Copyright © 2005, European Society of Cardiology
Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model
aDepartments of Medicine and Research Center, Montreal Heart Institute and University of Montreal, 5000 Belanger St E, Montreal, Quebec, Canada H1T 1C8
bDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
cUniversidad Complutense, Madrid, Spain
* Corresponding author. Departments of Medicine and Research Center, Montreal Heart Institute and University of Montreal, 5000 Belanger St E, Montreal, Quebec, H1T 1C8, Canada. Tel.: +1 514 376 3330x3990; fax: +1 514 376 1355. Email address: stanley.nattel{at}icm-mhi.org
Background: The hyperpolarization-activated cation current If contributes significantly to sinoatrial node pacemaker function and possibly to ectopic arrhythmogenesis. Little is known about the expression of corresponding hyperpolarization-activated cyclic nucleotide-gated (HCN) channel subunits in normal hearts and HCN remodeling by diseases, like congestive heart failure (CHF), associated with disturbances of cardiac rhythm.
Methods and results: We assessed expression of HCN1, 2 and 4 in normal mongrel dogs and dogs subjected to 2-week ventricular tachypacing-induced CHF. Competitive RT-PCR, Western blot and immunohistochemistry were used to quantify HCN subunit mRNA and protein expression in the right atrium (RA) and sinoatrial node. CHF approximately doubled sinus node recovery time, indicating suppressed sinus node pacemaker function. HCN expression under control conditions was HCN4>HCN2>>HCN1. HCN2 and HCN4 expression was greater at both protein and mRNA levels in sinoatrial node than RA. CHF significantly decreased sinus node HCN expression at both mRNA and protein levels (HCN2 by 78% and 82%; HCN4 by 42% and 77%, respectively). RA HCN2 expression was unaltered by CHF, but HCN4 was significantly upregulated (by 209%).
Conclusions: HCN4 is the dominant subunit in canine sinoatrial node and RA; strong sinus node HCN expression likely contributes to its pacemaker function; downregulation of HCN4 and HCN2 expression contribute to CHF-induced sinus node dysfunction; and upregulation of atrial HCN4 may help to promote atrial arrhythmia formation. These findings provide novel information about the molecular basis of normal and disease-related impairments of cardiac impulse formation.
KEYWORDS Pacemaker current; Sinoatrial node; Congestive heart failure; Ion channels; Remodeling
Time for primary review 18 days
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