Atrial Fibrillation: Focus on Myocardial Connexins and Gap Junctions

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia globally, causing significant morbidity, mortality, and socioeconomic impact.
• Genetic factors play a crucial role in AF development, with mutations identified in over 50 genes, many encoding ion channels, structural proteins, transcription factors, and gap junction proteins.
• Gap junctions, formed by connexins (Cxs), are vital for cardiomyocyte electrical coupling and coordinated heart function.

Purpose of the Study:

• To provide an overview of the genetic basis of atrial fibrillation (AF).
• To focus on the role of mutant myocardial connexins and gap junctions in AF pathogenesis.
• To underscore the hypothesis that cardiac connexins are a major molecular target for AF management.

Main Methods:

• Review of existing scientific literature on AF genetics.
• Analysis of studies linking connexin mutations and polymorphisms to AF susceptibility.
• Examination of the structural and functional consequences of altered gap junction channels in the heart.

Main Results:

• Multiple causative mutations and polymorphisms in four connexin isoforms (Cx37, Cx40, Cx43, Cx45, Cx46) have been identified as predisposing factors for AF.
• Structural remodeling of gap junction channels, including altered connexin distribution and protein levels, impairs cardiomyocyte electrical coupling.
• This abnormal electrical coupling significantly enhances susceptibility to atrial fibrillation.

Conclusions:

• Cardiac connexins and gap junctions are critically involved in the pathogenesis of atrial fibrillation.
• Mutations affecting myocardial connexins disrupt normal cardiac electrical activity, leading to AF.
• Cardiac connexins represent a promising molecular target for future therapeutic strategies in managing AF.