Immune Checkpoint Inhibitor–Associated Myocarditis in Cancer Patients: A Systematic Review of Clinical Presentation, Management, and Outcomes

Immune Checkpoint Inhibitor–Associated Myocarditis in Cancer Patients: A Systematic Review of Clinical Presentation, Management, and Outcomes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Immune Checkpoint Inhibitor–Associated Myocarditis in Cancer Patients: A Systematic Review of Clinical Presentation, Management, and Outcomes Moontasir Ahmed, Jannatara Tina, Shadman Newaz, Rashid Shahriar Sazal, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9242293/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Immune checkpoint inhibitor-associated myocarditis (ICI-M) is a rare but life-threatening toxicity. This systematic review synthesizes the current evidence on the epidemiology, clinical presentation, diagnostic approaches, management strategies, and outcomes of ICI-M to guide clinical practice. Methods We systematically searched PubMed from inception to January, 2026 for studies reporting on ICI-M in cancer patients. Data on patient demographics, clinical features, diagnostic findings, treatment, and outcomes were extracted. The risk of bias was assessed using appropriate tools. Results 43 studies were included. ICI-M predominantly affected older adults (median age 65–74 years) with metastatic melanoma, non-small cell lung cancer, or renal cell carcinoma. The highest risk was associated with combination ICI therapy (anti-PD-1/PD-L1 + anti-CTLA-4). Clinical presentation ranged from asymptomatic biomarker elevation to fulminant heart failure, with a high frequency of concurrent myositis. Key diagnostic findings included elevated troponin (> 90% of cases), ECG abnormalities, and reduced global longitudinal strain on echocardiography. Management universally involved ICI discontinuation and high-dose corticosteroids. Second-line immunosuppression (e.g., IVIG, infliximab, abatacept) was used in refractory cases. Despite treatment, mortality remained high (25–50%). Poor prognostic factors included high troponin levels, reduced left ventricular ejection fraction, and conduction abnormalities. Conclusion ICI-M is a severe complication with high mortality. Early recognition via proactive monitoring, prompt diagnosis using a multi-modal approach, and immediate, aggressive immunosuppression are critical. Future research should focus on predictive biomarkers and randomized trials to optimize management. Immune checkpoint inhibitors Myocarditis Cardio-oncology Immunotherapy Immune-related adverse events Systematic review Figures Figure 1 Figure 2 1. Introduction Immune checkpoint inhibitors (ICIs) have revolutionized oncology by harnessing the immune system to fight cancer. However, this enhanced immunity can also lead to immune-related adverse events (irAEs), affecting various organs. Among these, ICI-associated myocarditis (ICI-M) is one of the most severe, with a fatality rate exceeding many other irAEs ( 1 , 2 ). Despite its rarity, ICI-M presents a significant clinical challenge due to its non-specific presentation, rapid progression, and high mortality ( 3 , 4 ). The clinical spectrum is broad, ranging from subclinical disease detected only by biomarker elevation to fulminant myocarditis and cardiogenic shock. Early diagnosis and intervention are paramount, yet standardized guidelines are still evolving based on accumulating evidence from cohort studies, registries, and case series. Over the past decade, numerous studies have characterized the risk factors, clinical course, and outcomes of ICI-M. However, a comprehensive synthesis of this evidence is needed to consolidate our understanding and inform clinical decision-making. This systematic review aims to provide a detailed analysis of the global research landscape, patient characteristics, diagnostic findings, management strategies, and outcomes of ICI-M, integrating data from a wide range of published studies to offer a definitive overview for clinicians and researchers. 2. Methods This systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 2.1. Search Strategy and Selection Criteria A systematic search was performed in PubMed from database inception to January, 2026. The search strategy combined terms related to ("immune checkpoint inhibitor" OR "anti-PD-1" OR "anti-PD-L1" OR "anti-CTLA-4") AND ("myocarditis" OR "cardiotoxicity" OR "cardiovascular adverse event"). Proceedings from key cardiology and oncology conferences were also screened. Studies were included if they: ( 1 ) reported on human cancer patients diagnosed with ICI-M; ( 2 ) provided original data on epidemiology, clinical presentation, diagnosis, management, or outcomes; and ( 3 ) were published in English. Case reports, cohort studies, registries, and clinical trials were eligible. 