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(Circulation Research. 2009;104:1113.)
© 2009 American Heart Association, Inc.

Cellular Biology

Ion Channel Subunit Expression Changes in Cardiac Purkinje Fibers

A Potential Role in Conduction Abnormalities Associated With Congestive Heart Failure

Ange Maguy^*, Sabrina Le Bouter^*, Philippe Comtois, Denis Chartier, Louis Villeneuve, Reza Wakili, Kunihiro Nishida, Stanley Nattel

From the Department of Medicine (A.M., S.L.B., D.C., L.V., R.W., K.N., S.N.), Department of Physiology (P.C.), and Institute of Biomedical Engineering (P.C.), Montreal Heart Institute and Université de Montréal, Quebec, Canada; Department of Pharmacology and Therapeutics (S.N.), McGill University, Montreal, Quebec, Canada; and Department of Internal Medicine 1 (R.W.), Ludwig-Maximilians University, Munich, Germany.

Correspondence to Stanley Nattel, 5000 Belanger St East, Montreal, Quebec, H1T 1C8, Canada. E-mail Stanley.nattel{at}icm-mhi.org

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.

Key Words: heart failure • remodeling • ventricular dyssynchrony • connexins • specialized conducting system