{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T15:30:19Z","timestamp":1778859019594,"version":"3.51.4"},"reference-count":47,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2019,6,12]],"date-time":"2019-06-12T00:00:00Z","timestamp":1560297600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/13\/31\/30156"],"award-info":[{"award-number":["PG\/13\/31\/30156"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2019,7]]},"abstract":"Key points<\/jats:title>\nEarly\u2010afterdepolarizations (EADs) are abnormal action potential oscillations and a known cause of cardiac arrhythmias. Ventricular EADs involve reactivation of a Ca2+<\/jats:sup> current (I<\/jats:italic>CaL<\/jats:sub>) in its \u2018window region\u2019 voltage range. However, electrical mechanisms of atrial EADs, a potential cause of atrial fibrillation, are poorly understood.<\/jats:p><\/jats:list-item>\nAtrial cells were obtained from consenting patients undergoing heart surgery, as well as from rabbits. I<\/jats:italic>CaL<\/jats:sub> was blocked with nifedipine and then a hybrid patch clamp\/mathematical\u2010modelling technique, \u2018dynamic clamping\u2019, was used to record action potentials at the same time as injecting an artificial, modifiable, I<\/jats:italic>CaL<\/jats:sub> (I<\/jats:italic>CaL,D\u2010C<\/jats:sub>).<\/jats:p><\/jats:list-item>\nProgressively widening the I<\/jats:italic>CaL,D\u2010C<\/jats:sub> window region produced EADs of various types, dependent on window width. EAD production was strongest upon moving the activation (vs<\/jats:italic>. inactivation) side of the window.<\/jats:p><\/jats:list-item>\nEADs were then induced by a different method: increasing I<\/jats:italic>CaL,D\u2010C<\/jats:sub> amplitude and\/or K+<\/jats:sup> channel\u2010blockade (4\u2010aminopyridine). Narrowing of the I<\/jats:italic>CaL,D\u2010C<\/jats:sub> window by \u223c10\u00a0mV abolished these EADs.<\/jats:p><\/jats:list-item>\nAtrial I<\/jats:italic>CaL<\/jats:sub> window narrowing is worthy of further testing as a potential anti\u2010atrial fibrillation drug mechanism.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>Abstract<\/jats:title>Atrial early\u2010afterdepolarizations (EADs) may contribute to atrial fibrillation (AF), perhaps involving reactivation of L\u2010type Ca2+<\/jats:sup> current (I<\/jats:italic>CaL<\/jats:sub>) in its window region voltage range. The present study aimed (i) to validate the dynamic clamp technique for modifying the I<\/jats:italic>CaL<\/jats:sub> contribution to atrial action potential (AP) waveform; (ii) to investigate the effects of widening the window I<\/jats:italic>CaL<\/jats:sub> on EAD\u2010propensity; and (iii) to test whether EADs from increased I<\/jats:italic>CaL<\/jats:sub> and AP duration are supressed by narrowing the window I<\/jats:italic>CaL<\/jats:sub>. I<\/jats:italic>CaL<\/jats:sub> and APs were recorded from rabbit and human atrial myocytes by whole\u2010cell\u2010patch clamp. During AP recording, I<\/jats:italic>CaL<\/jats:sub> was inhibited (3\u00a0\u00b5m<\/jats:sc> nifedipine) and replaced by a dynamic clamp model current, I<\/jats:italic>CaL,D\u2010C<\/jats:sub> (tuned to native I<\/jats:italic>CaL<\/jats:sub> characteristics), computed in real\u2010time (every 50\u00a0\u00b5s) based on myocyte membrane potential. I<\/jats:italic>CaL,D\u2010C<\/jats:sub>\u2010injection restored the nifedipine\u2010suppressed AP plateau. Widening the window I<\/jats:italic>CaL,D\u2010C<\/jats:sub>, symmetrically by stepwise simultaneous equal shifts of half\u2010voltages (V<\/jats:italic>0.5<\/jats:sub>) of I<\/jats:italic>CaL,D\u2010C<\/jats:sub> activation (negatively) and inactivation (positively), generated EADs (single, multiple or preceding repolarization failure) in a window width\u2010dependent manner, as well as AP alternans. A stronger EAD\u2010generating effect resulted from independently shifting activation V<\/jats:italic>0.5<\/jats:sub> (asymmetrical widening) than inactivation V<\/jats:italic>0.5<\/jats:sub>; for example, a 15\u00a0mV activation shift produced EADs in nine of 17 (53%) human atrial myocytes vs<\/jats:italic>. 0 of 18 from inactivation shift (P<\/jats:italic>\u00a0<\u00a00.05). In 11 rabbit atrial myocytes in which EADs were generated either by increasing the conductance of normal window width I<\/jats:italic>CaL,D\u2010C<\/jats:sub> or subsequent 4\u2010aminopyridine (2\u00a0mm<\/jats:sc>), window I<\/jats:italic>CaL,D\u2010C<\/jats:sub> narrowing (10\u00a0mV) abolished EADs of all types (P<\/jats:italic>\u00a0<\u00a00.05). The present study validated the dynamic clamp for I<\/jats:italic>CaL<\/jats:sub>, which is novel in atrial cardiomyocytes, and showed that EADs of various types are generated by widening (particularly asymmetrically) the window I<\/jats:italic>CaL<\/jats:sub>, as well as abolished by narrowing it. Window I<\/jats:italic>CaL<\/jats:sub> narrowing is a potential therapeutic mechanism worth pursuing in the search for improved anti\u2010AF drugs.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp277827","type":"journal-article","created":{"date-parts":[[2019,5,16]],"date-time":"2019-05-16T00:13:31Z","timestamp":1557965611000},"page":"3619-3638","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Dynamic clamping human and rabbit atrial calcium current: narrowing I<\/i>CaL<\/sub> window abolishes early afterdepolarizations"],"prefix":"10.1113","volume":"597","author":[{"given":"Sarah","family":"Kettlewell","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular & Medical Sciences University of Glasgow Glasgow UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priyanka","family":"Saxena","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular & Medical Sciences University of 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