What are the cardiac side effects of Doxorubicin (anthracycline antibiotic)

From the Guidelines

Doxorubicin can cause significant cardiac side effects, most notably dose-dependent cardiotoxicity that may lead to heart failure, with a risk that increases substantially at cumulative lifetime doses exceeding 400-450 mg/m² 1.

Cardiac Side Effects of Doxorubicin

The cardiac side effects of doxorubicin are a major concern in the management of patients receiving this chemotherapy agent. The risk of cardiotoxicity is dose-dependent, with higher cumulative doses associated with a greater risk of heart failure.

• The risk of cardiotoxicity increases substantially at cumulative lifetime doses exceeding 400-450 mg/m² 1.
• Patients should be monitored with baseline and periodic cardiac function assessments, including echocardiograms or MUGA scans before treatment and at regular intervals during therapy.
• Early signs of cardiotoxicity include decreased left ventricular ejection fraction and arrhythmias.

Mechanisms of Cardiotoxicity

The damage occurs through multiple mechanisms, including:

• Oxidative stress
• Mitochondrial dysfunction
• Direct DNA damage to cardiac cells

Risk Factors for Cardiotoxicity

Risk factors that increase susceptibility to cardiotoxicity include:

• Pre-existing heart disease
• Hypertension
• Age over 65
• Previous chest radiation
• Concurrent use of other cardiotoxic agents

Cardioprotective Strategies

Cardioprotective strategies include:

• Using dexrazoxane in selected patients
• Liposomal formulations of doxorubicin which have lower cardiac toxicity
• Continuous infusion rather than bolus administration
• Optimization of risk factor control and prophylactic cardioprotective medication regimens in patients with high baseline cardiotoxicity risk 1.

Importance of Prevention and Early Detection

Once doxorubicin-induced cardiomyopathy develops, it can be irreversible, so prevention and early detection are crucial for patient management. Measurement of cardiac biomarkers during chemotherapy could be a useful diagnostic tool for identification, assessment, and monitoring of cardiotoxicity with cancer therapy 1.

From the FDA Drug Label

Doxorubicin may cause heart problems that may lead to death. These problems can happen during your treatment or months to years after stopping treatment. The probability of developing impaired myocardial function, based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m 2 of doxorubicin, 3 to 5% at a dose of 400 mg/m 2,5 to 8% at 450 mg/m 2 and 6 to 20% at 500 mg/m 2 Cardiotoxicity may occur at lower doses in patients with prior mediastinal/pericardial irradiation, concomitant use of other cardiotoxic drugs, doxorubicin exposure at an early age, and advanced age Data also suggest that pre-existing heart disease is a co-factor for increased risk of doxorubicin cardiotoxicity.

Doxorubicin and Cardiac Side Effects: Doxorubicin may cause serious cardiac side effects, including heart problems that can lead to death. The risk of cardiac toxicity increases with cumulative doses of doxorubicin, especially above 400 mg/m². Factors that increase the risk of cardiac toxicity include prior mediastinal/pericardial irradiation, concomitant use of other cardiotoxic drugs, doxorubicin exposure at an early age, advanced age, and pre-existing heart disease.

• Key Risk Factors:
  • Prior mediastinal/pericardial irradiation
  • Concomitant use of other cardiotoxic drugs
  • Doxorubicin exposure at an early age
  • Advanced age
  • Pre-existing heart disease
• Estimated Risk of Cardiac Toxicity:
  • 1-2% at 300 mg/m²
  • 3-5% at 400 mg/m²
  • 5-8% at 450 mg/m²
  • 6-20% at 500 mg/m² 2, 2, 2

From the Research

Doxorubicin and Cardiac Side Effects

• Doxorubicin is a chemotherapeutic agent that can cause various side effects, including cardiac damage, with cardiomyopathy being the most dangerous side effect, leading to congestive heart failure 3.
• The exact mechanisms of doxorubicin-induced cardiotoxicity are not fully understood, but alteration in myocardial structure and functional cardiac disorders, inflammatory cytokines, oxidative stress pathways, mitochondrial damage, and intracellular Ca2+ overload are thought to play critical roles 3, 4.
• Doxorubicin-induced cardiotoxicity can manifest in several ways, including changes in electrocardiograms, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, heart failure, and congestive heart failure 4.
• Early decline in left ventricular ejection fraction (LVEF) can predict doxorubicin cardiotoxicity in lymphoma patients, with a decrease in LVEF of more than 10% units to a final LVEF ≤50% being a significant indicator of cardiotoxicity 5.
• Serial cardiac function monitoring with equilibrium radionuclide angiocardiography can help prevent congestive heart failure by identifying patients at risk of cardiotoxicity, with an incipient fall in LVEF detected on serial monitoring providing a cost-effective approach for predicting and preventing impending CHF 6.
• Doxorubicin-induced cardiotoxicity is thought to involve bioenergetic failure and cell death, with mitochondrial oxidative damage and loss of cardiomyocytes being key mechanisms, and pharmaceutical and nonpharmaceutical approaches may help decrease DOX cardiac alterations in animal models and humans 7.

Mechanisms of Cardiotoxicity

• Mitochondrial damage and oxidative stress are thought to be key mechanisms of doxorubicin-induced cardiotoxicity, with the activation of DOX molecule into a more reactive semiquinone by mitochondrial Complex I resulting in increased oxidative stress 3, 7.
• Inflammatory cytokines, intracellular Ca2+ overload, and iron-free radical production also play critical roles in the pathophysiology of doxorubicin-induced cardiotoxicity 3, 4.
• Alterations of mitochondrial metabolism and the unique characteristics of DOX delayed toxicity can interfere with how the cardiac muscle handles a "second-hit stress" 7.

Prevention and Monitoring

• Serial cardiac function monitoring with equilibrium radionuclide angiocardiography can help prevent congestive heart failure by identifying patients at risk of cardiotoxicity 6.
• Early decline in left ventricular ejection fraction can predict doxorubicin cardiotoxicity in lymphoma patients, and monitoring LVEF can help identify patients at risk of cardiotoxicity 5.
• Pharmaceutical and nonpharmaceutical approaches may help decrease DOX cardiac alterations in animal models and humans, although the limitations of each strategy need to be considered 7.