2.2. Data Extraction and Quality Assessment Two reviewers independently screened titles, abstracts, and full-text articles. Data were extracted using a standardized form, capturing information on study design, patient demographics, cancer types, ICI regimens, diagnostic criteria, management, and outcomes. The risk of bias for RCTs was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool. 2.3. Data Synthesis Given the heterogeneity in study designs and reporting, a narrative synthesis was conducted. Data are presented in summary tables and descriptive text. 3. Results 3.1. Study Selection and Characteristics The initial search yielded 944 records. After removing duplicates and screening titles and abstracts, 104 full-text articles were assessed for eligibility. Ultimately, 43 studies were included in the final synthesis (Fig. 1 ). 3.2. Risk of Bias Assessment The methodological quality of the included studies was assessed. The overall risk of bias was low to moderate. Common limitations included the retrospective nature of most studies and potential selection bias in single-center cohorts. The risk of bias summary and graph are presented in Figs. 2 a and 2 b. 3.3. Geographical Distribution and Research Output The 43 included studies originated from a range of countries, with the United States (37.2%), China (20.9%), and Japan (14.0%) being the largest contributors (Table 1 ). This distribution highlights a significant geographical evidence gap, with vast regions like South America, Africa, and Eastern Europe unrepresented. Table 1 Geographical Distribution and Research Output of Included Studies Country Number of Studies Percentage of Total (n = 43) Study Types (Representative Examples) United States (USA) 16 37.2% Multicenter registries, Single-center cohorts, Systematic Reviews, Case Reports, Preclinical/Translational China 9 20.9% Retrospective multicenter cohorts, Single-center cohorts, Case Series, Bioinformatics analysis, Review Articles Japan 6 14.0% Prospective observational studies, Retrospective cohort studies, Case Reports France 3 7.0% Case-Control Studies, Case Reports with novel therapeutics Germany 2 4.7% Prospective cohort, Preclinical/Clinical study Multi-National 2 4.7% International retrospective cohort, International multicenter study Australia 1 2.3% Case Report Switzerland 1 2.3% Case Report The Netherlands 1 2.3% Review Article Canada 1* 2.3% Part of a multicenter study United Kingdom 1* 2.3% Collaborator in a preclinical study Austria 1* 2.3% Collaborator in a preclinical study *Note: Studies where the country was a collaborator rather than the primary site. This table provides a critical analysis of the global research landscape for ICI-associated myocarditis. The distribution is not uniform, revealing clear leaders and significant gaps. The dominance of the United States, contributing over a third of the studies, reflects its pioneering role in immuno-oncology, the high volume of patients treated at major cancer centers, and the early establishment of dedicated cardio-oncology research programs ( 3 , 8 , 11 , 37 , 39 , 41 ). This leadership is evidenced by a diverse output, from large, foundational multicenter registries to cutting-edge translational science. China's position as the second-largest contributor signals its rapidly expanding capacity and focus in this field, often characterized by large-scale retrospective clinical cohorts that leverage its vast patient population to generate significant real-world evidence ( 12 , 22 , 23 , 29 , 30 ). Japan's significant output, while smaller in volume, is marked by high-quality, meticulous prospective and observational studies that have been instrumental in characterizing subclinical disease and detailed management ( 9 , 16 , 31 , 35 , 40 , 43 ). The European contributions, particularly from France and Germany, are notable for their highly specialized and innovative nature, such as pioneering the use of novel therapeutic agents like abatacept ( 5 , 6 ) and producing key prospective biomarker studies ( 2 ). The presence of multi-national collaborations ( 2 , 8 ) underscores the importance of pooling data to study this rare condition. Crucially, this map highlights a substantial evidence gap, with vast regions of the world (e.g., South America, Africa, Southeast Asia, Eastern Europe) unrepresented. This lack of geographical diversity may limit the generalizability of findings, as genetic backgrounds, regional cancer types, and healthcare delivery systems can influence the presentation and management of ICI-myocarditis. 3.4. Baseline Patient Characteristics The "typical" patient with ICI-M was an older adult (median age 65–74 years) with metastatic cancer, most commonly melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) (Table 2 ). Hypertension and diabetes were the most frequent comorbidities. A subset of patients had a pre-existing autoimmune condition. Table 2 Baseline Characteristics of Patients with Immune Checkpoint Inhibitor-Associated Myocarditis (ICI-M) Characteristic Summary Finding (Range or Most Frequent) Details / Specifics Key References Median Age 65–74 years The patient population predominantly comprised older adults. Mahmood et al., 2018 (65 ± 13) ( 3 ); Dubey et al., 2025 (74 IQR 68–78) ( 11 ); Alexander et al., 2025 (74 ± 9.4) ( 18 ); Puzanov et al., 2021 (73 IQR 66–79) ( 37 ) Common Cancer Types Melanoma, Lung Cancer, Renal Cell Carcinoma (RCC) Melanoma was the most frequently reported cancer. Lehmann et al., 2023 (Melanoma 20%, NSCLC 40%, RCC 10%) ( 2 ); Mahmood et al., 2018 (Melanoma 46%, NSCLC 11%) ( 3 ); Awadalla et al., 2020 (Melanoma 41%, Lung 16%, RCC 8%) ( 8 ); Jensen et al., 2025 (Melanoma, NSCLC, RCC) ( 17 ) Cancer Stage Predominantly Metastatic (Stage IV) The vast majority of patients had advanced or metastatic disease. Dubey et al., 2025 (Majority Stage IV) ( 11 ); Todo et al., 2025 (Metastatic) ( 16 ); Cao et al., 2025 (Stage III-IV NSCLC) ( 22 ); Tang et al., 2023 (71.6% Stage IV) ( 30 ) Common Comorbidities Hypertension, Diabetes Mellitus, Coronary Artery Disease Hypertension was the most prevalent comorbidity. Mahmood et al., 2018 (Hypertension 34%, Diabetes 34%) ( 3 ); Awadalla et al., 2020 (Hypertension 57%, Diabetes 24%) ( 8 ); Zheng et al., 2024 (Hypertension 38.6%, Diabetes 18.2%) ( 12 ); Alexander et al., 2025 (Hypertension 78%, Diabetes 28%) ( 18 ) Pre-existing Autoimmune Condition Present in a subset of patients Noted in several case reports and cohorts. Ganatra & Neilan, 2018 (Hashimoto's thyroiditis) ( 13 ); Stein-Merlob et al., 2021 (Graves' disease) ( 27 ) This table synthesizes the demographic and clinical foundation of the studied population, painting a picture of the "typical" patient at risk for this severe toxicity. The consistency across numerous international cohorts strongly suggests that ICI-M, while rare, does not occur randomly but is more likely in a specific patient profile. The predominance of older patients ( 3 , 11 , 18 , 37 ) likely reflects both the higher incidence of cancers treated with ICIs in this age group and a potentially altered immune response. The recurrence of melanoma, NSCLC, and RCC ( 2 , 3 , 8 , 17 ) is expected, as these were among the first malignancies with approved ICI therapies, leading to extensive clinical experience and larger patient pools for observation. The overwhelming representation of metastatic disease ( 11 , 16 , 22 , 30 ) is a critical confounder; it is unclear whether advanced cancer stage is an independent risk factor or if the association is simply because these patients are the primary recipients of ICIs. The high prevalence of hypertension and other cardiovascular comorbidities ( 3 , 8 , 12 , 18 ) indicates that a compromised cardiovascular system may be more susceptible to immune-mediated injury, a key consideration for pre-therapy risk assessment. 3.5. Treatment-Related Factors Combination ICI therapy (e.g., ipilimumab + nivolumab) was the strongest risk factor for ICI-M (Table 3 ). The median time to onset was early, typically within the first 1–4 cycles (17–65 days). A significant proportion of patients received concurrent therapies like chemotherapy or radiotherapy. Table 3 Treatment-Related Factors Preceding ICI-Associated Myocarditis Onset Factor Summary Finding Details / Specifics Key References Most Common ICI Classes Anti-PD-1, Anti-PD-L1, Anti-CTLA-4 Myocarditis was reported with all major ICI classes. Moslehi et al., 2021 ( 1 ); Palaskas et al., 2020 ( 7 ); Turker & Johnson, 2023 ( 21 ) Highest Risk Regimen Combination ICI Therapy (e.g., Ipilimumab + Nivolumab) Combination therapy was consistently identified as the strongest risk factor. Moslehi et al., 2021 ( 1 ); Mahmood et al., 2018 (34% on combination) ( 3 ); Ganatra & Neilan, 2018 ( 13 ); Jensen et al., 2025 ( 17 ) Median Time to Onset 17–65 days Onset was often early in the treatment course. Mahmood et al., 2018 (34 days) ( 3 ); Palaskas et al., 2020 (27–65 days) ( 7 ); Todo et al., 2025 (25 days) ( 16 ); Turker & Johnson, 2023 (27–34 days) ( 21 ); Atallah-Yunes et al., 2019 (22.5 days) ( 32 ) Typical Cycle of Onset Within first 1–4 cycles Many cases occurred after the first or second dose. Atallah-Yunes et al., 2019 (1–2 doses in majority) ( 32 ); Cao et al., 2025 (48.4% within first 2 cycles) ( 22 ) Concurrent Therapies Chemotherapy, Targeted Therapy, Radiotherapy A significant proportion received concurrent treatments. Cao et al., 2025 (84.8% ICI combo with chemo) ( 22 ); Tang et al., 2023 (54.3% concurrent chemo) ( 30 ); Matsumoto et al., 2022 (prior radiotherapy) ( 40 ) This table moves from who is at risk to what precipitates the event, highlighting modifiable risk factors. The strong, consistent signal across nearly all studies that combination ICI therapy (most notably anti-PD-1 + anti-CTLA-4) is the single greatest risk factor ( 1 , 3 , 7 , 13 , 17 ) is perhaps the most critical clinical finding. This makes biological sense, as dual checkpoint blockade induces a more potent and broader immune activation, inadvertently increasing the risk of breaking self-tolerance. The early median time to onset ( 3 , 7 , 16 , 21 , 32 ) underscores the need for heightened vigilance during the initial treatment cycles, fundamentally shaping monitoring guidelines. However, the reports of late-onset cases ( 21 , 35 , 41 ) remind clinicians that risk never completely dissipates. The data on concurrent therapies is more ambiguous, as many patients receive multi-modal treatment; while not definitively proven to be independent risk factors, chemotherapy and radiotherapy may create a pro-inflammatory environment that lowers the threshold for myocarditis ( 22 , 30 , 40 ). 