Arrhythmogenic mechanisms in a mouse model of catecholaminergic polymorphic ventricular tachycardia

Marina Cerrone, Sami F. Noujaim, Elena G. Tolkacheva, Arkadzi Talkachou, Ryan O'Connell, Omer Berenfeld, Justus Anumonwo, Sandeep V. Pandit, Karen Vikstrom, Carlo Napolitano, Silvia G. Priori, José Jalife

Research output: Contribution to journalArticle

192 Citations (Scopus)

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 Ca 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) mouse model to investigate the arrhythmogenic mechanisms in catecholaminergic polymorphic VT. In isolated hearts, spontaneous ventricular arrhythmias occurred in 54% of 13 RyR2/RyR2 and in 9% of 11 wild-type (P=0.03) littermates perfused with Caand isoproterenol; 66% of 12 RyR2/RyR2 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 mice. Under current clamp, single Purkinje cells from RyR2/RyR2 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.

Original languageEnglish (US)
Pages (from-to)1039-1048
Number of pages10
JournalCirculation research
Volume101
Issue number10
DOIs
StatePublished - Nov 1 2007

Fingerprint

Ryanodine Receptor Calcium Release Channel
Ventricular Tachycardia
Cardiac Arrhythmias
Ventricular Fibrillation
Polymorphic catecholergic ventricular tachycardia
Epicardial Mapping
Purkinje Fibers
Bundle-Branch Block
Purkinje Cells
Caffeine
Isoproterenol
Constriction
Adrenergic Agents
Epinephrine

Keywords

  • Bidirectional ventricular tachycardia
  • CPVT
  • Ryanodine receptor
  • Sudden cardiac death
  • Transgenic mice

Cite this

Arrhythmogenic mechanisms in a mouse model of catecholaminergic polymorphic ventricular tachycardia. / Cerrone, Marina; Noujaim, Sami F.; Tolkacheva, Elena G.; Talkachou, Arkadzi; O'Connell, Ryan; Berenfeld, Omer; Anumonwo, Justus; Pandit, Sandeep V.; Vikstrom, Karen; Napolitano, Carlo; Priori, Silvia G.; Jalife, José.

In: Circulation research, Vol. 101, No. 10, 01.11.2007, p. 1039-1048.

Research output: Contribution to journalArticle

Cerrone, M, Noujaim, SF, Tolkacheva, EG, Talkachou, A, O'Connell, R, Berenfeld, O, Anumonwo, J, Pandit, SV, Vikstrom, K, Napolitano, C, Priori, SG & Jalife, J 2007, 'Arrhythmogenic mechanisms in a mouse model of catecholaminergic polymorphic ventricular tachycardia', Circulation research, vol. 101, no. 10, pp. 1039-1048. https://doi.org/10.1161/CIRCRESAHA.107.148064
Cerrone, Marina ; Noujaim, Sami F. ; Tolkacheva, Elena G. ; Talkachou, Arkadzi ; O'Connell, Ryan ; Berenfeld, Omer ; Anumonwo, Justus ; Pandit, Sandeep V. ; Vikstrom, Karen ; Napolitano, Carlo ; Priori, Silvia G. ; Jalife, José. / Arrhythmogenic mechanisms in a mouse model of catecholaminergic polymorphic ventricular tachycardia. In: Circulation research. 2007 ; Vol. 101, No. 10. pp. 1039-1048.
@article{c191575af4474e76a0bb168067382620,
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 Ca 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) mouse model to investigate the arrhythmogenic mechanisms in catecholaminergic polymorphic VT. In isolated hearts, spontaneous ventricular arrhythmias occurred in 54{\%} of 13 RyR2/RyR2 and in 9{\%} of 11 wild-type (P=0.03) littermates perfused with Caand isoproterenol; 66{\%} of 12 RyR2/RyR2 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 mice. Under current clamp, single Purkinje cells from RyR2/RyR2 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.",
keywords = "Bidirectional ventricular tachycardia, CPVT, Ryanodine receptor, Sudden cardiac death, Transgenic mice",
author = "Marina Cerrone and Noujaim, {Sami F.} and Tolkacheva, {Elena G.} and Arkadzi Talkachou and Ryan O'Connell and Omer Berenfeld and Justus Anumonwo and Pandit, {Sandeep V.} and Karen Vikstrom and Carlo Napolitano and Priori, {Silvia G.} and Jos{\'e} Jalife",
year = "2007",
month = "11",
day = "1",
doi = "10.1161/CIRCRESAHA.107.148064",
language = "English (US)",
volume = "101",
pages = "1039--1048",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "10",

}

TY - JOUR

T1 - Arrhythmogenic mechanisms in a mouse model of catecholaminergic polymorphic ventricular tachycardia

AU - Cerrone, Marina

AU - Noujaim, Sami F.

AU - Tolkacheva, Elena G.

AU - Talkachou, Arkadzi

AU - O'Connell, Ryan

AU - Berenfeld, Omer

AU - Anumonwo, Justus

AU - Pandit, Sandeep V.

AU - Vikstrom, Karen

AU - Napolitano, Carlo

AU - Priori, Silvia G.

AU - Jalife, José

PY - 2007/11/1

Y1 - 2007/11/1

N2 - 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 Ca 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) mouse model to investigate the arrhythmogenic mechanisms in catecholaminergic polymorphic VT. In isolated hearts, spontaneous ventricular arrhythmias occurred in 54% of 13 RyR2/RyR2 and in 9% of 11 wild-type (P=0.03) littermates perfused with Caand isoproterenol; 66% of 12 RyR2/RyR2 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 mice. Under current clamp, single Purkinje cells from RyR2/RyR2 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.

AB - 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 Ca 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) mouse model to investigate the arrhythmogenic mechanisms in catecholaminergic polymorphic VT. In isolated hearts, spontaneous ventricular arrhythmias occurred in 54% of 13 RyR2/RyR2 and in 9% of 11 wild-type (P=0.03) littermates perfused with Caand isoproterenol; 66% of 12 RyR2/RyR2 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 mice. Under current clamp, single Purkinje cells from RyR2/RyR2 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.

KW - Bidirectional ventricular tachycardia

KW - CPVT

KW - Ryanodine receptor

KW - Sudden cardiac death

KW - Transgenic mice

UR - http://www.scopus.com/inward/record.url?scp=36048938672&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36048938672&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.107.148064

DO - 10.1161/CIRCRESAHA.107.148064

M3 - Article

C2 - 17872467

AN - SCOPUS:36048938672

VL - 101

SP - 1039

EP - 1048

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 10

ER -