Cardiomyopathy, Chemical-Induced

Stephen A. Gannon, M.D.
Aravind Rao Kokkirala, M.D.

Definition

Cardiomyopathy, chemical-induced (CMc), is a change in cardiac structure and/or function caused by chemical compounds. Many chemicals, including environmental substances, prescription drugs, and illicit drugs, are associated with cardiomyopathy (CM). These include (but are not limited to) alcohol, cocaine, amphetamines, anabolic steroids, anthracyclines, 5-fluorouracil (5-FU), zidovudine, tyrosine kinase inhibitors, and trastuzumab.

Synonyms

Alcoholic cardiomyopathy (ACM)
Cocaine-induced CM
Anabolic steroid-induced CM
Anthracycline-induced CM
Chemotherapy-induced CM

ICD-10CM CODES
I42.7	Cardiomyopathy due to drug and external agent

Epidemiology & Demographics

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ACM occurs in about 10% of alcoholics and accounts for 21% to 36% of dilated cardiomyopathy in high-income countries. Alcohol intake is generally >80 to 100 g/day for 10 years or more.
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The risk of doxorubicin-induced cardiotoxicity is dose dependent: 3% to 5% with 400 mg/m², 7% to 26% at 550 mg/m²², and 18% to 48% at 700 mg/m².
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The addition of trastuzumab to an anthracycline-based chemotherapy regimen markedly increases the incidence of heart failure (28% vs. 1.7%-21% with trastuzumab alone). The incidence can be significantly reduced by introducing a drug-free interval between the agents. Long-term follow-up data regarding trastuzumab cardiotoxicity are favorable, as the cardiotoxic effects generally manifest during treatment and are reversible.

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Other chemotherapeutic agents known to cause cardiomyopathy include idarubicin (>90 mg/m², 5%-18%), epirubicin (>900 mg/m², 0.9%-11.4%), docetaxel (2.3%-13%), cyclophosphamide (7%-28%), bortezomib (2%-5%), sunitinib (2.7%-19%), 5-fluorouracil [5-FU] (6%-7%), and carfilzomib (11%-25%). Table 1 summarizes chemotherapeutic agents implicated in clinical syndromes of cardiotoxicity.

TABLE1 Chemotherapeutic Agents Implicated in Clinical Syndromes of CardiotoxicityFrom Mann DL, Zipes DP, Libby P, Bonow RO: Braunwald’s heart disease, ed 10, Philadelphia, 2015, Elsevier.

Agent	Frequency of Cardiotoxicity^∗	Comments
Left Ventricular Dysfunction–Heart Failure
Chemotherapeutics
Anthracyclines
Doxorubicin	+++	Highly dose-dependent Risk factors include age (old and young), prior mediastinal radiation, history of heart disease, decreased ejection fraction; drop in ejection fraction on drug therapy, female sex (for children), and other agents (especially trastuzumab) Risk decreased by liposomal encapsulation or dexrazoxane
Epirubicin	+
Idarubicin	++
Alkylating agents
Cyclophosphamide	+++	Primarily seen with high-dose “conditioning” regimens Risk factors are previous mediastinal irradiation and anthracycline drug therapy Also can have myocarditis, pericarditis, myocardial necrosis
Ifosfamide	+++
Taxanes
Paclitaxel	+/++	Also employed in paclitaxel-eluting stent
Docetaxel	+
Proteasome inhibitor
Bortezomib	+/++	Moderately high rates of HF seen in trials (5%), but rates only minimally higher than in patients receiving dexamethasone
Targeted Therapeutics
Monoclonal antibodies
Trastuzumab	++	Not common as single agent Increased risk with anthracyclines, paclitaxel, cyclophosphamide
Pertuzumab	+/++	Targets HER2 Rates of LV dysfunction as high as ∼25% in one series
Bevacizumab	+/++	Targets VEGF-A (ligand for VEGFRs) and serves as a trap, preventing interaction with its receptor HF can be seen in setting of severe hypertension, which occurs in 10%-25% of patients, depending on dose; anthracyclines may increase HF risk
Tyrosine kinase inhibitors
Imatinib, nilotinib	+	Can cause severe fluid retention with peripheral edema, pleural and pericardial effusion not secondary to LV dysfunction
Dasatinib	++	Same as above regarding fluid retention Can cause severe pulmonary hypertension; mechanism unclear
Sunitinib	+++	LV dysfunction common; hypertension likely plays role
Sorafenib	++	Rate of cardiotoxicity not clear as of yet
Ischemic Syndromes
Fluorouracil, capecitabine	++	ACS; patients with CAD at increased risk Recurs with rechallenge; multiple mechanisms proposed; etiology remains unknown
Cisplatin, carboplatin	+	ACS caused by vasospasm or vascular injury Hypertension common; thromboembolism more common (see below)
Interferon-α	+	Risk of ischemia increased in patients with CAD; hypertension common
Paclitaxel	+	Myocardial ischemia in 1%-5%; serious ischemic cardiac events not common
Docetaxel	+	Limited data, but rate probably ∼1%
Bevacizumab	++	Arterial thrombotic events including MI and stroke
Vinca alkaloids	+	∼1% risk of cardiac events; ischemia possibly caused by coronary spasm
Sorafenib	+/++	∼2.5% risk of ACS
Erlotinib Nilotinib	+/++	Limited data, but rate ∼2% Concern over possible increase in peripheral vascular events
Hypertension
Cisplatin	++++
Bevacizumab	++++	Extremely common with all anti-VEGF therapeutics to date
Sunitinib	++++	Intrinsic in mechanism of action of these agents
Sorafenib	+++
Venous Thrombosis
Cisplatin	+++	Deep vein thrombosis or pulmonary embolism in 8.5%; most occur early in treatment Additional risk factors for deep vein thrombosis often present
Thalidomide	++++	Uncommon with monotherapy, but risk rises with concurrent chemotherapy
Lenalidomide	+++	See comments for thalidomide
Erlotinib	++	Rate with erlotinib plus gemcitabine ∼2% over that with gemcitabine alone
ACS, acute coronary syndrome; CAD, coronary artery disease; HER2, human epidermal growth factor receptor 2; LV, left ventricular; MI, myocardial infarction; VEGF, vascular endothelial cell growth factor; VEGFR, vascular endothelial cell growth factor receptor.

