Work

Downregulation of L-type Ca2+ current in patients with atrial fibrillation results from altered channel gating and disruption of membrane microdomains

Year: 2026

Type: article

Abstract: Background Atrial fibrillation (AF) is associated by alterations in cardiomyocyte membrane microdomain organization that can modify the distribution and biophysical properties of L-type Ca 2+ channels (LTCCs), contributing to downregulation of the L-type Ca 2+ current ( I Ca,L ). Objective To examine the role of cellular microarchitecture and microdomain-specific changes of single LTCCs in I Ca,L remodeling in chronic AF. Methods Right (RA) and left (LA) atrial biopsies from patients in sinus rhythm (SR, n=51) and AF (n=61) were analyzed to assess cardiomyocyte microarchitecture and microdomain-specific remodeling of single LTCCs and I Ca,L . Computational modeling estimated the contributions of different cellular components in I Ca,L reduction. Results In AF, I Ca,L was reduced in RA (∼32%, P<0.05) and LA (∼71%, P<0.01). In RA, this was associated with preserved T-tubular LTCCs (T-LTCCs) density and decreased extratubular (crest, C-LTCCs) density. In LA-AF, densities of both T- and C-LTCCs were reduced. These changes paralleled T-tubule downregulation in both atria and an LA-specific decrease in caveolin-3 expression. In AF, the open probabilities of T- and C-LTCCs in both atria were 3-5-fold higher than in SR and accompanied by 2-fold increase in protein kinase A and phosphorylated Ca 2+ /calmodulin kinase II activities. However, computational simulations showed that enhanced LTCC open probability did not compensate for reduced channel density. Caveolin-3 overexpression in LA-AF cardiomyocytes increased Ca V 1.2 membrane expression, partially restoring I Ca,L . Conclusion I Ca,L downregulation in AF is driven by chamber-specific degradation of membrane structures and loss of functional LTCCs, not offset by increased channel activity. Caveolin-3 is crucial for maintaining functional LTCCs at the sarcolemma.

Source: Heart Rhythm

DOI: 10.1016/j.hrthm.2026.03.1953