3.6. Clinical Presentation and Diagnostic Findings The clinical presentation of ICI-M was highly variable (Table 4 ). Dyspnea was the most common symptom, but a significant proportion of patients were asymptomatic. Overlap with myositis and myasthenia gravis was frequent. Key diagnostic findings included elevated troponin, ECG abnormalities, and reduced global longitudinal strain (GLS) on echocardiography. Cardiac MRI and endomyocardial biopsy were crucial for confirmation. Table 4 Clinical Presentation and Diagnostic Findings in ICI-Associated Myocarditis Category Finding Details / Specifics Key References Common Symptoms Dyspnea, Chest Pain, Fatigue Dyspnea was the most common symptom. A significant proportion were asymptomatic. Mahmood et al., 2018 (Dyspnea 71%) ( 3 ); Tanabe et al., 2021 (Asymptomatic) ( 9 ); Todo et al., 2025 (Some asymptomatic) ( 16 ); Cao et al., 2025 (45.5% symptomatic) ( 22 ); Nishikawa et al., 2022 (Mostly asymptomatic) ( 31 ) Overlap Syndromes Myositis, Myasthenia Gravis Concomitant myositis was very common. Lehmann et al., 2023 (~ 68% myositis) ( 2 ); Nguyen et al., 2022 (concurrent myositis) ( 5 ); Salem et al., 2019 (myositis) ( 6 ); Ke et al., 2023 (myositis & MG) ( 23 ); Sessums et al., 2020 (myositis) ( 26 ) ECG Abnormalities Conduction Disorders, Arrhythmias Abnormal ECGs were found in 50–89% of cases. Mahmood et al., 2018 (89% abnormal) ( 3 ); Palaskas et al., 2020 ( 7 ); Dubey et al., 2025 (34.3% conduction abnormalities) ( 11 ) Key Biomarkers Elevated Troponin, Elevated CK, Elevated NT-proBNP Troponin was elevated in > 90% of cases. Mahmood et al., 2018 (Troponin elevated 94%) ( 3 ); Palaskas et al., 2020 ( 7 ); Awadalla et al., 2020 (Troponin elevated 97%) ( 8 ); Dubey et al., 2025 (High TnT predicts mortality) ( 11 ) Echocardiography Preserved or Reduced LVEF, Reduced GLS LVEF was preserved (> 50%) in approximately half of the patients. GLS was a more sensitive marker. Mahmood et al., 2018 (51% had normal LVEF) ( 3 ); Awadalla et al., 2020 (60% had preserved EF; GLS predicted MACE) ( 8 ); Sessums et al., 2020 (Normal LVEF) ( 26 ) Cardiac MRI (CMR) Late Gadolinium Enhancement (LGE), T2-Weighted Edema CMR was a key diagnostic tool. Palaskas et al., 2020 ( 7 ); Ganatra & Neilan, 2018 ( 13 ); Jensen et al., 2025 ( 17 ) Endomyocardial Biopsy (Gold Standard) T-cell Lymphocytic Infiltration Biopsy findings typically revealed a T-cell-predominant infiltrate. Mahmood et al., 2018 (T-cell infiltrate) ( 3 ); Nguyen et al., 2022 (CD3 + T-cells) ( 5 ); Ganatra & Neilan, 2018 (CD8 + T cells) ( 13 ) This table captures the clinical essence of the disease, revealing a spectrum from silent, biomarker-only disease to catastrophic failure. The high rate of asymptomatic or mildly symptomatic presentation ( 9 , 16 , 22 , 31 ) is a pivotal finding; it argues strongly for proactive biomarker screening rather than relying on symptom reporting alone. The frequent overlap with myositis and myasthenia gravis ( 2 , 5 , 6 , 23 , 26 ) is a unique and dangerous feature, suggesting a shared antigenicity between cardiac, skeletal muscle, and neuromuscular junctions that is unmasked by ICIs. The diagnostic pillars are clearly established: Troponin is the cornerstone biomarker ( 3 , 7 , 8 , 11 ), with its peak level being profoundly prognostic. Echocardiography often reveals preserved LVEF ( 3 , 8 , 26 ), but the superior sensitivity of GLS provides critical prognostic information even when LVEF appears normal ( 8 , 9 ). Cardiac MRI is the best non-invasive tissue characterization tool ( 7 , 13 , 17 ), yet its false-negative rate confirms that it should complement, not replace, clinical judgment. The gold standard remains endomyocardial biopsy ( 3 , 5 , 13 ), which definitively reveals the T-cell-mediated pathology. 3.7. Management Strategies Management was stratified by severity (Table 5 ). The universal first step was ICI discontinuation. High-dose corticosteroids were the cornerstone of initial immunosuppression. For steroid-refractory cases, second-line agents (e.g., IVIG, mycophenolate, infliximab) and novel targeted agents (e.g., abatacept) were used. Fulminant cases required advanced supportive care, including mechanical circulatory support. Table 5 Management Strategies for ICI-Associated Myocarditis Management Strategy Application & Details Notes / Evidence Key References ICI Discontinuation Universal first step upon diagnosis ICI therapy was permanently discontinued in the majority of severe cases. Mahmood et al., 2018 ( 3 ); Palaskas et al., 2020 ( 7 ); Ganatra & Neilan, 2018 ( 13 ) First-Line Immunosuppression High-Dose Corticosteroids IV methylprednisolone was the most common initial treatment. Mahmood et al., 2018 (89% received steroids) ( 3 ); Palaskas et al., 2020 ( 7 ); Heemelaar et al., 2024 ( 15 ); Puzanov et al., 2021 (All severe patients received IV steroids) ( 37 ) Second-Line Immunosuppression For steroid-refractory cases A variety of agents were used. Mahmood et al., 2018 (IVIG, Mycophenolate, Infliximab, ATG) ( 3 ); Palaskas et al., 2020 ( 7 ); Heemelaar et al., 2024 ( 15 ); Liu et al., 2022 (Infliximab review) ( 33 ) Novel / Targeted Agents For severe, refractory cases Emerging evidence from case reports. Nguyen et al., 2022 (Abatacept & Ruxolitinib) ( 5 ); Salem et al., 2019 (Abatacept) ( 6 ); Doms et al., 2020 (Tocilizumab) ( 24 ) Supportive Care & Advanced