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Immune checkpoint inhibitors (ICIs) have marked a major breakthrough in oncology by boosting the immune system’s ability to attack tumors through the inhibition of regulatory pathways such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1). There are different types of ICIs, including CTLA-4 inhibitors (ipilimumab), PD-1 inhibitors (nivolumab, pembrolizumab, cemiplimab), and PD-L1 inhibitors (atezolizumab, avelumab, durvalumab). Despite their clinical success, ICIs can trigger immune-related adverse events (irAEs), affecting organs such as the gastrointestinal tract, skin, liver, and endocrine glands, particularly when used in combination therapies. Although most irAEs respond to treatment interruption and immunosuppression, cardiac side effects such as myocarditis can be severe and potentially fatal [,,].

Myocarditis is the most common and serious form of ICI-associated cardiotoxicity, though other cardiac complications such as cardiomyopathy, arrhythmias, acute coronary syndrome, and vasculitis have also been reported [,,]. The incidence of immune myocarditis among cancer patients enrolled in clinical trials receiving ICIs has been reported to range from 0.06% to 1% []. Moreover, a study by Johnson et al. demonstrated a significant difference in incidence between treatment regimens: 0.06% in patients treated with nivolumab alone and 0.27% in those receiving combination therapy with nivolumab and ipilimumab []. The exact mechanism remains unclear, but shared antigens between tumor and heart tissues may play a role. Additionally, animal studies suggest that CTLA-4, PD-1, and PD-L1 have cardioprotective effects, and their inhibition may increase the heart’s vulnerability to immune damage [,,].

Recent guidelines from the European Society of Cardiology (ESC) and the European Society for Medical Oncology (ESMO) offer clear recommendations for diagnosing and managing ICI-associated myocarditis [,]. Similarly, the American Society of Clinical Oncology (ASCO) has published guidelines for managing irAEs in patients treated with ICIs []. The 2022 ESC Cardio-Oncology Guidelines stress early detection and prompt treatment, advising immediate cessation of ICI therapy upon suspicion of myocarditis and initiation of high-dose corticosteroids (e.g., methylprednisolone 500–1000 mg IV daily) for 3–5 days or until improvement. If needed, additional immunosuppressants such as infliximab, antithymocyte globulin (ATG), or intravenous immunoglobulin may be used. The guidelines also emphasize the importance of multidisciplinary care tailored to the patient. Similarly, the ESMO Clinical Practice Guideline recommends stopping ICI therapy and initiating high-dose corticosteroids promptly, along with close monitoring and supportive care, with consideration of additional immunosuppressive treatments when appropriate [,].

Here, we present a case report from our hospital and the fatal outcome of this patient despite the timely and coordinated efforts of oncologists, cardiologists, and rheumatologists. Additionally, we conducted a literature review to identify all relevant articles reporting similar cases.

A 71-year-old man presented to the emergency department with palpitations, generalized weakness, fatigue, and easy exhaustion with minimal exertion for the past three days. He denied chest pain or shortness of breath. His medical history included arterial hypertension, dyslipidemia, and a 70-pack-year smoking history. In 2003, he underwent a radical prostatectomy as definitive treatment for prostate cancer. In May 2024, he underwent a left upper lobectomy for stage IIIA (pT2N2) lung adenocarcinoma characterized by a Ki-67 index of 20–25%, PD-L1 expression of 10%, and mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) (exon 2), serine/threonine kinase 11 (STK11), and tumor protein 53 (TP53). He subsequently received adjuvant chemotherapy with cisplatin and pemetrexed. Sixteen days prior to presentation, he received his first cycle of adjuvant pembrolizumab according to the PEARLS/KEYNOTE-091 trial []. shows the positron emission tomography/computed tomography (PET/CT) scan performed for diagnosis. The patient’s blood pressure was 140/78 mmHg, and his heart rate was 104 beats per minute with a regular rhythm. His body temperature was 36.4 °C. On physical examination, there was no lower limb swelling or jugular vein distension. S1 and S2 were audible, and no murmurs were heard on cardiac auscultation. Lung examination revealed bilateral wheezing.

