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Cardiotoxicity of Cancer Therapy & Toxic Cardiomyopathies

Name: Cardiotoxicity of Cancer Therapy & Toxic Cardiomyopathies
Creator: Veli Bakalov, MD

Match each drug to its injury: dose, reversibility and timing

Cardiology·Heart Failure & Cardiomyopathy·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Anthracyclines cause cumulative, mostly irreversible myocyte death (type I); heart failure risk rises steeply above ~400–450 mg/m² cumulative doxorubicin.
Chest radiation, age under 18 or over 65, preexisting heart disease and added trastuzumab amplify anthracycline risk.
Obtain a baseline LVEF (echo or MUGA) before anthracyclines or trastuzumab; dexrazoxane, an iron chelator, is cardioprotective at high doxorubicin doses.
Trastuzumab dysfunction is dose-independent and usually reversible: LVEF every 3 months, label rule: hold for a ≥16-point fall (or ≥10 points to below normal), resume after recovery; ESC 2022 allows continuing with asymptomatic LVEF 40 to 49% on an ACE inhibitor or ARB plus beta-blocker, and holds for LVEF below 40% or symptomatic HF.
5-FU and capecitabine cause coronary vasospasm with ST elevation; stop the drug and give nitrates plus a calcium channel blocker.
Checkpoint-inhibitor myocarditis appears within weeks with rising troponin and AV block, often with myositis; hold the drug and give high-dose IV methylprednisolone.
VEGF inhibitors cause hypertension (treat with ACE inhibitor/ARB or amlodipine); arsenic trioxide and some TKIs prolong QT (hold if QTc >500 ms).
Mediastinal radiation causes premature ostial CAD, calcific valve disease and constrictive pericarditis 10–20+ years later.
Alcohol, cocaine and methamphetamine cardiomyopathy can improve markedly with abstinence plus guideline-directed HF therapy.

Overview: how cancer therapy injures the heart

Patterns. Oncology treatments damage the heart in predictable ways: myocyte death, reversible contractile dysfunction, coronary vasospasm, hypertension, QT prolongation, immune myocarditis and radiation fibrosis. The drug, cumulative dose and time since exposure identify the culprit: hours to days (5-FU spasm), weeks (arsenic QT prolongation, checkpoint myocarditis), months (trastuzumab), the first year (most anthracycline injury) or 10–20+ years (radiation).

Defining dysfunction. Cancer therapy–related cardiac dysfunction is usually an LVEF fall of more than 10 percentage points to below normal (about 50–53%), with or without symptoms; a relative fall in global longitudinal strain of more than 15% or a rising troponin can come first.

Type I vs type II cardiac dysfunction

Feature	Anthracycline (type I)	Trastuzumab (type II)
Mechanism	Iron-driven free radicals, topoisomerase IIβ injury → myocyte death	HER2 (ErbB2) blockade removes a myocyte survival signal
Dose relation	Cumulative; risk climbs above ~400–450 mg/m² doxorubicin	Dose-independent
Biopsy	Myofibril loss, cytoplasmic vacuolization	No structural damage
Course	Mostly irreversible dilated cardiomyopathy	Usually recovers within months; rechallenge often possible

Anthracyclines

Mechanism and timing. Doxorubicin, daunorubicin and epirubicin generate reactive oxygen species through iron-dependent redox cycling and poison topoisomerase IIβ in cardiomyocytes. Lost myocytes do not regenerate, so injury accumulates cycle after cycle. Acute toxicity during infusion (arrhythmia, myopericarditis) is rare; most heart failure appears within the first year, but childhood survivors can present decades later and need lifelong surveillance.

Risk factors. Cumulative dose, prior or concurrent chest or mediastinal radiation, age under 18 or over 65, preexisting LV dysfunction or CAD, hypertension, diabetes, and sequential trastuzumab.

~400–450 mg/m²cumulative doxorubicin above which heart failure risk rises steeply

~300 mg/m²cumulative doxorubicin at which dexrazoxane is typically added

Monitoring and prevention. Measure LVEF by echo (or MUGA) before the first dose, during treatment and after completion; stop or modify the drug if EF falls. (Pulmonary function tests are the baseline study for bleomycin, not doxorubicin.) Dexrazoxane, an iron chelator, blunts free-radical injury; liposomal doxorubicin, slower infusion and the lifetime dose limit also help. Treat established dysfunction as HFrEF, starting with an ACE inhibitor or ARB plus a beta-blocker.

