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Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by

Carlos J Miranda1, Hortence Makui, Ricardo J Soares

  • 1Hôpital Notre-Dame, Centre Hospitalier de l'Université de Montréal, QC, Canada.

Blood
|June 14, 2003
PubMed

Insights

Hfe deficiency, linked to iron metabolism, worsens doxorubicin (DOX) cardiotoxicity in mice. This suggests iron-related genetic defects may increase human susceptibility to DOX heart damage.

Area of Science:

  • Biochemistry
  • Genetics
  • Cardiology

Background:

  • Doxorubicin (DOX) chemotherapy is limited by cardiotoxicity.
  • Iron's role in DOX-induced cardiotoxicity is suggested by cardioprotective effects of iron chelators.
  • Hereditary hemochromatosis involves iron overload and is common in individuals of European descent.

Purpose of the Study:

  • To investigate if Hfe deficiency, a cause of iron metabolism defects, increases susceptibility to DOX-induced cardiotoxicity.
  • To compare acute and chronic cardiotoxicity and iron changes in Hfe knock-out (Hfe-/-) mice and wild-type mice after DOX treatment.

Main Methods:

  • Acute and chronic toxicity studies using doxorubicin (DOX) in Hfe knock-out (Hfe-/-) and wild-type mice.
  • Assessment of iron accumulation in heart, liver, pancreas, and spleen.
  • Measurement of serum creatine kinase and aspartate aminotransferase levels.
  • Histopathological examination of cardiac tissue for mitochondrial damage and iron deposits.

Main Results:

  • Hfe-/- mice showed intensified DOX-induced iron metabolism changes, accumulating more iron in the heart, liver, and pancreas, but less in the spleen.
  • Hfe-deficient mice exhibited greater sensitivity to DOX-induced elevations in serum creatine kinase and aspartate aminotransferase.
  • Increased mortality was observed in Hfe-/- and Hfe+/- mice after chronic DOX treatment compared to wild-type mice.
  • DOX-treated Hfe-/- mice displayed more severe mitochondrial damage and cardiac iron deposits.

Conclusions:

  • Hfe deficiency in mice significantly increases susceptibility to doxorubicin (DOX)-induced cardiotoxicity.
  • Genetic defects in iron metabolism, such as Hfe deficiency, may contribute to doxorubicin cardiotoxicity in humans.
  • These findings highlight the importance of considering iron metabolism in managing DOX therapy and patient risk stratification.

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