Alpha blockade potentiates CPVT therapy in calsequestrin-mutant mice

BACKGROUND Spontaneous calcium release evoking delayed afterdepolarization is believed to cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a lethal human arrhythmia provoked by exercise or emotional stress. beta-Adrenergic Mockers are the drug of choice, but fail to achieve complete arrhythmia control in some patients. These individuals often require flecainide, device implantation, and/or sympathetic denervation. OBJECTIVE To optimize the arrhythmia therapy by pharmacological inhibition of the sympathetic nervous system in the homozygous calsequestrin knockout (CASQ2(Delta/Delta)) mouse model of CPVT2. METHODS A heart telemetry device was implanted for continuous electrocardiographic recording at rest and during provocation testing. Calcium transients and abnormal calcium release were studied in cardiomyocytes isolated from adult mice. Adrenergic receptor expression was determined by using Western blotting and confocal microscopy. RESULTS Adult CASQ2(Delta/Delta) mice suffer from complex ventricular arrhythmia at rest and ventricular tachycardia during treadmill exercise and after epinephrine injection. beta-Adrenergic Mockers, propranolol and metoprolol, attenuated arrhythmia at rest but not after stress. Reserpine had no efficacy in controlling arrhythmia. Agents with alpha-blocking activity, phentolamine or labetalol, abolished both exercise- and epinephrine-induced arrhythmia. In contrast, injection of alpha-adrenergic agonist phenylephrine reproducibly provoked ventricular tachycardia. Isolated cardiomyocytes from CASQ2(Delta/Delta) mice had delayed calcium release waves upon exposure to sympathetic agonists, which were abolished by phentolamine. Hearts of caLsequestrin-mutant mice expressed more alpha 1-adrenergic receptor than did wild type control mice (P < .05). CONCLUSION We identified a contribution of the alpha-adrenergic pathway to the pathogenesis of catecholamine-induced arrhythmia. alpha-Blockade emerges as an effective therapy in the murine model of CPVT2 and should be tried in humans resistant to beta-blockers.