Trastuzumab and HER2-targeted therapy

Features. Trastuzumab dysfunction is dose-independent, shows no necrosis on biopsy and usually reverses within months of holding the drug. Risk is highest when it follows an anthracycline, so the two injuries often coexist in HER2-positive breast cancer.

Baseline LVEFEcho or MUGA before the first dose.
Every 3 monthsRepeat LVEF throughout therapy.
Significant fallEF down ≥16 points, or ≥10 points to below normal → hold trastuzumab for at least 4 weeks and start an ACE inhibitor or ARB plus a beta-blocker.
Recheck and resumeRepeat LVEF in about 4 weeks and resume once EF recovers; persistent dysfunction ends HER2 therapy. ESC 2022 differs: asymptomatic LVEF 40 to 49% can continue trastuzumab with cardioprotection and closer monitoring; LVEF below 40% or symptomatic HF interrupts it.

Vascular, electrical and immune toxicities

Fluoropyrimidines. 5-FU (especially continuous infusion) and its oral prodrug capecitabine cause coronary vasospasm: angina, ST elevation and occasionally MI, arrhythmia or sudden death during or shortly after dosing. Stop the drug, give nitrates and a calcium channel blocker, and avoid rechallenge when an alternative regimen exists.

Switching from 5-FU to capecitabine does not avoid vasospasm, and dexrazoxane protects only against anthracyclines.

Checkpoint-inhibitor myocarditis. Anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies can unleash T-cell myocarditis, usually within 3 months and most often with nivolumab plus ipilimumab. Clues are a rising troponin, new AV block or ventricular arrhythmias and heart failure; LVEF is normal in about half. Myositis (high CK) and myasthenia-like weakness (ptosis, diplopia, dyspnea) often coexist. Nearly half died in early case series.

Suspected ICI myocarditis: hold the checkpoint inhibitor and give IV methylprednisolone (~1 g daily for 3–5 days) without waiting for biopsy; use telemetry, pace for high-grade block, and add immunosuppression if steroid-refractory. NSAIDs and colchicine are not treatment.

Other agents and their cardiac effects

Agent	Cardiac effect	Management
Bevacizumab; sunitinib, sorafenib, pazopanib	Dose-related hypertension; proteinuria, arterial thrombosis, LV dysfunction	ACE inhibitor/ARB or amlodipine, usually continuing the drug; avoid diltiazem and verapamil (CYP3A4 inhibition raises TKI levels)
Arsenic trioxide (APL); nilotinib, vandetanib, ribociclib	QT prolongation, torsades	Baseline ECG, K >4 mEq/L and Mg replete, no other QT drugs; hold if QTc >500 ms
Ibrutinib	Atrial fibrillation	Rate control; weigh bleeding risk before anticoagulation
High-dose cyclophosphamide	Hemorrhagic myopericarditis	Supportive care; dose limitation

Amiodarone lengthens QT further and is not the fix for drug-induced QT prolongation.

Mediastinal radiation: the late toll

Spectrum. Radiation to the mediastinum or left chest (Hodgkin lymphoma, breast cancer) damages every cardiac layer 10–20+ years later: premature CAD with ostial and proximal lesions, thickened and calcified aortic and mitral valves, constrictive pericarditis (Kussmaul sign, pericardial knock, calcification), restrictive cardiomyopathy and conduction disease.

Approach. Anthracycline plus chest radiation is the classic double hit in Hodgkin survivors. They need lifelong risk-factor control and a low threshold for ischemic and valvular testing; angina at 40 is not too young for CAD in a survivor.

Toxic cardiomyopathies: alcohol and stimulants

Alcohol. Years of heavy drinking (often more than 80 g/day for over 5 years) cause dilated cardiomyopathy; binges can trigger atrial fibrillation (holiday heart). Thiamine deficiency (wet beriberi) is a separate high-output failure that responds to thiamine.

Cocaine and methamphetamine. Stimulants cause dilated cardiomyopathy as well as LVH, myocarditis and vasospasm; methamphetamine cardiomyopathy is increasingly seen in young adults.

For all three, complete abstinence plus standard HFrEF therapy can markedly improve or normalize EF, and sobriety is a prerequisite for transplant candidacy.