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EXPERIMENTAL STUDY

Triggers of ventricular tachyarrhythmias and therapeutic effects of nicorandil in canine models of LQT2 and LQT3 syndromes

Masaomi Chinushi, MD^*,*, Hidehiro Kasai, MD, Minoru Tagawa, MD, Takashi Washizuka, MD, Yukio Hosaka, MD, Yuko Chinushi, MD and Yoshifusa Aizawa, MD

^* School of Health Science,Niigata, Japan
First Department of Internal Medicine, Niigata University School of Medicine, Niigata, Japan

Manuscript received December 3, 2001; revised manuscript received March 19, 2002, accepted April 30, 2002.

^* Reprint requests and correspondence: Dr. Masaomi Chinushi, School of Health Science, Niigata University School of Medicine, 2-746 Asahimachi Niigata 951-8518, Japan.
masaomi{at}clg.niigata-u.ac.jp

OBJECTIVES: We sought to identify the triggers of ventricular tachyarrhythmia (VTA) in experimental models of long QT type 2 (LQT2) and long QT type 3 (LQT3) syndromes.

BACKGROUND: Most adverse cardiac events occurring in the long QT type 1 syndrome are related to sympathetic nerve activity. In contrast, various factors may trigger VTA in patients with LQT2 and LQT3.

METHODS: The mode of onset of VTA and therapeutic effects of the potassium-adenosine triphosphate channel opener nicorandil were compared in canine models of LQT2 and LQT3, using three induction protocols: 1) bradycardia produced by atrioventricular block (BRADY); 2) programmed ventricular stimulation; and 3) electrical stimulation of the left stellate ganglion (left stellate stimulation [LSS]). Transmural unipolar electrograms were recorded, and the activation-recovery interval (ARI) was measured.

RESULTS: Ventricular tachyarrhythmias developed during BRADY in all six experiments in the LQT3 model, but in none of the six experiments in LQT2. Programmed ventricular stimulation induced VTA in two experiments of the LQT2 model, but in none of the LQT3 experiments. Stimulation of the left stellate ganglion induced VTA in three experiments in LQT2 and in two experiments in LQT3. Nicorandil caused greater shortening of ARI and greater attenuation of transmural ARI dispersion in the LQT2 model than in the LQT3 model. After treatment with nicorandil, a single VTA was induced in the LQT2 model by LSS, whereas in the LQT3 model, VTA remained inducible by BRADY in four experiments and LSS in one experiment.

CONCLUSIONS: An abrupt increase in sympathetic activity appeared arrhythmogenic in both models. Nicorandil attenuated the heterogeneity of ventricular repolarization and suppressed the induction of VTA in the LQT2 model, but had a limited therapeutic effect in the LQT3 model.

Abbreviations and Acronyms   ARI   activation-recovery interval   BCL   basic cycle length   BRADY   bradycardia produced by atrioventricular block   K-ATP   potassium-adenosine triphosphate   LSS   left stellate (ganglion) stimulation   LQTS   long QT syndrome   LQT1   long QT type 1 syndrome   LQT2   long QT type 2 syndrome   LQT3   long QT type 3 syndrome   PVS   programmed ventricular stimulation   VTA   ventricular tachyarrhythmia