title: Ageing is a risk factor in imatinib mesylate cardiotoxicity.
abstract: OBJECTIVE
  Chemotherapy-induced heart failure is increasingly recognized as a major clinical challenge. Cardiotoxicity of imatinib mesylate, a highly selective and effective anticancer drug belonging to the new class of tyrosine kinase inhibitors, is being reported in patients, some progressing to congestive heart failure. This represents an unanticipated challenge that could limit effective drug use. Understanding the mechanisms and risk factors of imatinib mesylate cardiotoxicity is crucial for prevention of cardiovascular complications in cancer patients.
  
  
  RESULTS
  We used genetically engineered mice and primary rat neonatal cardiomyocytes to analyse the action of imatinib on the heart. We found that treatment with imatinib (200 mg/kg/day for 5 weeks) leads to mitochondrial-dependent myocyte loss and cardiac dysfunction, as confirmed by electron microscopy, RNA analysis, and echocardiography. Imatinib cardiotoxicity was more severe in older mice, in part due to an age-dependent increase in oxidative stress. Mechanistically, depletion of the transcription factor GATA4 resulting in decreased levels of its prosurvival targets Bcl-2 and Bcl-XL was an underlying cause of imatinib toxicity. Consistent with this, GATA4 haploinsufficient mice were more susceptible to imatinib, and myocyte-specific up-regulation of GATA4 or Bcl-2 protected against drug-induced cardiotoxicity.
  
  
  CONCLUSIONS
  The results indicate that imatinib action on the heart targets cardiomyocytes and involves mitochondrial impairment and cell death that can be further aggravated by oxidative stress. This in turn offers a possible explanation for the current conflicting data regarding imatinib cardiotoxicity in cancer patients and suggests that cardiac monitoring of older patients receiving imatinib therapy may be especially warranted.
authors: Wael
authors: W
authors: Maharsy
authors: Anne
authors: A
authors: Aries
authors: Omar
authors: O
authors: Mansour
authors: Hiba
authors: H
authors: Komati
authors: Mona
authors: M
authors: Nemer
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001549:Benzamides / Q000633:toxicity*; D066126:Cardiotoxicity; D004452:Echocardiography; D050991:GATA4 Transcription Factor / Q000378:metabolism; D000068877:Imatinib Mesylate; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects; D010879:Piperazines / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D012307:Risk Factors; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D001549:Benzamides; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D051020:bcl-X Protein; D000068877:Imatinib Mesylate