https://orcid.org/0000-0002-0385-7398
Abstract
Left ventricular thrombus (LVT) formation is an uncommon phenomenon, typically observed in acute cardiac settings and hypercoagulable states. Takotsubo cardiomyopathy (TC) is a reversible condition originally thought to be linked to immense emotional stress. The occurrence of chemotherapy-related cardiotoxicity presenting with TC and LVT formation is a relatively new concept that remains not fully understood.
We present the case of a 77-year-old woman with Stage IV breast cancer being treated with trastuzumab and capecitabine therapy, who presented to our hospital with symptoms of right-sided weakness, facial droop, and slurred speech. She was admitted for acute left frontal lobe infarction due to an occluded distal left posterior M2 branch of the left middle cerebral artery. As part of thromboembolic stroke work-up, transthoracic echocardiogram (TTE) was obtained, which showed moderately to severely decreased left ventricular systolic function (LVEF 35%) with wall motion abnormalities suggestive of TC and a 0.9 × 1 cm echogenic structure in the LV consistent with LVT. She was started on therapeutic anticoagulation and was discharged on oral warfarin with international normalized ratio (INR) goal of 2-3. Both capecitabine and trastuzumab were held during her hospitalization. Repeat TTE after 2 weeks showed an LVEF of 60% with normal LV systolic function and absence of any LVT. Symptoms-wise her right-sided weakness was improving. She was continued on capecitabine and warfarin for now, and continued to follow-up outpatient with oncology, cardiology and neurology.
This case highlights TC and LVT as rare but life-threatening complications of trastuzumab-induced cardiotoxicity. We emphasize the importance of early diagnosis to prevent further complications, such as acute thromboembolic stroke, and the necessity of prompt therapeutic interventions to reduce morbidity and mortality. Additionally, we address the multifactorial aetiology of TC and the need for frequent TTE monitoring in patients undergoing trastuzumab therapy to diagnose these complications early.
Takotsubo cardiomyopathy, also known as stress cardiomyopathy due to the catecholamine surge has a multifactorial pathogenesis in cancer patients on cardiotoxic chemotherapy like trastuzumab.
Frequent transthoracic echocardiogram monitoring is necessary in patients on trastuzumab therapy to diagnose rare but life-threatening complications like takotsubo cardiomyopathy and left ventricular thrombus.
Prompt discontinuation of chemotherapeutic agents and initiation of therapeutic anticoagulation are essential steps in preventing debilitating complications.
Introduction
A left ventricular thrombus (LVT) is a blood clot that forms in the left ventricle (LV) of the heart and is a serious complication typically associated with acute myocardial infarction (MI) or dilated cardiomyopathy (DCM). Its mechanism can be explained by Virchow’s Triad, which includes endothelial injury, blood stasis, and hypercoagulability.1 Although rare, LVT has been associated with the hypercoagulable state of cancer. Takotsubo cardiomyopathy (TC) is a type of reversible cardiomyopathy also known as stress cardiomyopathy, characterized by a presumed catecholamine-driven pathogenesis. It is diagnosed by transthoracic echocardiogram (TTE), which shows LV apical ballooning due to hypokinesis, dyskinesis, or akinesis in LV segments with regional wall motion abnormalities exceeding past a single vascular distribution. In rare cases, basal hyperkinesis or LV outflow tract obstruction (due to TC dynamics) might displace the anterior mitral leaflet, producing systolic anterior motion.2 Cancer, as a chronic condition, is associated with significant emotional and physical stress that increases the risk of stress cardiomyopathy. The inflammatory state of cancer, chemotherapy-related cardiotoxicity, and circulating paraneoplastic mediators may modify the adrenoreceptors in cardiac tissue, leading to contractile dysfunction and potentially resulting in TC. Additionally, some chemotherapeutic agents used in certain cancers have also been associated with TC.3 One such chemotherapeutic agent that is widely used in breast cancer treatment is trastuzumab, a recombinant DNA-derived humanized anti-HER2 monoclonal antibody. Although cardiotoxicity causing reduced LVEF is commonly seen with trastuzumab, TC has been rarely reported. We present a unique case of LVT formation in TC complicated by acute stroke in a patient with breast cancer undergoing trastuzumab therapy.
