Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase

Circulation. 2020 Dec 22;142(25):2443-2455. doi: 10.1161/CIRCULATIONAHA.120.049210. Epub 2020 Oct 23.


Background: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood.

Methods: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF.

Results: We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7; P<0.0001).

Conclusions: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215.

Keywords: BTK protein, human; CSK tyrosine-protein kinase; atrial fibrillation; electrophysiology; ibrutinib; protein kinase inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Adenine / analogs & derivatives*
  • Adenine / toxicity
  • Agammaglobulinaemia Tyrosine Kinase / deficiency
  • Agammaglobulinaemia Tyrosine Kinase / genetics
  • Animals
  • Antineoplastic Agents / toxicity*
  • Atrial Fibrillation / chemically induced*
  • Atrial Fibrillation / enzymology
  • Atrial Fibrillation / physiopathology
  • Atrial Function, Left / drug effects*
  • CSK Tyrosine-Protein Kinase / antagonists & inhibitors*
  • CSK Tyrosine-Protein Kinase / genetics
  • CSK Tyrosine-Protein Kinase / metabolism
  • Databases, Genetic
  • Heart Atria / drug effects*
  • Heart Atria / enzymology
  • Heart Atria / physiopathology
  • Heart Rate / drug effects*
  • Humans
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Knockout
  • Piperidines / toxicity*
  • Protein Kinase Inhibitors / toxicity*
  • Risk Assessment
  • Risk Factors


  • Antineoplastic Agents
  • Piperidines
  • Protein Kinase Inhibitors
  • ibrutinib
  • Agammaglobulinaemia Tyrosine Kinase
  • Btk protein, mouse
  • CSK Tyrosine-Protein Kinase
  • CSK protein, human
  • Adenine

Associated data

  • ClinicalTrials.gov/NCT03530215