BibTex format
@article{Balycheva:2026:10.1016/j.hrthm.2026.03.1953,
author = {Balycheva, M and Reilly-O'Donnell, B and Alvarez-Laviada, A and Zhang, K and Mazzola, M and Sanchez-Alonso, JL and Lucarelli, C and Medvedev, RY and Molina, CE and Schobesberger, S and Diakonov, I and Wright, PT and Poulet, CE and Bork, NI and Trayanova, NA and Faggian, G and Punjabi, P and Nikolaev, VO and Glukhov, AV and Gorelik, J},
doi = {10.1016/j.hrthm.2026.03.1953},
journal = {Heart Rhythm},
pages = {e1170--e1182},
title = {Downregulation of L-type Ca2+ current in patients with atrial fibrillation results from altered channel gating and disruption of membrane microdomains.},
url = {http://dx.doi.org/10.1016/j.hrthm.2026.03.1953},
volume = {23},
year = {2026}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - BACKGROUND: Atrial fibrillation (AF) is associated by alterations in cardiomyocyte membrane microdomain organization that can modify the distribution and biophysical properties of L-type Ca2+ channels (LTCCs), contributing to downregulation of the L-type Ca2+ current (ICa,L). OBJECTIVE: This study aimed to examine the role of cellular microarchitecture and microdomain-specific changes of single LTCCs in ICa,L remodeling in chronic AF. METHODS: Right atrial (RA) and left atrial (LA) 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 ICa,L. Computational modeling estimated the contributions of different cellular components in ICa,L reduction. RESULTS: In AF, ICa,L was reduced in RA (∼32%, P < .05) and LA (∼71%, P < .01). In RA, this was associated with preserved transverse (T)-tubular LTCCs (T-LTCCs) density and decreased extra-tubular (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 Ca2+/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 CaV1.2 membrane expression, partially restoring ICa,L. CONCLUSION: ICa,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.
AU - Balycheva,M
AU - Reilly-O'Donnell,B
AU - Alvarez-Laviada,A
AU - Zhang,K
AU - Mazzola,M
AU - Sanchez-Alonso,JL
AU - Lucarelli,C
AU - Medvedev,RY
AU - Molina,CE
AU - Schobesberger,S
AU - Diakonov,I
AU - Wright,PT
AU - Poulet,CE
AU - Bork,NI
AU - Trayanova,NA
AU - Faggian,G
AU - Punjabi,P
AU - Nikolaev,VO
AU - Glukhov,AV
AU - Gorelik,J
DO - 10.1016/j.hrthm.2026.03.1953
EP - 1182
PY - 2026///
SP - 1170
TI - Downregulation of L-type Ca2+ current in patients with atrial fibrillation results from altered channel gating and disruption of membrane microdomains.
T2 - Heart Rhythm
UR - http://dx.doi.org/10.1016/j.hrthm.2026.03.1953
UR - https://www.ncbi.nlm.nih.gov/pubmed/41933636
VL - 23
ER -