Summary figure
Case presentation
The patient was a 77-year-old woman with a history of well-controlled hypertension and Stage IV breast cancer, diagnosed in 2019. She was most recently on trastuzumab and capecitabine therapy. She presented to our hospital on 17 March 2024, with complaints of right-sided weakness, right facial droop, and slurred speech. She was vitally stable (blood pressure 156/75 mmHg, pulse 62 b.p.m., temperature 97.8°F, resp. rate 18, and SpO2 96 on room air). Physical exam showed a cooperative female who was not ill-appearing with atraumatic head appearance, a right-sided facial droop, moist mucosal membranes, clear lungs, normal heart sounds without murmurs or other abnormal sounds, soft, and non-tender abdomen, extremities with no pitting oedema or cyanosis and intact distal pulses, and dry and well-perfused skin. Neurological exam showed normal alertness, normal orientation to person, place and time, right facial droop, right-sided tongue deviation, marked slurring of speech, intact sensations, and normal movement of all extremities against gravity and resistance; however, weaker right upper extremity as compared with left with weak right-hand grasp compared with left. A stroke code was called for a National Institutes of Health Stroke Scale (NIHSS) score of 9. Computed tomography (CT) angiography of the head and neck showed an occluded distal left posterior M2 branch of the left middle cerebral artery but no large vessel occlusion. CT and magnetic resonance imaging (MRI) of the brain revealed left insular cortex and adjacent lateral frontal lobe infarction; hence, she was admitted for left frontal acute ischaemic stroke.
Her laboratory results were mostly unremarkable. Complete blood count showed hemoglobin (Hgb) 12.3 (12–16 g/dL), white blood cells (WBC) 6.1 (4.8–10.8 K/uL), and platelets 238 (130–400 K/uL). Chemistry showed creatinine (∼1.2 mg/dL, ref range 0.5–1 mg/dL), blood urea nitrogen (BUN) 20 (7–17 mg/dL), glomerular filtration rate (GFR) 48, and electrolytes within normal limits. Troponin 0.02 (0–0.033 ng/mL), HbA1c, and lipid panel results were within normal limits as well. Coagulation studies showed prothrombin time 12.5 (ref range 10–13 s), international normalized ratio (INR) 1.1 (ref range is 0.9–1.1), and partial thromboplastin time (PTT) 31.0 (ref range is 25.1–34.2 s). Liver panel showed bilirubin 0.9 (0.2–1.3 mg/dL), alanine transaminase (ALT) 23 (0–34 U/L), aspartate transaminase (AST) 51 (14–36 U/L), and alkaline phosphatase 119 (37–126 U/L).
Furthermore, TTE showed moderately to severely decreased left ventricular systolic function (LVEF 35%) with wall motion abnormalities involving the distal half of the septum, apex, distal anterolateral, and distal inferior walls, suggestive of TC. A 0.9 × 1 cm echogenic structure consistent with LVT was noted in the LV (Figures 1 and 2). There was grade I diastolic dysfunction, and no other atrial, valvular, or pericardial abnormalities were observed. An electrocardiogram (EKG) showed normal sinus rhythm at a rate of 66 b.p.m. with non-specific ST-T changes (Figure 3). The normal troponin levels and EKG findings were likely due to minimal cardiomyocyte necrosis in TC and timing of the measurement which was after the initial insult to the myocardium. For further images on MRI brain and TTE videos, check Supplementary material.
Apical four chamber view showing left ventricular thrombus (A).
Apical four chamber view showing apical ballooning of left ventricle (B) with left ventricular thrombus (A).
EKG at presentation.
