a case of epirubicin-associated cardiotoxicity progressing

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□ CASE REPORT □

A Case of Epirubicin-Associated Cardiotoxicity Progressingto Life-Threatening Heart Failure and

Splenic Thromboembolism

Yuji Okura 1, Takashi Kawasaki 2, Chizuko Kanbayashi 3 and Nobuaki Sato 3

Abstract

We present the case of a 42-year-old Japanese woman who developed acute heart failure after chemother-

apy with epirubicin for breast cancer. Echocardiography revealed a cardiac dysfunction with left ventricular

thrombus. Serial serum troponin T tests were positive over a 5-week period, and an endomyocardial biopsy

demonstrated ultrastructural lesions which were similar to those caused by cardiotoxicities due to doxorubi-

cin. Although the patient developed splenic thromboembolism, her cardiac function recovered gradually, and

she regained full range of her activities. This case report demonstrates that epirubicin-associated cardiotoxic-

ity causes life-threatening heart failure and supportive care is important until the patient recovers from acute

intoxication.

Key words: epirubicin, cardiotoxicity, thromboembolism

(Intern Med 51: 1355-1360, 2012)(DOI: 10.2169/internalmedicine.51.6973)

Case Report

A 42-year-old Japanese woman complained of shortness

of breath in July 2010, 5 weeks after she received a final

dose of epirubicin for chemotherapy for breast cancer. She

was diagnosed with mild congestive heart failure and pre-

scribed furosemide and enalapril. One month later, she de-

veloped dyspnea, general fatigue, and loss of appetite, and

she was admitted to our hospital with orthopnea in August

2010. A chest radiograph showed cardiomegaly and pulmo-

nary congestion (Fig. 1B). Electrocardiogram showed low

voltage in extremity leads and poor R-wave progression in

precordial leads (Fig. 2B). The patient’s height was 153 cm

and weight 57 kg. At the time of hospital admission, she

had gained 3 kg in weight since her last regular medical

check-up 4 weeks earlier. Physical examination showed third

heart sound, hypotension, and tachycardia (Fig. 3).

The patient had been diagnosed in November 2008 with

cancer of the left breast and metastasis to local lymph nodes

and ilium. She had received 9 months of combined endo-

crine therapy with ovarian suppressant drugs and tamoxifen,

a selective estrogen receptor modulator; however, the ther-

apy was ineffective. After cardiovascular screening, the pa-

tient received 13 cycles of 60 mg/m2 epirubicin (cumulative

dose of 780 mg/m2) in combination with 600 mg/m2 cyclo-

phosphamide (cumulative dose of 7,800 mg/m2) every 3

weeks from August 2009 through June 2010. The patient

did not receive mediastinal irradiation. Echocardiography

showed normal left ventricular ejection fraction (LVEF) and

LV size (Fig. 3). The patient did not display any clinical

symptoms of heart failure during chemotherapy. After che-

motherapy, the tumor size was reduced to a level below the

sensitivity of detection of computed tomography; the con-

centration of the tumor markers CEA and CA15-3 decreased

and then remained within their normal ranges. These results

clearly indicated that the chemotherapy was effective.

On hospital admission in August 2010, N-terminal pro-B-

type natriuretic peptide was elevated at 9,677 pg/mL

(Fig. 3). A test for serum troponin T (TnT; ElecsysⓇ tro-

ponin T STAT test) was positive, but creatine kinase levels

were normal. Platelet counts, prothrombin time, activated

１Department of Cardiology, Niigata Cancer Center Hospital, Japan, ２Department of Pathology, Niigata Cancer Center Hospital, Japan and ３De-

partment of Breast Surgery, Niigata Cancer Center Hospital, Japan

Received for publication November 21, 2011; Accepted for publication February 7, 2012

Correspondence to Dr. Yuji Okura, [email protected]

Intern Med 51: 1355-1360, 2012 DOI: 10.2169/internalmedicine.51.6973

1356

Figure　1.　Chest X-rays before administration of epirubicin (October 29, 2008; A) and at the time of hospital admission (August 10, 2010; B), at which point cardiomegaly and pulmonary congestion were indicated.

October 29, 2008 August 10, 2010A B

Figure　2.　Electrocardiograms before chemotherapy (October 29, 2008; A), at the time of hospital admission (August 10, 2010; B), and 1 year later (September 28, 2011; C). Heart rates were 65, 105, and 50 beats/min, respectively. Electrocardiogram showed low voltage in extremity leads and poor R-wave progression in precordial leads at hospital admission (B). One year later, the electrocardio-gram was almost normalized and it was similar to that recorded before chemotherapy (A, C).

October 29, 2008 August 10, 2010 September 28, 2011

I

II

III

aVR

aVL

aVF

I

II

III

aVR

aVL

aVF

I

II

III

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

V1

V2

V3

V4

V5

V6

V1

V2

V3

V4

V5

V6

A B C

partial thromboplastin time, and concentrations of fibrino-

gen, fibrin degradation products, and D-dimer were within

their normal ranges. Echocardiography revealed a dilated

and severely hypokinetic LV.

The patient was diagnosed with acute heart failure, and

she was administered oxygen, diuretics, and vasodilators. In-

travenous dobutamine also was initiated at 5.0 μg/kg/min

because hypoperfusion and pulmonary and liver congestion

were observed. Ambulatory monitoring showed frequent

runs of non-sustained ventricular tachycardia. On the 8th

hospital day, echocardiography showed LV hypokinesis as-

sociated with mural thrombus (Fig. 4A). Laboratory testing

for thrombophilia, including concentrations of plasma anti-

thrombin III, activated protein C, protein S, anti-cardiolipin

β2-glycoprotein-I, and dilute Russell viper venom time, was

normal. Although unfractionated heparin and warfarin were

administered and reduced the size of the LV thrombus, the

patient developed splenic thromboembolism associated with

acute pain in her left hypochondrium on the 18th hospital

day (Fig. 4B).


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Figure　3.　Clinical course. Systolic blood pressure in mid-July 2010, when the patient developed mild congestive heart failure, was lower than that measured during chemotherapy in August 2009 through June 2010. Sinus tachycardia continued for the first 5 weeks after admission. The cardio-thoracic ratio and LV diastolic dimension increased and the LVEF decreased after chemotherapy. N-terminal pro-B-type natriuretic peptide reached as high as 15,213 pg/mL. Serial serum TnT tests were positive over the first 6 weeks after hospital admission. After the serum TnT test turned nega-tive, all indicators of heart failure improved. A surge in D-dimer was observed during the develop-ment of LV thrombus. APTT/control: activated partial thromboplastin time/control time, LVEF: left ventricular ejection fraction, NT-pro BNP: N-terminal pro-B-type natriuretic peptide, PT-INR: prothrombin time-international normalized ratio, TnT: troponin T

Systolic blood pressure (mmHg)

Heart rate (/min)

OctoberSeptemberAugustJulyAug 2009-June 2010

VV

VVV

V VVVV VVVV

VV

V

VVVV

V VVV VV VVV VVVVVVVV

120110100

908070

130

LV diastolic dimension (mm) LVEF(%)

203040506070

VV V V V V

V V V V

V

V

Cardiothoracic ra o (%)

51 52 57 55 55 55 55 55 55 53 5238

NT-pro BNP (pg/mL)

15,00010,000

5,000 0

Troponin T + –+ + + – –+ –D-dimer ( g/mL)APTT / control PT-INR

1.01.0 1.0

1.0 1.1

4.9 2.0 1.2

5.1 2.1 1.1

21.0 3.0 1.5

4.3 2.4 1.5

2.5 3.0 1.1

0.8

2.6 2.0 2.6 2.0 2.3 2.2

Enalapril 2.5 mg/dFurosemide 20 80 mg/d

Spironolactone 25 mg/dWarfarin 1.0 3.0 2.5 2.0 1.5 mg/d

Digoxin 1.25 mg/dPimobendan 1.25 2. 5.0 mg/d

Amiodarone 200 00 50 mg/d

Dobutamine 5 g/kg/min

Heparin 16,000 unit/d

5 mg/d

50 mg/d

Figure　4.　Echocardiogram and computed tomography after hospital admission. (A) Echocardio-gram on day 8 after hospital admission showed a thrombus in the LV (arrowhead). The size was 27×13 mm. (B) Computed tomography on day 18 after hospital admission showed a splenic infarc-tion (arrowhead). LV: left ventricle, RA: right atrium, RV: right ventricle

LVRV

RA

A B

Cardiac catheterization and endomyocardial biopsy were

performed on day 17 after hospital admission. The patient

had been treated with intravenous dobutamine at 5.0 μg/kg/

min and intravenous furosemide at 20 mg every 6 hours.


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Figure　5.　Histopathological and immunohistochemical findings after endomyocardial biopsy. (A) Myocyte necrosis and degeneration associated with infiltration of mononuclear cells were observed (Hematoxylin and Eosin staining, original magnification 200×). (B) Interstitial fibrosis and edema were observed (Azan Mallory stain, 200×). (C) Some myocytes were not positive for anti-Desmin stain (Dako), 200×. (D) Most of the infiltrating cells were positive for anti-CD45RO stain (Dako), 200×.

A B

C D

Mean pulmonary artery wedge pressure, pulmonary artery

pressure, and cardiac index by thermodilution were 19

mmHg, 26 mmHg, and 1.4 L/min/m2, respectively. The pa-

tient’s coronary arteries were normal. Endomyocardial bi-

opsy from the right ventricle showed myocyte degeneration,

interstitial myocardial edema, fibrosis, and slight infiltration

of mononuclear cells, most of which were positive for

CD45RO (Dako) (Fig. 5) and negative for CD15. Some

myocytes were not stained by desmin (Dako). Electron mi-

crographs showed myofibrillar loss, swollen mitochondria

with loss of compact cristae, and dilated sarcoplasmic re-

ticulum (Fig. 6).

On the 25th hospital day, the patient was examined by201Tl and 123I-beta-methyl-p-iodophenyl-pentadecanoic acid

(BMIPP) myocardial single-photon emission computed to-

mography (SPECT) (Fig. 7). Myocardial uptake of 201Tl was

preserved, but that of 123I-BMIPP significantly decreased in

the anteroseptal and inferior walls of the LV. The distribu-

tion of 201Tl in the SPECT showed blood flow in the LV

walls and that of 123I-BMIPP showed fatty acid metabolism

in the myocardium. Therefore, her myocardial metabolism

seemed impaired. She also underwent 67Ga scintigraphy on

the 35th hospital day, and no accumulation was observed in

the myocardium.

Intravenous dobutamine was continued until day 35 after

hospital admission (i.e., 12 weeks after the last dose of

epirubicin), when the serum TnT test became negative. Car-

diac function gradually recovered, and the patient was dis-

charged on day 73 after hospital admission, with a LVEF of

43%. She had taken enalapril 2.5 mg, furosemide 80 mg,

spironolactone 50 mg, warfarin 1.5 mg, digoxin 1.25 mg,

pimobendan 5.0 mg, and amiodarone 50 mg daily. One year

later, the patient had resumed her full range of social and fa-

milial activities. She had no recurrence of breast cancer.

Electrocardiogram findings were almost normalized and

similar to those recorded before chemotherapy (Fig. 2A, C).

She had taken enalapril 5.0 mg, warfarin 2.5 mg, pimoben-

dan 2.5 mg, and bisoprolol 2.5 mg daily, and her LVEF had

recovered to 52%. A repeat endomyocardial biopsy was not

performed.

Discussion

Long-term administration of anthracycline-like agents

such as doxorubicin and epirubicin is known to cause life-

threatening heart failure owing to drug-associated myocar-

dial damage―a phenomenon called anthracycline-associated

cardiotoxicity (ACT). Acute ACT occurs during treatment,


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Figure　6.　Electron micrographic images after endomyocardial biopsy. (A) Myofibrillar disruption and loss, different sized clusters of mitochondria, and distorted Z-bands were observed (arrows). (B) Vacuolar changes, myofibrillar loss, and peripheral Z-band remnants in an apparently intact myo-cyte in the lower left side of the image were observed (arrows). (C) Some of the mitochondria ap-peared swollen with loss of compact cristae. (D) Dilatation of transverse tubules was observed (ar-rows).

A B

C D

Figure　7.　Dual SPECT with 201Tl and 123I-BMIPP on the 25th hospital day. Although a slight decrease in 201Tl accumu-lation was observed in the anterior and inferior wall of the LV, 201Tl distribution was preserved in the LV myocardium (upper image). Distribution of 123I-BMIPP significantly de-creased in the anteroseptal and inferior walls (lower image). Arrow-shaped accumulation at 8 o’clock in the lower image was an artifact created by the central venous catheter through which 123I-BMIPP was injected.

TI201

I-BMIPP123

often immediately after the first dose, and manifests itself

predominantly in the form of arrhythmias and rarely in the

form of pericarditis, myocarditis, or acute LV failure (1).

Chronic ACT, which is typically manifested as clinical heart

failure or subclinical LV dysfunction, presents early, within

one year after termination of chemotherapy, or late, years or

even decades after termination of chemotherapy (2). The in-

cidence of ACT depends on the cumulative dose of the

drug (2).

Epirubicin is less cardiotoxic than doxorubicin on a milli-

gram per milligram basis; it is considered the preferred an-

thracycline for solid-tumor chemotherapy (3). In patients

with metastatic breast cancer, however, an increased cumula-

tive dosage of epirubicin can cause cardiotoxicity. Ryberg et

al. reported that the risk of developing congestive heart fail-

ure increased during the first 6 months after discontinuation

of epirubicin treatment and reached a near plateau by the

end of the 2.5-year follow-up period (4). The risk for a 40-

year-old woman was 5% if the patient was treated with 800

mg/m2 epirubicin. Previous anti-hormonal treatment was one

risk factor for cardiotoxicity that exacerbates the condition.

We suspected, therefore, that epirubicin might have caused

life-threatening heart failure due to ACT in the present pa-

tient.

Biopsy-proven ACT due to epirubicin has been reported

rarely. Torti et al. used endomyocardial biopsy to examine


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29 patients at high risk of ACT and reported that epirubicin

caused less myocardial injury than doxorubicin, when com-

pared at the same doses (5). At a dose of 450 mg/m2 or

greater, moderate to severe ACT was observed in 65% of

patients who received doxorubicin compared to 15% of pa-

tients who received epirubicin. The authors estimated that

approximately 180 mg/m2 more epirubicin than doxorubicin

could be administered before a similar degree of cardiac in-

jury would occur. In the present patient, the histopathologi-

cal findings were consistent with ACT, as described (5, 6).

A significant accumulation of epirubicin might cause myo-

cardial injury and ongoing toxic reaction even 2 months af-

ter the termination of chemotherapy.

Desmin is an intermediate filament abundantly expressed

in cardiac muscle. Desmin filaments surround the Z discs

connecting the entire contractile apparatus to cytoskeletal

network, nucleus and cytoplasmic organelles (7). These net-

works provide maintenance of cellular integrity, force trans-

mission, and mechanochemical signaling. Because desmin

disappears fast in damaged myocytes, desmin stain is a

valuable tool to detect early myocardial ischemia/infarc-

tion (8). In the present case, a substantial number of myo-

cytes was not stained properly with antibodies against

desmin (Fig. 5C). We suspected that there was diffuse de-

generation of myocytes and that myocyte dysfunction

caused the heart failure.

Mononuclear infiltrates, which were infrequently observed

in the myocardium and thus were not indicative of a diagno-

sis of myocarditis, were characterized by immunohistochem-

istry. Those cells were stained not by CD15 antibody but by

CD45RO antibody (Fig. 5D). As granulocytes are stained by

CD15 antibody and T lymphocytes are stained by CD45RO,

those infiltrates were identified as T lymphocytes. Eosino-

phils, which are often observed in drug-induced myocarditis,

were not observed in the present case. Accordingly, we con-

cluded that myocytes were injured not by drug allergy but

by drug toxicity.

Myocyte damage has been attributed to the production of

toxic oxygen free radicals and an increase in oxidative

stress, which causes lipid peroxidation of membranes, lead-

ing to vacuolation and irreversible damage (1, 9). Wojnow-

ski et al. reported that NAD(P)H oxidase and multidrug-

resistant protein gene polymorphisms are associated with

ACT, and those genetic variants might underlie variations in

individual sensitivity to ACT (1). Myocarditis was observed

in both acute and chronic ACT cases (9, 10). Gaudin et al.

reported 4 cases of biopsy-proven myocarditis in 11 patients

who had been treated with doxorubicin at a dose of approxi-

mately 500 mg/m2 (11). Although myocarditis usually is not

associated with ACT, and the role of inflammatory infiltrates

in ACT is controversial, the authors noted that some patients

had a course more typical of patients with myocarditis than

patients with ACT alone.

For the present patient, the clinical manifestations of

epirubicin-associated cardiotoxicity, including reversal of

systolic dysfunction, clot formation in the LV cavity, fre-

quent ventricular arrhythmia, sustained elevation of serum

TnT for several weeks, and myocardial injury associated

with mononuclear cells, were similar to those observed for

myocarditis. However, mononuclear cells were compara-

tively few, even though the ultrastructural damage was sig-

nificant. Although her heart failure was extremely severe

and sustained for three months, this patient fully recovered

one year later. We believe that the supportive care was im-

portant until the patient recovered from acute intoxication.

The authors state that they have no Conflict of Interest (COI).

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Ⓒ 2012 The Japanese Society of Internal Medicine

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a case of epirubicin-associated cardiotoxicity progressing

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