Can cyclophosphamide increase left ventricular ejection fraction?

Cyclophosphamide Does Not Increase Ejection Fraction—It Causes Cardiotoxicity

Cyclophosphamide does not increase left ventricular ejection fraction; rather, it is a cardiotoxic chemotherapeutic agent that causes left ventricular dysfunction and heart failure in 7-28% of patients, particularly at high doses (≥140-150 mg/kg). 1

Mechanism and Pattern of Cyclophosphamide Cardiotoxicity

Cyclophosphamide causes direct myocardial injury through its metabolite acrolein, leading to:

• Hemorrhagic myopericarditis with endothelial injury documented on histopathology 2, 3
• Acute onset cardiac dysfunction typically occurring within 2-8 days after the first dose 4, 2
• Myocardial edema manifesting as reversible increases in left ventricular mass index (+10%) and decreased ECG voltage (-20%) 5
• Diastolic dysfunction (abnormal E/A ratio) appearing before systolic dysfunction in the early course 4

Dose-Dependent Risk Profile

The cardiotoxicity risk is directly proportional to cumulative dose:

• 100 mg/kg total dose: 0% incidence of cardiac failure 4
• 120 mg/kg total dose: 1.2% incidence of cardiac failure 4
• ≥140-150 mg/kg: Cardiotoxicity becomes clinically significant 1
• 174-200 mg/kg: 8.5% incidence of fatal cardiac failure 5, 4
• 180 mg/kg over 4 days: 28% developed congestive heart failure, with 19% mortality 2

Clinical Presentation and Outcomes

When cyclophosphamide cardiotoxicity occurs, the clinical course is characterized by:

• Acute heart failure developing within days of drug administration 1
• Pericardial effusion in 33% of affected patients 2
• Cardiac tamponade in 19% of cases 2
• High mortality rate: 11 of 12 patients (92%) with fatal cardiac failure died at a median of 7 days after first CY dose 4

Recovery Potential vs. Permanent Damage

Some patients may experience partial recovery of ejection fraction if cardiotoxicity is detected early and treated aggressively:

• In one case report, LVEF improved from 31% to 37% at discharge and normalized to 60% after 1 month with heart failure treatment 6
• Reversible ECG voltage changes and left ventricular mass increases resolve by the third week following cyclophosphamide in patients without clinical heart failure 5

However, this represents recovery from acute injury, not an increase above baseline. The drug itself does not have any mechanism to improve cardiac function.

Risk Factors for Severe Cardiotoxicity

Patients at highest risk for irreversible cardiac damage include those with:

• Prior congestive heart failure or baseline LVEF <50% (independent predictor of clinical cardiotoxicity, P<0.05) 5
• Combination therapy with anthracyclines (doxorubicin), which dramatically amplifies cardiotoxicity 1, 6
• Older age 1
• Prior mediastinal irradiation 1

Critical Clinical Pitfall

Do not confuse partial recovery of ejection fraction after acute cyclophosphamide cardiotoxicity with the drug having a beneficial effect on cardiac function. 6 The improvement represents healing from acute myocardial injury, not enhancement of baseline cardiac performance. Cyclophosphamide remains contraindicated in patients with pre-existing cardiac dysfunction, and the drug should be avoided or dose-reduced in high-risk patients whenever oncologically feasible. 1