title: Role of T-type calcium channel subunits in post-myocardial infarction remodelling probed with genetically engineered mice.
abstract: OBJECTIVE
  Previous studies suggested that T-type Ca(2+)-current (I(CaT))-blockers improve cardiac remodelling, but all available I(CaT)-blockers have non-specific actions on other currents and/or functions. To clarify the role of I(CaT) in cardiac remodelling, we studied mice with either of the principal cardiac I(CaT)-subunits (Cav3.1 or Cav3.2) knocked out.
  
  
  RESULTS
  Adult male Cav3.1- or Cav3.2-knockout (Cav3.1(-/-), Cav3.2(-/-)) mice and respective wild-type (WT) littermate controls were subjected to left anterior descending coronary artery ligation to create myocardial infarction (MI). Echocardiography and programmed electrical stimulation were performed at baseline and 4 weeks post-MI. At baseline, Cav3.1(-/-) mice had slowed heart rates and longer PR intervals vs. WT, but no other electrophysiological and no haemodynamic differences. Cav3.2(-/-) showed no differences vs. WT. Contractile indices (left ventricular fractional shortening and ejection fraction) decreased more post-MI in Cav3.1(-/-) mice than in Cav3.1(+/+) (e.g. by 34 and 29% for WT; 50 and 45% for Cav3.1(-/-), respectively; P < 0.05 for each). Cav3.1(-/-) mice had increased ventricular tachycardia (VT) inducibility post-MI (9 of 11, 82%) vs. WT (3 of 10, 30%; P < 0.05). Cav3.2(-/-) mice were not different in cardiac function or VT inducibility vs. WT. Quantitative polymerase chain reaction showed that Cav3.1 is the major I(CaT)-subunit and that no compensatory Cav3.2 up-regulation occurs in Cav3.1(-/-) mice. Cav3.1(-/-) and Cav3.2(-/-) mice had no mRNA expression for the knocked-out gene, at baseline or post-MI.
  
  
  CONCLUSIONS
  Our findings suggest that, contrary to suggestions from previous studies with (imperfectly selective) pharmacological agents having T-type Ca(2+)-channel-blocking actions, elimination of Cav3.1 expression leads to impaired cardiac function and enhanced arrhythmia vulnerability post-MI, whereas Cav3.2 elimination has no effect.
authors.affiliation: Research Center and Departments of Medicine, Université de Montréal and Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, Canada.
authors.forename: Khai
authors.initials: K
authors.lastname: Le Quang
authors.forename: Patrice
authors.initials: P
authors.lastname: Naud
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Qi
authors.forename: Francine
authors.initials: F
authors.lastname: Duval
authors.forename: Yan-Fen
authors.initials: YF
authors.lastname: Shi
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Gillis
authors.forename: Philippe
authors.initials: P
authors.lastname: Comtois
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Danshi
authors.initials: D
authors.lastname: Li
authors.forename: Paul C
authors.initials: PC
authors.lastname: Levesque
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: D000818:Animals; D020747:Calcium Channels, T-Type / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004562:Electrocardiography; D006339:Heart Rate; D006439:Hemodynamics; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013318:Stroke Volume; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014463:Ultrasonography; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: C498197:Cacna1g protein, mouse; C504883:Cacna1h protein, mouse; D020747:Calcium Channels, T-Type; D012333:RNA, Messenger