Predominant Sex and Age

The prevalence of ACM appears to be similar among alcoholic men and women, with women developing left ventricular (LV) dysfunction at a lower ethanol dose than men. Significant racial differences exist, with blacks having higher mortality rates than non-Hispanic whites. Anthracycline- and trastuzumab-induced cardiomyopathy is more common in those aged >50 years.

Genetics

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In patients with ACM, the deletion (DD) genotype of angiotensin-converting-enzyme (ACE) is more common than insertion (II) and deletion, insertion (DI) genotypes. The underlying mechanism involves direct toxicity of ethanol to the myocardium through uncoupling of adenosine triphosphate.
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Anthracycline-induced CM is linked to an increase in cardiac oxidative stress via the pathways of mitochondrial nitric oxide synthesis, and nicotinamide adenine dinucleotide phosphate reduction.
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One study suggests that polymorphisms in the carbonyl reductase genes could be related to anthracycline-induced CM.

Risk Factors

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Consumption of more than 80 to 100 g/day of alcohol for more than 10 years significantly increases the risk of ACM.
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The occurrence of chronic anthracycline-induced CM is correlated to cumulative dose, age, preexisting heart disease, concomitant chemotherapy, and history of mediastinal radiation therapy. Children are more susceptible to anthracycline-induced CM.
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Infusional dosing may reduce the risk for cardiotoxicity compared to bolus regimens.

Physical Findings & Clinical Presentation

The majority of clinical characteristics of CMc are similar to dilated cardiomyopathy of other etiologies. Symptoms may be insidious or acute in onset.

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Acute anthracycline-induced CM can start at any time after the first dose and may present with arrhythmias (most commonly supraventricular tachycardia), LV dysfunction, or pericardial disease. Typically the first manifestation of anthracycline-induced cardiotoxicity is subtle diastolic dysfunction noted on tissue Doppler. The subacute and chronic symptoms may occur 3 months to 10 years after the last dose. Patients usually present with heart failure. More recently, mortality has improved as a result of medical treatment with ACE inhibitors and beta-blockers. In fact, recent trials, including the OVERCOME trial, have demonstrated a benefit in preemptively treating low-cardiac-risk patients undergoing anthracycline therapy with beta-blockers and ACE-inhibitors to prevent the development of CM.
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Cardiac symptoms after 5-FU treatment include angina (most common), myocardial infarction, arrhythmia, acute pulmonary edema, cardiac arrest, and pericarditis. The mechanism of angina and myocardial infarction is coronary vasospasm and endothelial injury. The overall incidence of angina is approximately 10%.
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ACM typically occurs after years of heavy drinking. Concurrent cirrhosis may be present. The presentation is typically heart failure with or without arrhythmia. Atrial fibrillation is the most common arrhythmia associated with chronic alcohol abuse and can also be seen with acute intoxication (holiday heart syndrome).
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Patients with cocaine-induced CM may present with adrenergic symptoms (palpitations, pallor, diaphoresis, and anxiety), hypertension, angina, atrial and ventricular arrhythmias, and heart failure.
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Anabolic steroids can cause LV hypertrophy and dilation, and lead to heart failure, arrhythmia, myocardial infarction, hypertension, and sudden death.

