Distinct Effects of Ibrutinib and Acalabrutinib on Mouse Atrial and Sinoatrial Node Electrophysiology and Arrhythmogenesis

Background Ibrutinib and acalabrutinib are Bruton tyrosine kinase inhibitors used in the treatment of B‐cell lymphoproliferative disorders. Ibrutinib is associated with new‐onset atrial fibrillation. Cases of sinus bradycardia and sinus arrest have also been reported following ibrutinib treatment. C...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Jari M. Tuomi, Loryn J. Bohne, Tristan W. Dorey, Hailey J. Jansen, Yingjie Liu, Douglas L. Jones, Robert A. Rose
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	acalabrutinib atrial fibrillation ibrutinib ion channels sinoatrial node Diseases of the circulatory (Cardiovascular) system RC666-701
Acceso en línea:	https://doaj.org/article/5b8c21de6e6247fe86ccf4e7765fb41d
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5b8c21de6e6247fe86ccf4e7765fb41d
record_format	dspace
spelling	oai:doaj.org-article:5b8c21de6e6247fe86ccf4e7765fb41d2021-11-16T10:22:43ZDistinct Effects of Ibrutinib and Acalabrutinib on Mouse Atrial and Sinoatrial Node Electrophysiology and Arrhythmogenesis10.1161/JAHA.121.0223692047-9980https://doaj.org/article/5b8c21de6e6247fe86ccf4e7765fb41d2021-11-01T00:00:00Zhttps://www.ahajournals.org/doi/10.1161/JAHA.121.022369https://doaj.org/toc/2047-9980Background Ibrutinib and acalabrutinib are Bruton tyrosine kinase inhibitors used in the treatment of B‐cell lymphoproliferative disorders. Ibrutinib is associated with new‐onset atrial fibrillation. Cases of sinus bradycardia and sinus arrest have also been reported following ibrutinib treatment. Conversely, acalabrutinib is less arrhythmogenic. The basis for these different effects is unclear. Methods and Results The effects of ibrutinib and acalabrutinib on atrial electrophysiology were investigated in anesthetized mice using intracardiac electrophysiology, in isolated atrial preparations using high‐resolution optical mapping, and in isolated atrial and sinoatrial node (SAN) myocytes using patch‐clamping. Acute delivery of acalabrutinib did not affect atrial fibrillation susceptibility or other measures of atrial electrophysiology in mice in vivo. Optical mapping demonstrates that ibrutinib dose‐dependently impaired atrial and SAN conduction and slowed beating rate. Acalabrutinib had no effect on atrial and SAN conduction or beating rate. In isolated atrial myocytes, ibrutinib reduced action potential upstroke velocity and Na+ current. In contrast, acalabrutinib had no effects on atrial myocyte upstroke velocity or Na+ current. Both drugs increased action potential duration, but these effects were smaller for acalabrutinib compared with ibrutinib and occurred by different mechanisms. In SAN myocytes, ibrutinib impaired spontaneous action potential firing by inhibiting the delayed rectifier K+ current, while acalabrutinib had no effects on SAN myocyte action potential firing. Conclusions Ibrutinib and acalabrutinib have distinct effects on atrial electrophysiology and ion channel function that provide insight into the basis for increased atrial fibrillation susceptibility and SAN dysfunction with ibrutinib, but not with acalabrutinib.Jari M. TuomiLoryn J. BohneTristan W. DoreyHailey J. JansenYingjie LiuDouglas L. JonesRobert A. RoseWileyarticleacalabrutinibatrial fibrillationibrutinibion channelssinoatrial nodeDiseases of the circulatory (Cardiovascular) systemRC666-701ENJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, Vol 10, Iss 22 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	acalabrutinib atrial fibrillation ibrutinib ion channels sinoatrial node Diseases of the circulatory (Cardiovascular) system RC666-701
spellingShingle	acalabrutinib atrial fibrillation ibrutinib ion channels sinoatrial node Diseases of the circulatory (Cardiovascular) system RC666-701 Jari M. Tuomi Loryn J. Bohne Tristan W. Dorey Hailey J. Jansen Yingjie Liu Douglas L. Jones Robert A. Rose Distinct Effects of Ibrutinib and Acalabrutinib on Mouse Atrial and Sinoatrial Node Electrophysiology and Arrhythmogenesis