The electrocardiogram (ECG) showed sinus tachycardia with a newly diagnosed right bundle branch block. illustrates the ECG recorded before the patient arrived at the emergency unit (EU), and shows the ECG obtained upon arrival. Echocardiography revealed a right ventricle of normal size but with impaired function.

On evaluation in the EU, laboratory tests revealed a hemoglobin level of 16.1 g/dL (normal for men: 13.5–17.5 g/dL), a white blood cell count of 12,550/μL (normal: 4000–11,000/μL), and a platelet count of 234,000/μL (normal: 150,000–450,000/μL). Renal function was within normal limits, with a creatinine level of 0.73 mg/dL (normal: 0.6–1.2 mg/dL) and urea at 34 mg/dL (normal: 11–54 mg/dL). Liver enzymes were markedly elevated, with aspartate aminotransferase (AST) at 566 IU/L (normal: 10–35 IU/L) and alanine aminotransferase (ALT) at 277 IU/L (normal: 10–35 IU/L). Electrolytes were within normal ranges, with sodium at 137 mEq/L (normal: 136–146 mEq/L) and potassium at 4.84 mEq/L (normal: 3.5–5.3 mEq/L). Lactate dehydrogenase (LDH) was significantly elevated at 979 U/L (normal: 115–230 U/L). Coagulation parameters showed an international normalized ratio (INR) of 1.15 (normal: 0.8–1.2). High-sensitivity cardiac troponin I was markedly elevated at 13,983.1 pg/mL (normal: <14 pg/mL), along with creatine kinase (CK) at 7166 IU/L (normal for men: 40–190 IU/L) and CK-MB at 173 U/L (normal: <25 U/L). D-dimer levels were elevated at 2.88 μg/mL (normal: <0.5 μg/mL), and C-reactive protein (CRP) was significantly elevated at 79 mg/L (normal: <6 mg/L). Arterial blood gas analysis revealed a lactate level of 0.9 mmol/L (normal: 0.5–2.2 mmol/L).

The patient was admitted to the coronary care unit due to a high suspicion of non–ST-elevation myocardial infarction (NSTEMI). Initially, acute coronary syndrome was ruled out by performing an emergent coronary angiography, which revealed no significant stenosis in the coronary arteries (). Subsequently, a computed tomography pulmonary angiography (CTPA) was performed, which also ruled out pulmonary embolism (). A full viral blood workup, including a coronavirus disease 2019 (COVID-19) test, as well as tests for tuberculosis and blood cultures, was obtained, all of which eventually returned negative. Cardiac magnetic resonance imaging (MRI) performed the next day confirmed the diagnosis. Specifically, the MRI showed diffuse delayed enhancement of the myocardium throughout all walls of the left ventricle, with particularly patchy, almost transmural enhancement observed in the apical inferior and apical regions. These findings were suggestive of myocarditis related to immune checkpoint inhibitor therapy, according to the modified Lake Louise criteria [].

Since an endomyocardial biopsy could not be performed at our center, the diagnosis of ICIs myocarditis was made according to the 2022 ESC Cardio-Oncology Guidelines. Diagnosis requires elevated troponin (after ruling out other causes such as acute infectious myocarditis and acute coronary syndrome) plus either one major criterion (diagnostic cardiac MRI) or at least two minor criteria. In this case, the patient presented with a clinical syndrome, immune-related adverse events, and suggestive cardiac MRI findings (three minor criteria), accompanied by elevated troponin levels. Given the recent initiation of immunotherapy with pembrolizumab, the patient was diagnosed with immunotherapy-induced myocarditis and was immediately started on high-dose corticosteroid therapy (1 g IV methylprednisolone for 3–5 consecutive days), along with optimal cardiovascular medical therapy, including ramipril 5 mg once daily and bisoprolol 5 mg once daily.

