Pembrolizumab-induced nonischemic cardiomyopathy: a case report of a rare immune-related adverse event

Introduction

Immune checkpoint inhibitors (ICIs) like pembrolizumab and nivolumab are immunomodulatory antibodies used to treat various cancers, significantly improving patient prognosis and survival since the Food and Drug Administration (FDA)’s approval of ipilimumab in 2011 (1). However, these agents come with a spectrum of toxicities known as immune-related adverse events (irAEs), commonly affecting the skin, gastrointestinal tract, liver, endocrine system, and other less frequent inflammatory reactions (2,3). Proposed mechanisms for irAEs include autoantibodies, T-cell infiltration, and the release of interleukins and other inflammatory cytokines (4). ICIs can also induce severe cardiovascular irAEs, including myocarditis, pericarditis, cardiomyopathy, myocardial infarction, and arrhythmias, with myocarditis being the most common and often fatal manifestation (5). The exact incidence of ICI-associated myocarditis remains uncertain, with reported rates ranging from 0.06% to 1.14% depending on the type and combination of ICIs used (6,7). T-cell infiltration into myocardial tissue is postulated as the underlying pathophysiological mechanism (8). Symptoms of ICI-related myocarditis typically include chest pain, dyspnea, elevated troponin levels, and electrocardiogram (ECG) abnormalities. While cardiomyopathy is a rare side effect of ICIs, it can manifest as dilated cardiomyopathy or Takotsubo cardiomyopathy (9). High-dose corticosteroids serve as the first-line treatment for ICI-related myocarditis (10). Here, we present a case of pembrolizumab-induced myocarditis complicated by severe cardiomyopathy, left ventricular (LV) thrombus, and critical lower limb ischemia. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-147/rc).

Case presentation

A 63-year-old woman with a medical history significant for stage IV lung adenocarcinoma with brain metastases, atrial fibrillation, peripheral artery disease, and deep vein thrombosis (DVT) on Apixaban, presented to the hospital with a 1-week history of nausea, vomiting, chest pain, and intermittent shortness of breath. She described the chest pain as pressure-like, localized to the lower chest, and denied orthopnea, paroxysmal nocturnal dyspnea (PND), or lower extremity swelling. On physical examination, she appeared mildly distressed and diaphoretic. Heart and lung auscultation were unremarkable. ECG revealed a new right bundle branch block (RBBB) without ST-segment elevation or depression. The cardiac monitor showed supraventricular tachycardia with a heart rate of 150 bpm. Laboratory investigations showed elevated troponin (938 ng/L), creatinine (1.29 mg/dL), and C-reactive protein (CRP) (219 mg/L). Chest computed tomography (CT) scan ruled out pulmonary embolism (PE). The patient was started on heparin infusion for possible acute coronary syndrome and received adenosine and intravenous metoprolol which normalized her heart rate. Transthoracic echocardiogram (TTE) revealed normal LV size and thickness but mildly decreased LV systolic function with apical ballooning consistent with Takotsubo cardiomyopathy (Figure 1, Video 1). Left heart catheterization (LHC) ruled out obstructive disease (Figure 2), leading to the cessation of ACS treatment, and the patient was discharged.

Figure 1 Two-dimensional TTE, apical 4 chamber view, illustrating apical ballooning suggestive of Takotsubo cardiomyopathy. LV, left ventricle; TTE, transthoracic echocardiogram.

Figure 2 Coronary angiogram showing patent coronary arteries with no obstruction.

Ten days later, she returned with worsening chest pain, shortness of breath, and fatigue. ECG showed normal sinus rhythm with nonspecific T-wave abnormalities and occasional premature ventricular complexes (Figure 3). Laboratory tests revealed significantly elevated troponins (4,915 and 5,521 ng/L), and BNP (5,818 pg/mL). Repeat TTE showed severely decreased LV function, dilated and hypokinetic right ventricle (RV), and no specific regional wall motion abnormalities, reducing suspicion of cardiac ischemia. Repeat LHC was not performed. The patient was started on intravenous methylprednisolone for treatment of immune-mediated myocarditis secondary to pembrolizumab and discharged with a wearable cardioverter defibrillator. In terms of her oncological history, the patient had stage IVB lung adenocarcinoma with brain and nodal metastases. Molecular testing revealed programmed death-ligand-1 (PD-L1) expression of 0%, tumor mutational burden of 10, and mutations in STK11, TP53, and KEAP1, with no actionable EGFR or ALK alterations. Based on the KEYNOTE-189 trial (11), she was treated with carboplatin, pemetrexed, and pembrolizumab (200 mg IV per cycle) for five cycles, followed by maintenance pembrolizumab and pemetrexed. She tolerated therapy well without other treatment-related adverse events until the development of suspected immune-mediated myocarditis, which prompted discontinuation.

Figure 3 Twelve-lead ECG demonstrating sinus rhythm with occasional premature ventricular complexes (shown by red arrow) along with nonspecific T-wave abnormalities. ECG, electrocardiogram.

