Abstract 262: Identification Of Novel Therapeutic Targets For Catecholaminergic Polymorphic Ventricular Tachycardias In A Knock-in Mouse Model With Ryanodine Receptor Mutation R4496C.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a disease caused by mutations in the RYR2 gene encoding the cardiac ryanodine receptor and characterized by adrenergically mediated polymorphic VT. Triggered activity (TA) mediated delayed afterdepolarizations (DADs) are considered the arrhythmogenic mechanism of CPVT. Since DADs/TA develop during intracellular calcium overload and at fast heart rate we tested 4 compounds acting on targets that are critical for calcium homeostasis [L-type Ca++ Channel blocker Verapamil (VER); Na+-Ca++ exchanger blocker (NCX) SEA0400 (SEA); RyR2 blocker Tetracaine (TETR)]; or implicated in heart rate control Ivabradine (IVA). TA was induced in 67% ventricular myocytes (n=15) isolated from heterozygous (He) miceR4496C exposed to Caffeine (Caf, 300μmol/L) and Epinephrine (Epi, 200nmol/L) but in none of the wild type myocytes (n=12). 50μM TETR, 10μM SEA and 10μM VER completely abolished TA in myocytes from He-miceR4496C: lower dosages of all drugs failed to abolish TA. IVA 10μM did not prevent TA in paced myocytes from He-miceR4496C. Administration of Caf (120mg/kg) and Epi (2mg/kg) in vivo induced VT in 15/31 (48%) He-miceR4496C: occurrence of VT was unchanged by chronic (5 days intraperitoneal) administration of TETR and SEA. Conversely, VERA (40mg/kg/day) prevented VT. Interestingly IVA (5mg/kg/d) had a powerful protective effect (VT= 1/12, P<0.01 vs no drug). Results show in the table⇓. Our data show that:
targeting NCX or RYR2 with blocking drugs abolishes TA in vitro but is not effective in preventing arrhythmias in vivo.
Blockade of L-type calcium channels prevents TA in vitro and VT in vivo.
Lowering heart rate by blocking If current with IVA prevents arrhythmias in vivo; the lack of efficacy of IVA in paced myocytes support the view that its antiarrhythmic action is played by the reduction of rate.