title: 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.
  
  
  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.affiliation: Department of Medicine and Research Centre, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Khai
authors.initials: K
authors.lastname: Le Quang
authors.forename: Begoña
authors.initials: B
authors.lastname: Benito
authors.forename: Patrice
authors.initials: P
authors.lastname: Naud
authors.forename: Xiao Yan
authors.initials: XY
authors.lastname: Qi
authors.forename: Yan Fen
authors.initials: YF
authors.lastname: Shi
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Gillis
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Flavien
authors.initials: F
authors.lastname: Charpentier
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000200:Action Potentials; D000818:Animals; D054537:Atrioventricular Block / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001919:Bradycardia / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D020747:Calcium Channels, T-Type / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D004195:Disease Models, Animal; D015716:Electrocardiography, Ambulatory; D022062:Electrophysiologic Techniques, Cardiac; D005786:Gene Expression Regulation; D006329:Heart Conduction System / Q000378:metabolism* / Q000503:physiopathology; D006339:Heart Rate; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010507:Periodicity; D012333:RNA, Messenger / Q000378:metabolism; D013686:Telemetry; D013997:Time Factors; D016171:Torsades de Pointes / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D020257:Ventricular Remodeling
chemical_list: C498197:Cacna1g protein, mouse; D020747:Calcium Channels, T-Type; D012333:RNA, Messenger
keywords: Cav3.1 protein, mouse; T-type calcium channel; atrioventricular block; cardiac remodeling, ventricular; tachycardia, ventricular