Altered connexin expression in human congestive heart failure

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cardiac Electrophysiology

Background:

• Congestive heart failure (CHF) elevates the risk of life-threatening ventricular arrhythmias.
• Connexin43 (CX43) down-regulation is linked to arrhythmias in ischemic heart disease, but its role in idiopathic dilated cardiomyopathy (IDC) and CHF is unclear.
• The transcriptional or translational regulation of CX43 and alterations in other connexin isotypes in CHF require investigation.

Purpose of the Study:

• To investigate connexin expression (CX43, CX40, CX45, CX37) at mRNA and protein levels in explanted hearts from CHF patients.
• To determine if CX43 down-regulation in CHF is due to transcriptional or translational changes.
• To assess changes in other connexin isotypes in the failing heart.

Main Methods:

• Analysis of explanted hearts from end-stage heart failure patients (NYHA class 4).
• Utilized immunoconfocal microscopy, northern blotting, and western blotting to quantify connexin mRNA and protein levels.
• Examined CX43, CX40, CX45, and CX37 expression in both ischemic cardiomyopathy and idiopathic dilated cardiomyopathy.

Main Results:

• Marked down-regulation of CX43 mRNA and protein in the left ventricle of CHF patients (ischemic and IDC).
• CX43 content exhibited spatial heterogeneity in diseased ventricles.
• Increased CX40 mRNA and protein in the ischemic group, particularly in the left ventricle, suggesting a compensatory mechanism.

Conclusions:

• CHF is associated with significantly reduced left ventricular CX43, potentially contributing to arrhythmogenicity and contractile dysfunction.
• The primary driver of CX43 down-regulation in CHF is a reduced transcript steady-state level.
• Elevated CX40 may serve as a compensatory response to improve electrical impulse propagation in the compromised ischemic ventricle.