Support For fulminant cases Included management in the Cardiac ICU and MCS. Nguyen et al., 2022 (ECLS) ( 5 ); Stein-Merlob et al., 2021 (Impella, VA-ECMO) ( 27 ); Matsumoto et al., 2022 (IABP) ( 40 ) This table outlines the escalation of care, which is directly tied to disease severity (as defined in Table 7 ). The universal first step is ICI discontinuation ( 3 , 7 , 13 ), a high-stakes decision in a cancer patient that underscores the life-threatening nature of this toxicity. The cornerstone of medical management is high-dose corticosteroids ( 3 , 7 , 15 , 37 ), with an emphasis on early initiation and high dose (e.g., 1g methylprednisolone), as delays and lower doses are associated with worse outcomes ( 3 , 11 ). For steroid-refractory cases, a range of second-line agents are used empirically ( 3 , 7 , 15 , 33 ), reflecting the lack of RCTs. The most compelling advances come from novel/targeted agents used in severe cases: Abatacept (a CTLA-4 agonist) to directly counter the ICI's mechanism ( 5 , 6 ), Ruxolitinib (a JAK inhibitor) to block inflammatory signaling ( 5 ), and Tocilizumab (an IL-6 blocker) ( 24 ), showing a shift towards pathophysiology-driven therapy. In fulminant cases, mechanical circulatory support (MCS) like VA-ECMO ( 5 , 27 , 40 ) is a life-saving bridge to recovery, allowing time for immunosuppression to work. 3.8. Outcomes and Prognostic Factors ICI-M carried a high mortality rate (25–50%) and a high incidence of major adverse cardiac events (MACE) (Table 6 ). Negative prognostic factors included combination ICI therapy, high troponin levels, low GLS, and conduction abnormalities. Early steroid administration and specific biomarker trends were associated with better outcomes. Table 6 Outcomes and Prognostic Factors in ICI-Associated Myocarditis Outcome / Factor Summary Finding Details / Specifics Key References Overall Mortality 25% − 50% ICI-associated myocarditis carried a high fatality rate. Moslehi et al., 2021 (40–50%) ( 1 ); Mahmood et al., 2018 (High fatality) ( 3 ); Palaskas et al., 2020 (25–50%) ( 7 ); Jensen et al., 2025 (~ 40%) ( 17 ); Wang et al., 2023 (47.4% death) ( 28 ); Moradi et al., 2023 (up to 50%) ( 34 ) Major Adverse Cardiac Events (MACE) Common (up to 51%) MACE occurred in a significant proportion of patients. Mahmood et al., 2018 (46% MACE) ( 3 ); Awadalla et al., 2020 (51% MACE) ( 8 ); Dubey et al., 2025 (62.9% died within 1 year) ( 11 ); Tang et al., 2023 (34.6% MACE) ( 30 ) Cardiac Recovery Variable Left ventricular function recovered in many survivors. Awadalla et al., 2020 (GLS improvement) ( 8 ); Ganatra & Neilan, 2018 (LVEF improved to 54%) ( 13 ) Negative Prognostic Factors Combination ICI, High Troponin, Low GLS, Conduction Abnormalities Factors consistently associated with worse outcomes. Mahmood et al., 2018 (High troponin, low steroid dose) ( 3 ); Awadalla et al., 2020 (Low GLS predicts MACE) ( 8 ); Dubey et al., 2025 (High TnT, low LVEF, conduction abnormalities) ( 11 ); Atallah-Yunes et al., 2019 (Complete heart block) ( 32 ) Positive Prognostic Factors Early Steroid Administration, Specific Biomarker Trends Early initiation of high-dose steroids was associated with improved survival. Dubey et al., 2025 (TnT decrement by day 8) ( 11 ); Puzanov et al., 2021 (Weekly troponin monitoring associated with better outcomes) ( 37 ) This table delivers the "so what," quantifying the severe impact of ICI-M and identifying which patients are most vulnerable. The persistently high mortality rate (25–50%) ( 1 , 3 , 7 , 17 , 28 , 34 ) across a decade of literature highlights that despite increased awareness, this remains a very dangerous complication. The high incidence of MACE ( 3 , 8 , 11 , 30 ) clarifies that death is often preceded by discrete, catastrophic cardiovascular events. Prognostication is key, and robust factors have emerged: biomarker levels (peak and trend of troponin) ( 3 , 11 , 37 ), functional cardiac impairment (reduced GLS and LVEF) ( 8 , 11 ), and electrical instability (heart block, VT) ( 3 , 11 , 32 ) are powerful predictors. The silver lining is that early, aggressive intervention can alter this trajectory, with rapid steroid initiation and a subsequent drop in troponin being associated with survival ( 11 , 37 ). 3.9. Spectrum and Severity Grading The severity of ICI-M spans a wide spectrum, from subclinical disease (Grade 1) to life-threatening fulminant myocarditis (Grade 4) (Table 7 ). Management is directly tied to the severity grade. Table 7 Emerging Biomarkers, Mechanisms, and Future Directions Category Key Findings Implications Key References Proposed Mechanisms T-cell-mediated cytotoxicity, Shared Antigens, Macrophage Polarization The prevailing mechanism involves clonally expanded T cells. Zhu et al., 2022 (Clonal CD8+ Temra cells) ( 39 ); Zhang et al., 2018 (Shared antigens) ( 20 ) Emerging Biomarkers Immune Cell Subsets, Cytokines, Genetic Markers Research is exploring new predictive and diagnostic tools. Jaber Chehayeb et al., 2024 (CHIP associated with 2.7x risk) ( 41 ); Zhu et al., 2022 (CD8 + Temra cells) ( 39 ); Qu et al., 2025 (Gene signatures NKG7, GZMH) ( 29 ) Novel Therapeutic Targets NLRP3 Inflammasome, JAK/STAT Pathway, T-cell Metabolism Preclinical