T-type calcium current contributes to escape automaticity and governs the occurrence of lethal arrhythmias after atrioventricular block in mice.

Abstract

BACKGROUND:

When complete atrioventricular block (AVB) occurs, infranodal escape rhythms are essential to prevent bradycardic death. The role of T-type Ca(2+) channels in pacemaking outside the sinus node is unknown. We investigated the role of T-type Ca(2+) channels in escape rhythms and bradycardia-related ventricular tachyarrhythmias after AVB in mice.

METHODS AND RESULTS:

Adult male mice lacking the main T-type Ca(2+) channel subunit Cav3.1 (Cav3.1(-/-)) and wild-type (WT) controls implanted with ECG telemetry devices underwent radiofrequency atrioventricular node ablation to produce AVB. Before ablation, Cav3.1(-/-) mice showed sinus bradycardia (mean±SEM; RR intervals, 148±3 versus 128±2 ms WT; P<0.001). Immediately after AVB, Cav3.1(-/-) mice had slower escape rhythms (RR intervals, 650±75 versus 402±26 ms in WT; P<0.01) but a preserved heart-rate response to isoproterenol. Over the next 24 hours, mortality was markedly greater in Cav3.1(-/-) mice (19/31; 61%) versus WT (8/26; 31%; P<0.05), and Torsades de Pointes occurred more frequently (73% Cav3.1(-/-) versus 35% WT; P<0.05). Escape rhythms improved in both groups during the next 4 weeks but remained significantly slower in Cav3.1(-/-). At 4 weeks after AVB, ventricular tachycardia was more frequent in Cav3.1(-/-) than in WT mice (746±116 versus 214±78 episodes/24 hours; P<0.01). Ventricular function remodeling was similar in Cav3.1(-/-) and WT, except for smaller post-AVB fractional-shortening increase in Cav3.1(-/-). Expression changes were seen post-AVB for a variety of genes; these tended to be greater in Cav3.1(-/-) mice, and overexpression of fetal and profibrotic genes occurred only in Cav3.1(-/-).

CONCLUSIONS:

This study suggests that T-type Ca(2+) channels play an important role in infranodal escape automaticity. Loss of T-type Ca(2+) channels worsens bradycardia-related mortality, increases bradycardia-associated adverse remodeling, and enhances the risk of malignant ventricular tachyarrhythmias complicating AVB.

• Authors: Khai Le Quang, Begoña Benito, Patrice Naud, Xiao Yan Qi, Yan Fen Shi, Jean-Claude Tardif, Marc-Antoine Gillis, Dobromir Dobrev, Flavien Charpentier, Stanley Nattel
• Journal: Circulation. Arrhythmia and electrophysiology (Circ Arrhythm Electrophysiol) Vol. 6 Issue 4 Pg. 799-808 (Aug 2013) ISSN: 1941-3084 [Electronic] United States
• PMID: 23884198 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cacna1g protein, mouse
• Calcium Channels, T-Type
• RNA, Messenger

Topics

• Action Potentials
• Animals
• Atrioventricular Block (diagnosis, genetics, metabolism, physiopathology)
• Bradycardia (diagnosis, genetics, metabolism, physiopathology, prevention & control)
• Calcium Channels, T-Type (deficiency, genetics, metabolism)
• Calcium Signaling
• Disease Models, Animal
• Electrocardiography, Ambulatory
• Electrophysiologic Techniques, Cardiac
• Gene Expression Regulation
• Heart Conduction System (metabolism, physiopathology)
• Heart Rate
• Male
• Mice
• Mice, Knockout
• Periodicity
• RNA, Messenger (metabolism)
• Telemetry
• Time Factors
• Torsades de Pointes (diagnosis, genetics, metabolism, physiopathology, prevention & control)
• Ventricular Remodeling