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Related Concept Videos

Heart Failure Drugs: Inotropic Agents01:26

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Positive inotropic agents are commonly used as the first line of treatment for heart failure. One such agent is digoxin, derived from the genus Digitalis, which has been known for centuries but effectively utilized since 1785. However, these cardiac glycosides can have potentially toxic effects due to their mechanism of action, which involves inhibiting Na+/K+-ATPase and increasing contractility. Digoxin is absorbed orally and distributed in various tissues, including the CNS. It has a long...
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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
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Osimertinib induces reversible cardiac dysfunction through the GATA4-MYLK3-MYL2 axis.

Kai Zhang1,2,3, Alyssa Ayala3, Ignacio Norambuena-Soto1

  • 1Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA.

European Heart Journal
|December 2, 2025
PubMed
Summary

Osimertinib causes reversible heart dysfunction by disrupting sarcomere function, not cell death. Myosin activation may prevent or treat this cardiotoxicity in non-small cell lung cancer patients.

Keywords:
CardiotoxicityContractilityGATA binding protein 4Heart failureMyosin light chain 2Myosin light chain kinase 3OsimertinibSarcomereTyrosine kinase inhibitor

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Area of Science:

  • Cardiology
  • Oncology
  • Molecular Biology

Background:

  • Osimertinib, a tyrosine kinase inhibitor, treats non-small cell lung cancer but can cause heart failure.
  • Understanding osimertinib cardiotoxicity mechanisms is crucial for patient safety.

Purpose of the Study:

  • Investigate the molecular mechanisms of osimertinib-induced cardiotoxicity.
  • Explore potential cardioprotective strategies against osimertinib.

Main Methods:

  • Utilized human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and a mouse model with transverse aortic constriction.
  • Employed single-nucleus RNA sequencing and in vitro assays to analyze molecular changes.

Main Results:

  • Osimertinib induced cardiac contractile dysfunction without cell death, inflammation, or fibrosis.
  • Identified MYLK3 downregulation and decreased MYL2 phosphorylation, leading to sarcomere disarray.
  • Discovered GATA4 dephosphorylation links to MYLK3 suppression; dysfunction was reversible.
  • Omecamtiv, a myosin activator, effectively prevented osimertinib cardiotoxicity.

Conclusions:

  • Osimertinib causes reversible cardiac dysfunction via MYL2 phosphorylation disruption through GATA4/MYLK3 pathway.
  • Myosin activation presents a promising strategy for preventing or rescuing osimertinib cardiotoxicity.