description	Background Ibrutinib and acalabrutinib are Bruton tyrosine kinase inhibitors used in the treatment of B‐cell lymphoproliferative disorders. Ibrutinib is associated with new‐onset atrial fibrillation. Cases of sinus bradycardia and sinus arrest have also been reported following ibrutinib treatment. Conversely, acalabrutinib is less arrhythmogenic. The basis for these different effects is unclear. Methods and Results The effects of ibrutinib and acalabrutinib on atrial electrophysiology were investigated in anesthetized mice using intracardiac electrophysiology, in isolated atrial preparations using high‐resolution optical mapping, and in isolated atrial and sinoatrial node (SAN) myocytes using patch‐clamping. Acute delivery of acalabrutinib did not affect atrial fibrillation susceptibility or other measures of atrial electrophysiology in mice in vivo. Optical mapping demonstrates that ibrutinib dose‐dependently impaired atrial and SAN conduction and slowed beating rate. Acalabrutinib had no effect on atrial and SAN conduction or beating rate. In isolated atrial myocytes, ibrutinib reduced action potential upstroke velocity and Na+ current. In contrast, acalabrutinib had no effects on atrial myocyte upstroke velocity or Na+ current. Both drugs increased action potential duration, but these effects were smaller for acalabrutinib compared with ibrutinib and occurred by different mechanisms. In SAN myocytes, ibrutinib impaired spontaneous action potential firing by inhibiting the delayed rectifier K+ current, while acalabrutinib had no effects on SAN myocyte action potential firing. Conclusions Ibrutinib and acalabrutinib have distinct effects on atrial electrophysiology and ion channel function that provide insight into the basis for increased atrial fibrillation susceptibility and SAN dysfunction with ibrutinib, but not with acalabrutinib.
format	article
author	Jari M. Tuomi Loryn J. Bohne Tristan W. Dorey Hailey J. Jansen Yingjie Liu Douglas L. Jones Robert A. Rose
author_facet	Jari M. Tuomi Loryn J. Bohne Tristan W. Dorey Hailey J. Jansen Yingjie Liu Douglas L. Jones Robert A. Rose
author_sort	Jari M. Tuomi
title	Distinct Effects of Ibrutinib and Acalabrutinib on Mouse Atrial and Sinoatrial Node Electrophysiology and Arrhythmogenesis
title_short	Distinct Effects of Ibrutinib and Acalabrutinib on Mouse Atrial and Sinoatrial Node Electrophysiology and Arrhythmogenesis
title_full	Distinct Effects of Ibrutinib and Acalabrutinib on Mouse Atrial and Sinoatrial Node Electrophysiology and Arrhythmogenesis
title_fullStr	Distinct Effects of Ibrutinib and Acalabrutinib on Mouse Atrial and Sinoatrial Node Electrophysiology and Arrhythmogenesis
title_full_unstemmed	Distinct Effects of Ibrutinib and Acalabrutinib on Mouse Atrial and Sinoatrial Node Electrophysiology and Arrhythmogenesis
title_sort	distinct effects of ibrutinib and acalabrutinib on mouse atrial and sinoatrial node electrophysiology and arrhythmogenesis
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/5b8c21de6e6247fe86ccf4e7765fb41d
work_keys_str_mv	AT jarimtuomi distincteffectsofibrutinibandacalabrutinibonmouseatrialandsinoatrialnodeelectrophysiologyandarrhythmogenesis AT lorynjbohne distincteffectsofibrutinibandacalabrutinibonmouseatrialandsinoatrialnodeelectrophysiologyandarrhythmogenesis AT tristanwdorey distincteffectsofibrutinibandacalabrutinibonmouseatrialandsinoatrialnodeelectrophysiologyandarrhythmogenesis AT haileyjjansen distincteffectsofibrutinibandacalabrutinibonmouseatrialandsinoatrialnodeelectrophysiologyandarrhythmogenesis AT yingjieliu distincteffectsofibrutinibandacalabrutinibonmouseatrialandsinoatrialnodeelectrophysiologyandarrhythmogenesis AT douglasljones distincteffectsofibrutinibandacalabrutinibonmouseatrialandsinoatrialnodeelectrophysiologyandarrhythmogenesis AT robertarose distincteffectsofibrutinibandacalabrutinibonmouseatrialandsinoatrialnodeelectrophysiologyandarrhythmogenesis
_version_	1718426548591132672

Distinct Effects of Ibrutinib and Acalabrutinib on Mouse Atrial and Sinoatrial Node Electrophysiology and Arrhythmogenesis

Ejemplares similares