Etiology

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The underlying mechanism of chemotherapy-induced cardiotoxicity is not well established. Several pathways have been proposed, including an increase in oxidative stress, free radical production, apoptosis, disturbance of DNA, RNA and protein synthesis, and vasospasm.
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Nutritional deficiencies, such as thiamine deficiency, also play a role in ACM.

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Table 2 describes mechanisms of ethanol-induced myocardial injury. Table 3 summarizes the effects of light-to-moderate and heavier alcohol intake on cardiovascular risk factors and outcomes.

TABLE2 Mechanisms of Ethanol-Induced Myocardial InjuryFrom Mann DL, Zipes DP, Libby P, Bonow RO: Braunwald’s heart disease, ed 10, Philadelphia, 2015, Elsevier.

Direct Toxic Effects

Uncoupling of the excitation/contraction system

Reduced calcium sequestration in the sarcoplasmic reticulum

Inhibition of the sarcolemmal adenosine triphosphate–dependent Na⁺/K⁺ pump

Reduction in the mitochondrial respiratory ratio

Altered substrate uptake

Increased interstitial/extracellular protein synthesis

Toxic Effect of Metabolites

Acetaldehyde

Ethyl esters

Nutritional or Trace Metal Deficiencies

Thiamine

Selenium

Electrolyte Disturbances

Hypomagnesemia

Hypokalemia

Hypophosphatemia

Toxic Additives

Cobalt

Lead

Arsenic

TABLE3 Qualitative Effects of Light-to-Moderate and Heavier Alcohol Intake on Cardiovascular Risk Factors and OutcomesFrom Mann DL, Zipes DP, Libby P, Bonow RO: Braunwald’s heart disease, ed 10, Philadelphia, 2015, Elsevier.

Cardiovascular Risk Factors and Outcomes	Light-to-Moderate Alcohol Intake (<2 Drinks per Day)	Heavier Alcohol Intake (>2 Drinks per Day)
Blood pressure	↔	↑↑
HDL cholesterol	↑↑	↑↑↑
Triglycerides	↑	↑↑
LDL cholesterol	↔ or ↓	↑
Platelet aggregability/coagulability	↓	↓↓
Systemic inflammation	↓	↑
Congestive heart failure	↓	↑↑
Coronary artery disease (angina, nonfatal MI)	↓↓	↓
Atrial fibrillation	↔	↑↑
Stroke	↓	↑↑
Sudden cardiac death	↓↓	↑

Diagnosis

Differential Diagnosis

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Infectious cardiomyopathy: viral, HIV related, Lyme disease, Chagas disease
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Ischemic cardiomyopathy
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Dilated cardiomyopathy, related to valvular disease or hypertension
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Cirrhotic cardiomyopathy
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Tachycardia-induced cardiomyopathy
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Stress-related (takotsubo) cardiomyopathy
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Peripartum cardiomyopathy
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Genetic causes of dilated cardiomyopathy

Workup

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Chemical exposure history
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Electrocardiogram, serum electrolytes, renal function, and hepatic function.
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Serum troponin and brain natriuretic peptide (BNP) levels.
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Transthoracic echocardiogram for the evaluation of heart structure and function.
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Rule out the diagnosis of coronary artery disease by coronary angiography.
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Cardiac magnetic resonance (CMR) imaging can be used to evaluate for myocardial scar and fibrosis.

Laboratory Tests

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There are no specific diagnostic tests to help differentiate CMc from other forms of CM, but the following laboratory tests are generally helpful; serum electrolytes, renal function, hepatic function, thyroid-stimulating hormone, iron profile, and inflammatory markers.
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Recent studies have suggested that early elevation of troponin levels, BNP, and myeloperoxidase following chemotherapy may be a predictor of future development of cardiomyopathy.

Imaging Studies

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ECG

Nonspecific findings of a cardiomyopathy may be present, including sinus tachycardia, nonspecific ST-T wave changes, decreased QRS voltage, interventricular conduction delay or bundle branch block, and QT interval abnormalities. In 5-FU toxicity, significant ST segment deviations may present.

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Echocardiogram
1. 1.
  