About 2 months later, she presented with left lower extremity pain, skin discoloration, subacute malaise, and weakness. Physical examination revealed dry, flaky skin, cool extremities with pitting edema, and blisters on both feet. Abdominal CT angiography showed extensive atherosclerotic disease and clots throughout the abdominal aorta and major branches, as well as LV, aortic, and pulmonary emboli. Repeat TTE demonstrated severely decreased LV function and a large apical LV thrombus (Figure 4, Video 2). Critical limb ischemia was diagnosed, and the patient was started on a heparin infusion. Surgical intervention was deemed high risk, and she was discharged on oral anticoagulation therapy. A repeat TTE performed approximately 1 year later showed LVEF recovery to 50–55%, supporting the role of early corticosteroid intervention and guideline-directed medical therapy (GDMT) in improving cardiac function. Pembrolizumab was permanently discontinued following the episode of immune-mediated myocarditis. No further systemic antitumor therapy was initiated thereafter. On serial imaging, the patient has remained in radiographic remission without evidence of disease progression for approximately 6 months following discontinuation.

Figure 4 Two-dimensional TTE, apical 2 chamber view, demonstrating large mobile apical thrombus in the LV (yellow arrow). LV, left ventricle; TTE, transthoracic echocardiogram.

Ethical consideration

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report, accompanying images and videos. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

ICIs have revolutionized cancer treatment by enhancing the immune system’s ability to combat cancer cells. Data suggest that up to 36% of cancer patients may be eligible for treatment with ICIs (12). FDA-approved ICIs and their targeting pathways include; cytotoxic T-lymphocyte associated-antigen-4 (CTLA-4) (ipilimumab), programmed death receptor-1 (PD-1) (pembrolizumab, nivolumab, and cemiplimab), and PD-L1 (atezolizumab, avelumab, and durvalumab) (13).

While pembrolizumab-related myocarditis is documented in the literature, severe cardiomyopathy and heart failure are rarely reported. Prior cases of pembrolizumab-induced myocarditis exist (14,15), but data on severe nonischemic cardiomyopathy and subsequent LV apical thrombus are scarce. Our patient’s condition was complicated by systolic heart failure with EF 10–15% and subsequent LV thrombus and PE. Although pembrolizumab has been reported to be associated with acute thrombosis and PE (16), it remains unclear whether it increases the risk of LV thrombus formation independent of existing predisposing factors like cancer and atrial fibrillation. Additionally, it’s unknown if pembrolizumab-induced cardiomyopathy carries a higher risk of LV thrombus formation compared to other cardiomyopathies. Further research is needed to clarify the relationship between pembrolizumab and LV thrombus formation, along with the underlying pathophysiological mechanisms.

The clinical spectrum of ICI-related myocarditis ranges from asymptomatic cardiac biomarker elevations to severe decompensation with end-organ damage. Initially presenting with chest pain and mild troponin elevation, our patient rapidly deteriorated to severe systolic heart failure, resulting in LV thrombus formation. Future research should investigate the significance of atypical or subtle myocarditis symptoms in pembrolizumab-treated patients, as in our case where suspicion for ICI-related myocarditis was initially low. While cardiac magnetic resonance imaging (MRI) is optimal for diagnosis, endomyocardial biopsy is the gold standard (17). However, technical issues precluded MRI for our patient, necessitating reliance on clinical presentation and troponin levels for diagnosis. Negative LHC and absence of prior cardiac disease further supported the diagnosis.

Management of ICI-related myocarditis involves discontinuing the culprit drug and initiating high-dose steroids, typically methylprednisolone 1,000 mg daily followed by 1 mg/kg daily of oral or intravenous steroids. Additional immunosuppression options such as intravenous immunoglobulins, mycophenolate mofetil, infliximab, anti-thymocyte globulin, plasmapheresis, alemtuzumab, and abatacept may be considered for non-responsive patients (17). Delayed treatment can contribute to mortality in ICI-related myocarditis cases (18). In our case, treatment initiation was delayed due to uncertain diagnosis, possibly exacerbating cardiomyopathy. The optimal duration and dosage of immunosuppressive therapy remain unclear, necessitating further research to establish the efficacy of steroids as first-line therapy. Mortality rates in ICI-associated myocarditis are high, with a study reporting up to 89% within a year of diagnosis (5). Timely recognition and interruption of ICI therapy are crucial to prevent further aggravation of irAEs. With appropriate management, outcomes can be favorable, as demonstrated by the resolution of our patient’s cardiac symptoms. Importantly, emerging evidence suggests that non-small cell lung cancer (NSCLC) patients who develop irAEs may experience improved oncologic outcomes compared with those without irAEs (19).

Conclusions

Pembrolizumab-induced myocarditis and cardiomyopathy are rare but potentially life-threatening complications of ICIs. Effective management requires multidisciplinary collaboration among cardiologists, oncologists, and other healthcare professionals to ensure timely recognition, diagnosis, and treatment. Further research is needed to refine diagnostic strategies and develop tailored treatment approaches.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-147/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-147/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-147/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report, accompanying images and videos. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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