1. Academic Validation
  2. Ibrutinib Displays Atrial-Specific Toxicity in Human Stem Cell-Derived Cardiomyocytes

Ibrutinib Displays Atrial-Specific Toxicity in Human Stem Cell-Derived Cardiomyocytes

  • Stem Cell Reports. 2019 May 14;12(5):996-1006. doi: 10.1016/j.stemcr.2019.03.011.
Sanam Shafaattalab 1 Eric Lin 2 Effimia Christidi 3 Haojun Huang 3 Yulia Nartiss 4 Analucia Garcia 4 Jeehon Lee 4 Stephanie Protze 5 Gordon Keller 6 Liam Brunham 3 Glen F Tibbits 1 Zachary Laksman 7
Affiliations

Affiliations

  • 1 Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1A6, Canada; British Columbia Children's Hospital Research Institute, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
  • 2 Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1A6, Canada.
  • 3 University of British Columbia, 170-6371 Crescent Road, Vancouver, BC V6T 1Z2, Canada.
  • 4 McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
  • 5 McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 6 McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • 7 Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1A6, Canada; University of British Columbia, 170-6371 Crescent Road, Vancouver, BC V6T 1Z2, Canada. Electronic address: [email protected]
Abstract

Ibrutinib (IB) is an oral Bruton's tyrosine kinase (Btk) inhibitor that has demonstrated benefit in B cell cancers, but is associated with a dramatic increase in atrial fibrillation (AF). We employed cell-specific differentiation protocols and optical mapping to investigate the effects of IB and other tyrosine kinase inhibitors (TKIs) on the voltage and calcium transients of atrial and ventricular human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). IB demonstrated direct cell-specific effects on atrial hPSC-CMs that would be predicted to predispose to AF. Second-generation Btk inhibitors did not have the same effect. Furthermore, IB exposure was associated with differential chamber-specific regulation of a number of regulatory pathways including the receptor tyrosine kinase pathway, which may be implicated in the pathogenesis of AF. Our study is the first to demonstrate cell-type-specific toxicity in hPSC-derived atrial and ventricular cardiomyocytes, which reliably reproduces the clinical cardiotoxicity observed.

Keywords

RNA-seq; atrial fibrillation; cardiac electrophysiology; drug screening; optical mapping; tyrosine kinase inhibitors.

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