gene programs, show progressive dilated cardiomyopathy and sudden arrhythmic death. We have investigated mechanisms of lethal ventricular arrhythmias (VT/VFs) in this model.
Methods: Optical action potential signals were recorded from ventricles of Langendorff-perfued hearts of dnNRSF and wild-type mice.
Results: The action potential duration (APD) was prolonged and VT/VFs were initiated following early afterdepolarization (EAD)-mediated triggered activities in all (4/4) hearts of dnNRSF mice, while in none (0/4) of wild-type mice. A breakthrough-type focal activation was observed during the initial phase of VT/VFs, while interplay between focal discharges and reentrant activities was involved in the maintenance of sustained VT/VFs. Under constant pacing (n=3), APD was significantly prolonged (121±38% at 4 Hz, p<0.05) and conduction velocity was remarkably slowed (66±3%, p<0.05) in dnNRSF compared with wild-type mice.
Conclusions: EAD-type triggered activity induced by excessive APD prolongation and functional reentry associated with decreased conduction velocity may be responsible for the initiation and maintenance of VT/VF in failing hearts of dnNRSF mice.