Immune Checkpoint Inhibitor–Associated Myocarditis Mimicking Takotsubo Cardiomyopathy

Abstract

Background

Pembrolizumab-induced myocarditis is a rare but life-threatening immune-related adverse event.

Case Summary

A 72-year-old woman with stage IV EGFR exon 19 deletion–positive left lung adenocarcinoma received osimertinib as first-line therapy. After disease progression, she underwent pembrolizumab plus pemetrexed-carboplatin as second-line therapy, then docetaxel plus ramucirumab as third-line therapy. She presented with nausea and anorexia, and electrocardiograms revealed widespread ST-segment elevation. Coronary angiography revealed no significant stenosis; left ventriculography revealed an apical ballooning pattern. Although Takotsubo cardiomyopathy was suspected, endomyocardial biopsy confirmed pembrolizumab-induced myocarditis. High-dose corticosteroids improved her cardiac function; however, the underlying malignancy progressed.

Discussion

Immune checkpoint inhibitor–associated myocarditis can mimic atypical Takotsubo cardiomyopathy, with persistent changes on electrocardiograms or elevated biomarkers, warranting endomyocardial biopsy for diagnosis and treatment with steroids.

Take-Home Message

In patients receiving immune checkpoint inhibitors, consider myocarditis in atypical Takotsubo presentations; biopsy and early steroids improve outcomes.

Visual Summary

History of presentation

A 72-year-old woman presented to our hospital with nausea and anorexia. Upon physical examination, she was alert and showed no signs of distress. Her vital signs were as follows: blood pressure, 127/93 mm Hg; heart rate, 104 beats/min and regular; respiratory rate, 18 breaths/min; body temperature, 36.8 °C; and oxygen saturation, 97% in ambient air. She reported no chest pain, dyspnea, or other systemic symptoms such as fever, rash, or arthralgia.

Take-Home Messages

• •In patients with advanced cancer receiving immune checkpoint inhibitors, myocarditis can present as an atypical form of Takotsubo cardiomyopathy, with persistent ECG changes or elevated cardiac biomarkers.
• •Endomyocardial biopsy is crucial for definitive diagnosis, and CMR can be a useful noninvasive tool. Early recognition and prompt corticosteroid therapy are essential for improving patient outcomes.

Past medical history

At 17 months before presentation, the patient was diagnosed with stage IV T1cN0M1c left lung adenocarcinoma harboring an EGFR exon 19 deletion mutation and multiple brain and bone metastases. She underwent whole-brain irradiation for brain metastases and received osimertinib as first-line therapy. Owing to disease progression, she was subsequently treated with pembrolizumab plus pemetrexed-carboplatin combination therapy as second-line treatment for 2 cycles at 4 months before presentation. As the disease progressed, she underwent Gamma Knife radiosurgery for brain metastases and was treated with docetaxel plus ramucirumab combination therapy for 3 cycles as third-line treatment at 2 months before presentation. She had no other significant medical history besides lung cancer, including no history of cardiovascular disease.

Differential diagnosis

The differential diagnoses included advanced lung cancer, treatment-related adverse effects of chemotherapy or immune checkpoint inhibitors (ICIs), and other gastrointestinal and cardiac diseases.

Social history

The patient had a history of smoking approximately 10 cigarettes per day for 2 years, starting at the age of 20 years. She did not consume alcohol and had no history of recreational drug use.

Medications

At the time of presentation, her daily medications included celecoxib 200 mg, vonoprazan 10 mg, magnesium oxide 990 mg, clarithromycin 200 mg, and L-carbocisteine 1,500 mg. None of these agents is commonly associated with cardiotoxicity.

Investigations

At the respiratory medicine department of our hospital, the patient underwent blood tests, a 12-lead electrocardiogram (ECG), chest radiography, and chest computed tomography.

Laboratory tests on admission revealed elevated cardiac troponin I (1.2 ng/mL, normal: <0.04 ng/mL), creatine phosphokinase (1,359 IU/L, normal: 55-170 IU/L), and creatine phosphokinase-MB (63 IU/L, normal: <25 IU/L). Her C-reactive protein level was 4.6 mg/L (normal: <3.0 mg/L), white blood cell count was 14,670/μL (normal: 4,000-10,000/μL), serum creatinine was 0.83 mg/dL (normal: 0.6-1.1 mg/dL), and hemoglobin was 14.3 g/dL (normal: 13.5-17.5 g/dL).

