Conflict of interest br Introduction Nifekalant hydrochlorid

Conflict of interest
Introduction Nifekalant hydrochloride was first approved by the Japanese Ministry of Health, Labour and Welfare in 1999 and is now used as a first-line antiarrhythmic drug for refractory ventricular tachyarrhythmias in the country [1]. Nifekalant is a class III antiarrhythmic agent; thus, it highly selectively blocks the IKr channel and increases the duration of the histone deacetylase inhibitors in myocardial cells, which prolongs the effective refractory period and exerts strong antiarrhythmic effects[2–4]. In recent clinical studies, nifekalant was reported to be safe [5] and effective for terminating arrhythmia attacks and preventing the recurrence of life-threatening refractory ventricular arrhythmia [6–8]. In addition, it suppressed the induction of ventricular tachycardia (VT) and ventricular fibrillation (VF) induced by programmed electrical stimulation [9,10]. Moreover, it improved the rate of return of spontaneous circulation in patients with shock-resistant in-hospital [11] or out-of-hospital cardiac arrest [12]).
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Potential conflicts of interests
Financial support
Acknowledgment
Introduction Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome. Mutations in 3 genes have been identified as causative factors for CPVT: RYR2, encoding the cardiac ryanodine receptor (RyR2); CASQ2, encoding cardiac calsequestrin; and KCNJ2, encoding the inward rectifier potassium channel [1–5]. CPVT is characterized by bi-directional and/or polymorphic ventricular tachycardias induced by adrenergic stress in the absence of structural heart disease and is associated with a high incidence of sudden cardiac death [6–8]. Within the vast therapeutic arsenal of antiarrhythmic agents, β-blockers have been proven to reduce ventricular arrhythmias and improve mortality rates in CPVT patients [1,6–9]. Although implantable cardioverter defibrillators (ICDs) are used to prevent sudden death [10], painful shocks can increase the sympathetic tonus and trigger further arrhythmias, eventually leading to a malignant cycle of ICD shocks and, ultimately, death in patients with CPVT [11,12]. From a clinical perspective, therefore, the development of additional therapies to suppress ventricular arrhythmias is highly desirable. Flecainide, a class I sodium channel blocker, has recently been reported to block the RyR2 channel and prevent CPVT episodes [13–15]. However, the difference between β-blockers and flecainide in terms of their respective therapeutic effects in preventing CPVT episodes is yet to be investigated in detail. In the present study, we examined the effectiveness of adding flecainide to β-blocker treatment in inhibiting exercise-induced arrhythmias in CPVT patients with RYR2 mutations.
Methods
Results
Discussion Because ventricular tachyarrhythmias are induced by adrenergic stress in patients with CPVT, anti-adrenergic therapy—primarily achieved by the use of β-blockers—has been widely used to suppress CPVT [6–9,16]. Unfortunately, the effect of β-blockers on suppressing recurrences of ventricular tachyarrhythmias is ultimately incomplete [7,8]. In the present study, β-blockers reduced the response in terms of heart rate to exercise and increased the exercise workload at the onset of ventricular arrhythmias, which could be attributed to the anti-adrenergic properties of the drug, but failed to increase heart rate at the onset of arrhythmias. In contrast, flecainide increased the heart rate at the onset of arrhythmias during exercise testing and suppressed ventricular arrhythmias even at higher heart rates, suggesting that this unique action may be crucial in the suppression of CPVT. Spontaneous Ca2+ release from the destabilized RyR2 complex in the sarcoplasmic reticulum triggered by adrenergic stress is the mechanism underlying CPVT [17–19], and thus, the suppression of spontaneous Ca2+ release could potentially be of therapeutic value for CPVT. Flecainide was recently shown to directly reduce the probability of RyR2 channels being open in the sarcoplasmic reticulum, thereby suppressing triggered beats [13,14]. The drug also decreases the activity of Na+/Ca2+-exchangers via inhibition of the Na+ channel, which in turn reduces intracellular Ca2+ overload and thereby the rate of triggered beats [13,14]. Furthermore, flecainide increases the inward rectifier K+ current generated by Kir2.1 channels by reducing their affinity for intracellular polyamines and stabilizes the resting membrane potential, resulting in the suppression of triggered activity [20]. These multiple effects of flecainide may explain the mechanism by which the drug effectively prevents ventricular arrhythmias even at higher sinus rates during exercise and thus increases the heart rate at the onset of ventricular arrhythmias.