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Molecular basis of electrical remodeling in atrial fibrillation
D R Van Wagoner1, J M Nerbonne
1Department of Cardiology, The Cleveland Clinic Foundation, OH 44195, USA. vanwagd@ccf.org
Insights
Atrial fibrillation (AF) involves progressive atrial remodeling due to electrophysiological changes. Reduced calcium currents are key to AF
Area of Science:
- Cardiology
- Electrophysiology
- Molecular Biology
Background:
- Atrial fibrillation (AF) is a common arrhythmia linked to cardiovascular diseases, stroke, and mortality.
- AF progression involves cumulative electrophysiological and structural atrial remodeling.
- Understanding AF's molecular mechanisms is crucial for developing new therapies.
Purpose of the Study:
- To investigate the molecular mechanisms underlying atrial remodeling in AF.
- To identify key ionic current and calcium handling changes in AF-induced remodeling.
Main Methods:
- Cellular electrophysiological studies in human and canine AF models.
- Analysis of ion channel expression and calcium cycling proteins.
Main Results:
- Marked reductions in L-type Ca2+ current (I(Ca,L)), I(TO), and I(Kur) in atrial myocytes.
- Reduced I(Ca,L) correlates with decreased action potential duration and effective refractory period.
- Decreased sarcoplasmic reticulum Ca2+ ATPase expression suggests impaired calcium cycling.
Conclusions:
- Calcium overload and handling perturbations play significant roles in AF-related atrial remodeling.
- Reduced I(Ca,L) is sufficient to explain key electrical changes in remodeled atria.
- Further research into AF's structural, cellular, and molecular changes is warranted for improved therapeutic strategies.
Abstract:
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and is often associated with other cardiovascular disorders and diseases. AF can lead to thromboembolism, reduced left ventricular function and stroke, and, importantly, it is independently associated with increased mortality. AF is a progressive disease; numerous lines of evidence suggest that disease progression results from cumulative electrophysiological and structural remodeling of the atria. There is considerable interest in delineating the molecular mechanisms involved in the remodeling that occurs in the atria of patients with AF. Cellular electrophysiological studies have revealed marked reductions in the densities of the L-type voltage-gated Ca2+ current, I(Ca,L), the transient outward K+ current, I(TO), and the ultrarapid delayed rectifier K+ current, I(Kur), in atrial myocytes from patients in chronic AF. Similar (but not identical) changes in currents are evident in myocytes isolated from a canine model of AF and, in this case, the changes in currents are correlated with reduced expression of the underlying channel forming subunits. In both human and canine AF, the reduction in I(Ca,L) appears to be sufficient to explain the observed decreases in action potential duration and effective refractory period that are characteristic features of the remodeled atria. In addition, expression of the sarcoplasmic reticulum Ca2+ ATPase is reduced, suggesting that calcium cycling is affected in AF. These recent studies suggest that calcium overload and perturbations in calcium handling play prominent roles in AF-induced atrial remodeling. Although considerable progress has been made, further studies focused on defining the detailed structural, cellular and molecular changes that accompany the different stages of AF in humans, as well as in animal models of AF, are clearly warranted. It is anticipated that molecular insights gleaned from these studies will facilitate the development of improved therapeutic approaches to treat AF and to prevent the progression of the arrhythmia.