Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure...

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Cardiac Electrophysiology

Background:

• The hyperpolarization-activated cation current I(f) is crucial for heart pacemaker function.
• Expression patterns of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel subunits in normal and diseased hearts are not well understood.
• Congestive heart failure (CHF) is associated with cardiac rhythm disturbances.

Purpose of the Study:

• To investigate the expression of HCN1, HCN2, and HCN4 channel subunits in normal canine hearts.
• To determine how CHF affects HCN subunit expression in the sinoatrial node and right atrium.
• To elucidate the molecular basis of CHF-induced sinus node dysfunction and potential arrhythmia formation.

Main Methods:

• Assessed HCN1, HCN2, and HCN4 mRNA and protein expression using competitive RT-PCR, Western blot, and immunohistochemistry.
• Studied normal mongrel dogs and dogs with 2-week ventricular tachypacing-induced CHF.
• Quantified expression in the sinoatrial node and right atrium.

Main Results:

• HCN4 was the dominant subunit, followed by HCN2, with minimal HCN1 expression in normal hearts.
• Sinoatrial node HCN2 and HCN4 expression was significantly decreased in CHF at both mRNA and protein levels.
• Right atrial HCN4 expression was significantly upregulated in CHF, while HCN2 remained unchanged.

Conclusions:

• HCN4 is the predominant subunit in the canine sinoatrial node and right atrium.
• Downregulation of HCN2 and HCN4 in the sinus node contributes to CHF-induced pacemaker dysfunction.
• Upregulation of atrial HCN4 may play a role in promoting atrial arrhythmias in CHF.