A mouse model for juvenile doxorubicin-induced cardiac dysfunction.

Area of Science:

• Cardiology
• Pharmacology
• Toxicology

Background:

• Doxorubicin (DOX) is a vital chemotherapy drug but causes dose-dependent cardiotoxicity, particularly in children.
• Understanding the molecular mechanisms of DOX-induced cardiotoxicity is crucial for developing preventative strategies.
• Existing mouse models often use acute administration in adult animals, limiting insights into chronic effects.

Purpose of the Study:

• To establish and characterize a juvenile mouse model for chronic doxorubicin (DOX)-induced cardiotoxicity.
• To investigate the cardiac functional and structural changes during DOX treatment and subsequent recovery in young animals.
• To explore the underlying mechanisms of cardiac dysfunction in different phases of the model.

Main Methods:

• Juvenile mice (2 weeks old) received chronic doxorubicin (DOX) treatment over 5 weeks (25 mg/kg cumulative dose).
• Cardiac function was assessed, and cardiac tissues were analyzed for cardiomyocyte apoptosis, atrophy, and fibrosis.
• Animals underwent a 13-week recovery period post-DOX to evaluate long-term effects.

Main Results:

• Chronic DOX treatment in juvenile mice led to decreased cardiac systolic function, significant cardiac atrophy, and reduced growth velocity.
• Despite recovery of cardiac size, systolic function remained impaired after DOX withdrawal.
• Increased cardiomyocyte apoptosis and myocardial fibrosis were observed during the recovery phase.

Conclusions:

• This juvenile mouse model effectively recapitulates chronic doxorubicin (DOX)-induced cardiotoxicity and cardiac dysfunction.
• Cardiac dysfunction during DOX treatment and recovery phases involves distinct underlying mechanisms.
• The findings highlight the long-term cardiac risks associated with DOX therapy in young individuals.