title: Arrhythmogenic mechanisms in a mouse model of catecholaminergic polymorphic ventricular tachycardia.
abstract: Catecholaminergic polymorphic ventricular tachycardia (VT) is a lethal familial disease characterized by bidirectional VT, polymorphic VT, and ventricular fibrillation. Catecholaminergic polymorphic VT is caused by enhanced Ca2+ release through defective ryanodine receptor (RyR2) channels. We used epicardial and endocardial optical mapping, chemical subendocardial ablation with Lugol's solution, and patch clamping in a knockin (RyR2/RyR2(R4496C)) mouse model to investigate the arrhythmogenic mechanisms in catecholaminergic polymorphic VT. In isolated hearts, spontaneous ventricular arrhythmias occurred in 54% of 13 RyR2/RyR2(R4496C) and in 9% of 11 wild-type (P=0.03) littermates perfused with Ca2+and isoproterenol; 66% of 12 RyR2/RyR2(R4496C) and 20% of 10 wild-type hearts perfused with caffeine and epinephrine showed arrhythmias (P=0.04). Epicardial mapping showed that monomorphic VT, bidirectional VT, and polymorphic VT manifested as concentric epicardial breakthrough patterns, suggesting a focal origin in the His-Purkinje networks of either or both ventricles. Monomorphic VT was clearly unifocal, whereas bidirectional VT was bifocal. Polymorphic VT was initially multifocal but eventually became reentrant and degenerated into ventricular fibrillation. Endocardial mapping confirmed the Purkinje fiber origin of the focal arrhythmias. Chemical ablation of the right ventricular endocardial cavity with Lugol's solution induced complete right bundle branch block and converted the bidirectional VT into monomorphic VT in 4 anesthetized RyR2/RyR2(R4496C) mice. Under current clamp, single Purkinje cells from RyR2/RyR2(R4496C) mouse hearts generated delayed afterdepolarization-induced triggered activity at lower frequencies and level of adrenergic stimulation than wild-type. Overall, the data demonstrate that the His-Purkinje system is an important source of focal arrhythmias in catecholaminergic polymorphic VT.
authors.affiliation: Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Cerrone
authors.forename: Sami F
authors.initials: SF
authors.lastname: Noujaim
authors.forename: Elena G
authors.initials: EG
authors.lastname: Tolkacheva
authors.forename: Arkadzi
authors.initials: A
authors.lastname: Talkachou
authors.forename: Ryan
authors.initials: R
authors.lastname: O'Connell
authors.forename: Omer
authors.initials: O
authors.lastname: Berenfeld
authors.forename: Justus
authors.initials: J
authors.lastname: Anumonwo
authors.forename: Sandeep V
authors.initials: SV
authors.lastname: Pandit
authors.forename: Karen
authors.initials: K
authors.lastname: Vikstrom
authors.forename: Carlo
authors.initials: C
authors.lastname: Napolitano
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
authors.forename: José
authors.initials: J
authors.lastname: Jalife
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002036:Bundle of His / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002395:Catecholamines / Q000502:physiology; D016757:Death, Sudden, Cardiac; D004195:Disease Models, Animal; D004699:Endocardium / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018408:Patch-Clamp Techniques; D011690:Purkinje Fibers / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology*
chemical_list: D002395:Catecholamines; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium