doi: 10.2169/internalmedicine.4792-20
Intern Med 59: 2155-2160, 2020
http://internmed.jp【 CASE REPORT 】

Reversible Cancer Therapeutics-related Cardiac Dysfunction
Complicating Intra-cardiac Thrombi
Shingo Tsujinaga 1, Hiroyuki Iwano 1, Tomohiro Oshino 2, Takahide Kadosaka 1,
Yoshifumi Mizuguchi 1, Ko Motoi 1, Yasuyuki Chiba 1, Taro Koya 1, Taro Temma 1,Kiwamu Kamiya 1, Arata Fukushima 1, Takuya Koizumi 1, Tomoya Sato 1, Sakae Takenaka 1,Atsushi Tada 1, Suguru Ishizaka 1, Miwa Sarashina 1, Kazunori Omote 1, Rui Kamada 1,Takao Konishi 1, Takuma Sato 1, Toshiyuki Nagai 1, Hiroko Yamashita 2 and Toshihisa Anzai 1

Abstract:
Epirubicin-based chemotherapy carries a risk of inducing heart failure, although the frequency is rare.
Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, has recently been widely usedin patients with recurrent breast cancer as a first-line chemotherapeutic agent. Heart failure or arterial thromboembolism has been reported as a rare cardiovascular complication of bevacizumab. We herein report abreast cancer patient with reversible cancer therapeutics-related cardiac dysfunction associated with bevacizumab and epirubicin complicating intracardiac thrombi in the left atrium and left ventricle. This case underscores the importance of tailored medical planning according to the individual status in patients receiving
anti-cancer therapies.
Key words: epirubicin, bevacizumab, cardiotoxicity, heart failure, thrombus(Intern Med 59: 2155-2160, 2020)(DOI: 10.2169/internalmedicine.4792-20)

Introduction

Case Report

Anthracycline, including epirubicin-based chemotherapy,
improves the survival of breast cancer patients but is associated with an increased risk of heart failure (1).
In recent years, systemic therapy targeting vascular endothelial growth factor (VEGF) and its receptors has proven to
be a successful strategy in patients with cancer. Bevacizumab is a widely used anti-VEGF monoclonal antibody targeting the VEGF ligand. Although it has been shown to improve clinical outcomes in several malignancies including
advanced breast cancer (2), its use has been associated withmany cardiovascular events (3-5).
We herein report a breast cancer patient with reversible
cancer therapeutics-related cardiac dysfunction associatedwith bevacizumab along with epirubicin complicated by intracardiac thrombi in the left atrium and left ventricle.

A 65-year-old woman with a history of postoperative chemotherapy for right breast cancer was referred to our department due to congestive heart failure. The breast cancer had
been graded as clinical stage IIa, triple-negative invasive
ductal carcinoma [estrogen receptor 0%, progressive receptor
0%, and human epidermal growth factor receptor 2 (HER2)
immunohistochemistry 0%], and the Ki-67-positive cell index was 98.6%. She had received 4 courses of epirubicin(total dose: 327 mg/m2) and cyclophosphamide (total dose:2,183 mg/m2) followed by paclitaxel (total dose: 727 mg/m2)
and bevacizumab (total dose: 546 mg/m2).
Nine months after the end of epirubicin administrationand three months after the end of bevacizumab administration, she developed dyspnea on exertion despite denying any
history of cardiovascular diseases. Three months later, car-１

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Japan and ２ Departmentof Breast Surgery, Hokkaido University Hospital, Japan
Received: March 5, 2020; Accepted: April 10, 2020; Advance Publication by J-STAGE: June 2, 2020
Correspondence to Dr. Shingo Tsujinaga, shingo-t.0207@med.hokudai.ac.jp2155

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Figure 1. (A) Chest X-ray at admission showing lung congestion with apparent cardiomegaly andpleural effusion. (B) The electrocardiogram at admission showing sinus tachycardia with complete
right bundle branch block.