She was started on therapeutic anticoagulation with intravenous heparin, targeting a PTT of 50–70 s, and was subsequently switched to therapeutic subcutaneous enoxaparin twice daily. Eventually, she was bridged to oral warfarin (5 mg) with daily INR monitoring until a therapeutic range of two to three was achieved. She was prescribed atorvastatin 40 mg daily for stroke prevention, losartan 25 mg daily, and carvedilol 6.25 mg twice a day for guideline-directed medical therapy and hypertension. Both capecitabine and trastuzumab were held during her hospitalization. She was discharged home after a 7-day inpatient stay on warfarin, losartan, carvedilol, atorvastatin, and other supportive care medications and was scheduled for outpatient follow-up. The plan was to obtain further diagnostic testing with coronary angiogram and cardiac MRI on an outpatient basis if her LVEF does not improve after discontinuation of the chemotherapeutic agents.
Repeat TTE at her cancer treatment facility 2 weeks after discharge showed an LVEF of 60% and global longitudinal strain of −18.9, consistent with normal LV systolic function. No findings of LVT were noted. Her cardiac biomarkers, including troponin (normal ref range is ≤47 ng/L) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (ref range is <450 pg/mL), were within normal ranges. She had a previous episode of LV dysfunction with reduced LVEF on trastuzumab and capecitabine therapy, which had resolved after discontinuation of trastuzumab; hence the plan was to hold trastuzumab indefinitely. She was continued on capecitabine therapy only for the breast cancer. She remained on warfarin even after resolution of cardiomyopathy and absence of LVT due to cancer-related hypercoagulability pre-disposing her to multiple blood clots. Regarding her neurologic follow-up, repeat MRI brains were showing chronic infarct in the same left frontal lobe area; her symptoms were improving with residual mild right upper extremity weakness, which had significantly improved. No further cardiac work-up was indicated at this time, and she continued to follow-up outpatient with oncology, cardiology, and neurology.
Discussion
We presented a case of a female patient with breast cancer undergoing trastuzumab and capecitabine therapy, who presented with TC that was first complicated by LVT formation and subsequently acute thromboembolic stroke. The absence of typical symptoms, such as chest pain, and the lack of additional cardiac risk factors make MI a less likely pre-disposing event, which could be confirmed with a coronary angiogram. If her LVEF failed to improve after discontinuation of the chemotherapeutic agent, further work-up with coronary angiogram and cardiac CT or MRI for diagnosis of other causes of cardiomyopathy like ischaemic, infectious, inflammatory, and neoplastic would be necessary. Nevertheless, early diagnosis of trastuzumab-induced TC via TTE and prompt treatment, including discontinuation of trastuzumab and initiation of therapeutic anticoagulation, were crucial in preventing further morbidity from these complications.
The medical community continues to have an incomplete understanding of the underlying pathogenesis and pathophysiology of TC. While catecholamine-induced myocardial injury is the most well-known pathogenesis, numerous other pathways and abnormalities are emerging.4 Some relevant pre-disposing factors are genetic predisposition, chronic illness, and chronic stress from metastatic cancer. Trastuzumab, a chemotherapeutic agent used for HER-2-positive breast cancer, has known cardiotoxicity resulting from increased intracellular reactive oxygen species (ROS) generation in H9c2 cells. This intracellular ROS is closely correlated with the pathogenesis of cardiovascular diseases, including atherosclerosis, myocardial ischaemia/reperfusion injury, myocardial hypertrophy, and heart failure. Although trastuzumab-induced cardiotoxicity is common, only three cases of trastuzumab-induced TC have been reported thus far, making it a rare phenomenon.5–7 It remains unclear whether the pathophysiology of trastuzumab cardiotoxicity is the cause of trastuzumab-induced TC. The effect of trastuzumab on cardiomyocytes likely increases the risk of TC in patients with metastatic cancer, who are already under immense emotional stress.8
According to a systematic review of case reports by Kim et al., 9 capecitabine therapy has also been reported to cause cardiotoxicity, particularly acute coronary spasm. This raises the question of a combined effect of both chemotherapeutic agents contributing to TC in our patient.9 However, since the patient had always been on capecitabine therapy and the discontinuation of trastuzumab in December resulted in improved LVEF, the likelihood of capecitabine being the primary cause of TC is minimized. Furthermore, cancer itself can cause endothelial dysfunction in epicardial and microvascular coronary arteries, leading to global cardiac dysfunction. In conclusion, the increasing number of reports of trastuzumab-induced and cancer-related TC cases raises questions about whether the pathophysiology of TC is multifactorial rather than solely catecholamine driven.
