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.