Ion channel subunit expression changes in cardiac Purkinje fibers: a potential role in conduction abnormalities associated with congestive heart failure.
Purkinje fibers (PFs) play key roles in cardiac conduction and arrhythmogenesis. Congestive heart failure (CHF) causes well-characterized atrial and ventricular ion channel subunit expression changes, but effects on PF ion channel subunits are unknown. This study assessed changes in PF ion channel subunit expression (real-time PCR, immunoblot, immunohistochemistry), action potential properties, and conduction in dogs with ventricular tachypacing-induced CHF. CHF downregulated mRNA expression of subunits involved in action potential propagation (Nav1.5, by 56%; connexin [Cx]40, 66%; Cx43, 56%) and repolarization (Kv4.3, 43%, Kv3.4, 46%). No significant changes occurred in KChIP2, KvLQT1, ERG, or Kir3.1/3.4 mRNA. At the protein level, downregulation was seen for Nav1.5 (by 38%), Kv4.3 (42%), Kv3.4 (57%), Kir2.1 (26%), Cx40 (53%), and Cx43 (30%). Cx43 dephosphorylation was indicated by decreased larger molecular mass bands (pan-Cx43 antibody) and a 57% decrease in Ser368-phosphorylated Cx43 (phospho-specific antibody). Immunohistochemistry revealed reduced Cx40, Cx43, and phospho-Cx43 expression at intercalated disks. Action potential changes were consistent with observed decreases in ion channel subunits: CHF decreased phase 1 slope (by 56%), overshoot (by 32%), and phase 0 dV/dt(max) (by 35%). Impulse propagation was slowed in PF false tendons: conduction velocity decreased significantly from 2.2+/-0.1 m/s (control) to 1.5+/-0.1 m/s (CHF). His-Purkinje conduction also slowed in vivo, with HV interval increasing from 35.5+/-1.2 (control) to 49.3+/-3.4 ms (CHF). These results indicate important effects of CHF on PF ion channel subunit expression. Alterations in subunits governing conduction properties may be particularly important, because CHF-induced impairments in Purkinje tissue conduction, which this study is the first to describe, could contribute significantly to dyssynchronous ventricular activation, a major determinant of prognosis in CHF-patients.
Department of Medicine, Montreal Heart Institute and Université de Montréal, Quebec, Canada.
Ange
A
Maguy
Sabrina
S
Le Bouter
Philippe
P
Comtois
Denis
D
Chartier
Louis
L
Villeneuve
Reza
R
Wakili
Kunihiro
K
Nishida
Stanley
S
Nattel
D000200:Action Potentials; D000818:Animals; D002304:Cardiac Pacing, Artificial; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D004562:Electrocardiography; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics; D010766:Phosphorylation; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits; D011690:Purkinje Fibers / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D017180:Tachycardia, Ventricular / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors
D017630:Connexins; D015221:Potassium Channels; D021122:Protein Subunits; D012333:RNA, Messenger; D015222:Sodium Channels