diac enlargement with pleural effusion and intracardiac
thrombi were detected by contrast-enhanced computed tomography (CT). Subsequently, she was introduced to ourdepartment and admitted for the management of heart failure
and intracardiac thrombi.
On admission, she showed a blood pressure of 150/101
mmHg, pulse rate of 102/min, and transcutaneous oxygen
saturation of 98% in room air. A clinical examination revealed jugular vein distension, third heart sound, and abdominal fullness. Chest X-ray showed lung congestion withapparent cardiomegaly and pleural effusion (Fig. 1A). The
electrocardiogram showed sinus tachycardia with complete
right bundle branch block (Fig. 1B). The serum N-terminalpro-B-type natriuretic peptide (NT-pro-BNP) level was
markedly increased to 7,648 pg/mL. Transthoracic echocardiography showed diffuse severe hypokinesis of the left ventricular (LV) wall [ejection fraction (EF): 24%] with amildly enlarged cavity and LV hypertrophy (Fig. 2A). Muralthrombus with a radius of 2 cm was observed in not only
the LV apex but also the left atrium (Fig. 2B, C), which wasconfirmed by contrast-enhanced CT taken after admission(Fig. 3A, B). The patient was diagnosed with heart failurecaused by cancer therapeutics-related cardiac dysfunction(CTRCD), and intravenous carperitide (0.025 μg/kg/min)and furosemide (40 mg/day) were initiated along with unfractionated heparin to maintain an activated partial thromboplastin time of 60 seconds followed by warfarin.
Soon after the infusion therapy, the congestion was relieved, and medication was switched to oral cardioprotective
drugs, such as enalapril (up to 2.5 mg/day) and carvedilol(up to 10 mg/day). A coronary angiogram performed at the10th day showed no coronary artery lesions, and the pathological findings in an endomyocardial biopsy specimen ob-

tained from the right side of the interventricular septum
showed mild cardiomyocyte hypertrophy and no myocardial
fibrosis or findings specific for secondary cardiomyopathy.
Anticoagulation therapy with warfarin was continued in order to maintain a prothrombin time international normalized
ratio !
2.0, resulting in the disappearance of the intracardiacthrombi on echocardiography on the 19th day without any
thromboembolic events. As a result, the patient was discharged on the 32nd day without any residual cardiovascularsymptoms.
Despite the favorable course of cardiovascular disease, local recurrence of breast cancer was found thereafter, and reoperation was performed 52 days after the discharge without
any cardiovascular events. Nevertheless, lymph node metastasis was found two months after the reoperation. Accordingly, postoperative chemotherapy with capecitabine wasplanned. A repeat echocardiogram showed a reduction in theLV size and an increase in the LV EF to 52%, and contrastenhanced CT showed no intracardiac thrombus. Because of
the potential interaction of capecitabine with warfarin, we
decided to discontinue warfarin based on the low estimatedrisk of recurrent thromboembolism thanks to the recovered
cardiac function.
Eight months after discharge, chest-X ray showed normal
findings in the heart (Fig. 4A), the serum NT-pro-BNP level
had decreased to 89 pg/mL, and an echocardiogram showeda normal LV systolic function (LV EF: 63%) (Fig. 4B).
Contrast-enhanced imaging confirmed no intracardiac thrombus (Fig. 4C). She is now receiving a new chemotherapy
regimen with a low risk of cardiotoxicity.

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Figure 2. (A) Apical four-chamber echocardiographic view at end diastole (left) and end systole(right) at admission showed a mildly enlarged left ventricle (left ventricular end-diastolic diameter:
57 mm), left ventricular hypertrophy (left ventricular mass index: 136 g/m2), and diffuse severe hypokinesis of wall motion (ejection fraction: 24%). (B) Parasternal long-axis view showing thrombus
formation (yellow arrow) in the left atrium. (C) Zoomed image of the apical four-chamber view focusing on the left ventricular apical thrombus (yellow arrow).

Discussion
In the treatment of breast cancer, anthracyclines are established as a main component of cancer therapy regimens,even though they have dose-dependent cardiotoxicity. The
incidence of heart failure after high-dose epirubicin exposure(approximately 900 mg/m2) is known to exceed 5-10%, but
substantial cardiotoxicity may occur at even lower doses, depending on the individual susceptibility (6). Heart failure
due to epirubicin typically manifests within several years after exposure (7). However, anthracyclines can also cause
myocardial injury in the acute (immediately after exposure)and subacute (within one year after exposure) phases, eventhough their frequencies are rare (acute: <1%; subacute: 16%) (8).