The 12-lead ECG demonstrated widespread ST-segment elevation in leads I, II, and aVL as well as precordial leads V₂ to V₆ (Figure 1). Chest radiography revealed a normal cardiothoracic ratio and sharp bilateral costophrenic angles. Transthoracic echocardiography demonstrated a left ventricular ejection fraction of 32% using the modified Simpson method, with severe hypokinesis to akinesis in the midapical septum and anterior wall, and akinesis in the apex.

Figure 1.

12-Lead Electrocardiogram on Admission

The electrocardiogram on admission demonstrated widespread ST-segment elevation in leads I, II, and aVL and precordial leads V₂ to V₆.

Initially, acute myocardial infarction was suspected, and the respiratory medicine team consulted the cardiology department for further evaluation and management. Coronary angiography revealed no significant stenosis in either coronary artery. Subsequently, left ventriculography demonstrated apical akinesis with basal hyperkinesis, consistent with apical ballooning (Figure 2). Based on these findings, Takotsubo cardiomyopathy was suspected.

Figure 2.

Findings on Coronary Angiography and Left Ventriculography

(A1 to A3) Coronary angiography revealed no significant coronary artery stenosis. (B1 and B2) Left ventriculography exhibited an apical ballooning pattern, consistent with Takotsubo-like cardiomyopathy.

After the initial diagnosis, the patient was managed with bed rest and continuous ECG monitoring. However, ST-segment elevation persisted on serial ECGs, which was atypical for Takotsubo cardiomyopathy. Considering the patient's history of treatment with ICIs, we included ICI-associated myocarditis in the differential diagnosis.

Cardiac magnetic resonance imaging (CMR) was performed to assess myocardial inflammation. However, the patient was unable to maintain sufficient immobility during the examination, resulting in poor image quality and limited diagnostic evaluation. Dual-isotope myocardial scintigraphy with BMIPP (β-methyl-p-iodophenyl-pentadecanoic acid) and thallium demonstrated an apical mismatch pattern characterized by reduced BMIPP uptake and preserved thallium uptake (Figure 3). This pattern is commonly associated with Takotsubo cardiomyopathy, but it may also occur in myocarditis. Therefore, in this patient, histopathological confirmation by endomyocardial biopsy was crucial for establishing the diagnosis of ICI-associated myocarditis.

Figure 3.

Dual-Isotope Myocardial Scintigraphy

(A) Thallium-201 imaging demonstrating preserved myocardial perfusion. (B) BMIPP (β-methyl-p-iodophenyl-pentadecanoic acid) imaging revealed reduced uptake in the apical region. This perfusion-metabolism mismatch suggested myocardial metabolic impairment, which can be observed in conditions such as myocarditis or Takotsubo cardiomyopathy.

We performed an endomyocardial biopsy on day 10 after admission for a definitive evaluation; 2 tissue samples were obtained from the interventricular septum of the right ventricle under fluoroscopic guidance. Histological examination revealed lymphocytic infiltration in the endocardium and myocardial necrosis. Immunohistochemical staining revealed infiltration of CD3⁺, CD4⁺, and CD8⁺ lymphocytes. Mild infiltration by CD68⁺ macrophages was also observed in the interstitial area. Myoglobin immunostaining revealed myocardial injury and myolysis. Congo red staining result was negative, which ruled out myocardial amyloidosis, whereas Masson's trichrome staining revealed mild interstitial fibrosis (Figure 4).

Figure 4.

Histopathological Findings From Endomyocardial Biopsy

(A1 to A3) Hematoxylin and eosin (HE) staining showed lymphocytic infiltration in the endocardium and evidence of myocardial necrosis. (B to D) Immunohistochemical staining demonstrated CD3-, CD4-, and CD8-positive lymphocytes in the myocardium. (E) CD68 staining showed mild infiltration of macrophages. (F) Masson trichrome (MT) staining revealed mild interstitial fibrosis.

Based on the clinical history of pembrolizumab administration and histopathological findings, the patient was diagnosed with ICI-associated myocarditis. In addition, viral serological testing, including paired antibody titers for common cardiotropic viruses, showed no significant increase in antibody levels, effectively ruling out viral myocarditis.

Management

On day 15 of admission, high-dose methylprednisolone therapy (500 mg/d) was initiated for 3 consecutive days, followed by oral prednisolone at 50 mg/d (approximately 1 mg/kg). The oral prednisolone dose was subsequently tapered by 10 mg per week.