On day 3, because troponin levels had not decreased by 50%, complicated myocarditis was diagnosed, and a rheumatology consultation was requested. Following the rheumatologist’s advice, mycophenolate mofetil was started at 500 mg twice daily for 3 days and then increased to 1000 mg twice daily. This escalation was consistent with ESC and ESMO recommendations, which advise introducing second-line immunosuppression when high-dose corticosteroids fail to achieve clinical or biochemical improvement and the patient shows signs of clinical worsening. On day 6, the patient developed conduction abnormalities with alternating blocks, ventricular arrhythmias, and biventricular dysfunction, with a reduced left ventricular ejection fraction (LVEF) of 35%. Troponin levels continued to rise, and blood gas analysis showed elevated lactate levels. shows the ECG recorded during hospitalization, demonstrating the occurrence of a serious complication—ventricular tachycardia (VT)—while illustrates the changes in troponin levels throughout the hospital stay.

Antiarrhythmic therapy with amiodarone and lidocaine was initiated, but due to hemodynamic instability and hypoxemia, the patient was intubated and supported hemodynamically with an intra-aortic balloon pump and vasopressors. Additionally, because of continued clinical and biomarker worsening, along with the development of malignant arrhythmias and hemodynamic instability, abatacept was administered intravenously at a dose of 750 mg, with plans for subsequent doses to be given subcutaneously. Despite third-line immunosuppressive therapy with abatacept, the patient did not respond to treatment. He subsequently developed renal failure, and continuous hemofiltration was initiated. Unfortunately, he passed away due to sepsis followed by multi-organ failure after 15 days of hospitalization. provides a summary of the timeline of the patient’s clinical events.

A structured literature search was conducted to identify all published case reports and case series describing myocarditis associated with ICI therapy. Searches were performed in PubMed, Scopus, and the Cochrane Library from database inception to May 2025. To maximize the sensitivity of the search, a broad and inclusive algorithm was used: (neoplasia OR cancer OR carcinoma) AND (immunotherapy OR immune checkpoint OR ICIs) AND (myocarditis OR myocardial involvement OR myotoxicity OR cardiac immune-related adverse events OR cardiological immune-related side effects). No filters related to study design, publication year, or article type were applied to avoid missing relevant reports. To further ensure completeness, the reference lists of all retrieved articles were manually screened for additional eligible publications. Two of the three databases returned relevant results, whereas the third did not generate any articles meeting the criteria.

Studies were included if they met the following criteria: (1) described myocarditis attributed to ICI therapy; (2) presented original patient data in the form of a case report or case series; (3) involved adult patients receiving ICIs; (4) were published in English; (5) provided full-text availability. We excluded non-English publications, non-human studies, mechanistic reports without patient cases, and articles describing myocarditis caused by infectious, ischemic, toxic, or autoimmune etiologies unrelated to ICIs. Reports focusing solely on other cardiac immune-related adverse events without myocarditis were also excluded.

The initial database search yielded a total of 1319 records (PubMed n = 1024; Cochrane n = 49; Scopus n = 246). After removing 13 duplicate records and 453 additional articles for reasons such as non-English language, non-human populations, or unrelated subject matter, 853 articles remained for title and abstract review. Of these, 705 were excluded because they did not meet predefined eligibility criteria. An additional 23 studies could not be retrieved. The remaining 125 full-text articles were reviewed in detail, and 30 publications reporting 45 individual cases of ICI-associated myocarditis were identified as eligible and included in the final analysis. The selection process is summarized in a PRISMA-style flow diagram (). Data extraction was performed independently by two reviewers (N.T and M.Y.) using a predefined structured form. Extracted variables included demographics, cancer type, ICIs regimen, timing of myocarditis onset, symptoms, ECG findings, cardiac biomarkers, imaging results, biopsy findings, treatment strategies, cardiac complications, and clinical outcomes. Disagreements were resolved through discussion and consensus.