studies suggest potential for new treatments. Lu et al., 2025 (NLRP3 inhibition with MCC950) ( 10 ); Nguyen et al., 2022 (Ruxolitinib) ( 5 ); Zheng et al., 2025 (Immune reprogramming) ( 25 ) Identified Research Gaps Lack of RCTs, Standardized Diagnostics, Predictive Biomarkers The literature consistently highlights the need for more research. Moslehi et al., 2021 ( 1 ); Jensen et al., 2025 ( 17 ); Zheng et al., 2025 ( 25 ) This table looks forward, summarizing the science that is shaping the future of ICI-M management. The proposed mechanisms move from observation to molecular understanding, with evidence of clonally expanded T-cells ( 39 ) and shared antigens explaining the overlap syndromes. Emerging biomarkers aim to shift from reaction to prediction; the association of Clonal Hematopoiesis (CHIP) with a 2.7x increased risk ( 41 ) is a paradigm-shifting finding, suggesting a pre-existing immune dysregulation that predisposes patients. The identification of specific cytotoxic CD8 + Temra cells and their chemokine signature in blood ( 39 ) offers a potential non-invasive diagnostic and monitoring tool. Novel therapeutic targets like the NLRP3 inflammasome ( 10 ) and JAK/STAT pathway ( 5 , 25 ) are promising because they aim to dissociate cardiotoxicity from antitumor efficacy. The consensus on research gaps ( 1 , 17 , 25 ) provides a clear roadmap for the field, emphasizing the critical need for RCTs, standardized definitions, and predictive biomarkers. 3.10. ICI Rechallenge After Myocarditis The decision to rechallenge with ICIs after an episode of myocarditis is high-risk (Table 8 ). Rechallenge after severe (G3/G4) myocarditis is generally contraindicated due to a very high risk of recurrence. The evidence for rechallenge after mild (G1/G2) disease is limited and suggests a moderate to high risk. Table 8 Spectrum and Severity Grading of ICI-Associated Myocarditis Severity Grade Clinical Presentation Diagnostic Findings Typical Management Approach Key References Subclinical / Grade 1 Asymptomatic. Discovered via routine biomarker screening. Elevated troponin with normal other tests. Close monitoring. Tanabe et al., 2021 ( 9 ); Nishikawa et al., 2022 ( 31 ); Puzanov et al., 2021 (Subclinical group) ( 37 ) Mild / Grade 2 Mild symptoms (e.g., fatigue, palpitations). Elevated troponin, possible minor ECG/echo changes. Hold ICI. Initiate oral corticosteroids. Puzanov et al., 2021 (Managed with steroids) ( 37 ) Severe / Grade 3 Significant symptoms (chest pain, dyspnea at rest). Evidence of heart failure or arrhythmias. Markedly elevated troponin, ECG abnormalities, reduced LVEF. Permanently discontinue ICI. Hospitalization. High-dose IV corticosteroids. Mahmood et al., 2018 ( 3 ); Palaskas et al., 2020 ( 7 ) Life-Threatening / Grade 4 Fulminant myocarditis. Cardiogenic shock, cardiac arrest. Profoundly elevated biomarkers. Severe LV dysfunction. Permanent ICI discontinuation. ICU. High-dose IV steroids + second-line immunosuppression. MCS. Nguyen et al., 2022 ( 5 ); Stein- Merlob et al., 2021 ( 27 ) Grade 5 Death. - - - This table provides a crucial framework for standardizing the description of ICI-M, which is essential for comparing studies and guiding therapy. The inclusion of subclinical (Grade 1) disease ( 9 , 31 , 37 ) is a modern concept driven by proactive screening; its natural history and management are still being defined. The distinction between Grade 2 and 3 is a critical decision point, often hinging on the presence of heart failure or significant arrhythmias, which mandates hospitalization and IV steroids ( 3 , 7 ). Grade 4 (fulminant) myocarditis represents a medical emergency characterized by cardiogenic shock, requiring a dual approach: maximal immunosuppression and advanced MCS to sustain life ( 5 , 27 ). This grading system directly correlates with the management strategies outlined in Table 4 , creating a clear clinical pathway. 3.11. Comparison with Other Cardiovascular Toxicities This diagnostic decision-tree table is invaluable for clinicians facing a cardiac complication in an ICI-treated patient. It emphasizes that not all cardiac irAEs are myocarditis and provides key differentiators to guide diagnosis and management. Table 9 Comparison of ICI-Myocarditis with Other ICI-Related Cardiovascular Toxicities Feature Myocarditis Pericarditis / Pericardial Effusion Takotsubo Syndrome Non-Inflammatory LV Dysfunction Primary Pathology Inflammatory cell infiltration. Inflammation of the pericardium. Stress-induced, transient myocardial stunning. Myocardial injury without prominent lymphocytic infiltration. Key Symptoms Chest pain, dyspnea, fatigue, arrhythmias. Pleuritic chest pain, dyspnea. Chest pain, dyspnea, often post-stress. Insidious onset of heart failure symptoms. Diagnostic Biomarkers Troponin (highly elevated), CK. Troponin usually normal or mildly elevated. Moderate troponin elevation. Troponin may be mildly elevated. BNP/NT-proBNP is key. ECG Findings Conduction delays, heart block, VT. Diffuse ST elevation, PR depression. ST elevation, T-wave inversions. Often non-specific. Echocardiography Regional or global LV dysfunction, reduced GLS. Pericardial effusion. Apical ballooning with basal hyperkinesis. Global