TY - JOUR
T1 - Differential Sodium Current Remodelling Identifies Distinct Cellular Proarrhythmic Mechanisms in Paroxysmal vs Persistent Atrial Fibrillation
AU - Casini, Simona
AU - Marchal, Gerard A.
AU - Kawasaki, Makiri
AU - Fabrizi, Benedetta
AU - Wesselink, Robin
AU - Nariswari, Fransisca A.
AU - Neefs, Jolien
AU - van den Berg, Nicoline W. E.
AU - Driessen, Antoine H. G.
AU - de Groot, Joris R.
AU - Verkerk, Arie O.
AU - Remme, Carol Ann
N1 - Funding Information: This study was funded by 2 Innovational Research Incentives Scheme Vidi grants from the Netherlands Organisation for Health Research and Development (ZonMw 91714371 to C.A.R. and ZonMw 016.146.310. to J.R.G); a ZonMw Priority Medicines (PM-Rare) grant (113303006 to C.A.R.); the Netherlands CardioVascular Research Initiative CVON (PREDICT2 CVON2018-30 to C.A.R.). Publisher Copyright: © 2023 The Authors
PY - 2023/3
Y1 - 2023/3
N2 - Background: The cellular mechanisms underlying progression from paroxysmal to persistent atrial fibrillation (AF) are not fully understood, but alterations in (late) sodium current (INa) have been proposed. Human studies investigating electrophysiological changes at the paroxysmal stage of AF are sparse, with the majority employing right atrial appendage cardiomyocytes (CMs). We here investigated action potential (AP) characteristics and (late) INa remodelling in left atrial appendage CMs (LAA-CMs) from patients with paroxysmal and persistent AF and patients in sinus rhythm (SR), as well as the potential contribution of the “neuronal” sodium channel SCN10A/NaV1.8. Methods: Peak INa, late INa and AP properties were investigated through patch-clamp analysis on single LAA-CMs, whereas quantitative polymerase chain reaction was used to assess SCN5A/SCN10A expression levels in LAA tissue. Results: In paroxysmal and persistent AF LAA-CMs, AP duration was shorter than in SR LAA-CMs. Compared with SR, peak INa and SCN5A expression were significantly decreased in paroxysmal AF, whereas they were restored to SR levels in persistent AF. Conversely, although late INa was unchanged in paroxysmal AF compared with SR, it was significantly increased in persistent AF. Peak or late Nav1.8-based INa was not detected in persistent AF LAA-CMs. Similarly, expression of SCN10A was not observed in LAAs at any stage. Conclusions: Our findings demonstrate differences in (late) INa remodeling in LAA-CMs from patients with paroxysmal vs persistent AF, indicating distinct cellular proarrhythmic mechanisms in different AF forms. These observations are of particular relevance when considering potential pharmacologic approaches targeting (late) INa in AF.
AB - Background: The cellular mechanisms underlying progression from paroxysmal to persistent atrial fibrillation (AF) are not fully understood, but alterations in (late) sodium current (INa) have been proposed. Human studies investigating electrophysiological changes at the paroxysmal stage of AF are sparse, with the majority employing right atrial appendage cardiomyocytes (CMs). We here investigated action potential (AP) characteristics and (late) INa remodelling in left atrial appendage CMs (LAA-CMs) from patients with paroxysmal and persistent AF and patients in sinus rhythm (SR), as well as the potential contribution of the “neuronal” sodium channel SCN10A/NaV1.8. Methods: Peak INa, late INa and AP properties were investigated through patch-clamp analysis on single LAA-CMs, whereas quantitative polymerase chain reaction was used to assess SCN5A/SCN10A expression levels in LAA tissue. Results: In paroxysmal and persistent AF LAA-CMs, AP duration was shorter than in SR LAA-CMs. Compared with SR, peak INa and SCN5A expression were significantly decreased in paroxysmal AF, whereas they were restored to SR levels in persistent AF. Conversely, although late INa was unchanged in paroxysmal AF compared with SR, it was significantly increased in persistent AF. Peak or late Nav1.8-based INa was not detected in persistent AF LAA-CMs. Similarly, expression of SCN10A was not observed in LAAs at any stage. Conclusions: Our findings demonstrate differences in (late) INa remodeling in LAA-CMs from patients with paroxysmal vs persistent AF, indicating distinct cellular proarrhythmic mechanisms in different AF forms. These observations are of particular relevance when considering potential pharmacologic approaches targeting (late) INa in AF.
UR - http://www.scopus.com/inward/record.url?scp=85148744840&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.cjca.2022.12.023
DO - https://doi.org/10.1016/j.cjca.2022.12.023
M3 - Article
C2 - 36586483
SN - 0828-282X
VL - 39
SP - 277
EP - 288
JO - Canadian Journal of Cardiology
JF - Canadian Journal of Cardiology
IS - 3
ER -