Quality assessment was conducted for all included case reports and case series to ensure reliability of the extracted data. Each article was evaluated for clarity of diagnosis, completeness of clinical information, adherence to recognized definitions of ICI-associated myocarditis, and adequacy of reported investigations and follow-up. Formal scoring tools were not applied due to the nature of case-based evidence, but emphasis was placed on diagnostic transparency and completeness of reporting. Only studies with sufficient information to support the diagnosis were included. Due to the heterogeneity of the included reports, particularly regarding clinical presentation, diagnostic evaluation, and treatment approaches, a quantitative meta-analysis was not feasible. Therefore, a descriptive narrative synthesis was performed. Findings across cases were summarized thematically and organized in tabular form (), highlighting the most common and less common clinical features and diagnostic pattern.

We identified 30 relevant articles presenting case reports of immune-associated myocarditis. Although some articles described more than one case, the total number of reported cases was 45 [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,]. Approximately 57.8% of the patients were male (26/45). The mean age was 66.68. The youngest patient was 35 years old [], and the oldest was 89 years old []. The mean time from the start of immunotherapy to the onset of myocarditis was 103 days. There were two cases in which myocarditis appeared much later—2.5 years and 8 months after the initiation of immunotherapy [,]. If these two outliers are excluded, the mean time to onset was 67 days. The earliest presentation occurred 3 days after the initiation of ICIs [], and the latest was at 2.5 years. None of the patients had autoimmune diseases. Most of the patients had hypertension (22/45) and diabetes (13/45). Atrial fibrillation was present in three patients, and coronary artery disease was also reported in three patients. Seven patients had no significant medical history, and for five patients, data on medical history were not available [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,].

The most common type of cancer was lung cancer (17/45), followed by renal cell carcinoma (8/45). In most cases, pembrolizumab was the immune checkpoint inhibitor used (12/45), followed by nivolumab (10/45) and the combination of ipilimumab and nivolumab (9/45). Immunotherapy was administered either in the adjuvant or metastatic setting [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,]. The most common presenting symptoms of immune-associated myocarditis were dyspnea (shortness of breath), fatigue, chest pain or discomfort, myalgia, and palpitations. These symptoms often appeared alone or in combination and reflect the cardiac, respiratory, and systemic involvement typical of immune-mediated toxicity. Neurological symptoms such as ptosis, diplopia, blurred vision, and weakness were also noted in several cases, indicating a possible overlap with myositis or myasthenia-like syndromes [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,]. In contrast, the rarest symptoms included cardiac arrest, right-sided facial droop, presyncope, asymptomatic presentation with only mild CK elevation, watery diarrhea with frequent premature ventricular contractions (PVCs), and severe asthenia due to subcutaneous tumor infiltration. These atypical manifestations highlight the broad and sometimes subtle clinical spectrum of myocarditis associated with immune checkpoint inhibitors [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,].

At presentation in the emergency department, the most common electrocardiographic findings included ST-segment elevation in various leads (anterolateral, inferolateral, V1–V6, II, III, and aVF), sinus tachycardia, and right bundle branch block (RBBB). These findings typically indicated acute myocardial injury or inflammation. Other frequent abnormalities were atrial fibrillation, PVCs, and T-wave inversions [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,]. Rare but severe ECG presentations included complete atrioventricular block (CAVB), ventricular tachycardia (VT), wide QRS complex arrhythmias, QT prolongation, alternating bundle branch blocks, asystole, and episodes of third-degree heart block with junctional escape rhythms. A few patients had normal ECGs or showed only minor changes such as lateral ST-segment depression or nonspecific ST-T wave abnormalities. This broad spectrum of ECG presentations highlights the variable cardiac involvement of immune-associated myocarditis at initial emergency evaluation [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,].

At presentation, LVEF varied widely among patients with immune-associated myocarditis. The most common findings included preserved or mildly reduced LVEF (50–60%), often accompanied by mild left ventricular hypertrophy (LVH), mild-to-moderate left atrial enlargement, and mild regurgitation of the aortic, mitral, and tricuspid valves. Many patients exhibited normal wall motion or mild diastolic dysfunction with preserved systolic function. Several cases also showed right ventricular dilation with preserved right ventricular systolic function [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,]. Conversely, severe left ventricular systolic dysfunction with markedly reduced LVEF (ranging from 10% to 35%) was noted in a subset of patients, often accompanied by diffuse hypokinesis, apical thrombi, and pericardial effusions. Some patients had new wall motion abnormalities, akinetic or hypokinetic segments, and signs of right heart failure such as right atrial dilation and hepatic vein reflux. A few cases reported hyperdynamic basal segments despite an overall reduced LVEF [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,].