LV dysfunction, reduced GLS. Cardiac MRI LGE (non-ischemic pattern), T2 edema. Pericardial enhancement, edema. Absence of LGE, reversible dysfunction. Absence of LGE/T2 edema. First-Line Treatment High-dose corticosteroids. NSAIDs/colchicine. Supportive care; heart failure management. Hold ICI; standard heart failure therapy. Key References ( 1 , 3 , 7 , 13 ) ( 7 , 17 ) ( 7 , 17 , 27 ) ( 4 , 17 ) This diagnostic decision-tree table is invaluable for clinicians facing a cardiac complication in an ICI-treated patient. It emphasizes that not all cardiac irAEs are myocarditis. Key differentiators include: the pattern of biomarker elevation (massive troponin in myocarditis vs. mild or BNP-predominant in others), electrical findings (conduction blocks are classic for myocarditis), and most importantly, tissue characterization on CMR (LGE and edema in myocarditis vs. its absence in Takotsubo and non-inflammatory dysfunction). This directs appropriate management: immunosuppression for inflammatory conditions vs. standard heart failure care or NSAIDs for others. 3.12. Emerging Biomarkers, Mechanisms, and Future Directions This table looks forward, summarizing the science that is shaping the future of ICI-M management, from understanding its causes to developing new treatments and identifying critical research gaps. Table 10 Detailed Analysis of ICI Rechallenge After Myocarditis Rechallenge Scenario Reported Outcomes Risk of Recurrence Contributing Factors & Recommendations Key References Rechallenge after Severe (G3/G4) Myocarditis Extremely limited data; generally, not recommended. Very High. Permanent discontinuation is the standard. Wang et al., 2023 (recurrence in 1 of 11) ( 28 ) Rechallenge after Mild/Subclinical (G1/G2) Myocarditis Possible but risky. Some success, but also recurrence. Moderate to High. May be considered if no alternatives. Ensure complete resolution. Wang et al., 2023 ( 28 ); Puzanov et al., 2021 (recurrence in 1 subclinical patient) ( 37 ) Overall Evidence Quality Very Low (based on case reports and small series). - Conclusion: A high-stakes decision without robust safety data. - This table addresses one of the most challenging dilemmas in cardio-oncology. The evidence is clear: rechallenge after severe (G3/G4) myocarditis is contra-indicated due to the unacceptably high risk of recurrence and fatal outcome ( 28 ). The data on mild (G1/G2) cases is sparse and conflicting, but suggests a non-negligible risk ( 28 , 37 ). The proposed strategies for a potential rechallenge in this scenario—such as ensuring complete resolution, switching ICI class, and using prophylactic steroids—are based on theoretical reasoning and anecdote rather than evidence. This table effectively communicates that any decision to rechallenge must be a shared, multidisciplinary decision made with the understanding that it constitutes an uncontrolled experiment. 3.13. Summary of Clinical Recommendations This table serves as a concise clinical practice guideline distilled from the entire body of evidence, creating a logical patient journey from pre-therapy risk assessment to long-term follow-up. Table 11 Summary of Key Recommendations from Included Studies Domain Key Recommendations Key References Pre-Treatment Screening & Risk Assessment • Obtain ECG, baseline troponin, and echocardiogram prior to ICI initiation. Lehmann et al., 2023 ( 2 ); Jaber Chehayeb et al., 2024 ( 41 ) Monitoring During Therapy • Be most vigilant during the first 6–12 weeks. • Implement serial troponin measurements. Puzanov et al., 2021 (Weekly x 6 weeks) ( 37 ); Oikawa et al., 2025 (Serial cTnI) ( 43 ) Diagnostic Workup • Any clinical suspicion should trigger an immediate ECG and troponin. • Use echocardiography (with GLS) and Cardiac MRI. Mahmood et al., 2018 ( 3 ); Awadalla et al., 2020 (GLS) ( 8 ) Management Principles • Permanently discontinue ICI in severe myocarditis. • Initiate high-dose intravenous corticosteroids immediately. Mahmood et al., 2018 ( 3 ); Palaskas et al., 2020 ( 7 ); Heemelaar et al., 2024 ( 15 ) Prognostication & Follow-up • Use high troponin levels, low GLS, and conduction abnormalities to identify high-risk patients. • Refer survivors to cardio-oncology for long-term follow-up. Dubey et al., 2025 (Prognostic factors) ( 11 ); Awadalla et al., 2020 (GLS predicts MACE) ( 8 ) This table serves as a concise clinical practice guideline distilled from the entire body of evidence. It creates a logical patient journey from pre-therapy risk assessment to long-term follow-up. The emphasis on baseline and serial troponin monitoring ( 2 , 11 , 37 , 43 ) is a central, evidence-based recommendation that can enable early diagnosis. The command to "hold ICI and start high-dose steroids immediately" is the universal refrain for managing confirmed cases ( 3 , 7 , 15 ). The call for multidisciplinary care is not just a formality but a necessity, integrating oncology, cardiology, and often neurology and immunology expertise to manage these complex patients. 