What is chemotherapy-induced cardiomyopathy?

Definition of Chemotherapy-Induced Cardiomyopathy

Chemotherapy-induced cardiomyopathy (CIMP) is defined as a decrease in cardiac left ventricular ejection fraction (LVEF) that can be either global or more severe in the septum, accompanied by symptoms or signs of heart failure, resulting from exposure to cardiotoxic cancer therapies. 1

Classification of Chemotherapy-Induced Cardiotoxicity

Chemotherapy-induced cardiotoxicity can be classified into two main types:

Type I (Non-reversible) Cardiotoxicity

• Characterized by irreversible myocardial cell damage and loss
• Primary example: Anthracyclines (doxorubicin, daunorubicin)
• Pathophysiology involves:
  • Free radical formation
  • Inhibition of topoisomerase 2β
  • DNA double-strand breaks
  • Mitochondrial dysfunction
  • Cardiomyocyte apoptosis 1, 2
• Dose-dependent risk increases with cumulative exposure
• Can manifest years to decades after treatment completion

Type II (Reversible) Cardiotoxicity

• Characterized by cellular dysfunction (mitochondrial and protein alterations)
• Usually temporary with no injury marker release
• Primary example: Trastuzumab (HER2 inhibitor)
• Often recovers with normalization of cardiac function after drug discontinuation 1

Clinical Presentation and Timing

Chemotherapy-induced cardiotoxicity can present in different timeframes:

1. Acute cardiotoxicity (<1% of patients)

   • Occurs immediately after infusion
   • Manifests as transient decline in myocardial contractility
   • Usually reversible 1

2. Early-onset chronic progressive cardiotoxicity (1.6-2.1% of patients)

   • Occurs during therapy or within first year after treatment
   • Presents as dilated cardiomyopathy in adults 1

3. Late-onset chronic progressive cardiotoxicity (1.6-5% of patients)

   • Occurs at least 1 year after completion of therapy
   • May not become clinically evident until 10-20 years after treatment
   • Progressive in nature 1

Diagnostic Criteria

According to the Cardiac Review and Evaluation Committee supervising trastuzumab clinical trials, left ventricular dysfunction (LVD) is characterized by:

1. Decrease in cardiac LVEF that is either global or more severe in the septum
2. Symptoms of congestive heart failure (CHF)
3. Associated signs of CHF (S3 gallop, tachycardia, or both)
4. Decline in LVEF of at least 5% to less than 55% with accompanying signs or symptoms of CHF, or a decline in LVEF of at least 10% to below 55% without accompanying signs or symptoms 1

Risk Factors

Several factors increase the risk of developing chemotherapy-induced cardiomyopathy:

• Drug-related factors:

  • Cumulative dose (strongest predictor for anthracyclines)
  • Intravenous bolus administration
  • Higher single doses
  • Combination of cardiotoxic therapies 1, 2, 3

• Patient-related factors:

  • History of prior irradiation
  • Female gender
  • Age extremes (young and elderly)
  • Pre-existing cardiovascular disease
  • Hypertension
  • Diabetes
  • Renal failure 1, 2

Clinical Significance and Outcomes

Chemotherapy-induced cardiomyopathy has significant implications:

• Reported in 1-5% of cancer survivors 1
• Higher all-cause mortality compared to idiopathic dilated cardiomyopathy 4
• May compromise the clinical effectiveness of cancer therapy
• Affects patient's quality of life independently of oncological prognosis 5
• For anthracyclines, risk of clinical cardiotoxicity increases with cumulative dose:
  • 3-5% with 400 mg/m²
  • 7-26% at 550 mg/m²
  • 18-48% at 700 mg/m² 1

Monitoring Recommendations

Cardiac monitoring is essential for early detection:

• Baseline cardiac assessment including LVEF measurement before chemotherapy
• Regular LVEF measurements during treatment (every 3 months)
• Continued monitoring after completion of therapy
• Consider cardiac biomarkers (troponin, BNP) for early detection 1, 2, 6

Prevention Strategies

Several approaches can reduce the risk of chemotherapy-induced cardiomyopathy:

• Limiting cumulative anthracycline dose (recommended maximum lifetime cumulative dose for doxorubicin: 400-550 mg/m²)
• Using continuous rather than bolus anthracycline infusions
• Considering liposomal doxorubicin formulations
• Avoiding concurrent use of multiple cardiotoxic agents when possible
• Aggressive management of cardiovascular risk factors 1, 2, 7

Chemotherapy-induced cardiomyopathy represents a significant clinical challenge that requires careful monitoring and management to minimize its impact on cancer survivors' long-term health and quality of life.