In some patients, echocardiograms were unremarkable, with normal LVEF and no regional wall motion abnormalities, while in others, data were not available. These findings highlight the heterogeneity of cardiac involvement in immune checkpoint inhibitor–associated myocarditis, ranging from subtle functional changes to severe cardiomyopathy. In half of the patients, MRI data were not available. Among the remaining cases, only three had MRI findings that were negative for myocarditis [,,]. At the emergency department, patients exhibited a wide range of cardiac biomarker levels, with troponin often markedly elevated, indicating ongoing myocardial injury. CK levels varied considerably, from normal to highly increased, reflecting muscle damage, while CK-MB values, when available, were frequently elevated. BNP or NT-proBNP levels ranged from normal to significantly increased, suggesting cardiac stress or heart failure [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,].

In addition, only 15 out of 44 cases underwent myocardial biopsy due to the difficulty of the procedure and safety concerns for the patients. In the case report by Hu Y., the biopsy revealed degeneration of myocardial cells and an inflammatory infiltrate consisting predominantly of CD3 + CD4 + CD8 + cells in the myocardium []. In the case report by Le Bras, the biopsy showed abnormalities suggestive of anti-PD-L1–related cardiac involvement, and the hypertrophy could be secondary to arterial hypertension []. In the study by Izumi, which presented four different case reports, myocardial biopsy was performed in all cases. In the first case, the biopsy revealed CD3 + T-cells (with CD8 predominating over CD4), CD68 + histiocytes, a few CD20 + B-cells, a few eosinophils, and high expression of Tenascin-C and PD-L1. The second case showed a similar pattern with CD3 + T-cells (CD8 > CD4), CD68 + histiocytes, a few CD20 + B-cells, neutrophils and eosinophils, and high levels of Tenascin-C and PD-L1. In the third case, the biopsy demonstrated CD3 + T-cells with equal CD4 and CD8 expression, CD68 + histiocytes, a few CD20 + B-cells, and moderate expression of Tenascin-C and PD-L1. Finally, in the fourth case, the biopsy showed CD3 + T-cells (CD8 > CD4), rare CD68 + histiocytes and CD20 + B-cells, with low expression of Tenascin-C and PD-L1 []. In the article by Lewis I., the myocardial biopsy showed distinct focal and diffuse interstitial fibrosis, suggestive of inflammation that likely preceded the out-of-hospital cardiac arrest (OHCA) subclinically by several months. In various areas, myocyte necrosis was observed in association with numerous CD3 + T-cells (100/mm 2 ), a large number of CD68 + macrophages expressing MHC II (200/mm 2 ), and scattered CD20 + B-lymphocytes, with no eosinophilic granulocytes or multinucleated giant cells present []. In the case report by Miyauchi Y., a myocardial biopsy performed during the acute phase showed marked lymphocytic infiltration, predominantly composed of CD4 + cells. A repeat biopsy on day 32 of steroid treatment revealed a mixed population of CD4 + and CD8 + T cells along with numerous histiocytes/macrophages, consistent with chronic smoldering myocarditis []. In the case report by Naganuma K., the biopsy revealed focal infiltration of inflammatory cells, predominantly CD8-positive T cells, around myocardial cells, without evidence of myocardial necrosis. Additionally, limited PD-L1 expression was observed in some myocardial cells []. In the article by Sakaguchi H., two different cases are presented. In one of them, a myocardial biopsy was performed. Histological examination revealed myocardial fibrosis and lymphocytic infiltration despite high-dose corticosteroid treatment, suggesting that corticosteroid monotherapy was insufficient for managing the myocarditis []. In the case report by Zadok O., the myocardial biopsy showed fulminant myocarditis with abundant lymphocytes, eosinophils, and histiocytes []. In addition, in Matson’s study, the heart biopsy revealed widespread lymphoplasmacytic infiltration with myocyte injury and necrosis. Granulation tissue and hemosiderin-laden macrophages were present, without notable eosinophils or neutrophils. Immunohistochemistry showed predominantly CD3-positive T-cells (CD4:CD8 ratio 1:2) and scattered CD20-positive B cells. No IgG4-positive lymphocytes were identified []. The last case report in which a biopsy was performed was that of Zhang L. et al., where the myocardial biopsy revealed lymphocytic myocarditis []. In Salem J.E.’s study, a muscle biopsy was performed and diagnosed as myositis [].