  Asymptomatic alcoholics may present with mild LV hypertrophy, diastolic dysfunction, LV dilation, and decrease in left ventricular ejection fraction (LVEF).
2. 2.
  Baseline LVEF should be performed before initiation of anthracycline-based chemotherapy, preferably with an echocardiogram or MUGA scan (multigated acquisition).
  1. •
    
    Anthracycline-based chemotherapy should generally be avoided for patients with an LVEF ≤40, or LVEF >40 but <50 with prior heart failure.
  2. •
    
    Total doxorubicin dose should be limited to 450 mg/m².
  3. •
    
    If baseline LVEF is ≥55%, then subsequent evaluation should be at the end of treatment if the doxorubicin dose is <200 mg/m² or serially at 200, 300, 350, and 400 mg/m² for higher doses. Doxorubicin therapy should be discontinued if there is a >15% absolute drop in LVEF, decease in LVEF to ≤40%, or symptomatic congestive heart failure with an LVEF <50. There has been no direct causal link between anthracyclines and the development of heart failure with a preserved ejection fraction.
  4. •
    
    Peak systolic global longitudinal strain imaging (GLS) is an emerging echocardiographic measurement. A 10% to 15% early decrease in GLS by speckle tracking echocardiography during treatment seems to be the most useful parameter for the early detection of cardiotoxicity. However, large population studies confirming the validity of GLS are pending.
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Radionuclide imaging (Fig. 1).
1. 1.
  
  If baseline LVEF is <50% with no prior history of heart failure, the cardiac risks vs. oncological benefits should be discussed with the patient, cardiologist, and oncologist before initiating therapy. Cardio-protective agents such as ACE inhibitors and beta-blockers should be initiated and serial LVEF measurements done after each dose.
2. 2.
  
  Even after chemotherapy, periodic screening with echocardiography and/or biomarkers should be considered for up to 10 years for those with high cumulative anthracycline doses or a history of reversible LV dysfunction during treatment.
FIG.1

Technetium-99m-pertechnetate multigated acquisition scans in a 47-year-old woman with breast cancer

Treatment

Prevention

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Noninvasive assessment of LV function before, during, and after anthracycline-containing chemotherapy with echocardiography or MUGA scan.
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To reduce the risk of doxorubicin cardiotoxicity, the lifetime cumulative dosage should be limited to <450 mg/m² in adults.
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Other approaches include the use of infusion rather than bolus dosing, liposomal encapsulated doxorubicin, less cardiotoxic analogs of doxorubicin such as epirubicin, and co-administration of protective agents such as dexrazoxane.
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5-FU treatment should be terminated if cardiac symptoms develop. Readministration is not recommended.

Acute General Rx

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Treat decompensated heart failure with diuresis and inotropes if there is a low cardiac output state.
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For angina in acute cocaine intoxication or induced by 5-FU, benzodiazepines, nitrites, and calcium channel blockers are first-line therapy. If ECG provides evidence of acute myocardial infarction, patients should proceed to emergent cardiac catheterization and coronary angiography.

Chronic Rx

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Dexrazoxane is an ethylenediaminetetraacetic acid-like chelator that acts by binding to iron, which prevents anthracycline cardiotoxicity. Cardio-oncology experts suggest a 10:1 ratio of dexrazoxane to anthracycline, given 15 to 30 minutes before doxorubicin administration. However, its routine use is not currently recommended in adults except in cases of a cumulative doxorubicin dose of 300 mg/m² or greater.
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Those developing anthracycline-induced CM generally should not be rechallenged with the drug, as the cardiac damage is usually irreversible due to cell death.
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Beta-blocker: Carvedilol and nebivolol have been shown to have protective effects on LV systolic function during anthracycline therapy.
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The following ACE inhibitors and angiotensin receptor blocker (ARB) have been shown to protect against anthracycline cardiotoxicity: enalapril, ramipril, and telmisartan.
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Thiamine, folic acid, and multivitamins are adjunctive treatments for ACM. Abstinence can usually reverse the cardiomyopathy.

Disposition

Prognosis depends on the dosage of chemicals and the severity of LV dysfunction.

Referral

Close follow-up with a cardiooncologist.

Pearls & Considerations

The presentation of chemotherapy-induced cardiac toxicity ranges from an asymptomatic decline in LVEF to overt heart failure. The incidence is dose-dependent in the case of anthracyclines and may manifest up to 10 years after the initial exposure. Therefore, regular clinical follow-up with echocardiographic surveillance is advised.

Ferri – Cardiomyopathy, Chemical-Induced