What is anthracycline-induced cardiac dysfunction?

Anthracycline-Induced Cardiac Dysfunction

Anthracycline-induced cardiac dysfunction is a dose-dependent cardiotoxic effect characterized by progressive damage to cardiomyocytes, leading to initial diastolic dysfunction followed by systolic dysfunction and heart failure, with manifestations occurring either acutely, early (within one year), or late (years after treatment). 1

Definition and Pathophysiology

Anthracycline-induced cardiotoxicity is characterized by:

• Cellular changes: Alterations in sarcoplasmic reticulum (vacuolization), myofibrils (distortion and depletion), and myocytes (cell death) 1
• Mechanism: Multiple pathways including:
  • Oxidative stress through reactive oxygen species (ROS) generation 1, 2
  • Mitochondrial dysfunction and DNA damage 1
  • Inhibition of topoisomerase 2β leading to cell death pathways activation 3
  • Disruption of calcium homeostasis 1

Classification of Cardiotoxicity

Anthracycline cardiotoxicity manifests in three distinct timeframes:

1. Acute/Subacute Cardiotoxicity (<1% of patients):

   • Occurs immediately or within a week after infusion
   • Manifests as transient LV dysfunction, arrhythmias, and ECG changes
   • Usually reversible but may indicate risk for long-term damage 1, 2

2. Early-Onset Chronic Progressive Cardiotoxicity:

   • Develops during treatment or within the first year after completion
   • Affects approximately 9% of treated patients
   • Often asymptomatic initially 1, 2

3. Late-Onset Chronic Progressive Cardiotoxicity:

   • Develops more than one year after treatment completion
   • Can manifest 10-20 years after treatment
   • Progressive in nature, affecting up to 65% of patients 1, 2

Clinical Presentation and Diagnosis

Anthracycline-induced cardiac dysfunction presents as:

• Asymptomatic cardiac dysfunction in up to 57% of patients 1, 4
• Restrictive or dilated cardiomyopathy resulting in congestive heart failure in up to 16-20% of patients 1
• Left ventricular dysfunction defined as:
  • Decline in LVEF of ≥5% to <55% with heart failure symptoms, or
  • Decline in LVEF of ≥10% to <55% without symptoms 2
• Subclinical dysfunction detected by global longitudinal strain (GLS) reduction of ≥10% 5

Risk Factors

Key risk factors for developing anthracycline-induced cardiotoxicity include:

Drug-Related Factors:

• Cumulative dose: Strongest predictor (5% risk at 400 mg/m², 48% at 700 mg/m²) 1, 2
• Administration method: IV bolus more toxic than continuous infusion 2
• Combination therapy: Particularly with other cardiotoxic agents 1, 2

Patient-Related Factors:

• Age: Both extremes (young and elderly >65 years) at higher risk 1, 2
• Sex: Females at higher risk 1, 2
• Pre-existing cardiovascular disease or risk factors: Hypertension, diabetes 1, 2
• Prior mediastinal radiation 2
• Genetic susceptibility 1, 3

Monitoring and Detection

Early detection is crucial for managing anthracycline cardiotoxicity:

• Baseline cardiac assessment with LVEF measurement before treatment 2
• Regular LVEF monitoring during and after treatment 2
• Global longitudinal strain (GLS) to detect subclinical dysfunction before LVEF decline 5, 3
• Cardiac biomarkers (troponin, BNP) for early detection of myocardial injury 2, 3

Clinical Implications

The significance of anthracycline-induced cardiotoxicity includes:

• High mortality: Anthracycline-induced CHF has mortality rates up to 79% 1
• Therapy resistance: Often resistant to standard heart failure therapies 1
• Impact on cancer treatment: May limit the use of effective cancer therapies 1
• Long-term consequences: Increased lifetime risk of heart failure (15-fold in pediatric cancer survivors) 1

Prevention Strategies

Approaches to reduce the risk of anthracycline cardiotoxicity include:

• Limiting cumulative dose of anthracyclines 2
• Using continuous rather than bolus infusions 2, 6
• Considering liposomal doxorubicin formulations 3, 6
• Dexrazoxane as a cardioprotectant that interferes with topoisomerase 2β binding 3, 6
• Early cardioprotective medications: ACE inhibitors and beta-blockers may prevent LV dysfunction when given during chemotherapy 3
• Avoiding concurrent use of multiple cardiotoxic agents when possible 2

Management

Treatment of established anthracycline-induced cardiotoxicity follows standard heart failure guidelines:

• Standard heart failure therapies: ACE inhibitors, beta-blockers, digoxin, and diuretics 2, 6
• Withholding anthracyclines if EF <45% 2
• Long-term cardiac surveillance for all patients who received anthracyclines 2
• Heart transplantation may be considered in severe cases 6

Early detection and prompt intervention are critical, as cardiac dysfunction detected and treated early has better functional recovery compared to late identification 1.