The most commonly administered treatment for ICI-associated myocarditis was high-dose intravenous methylprednisolone, typically 1 gram per day for 3 to 5 days, followed by a gradual taper using oral prednisone or prednisolone at doses ranging from 1 mg/kg/day to lower maintenance doses. Several patients also received intravenous immunoglobulin (IVIG), particularly in severe or steroid-refractory cases. Additional immunosuppressive agents such as mycophenolate mofetil (MMF), ATG, infliximab, methotrexate, tacrolimus, and abatacept were used in more complex or relapsing cases [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,]. Supportive therapies included cardiac medications such as beta-blockers (metoprolol, carvedilol), ACE inhibitors (lisinopril), diuretics (furosemide, IV diuretics), and, in some cases, inotropic support (e.g., norepinephrine) for hemodynamic instability. Rare but aggressive interventions included plasma exchange, hemodialysis, permanent pacemaker implantation, and multiple immunomodulatory cycles (e.g., repeat infliximab doses, IVIG courses, and extended MMF treatment) [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,].

During hospitalization, patients experienced a wide range of cardiac complications. Conduction abnormalities such as prolonged PR interval, left bundle branch block (LBBB), and complete heart block were reported, with some requiring urgent transvenous pacing or permanent pacemaker implantation. Ventricular arrhythmias, including bigeminy, trigeminy, sustained and refractory ventricular tachycardia, and ventricular fibrillation, were common. Several patients progressed to pulseless electrical activity or cardiac arrest, requiring resuscitation and defibrillation. In some cases, telemetry revealed frequent premature ventricular contractions despite the absence of symptoms [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,]. Cardiogenic shock developed in many patients, necessitating intensive care unit (ICU) admission, inotropic support, and mechanical circulatory assistance, including intra-aortic balloon pump (IABP) or extracorporeal membrane oxygenation (ECMO). LVEF frequently declined during the hospital stay, with some patients deteriorating rapidly from preserved function to an LVEF below 10%. A few patients responded to high-dose corticosteroids with gradual improvement in cardiac function and biomarker normalization, while others required second-line immunosuppressive therapies due to steroid-refractory disease [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,].

Non-cardiac complications included acute renal failure, septic shock, and hepatic dysfunction. Some patients exhibited overlapping immune toxicities such as myositis, hepatitis, and myasthenia, as confirmed by serologic testing [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,]. Outcomes varied, with some patients being discharged after clinical improvement, while others had prolonged hospitalizations or experienced fatal deterioration despite aggressive management. Specifically, among 45 patients with ICI-associated myocarditis, 25 (55.5%) were alive at follow-up, while 20 (44.5%) had passed away. Among the survivors, two patients remained alive with partial response (PR), three with stable disease (SD), and two were able to restart chemotherapy. One patient continued on long-term prednisone therapy, two had persistently elevated troponin levels, and one experienced three recurrences of irAEs.

In contrast, 20 patients died: four due to progression of the underlying disease (PD), three from ventricular tachycardia (VT) or pulseless VT, four from heart failure or cardiogenic shock with multi-organ failure, three from sepsis or septic shock, two from hemorrhagic or intracerebral stroke, one from acute myasthenic crisis, one from respiratory failure, and one from myocardial infarction. Overall, cardiovascular complications and infectious causes were the predominant contributors to mortality [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,].