Outcome and Follow-Up

After corticosteroid therapy, cardiac enzyme levels decreased and ST-segment elevation on ECG improved, with the subsequent development of T-wave inversions. Transthoracic echocardiography showed gradual improvement in left ventricular systolic function, with the left ventricular ejection fraction improving from 32% at presentation to 66% by day 30 of admission.

Unfortunately, despite improvement in cardiac function, the patient developed multiple progressive brain metastases, resulting in hemiparesis and impaired consciousness. Despite supportive care, the patient died 44 days after admission.

Discussion

ICI-associated myocarditis is a rare but potentially life-threatening immune-related adverse event. Although the reported incidence is relatively low (0.04%-1.14%), the estimated mortality rate is 25% to 50%.¹ Early recognition and prompt treatment are therefore critical for improving outcomes.

The reported median onset of ICI-associated myocarditis is ∼34 days after starting ICI therapy.² However, delayed onset may occur, as in the present case, where myocarditis was diagnosed several months after pembrolizumab discontinuation. This underscores the need for vigilance even after ICI cessation.

In the present case, myocarditis developed after pembrolizumab monotherapy (anti–PD-1 antibody). The risk of ICI-associated myocarditis is higher with anti–PD-1 plus anti–CTLA-4 combination therapy than with monotherapy. Mahmood et al² reported incidences of 0.27% with combination therapy and 0.06% with monotherapy, representing a 5-fold higher risk with combination regimens.

Our patient presented with ECG findings suggestive of Takotsubo cardiomyopathy, including widespread ST-segment elevation and apical ballooning on left ventriculography. However, persistent ST-segment elevation is atypical for Takotsubo cardiomyopathy, which usually shows rapid resolution of ECG changes within days.³

CMR was performed to evaluate myocarditis; however, the patient's inability to remain immobile produced suboptimal image quality and insufficient diagnostic information, as also noted by Zhang et al.⁴ In such cases, endomyocardial biopsy is recommended for definitive diagnosis. Because myocarditis cannot be excluded without definitive CMR findings, histopathological evaluation remains essential.⁴

Endomyocardial biopsy is the gold standard for diagnosing myocarditis.⁵ Histopathology typically reveals T cell–predominant lymphocytic infiltration, supporting the hypothesis that ICI-associated myocarditis is T cell–mediated.⁶

In our patient, biopsy showed lymphocytic infiltration, predominantly CD3⁺, CD4⁺, and CD8⁺ T cells, consistent with previously reported features of ICI-associated myocarditis.⁷ These findings are not typical of chemotherapy-related cardiotoxicity.⁸ Moreover, although the patient had received multiple chemotherapeutics, including osimertinib, pemetrexed, and carboplatin, these agents are not typically associated with immune-mediated myocarditis. Although skeletal muscle involvement was not formally evaluated, decreased limb strength suggested possible overlapping myositis with ICI-associated myocarditis.

Takotsubo syndrome is a rare cardiac complication of ICI therapy, with an estimated incidence of 0.03%.⁹ A recent systematic review identified 17 cases of Takotsubo-like cardiomyopathy in patients receiving ICI therapy.¹⁰ Approximately half were treated with corticosteroids, suggesting overlap in immune-mediated mechanisms between ICI-associated myocarditis and Takotsubo-like cardiomyopathy.¹⁰

As ICIs become more integral to cancer therapy, the incidence of ICI-related immune-related adverse events, including myocarditis, is expected to increase. ICI-associated myocarditis can be fatal, warranting early recognition through multimodal imaging, including CMR and confirmatory endomyocardial biopsy, for timely management.

In patients with advanced cancer receiving ICIs, comorbidities may predispose them to Takotsubo cardiomyopathy. Among such cases, ICI-associated myocarditis should be considered, as distinguishing between the two is crucial for treatment decisions. In the present case, the patient demonstrated an atypical Takotsubo pattern, and her medication history raised suspicion of ICI-related myocarditis. In cases of atypical Takotsubo cardiomyopathy with persistent ECG changes or elevated cardiac biomarkers, endomyocardial biopsy should be actively pursued for definitive diagnosis. Although CMR was suboptimal in our patient, it remains a valuable noninvasive tool in similar situations.

Conclusions

This case illustrates the diagnostic challenge of distinguishing ICI-associated myocarditis from Takotsubo cardiomyopathy. Clinicians should remain vigilant for myocarditis in patients receiving or with a history of ICI therapy, as early diagnosis and treatment are critical to improving outcomes.

Visual Summary.

Timeline of Case Presentation

ECG = electrocardiogram; ICI = immune checkpoint inhibitor.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.