However, in recent years, anti-VEGF monoclonal antibodies, such as bevacizumab, have become one of the first-line
therapies for human epidermal growth factor receptor type2-positive breast cancers (2). The use of bevacizumab is associated with class-effect adverse events, including hypertension, arterial thromboembolism, and congestive heart failure (3, 4), and the incidence of clinically significant heart
failure is reported to be approximately 2-4% (9). Cyclophosphamide also induces acute heart failure with an incidenceof 2-17%, although this often occurs within 48 hours after
the administration and sometimes within 2 or 3
weeks (10, 11). Cardiac toxicity caused by paclitaxel takesthe form of sub-acute or acute bradycardia, heart block, andatrial or ventricular arrhythmia with an incidence of 0.5%,
and paclitaxel itself does not induce heart failure (12).
In this particular patient, the time difference between the2157

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Figure 3. Contrast-enhanced computed tomography at admission showing left atrial thrombus (A,yellow arrow) and left ventricular apical thrombus (B, yellow arrow).

Figure 4. (A) Chest X-ray at eight months after discharge showing normal findings in the heart. (B)Apical four-chamber echocardiographic view at end diastole (left) and end systole (right) eightmonths after discharge showed a decrease in the left ventricular size (end-diastolic left ventricular
diameter: 46 mm) and increase in the ejection fraction to 63%. (C) Contrast-enhanced CT findings
eight months after discharge showing no intracardiac thrombus.

occurrence of heart failure symptoms and the final course of
epirubicin administration (9 months) and low amount of total use (327 mg/m2) suggest a relatively low probability of
epirubicin-associated heart failure, although the patient
might have suffered from epirubicin-induced subacute myocardial injury. As there were no data concerning cardiac

biomarkers and echocardiography during epirubicin administration, the latter could not be completely denied. Thesefindings, together with the short duration from the final
course of bevacizumab administration to the onset of heart
failure, suggested that bevacizumab was the main cause of
the incidence of LV systolic dysfunction and subsequent2158

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heart failure.
Bevacizumab therapy for breast cancer is reported to carrya substantially high risk of heart failure due to prior or concomitant exposure to other cardiotoxic medications (4). Inaddition, consistent with the typical manifestation of
bevacizumab-associated heart failure (13), the present patient
showed an elevated blood pressure and hypertrophied LV,
which also suggested probability of bevacizumab-associatedheart failure. Anthracyclines directly cause cell death, leading to irreversible myocyte destruction, even thoughanthracycline-induced subacute myocardial injury may occasionally be reversible when cardioprotective therapy is administered (14). In contrast, VEGF inhibitors alter the normal cellular function by affecting the mitochondrial system
and reducing protein synthesis, leading to reversible myocyte destruction (5). Cyclophosphamide and paclitaxel wereunlikely to be involved in heart failure in the present case,given the time course and their reported cardiac toxicity.
Fortunately, the patient was able to be successfully
treated, and the LV systolic function recovered after standard therapy using angiotensin-converting enzyme inhibitors
and beta blockers, which is recommended by the guidelines (15, 16).
In summary, the cause of cardiac dysfunction and heart
failure in this case was considered to be CTRCD associatedwith bevacizumab along with epirubicin that showed a response to cardioprotective therapy. Importantly, the present
case was complicated by intracardiac thrombi at the time ofworsening heart failure. A case of epirubicin-associatedheart failure with LV apical thrombus has been reported (17), and combination treatment of bevacizumab andanti-cancer agents is known to be associated with an increased risk of arterial thromboembolism, although the underlying mechanism remains unclear (5). Some researchers
have suggested that bevacizumab might reduce the antiinflammatory effects of VEGF exposure, leading to increased inflammation and thrombus formation (18). In addition to these agent-specific reasons, the hypercoagulation
status during the decompensated heart failure and intracavity
blood stasis due to severe LV and left atrial dysfunction may
have been associated with thrombus formation, according toVirchow’s triad.
To our knowledge, this is the first report of reversible
CTRCD associated with bevacizumab and epirubicin showing both left atrial and LV thrombus in a breast cancer patient. In addition, it is noteworthy that the thrombi were able
to be managed using anticoagulation therapy, and the medication was ultimately able to be discontinued without any
thromboembolic events owing to the recovered cardiac function, which aided in the management of her breast cancer.
This was an educational case suggesting the importance ofcardiology intervention in oncology and collaboration between cardiologists and oncologists.
Conclusion

with bevacizumab along with epirubicin showing intracardiac thrombi in a breast cancer patient. This case emphasizes the importance of tailored medical planning according
to the individual status in patients receiving anti-cancer
therapies.
The authors state that they have no Conflict of Interest (COI).

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