LVT is commonly seen in states of reduced ejection fraction, such as acute MI and DCM, due to injured or necrotic cardiomyocytes, which increase the risk of clot formation from the release of prothrombotic elements and underlying stasis. While LVT would be unexpected in TC, studies indicate that the prevalence of LVT in TC is approximately 5.7%.10–13 This suggests that although TC causes temporary myocardial wall dysfunction, it is sufficient to induce stasis, leading to LVT formation. While thrombus formation in all three conditions of MI, DCM, and TC involves stasis, the contributing factors differ due to the nature of myocardial dysfunction, the extent of necrosis, and the timing of risk. In MI, there is focal myocardial necrosis leading to endothelial injury and blood stasis, the risk is highest during 1–2 weeks post-MI), whereas in TC, there is acute reversible stasis caused by stunned cardiomyocytes where the risk is present until the duration of cardiomyopathy. Dilated cardiomyopathy has chronic stasis with long-term risk of thrombus formation. In terms of the effects of trastuzumab, only one case of severe LV dysfunction complicated by LVT has been reported in a patient undergoing trastuzumab therapy.11 Additionally, the hypercoagulable state associated with metastatic cancer can further elevate the risk of clot formation.
Thromboembolic complications of LVT, including acute stroke, are common; the mechanism and risk of such events are similar for LVT in TC, MI, and DCM. In their study on the prevalence of thromboembolic events and the role of anticoagulation in TC, Heckle et al.10 observed a prevalence of 9.2% for composite thromboembolic events, including both LVT and embolic strokes.
Notably, the referenced studies indicate the benefit of oral anticoagulation with warfarin in LVT to prevent thromboembolic stroke, along with the resolution of LVT within a few months of initial presentation in TC. This was also observed in our patient, highlighting the importance of early diagnosis of TC and LVT in patients undergoing trastuzumab therapy with frequent cardiac monitoring, as well as the need for prompt intervention to prevent complications. Transthoracic echocardiogram monitoring every 6 months for patients without any known cardiotoxicity and 3–4 months for patients with known cardiotoxicity, including TC, would be a good strategy for diagnosing these complications early. Furthermore, for patients who developed cardiotoxicity, optimizing strategies on restarting chemotherapy, which include adequate healing time for the myocardium, closer monitoring, and switching to alternate medications, should be considered. Whether therapeutic anticoagulation should be considered from the beginning in patients with trastuzumab-induced cardiotoxicity for the prevention of LVT is an important consideration that requires further research.
Conclusion
This rare case of a patient with breast cancer demonstrating trastuzumab-induced cardiotoxicity in the form of TC complicated by LVT and embolic stroke illustrates how trastuzumab’s effects on cardiovascular endothelium, combined with systemic hypercoagulability in metastatic cancer and stasis in low-LVEF states like TC, can contribute to LVT. Early diagnosis via TTE and prompt intervention, particularly discontinuation of trastuzumab and initiation of anticoagulation, are essential in preventing life-threatening complications. Consequently, these patients require frequent TTE monitoring and careful consideration when restarting therapy, with an understanding of the extent of cardiotoxicity once LVEF begins to decline.
Lead author biography
Passionate about cardiology, driven by a desire to advance field of cardiology through research.
Supplementary material
Supplementary material on brain MRI image and TTE videos are available at European Heart Journal – Case Reports online.
Consent: This study was conducted in accordance with the principles of the Declaration of Helsinki. Prior to participation, the patient was informed about the study’s purpose, procedures, potential risks, and benefits. The patient provided written informed consent to participate in this study and to have their data published. The confidentiality of the patient has been maintained, and identifying information has been anonymized.
Funding: Personal funds.
Data availability
The data supporting the findings of this study are available from the corresponding author upon reasonable request. Data are not publicly available due to institutional policies.
References
Author notes
Conflict of interest: None declared.
Comments