4. Discussion 4.1. Summary of Evidence This systematic review of 43 studies provides a comprehensive overview of ICI-associated myocarditis. The evidence paints a clear picture of a severe toxicity that typically affects older patients with metastatic cancer, particularly those on combination ICI therapy. The clinical presentation is heterogeneous, necessitating a high index of suspicion and a low threshold for investigation with troponin, ECG, and echocardiography. Management hinges on immediate ICI discontinuation and rapid initiation of high-dose corticosteroids, with escalation to second-line agents in refractory cases. Despite these measures, mortality remains high, underscoring the critical need for early detection and intervention. 4.2. Interpretation in the Context of Existing Literature Our findings consolidate and confirm the key observations from major registries and cohort studies published over the last several years ( 3 , 7 , 8 ). The strong association with combination ICI therapy is a consistent and critical theme, reinforcing the importance of weighing the enhanced anti-tumor efficacy of these regimens against their increased toxicity profile. The high rate of asymptomatic presentation argues compellingly for the implementation of proactive monitoring strategies, such as serial troponin measurements during the initial treatment cycles, as suggested by several studies ( 11 , 37 ). The dramatic efficacy of novel agents like abatacept in severe cases ( 5 , 6 ) represents a shift towards mechanism-driven therapy, targeting the specific immunopathology of ICI-M. Furthermore, the poor prognosis associated with specific factors like high troponin and low GLS provides clinicians with a framework for risk stratification, enabling more intensive monitoring and treatment for the most vulnerable patients. 4.3. Limitations This review has limitations. The included studies are predominantly retrospective and observational, subject to potential selection and reporting biases. The rarity of ICI-M means that even large studies have limited sample sizes, and no randomized controlled trials exist to guide management. The geographical concentration of research in North America, East Asia, and Western Europe limits the generalizability of findings to other populations. 4.4. Clinical Implications The findings from this review have immediate implications for practice: Vigilance and Screening: High vigilance is required, especially during the first 6–12 weeks of treatment and for patients on combination therapy. Consider baseline and serial monitoring with troponin and ECG. Rapid Diagnosis and Grading: Any clinical suspicion should trigger an immediate and structured diagnostic workup. The severity grading system (Table 7 ) should be used to standardize assessment and guide therapy. Aggressive and Escalating Management: The cornerstone of management is prompt ICI hold/discontinuation and initiation of high-dose corticosteroids. Have a low threshold for escalating to second-line immunosuppression in severe or refractory cases and involving a multidisciplinary team. Cautious Rechallenge: Rechallenge with ICIs after myocarditis is fraught with risk and should only be considered in select cases of mild, fully resolved toxicity when there are no other treatment options, following a thorough multidisciplinary discussion. 5. Conclusion Immune checkpoint inhibitor-associated myocarditis is a severe, potentially fatal complication that requires a high index of suspicion, prompt diagnosis, and immediate, aggressive management. A structured approach involving risk stratification, proactive monitoring, and a graded treatment algorithm is essential to improve outcomes. Future research should focus on validating predictive biomarkers, understanding underlying mechanisms, and conducting prospective trials to optimize immunosuppressive strategies. Declarations Funding Resource This research did not receive any external funding or support from external entities. All aspects of this work were conducted independently, and there are no financial or material conflicts of interest to disclose. Author's Contribution MA developed the methodology and wrote the methodology section. MA also conducted data extraction using a predesigned Excel spreadsheet, capturing key study details. Additionally, MA oversaw the entire review process and coordinated the writing of the manuscript. JT independently verified 50% of the extracted data to ensure accuracy and consistency. JT also wrote the results section, contributed to the final review of the manuscript, played a role in developing the study design, and assisted in refining the methodology section. SN contributed to refining the search strategy, participated in the full-text review process, and assisted in synthesizing the extracted data. SN also built the tables and diagrams for the manuscript and helped review the methodology section. RS independently conducted the title and abstract screening using Rayyan software, ensuring the initial selection of studies. RS also conducted the full-text review for studies meeting the inclusion criteria and wrote the discussion section. LA independently verified 50% of the extracted data alongside JT to enhance data accuracy. LA also contributed to refining the study methodology and participated in manuscript revisions. FK wrote the introduction section and assisted in optimizing the search strategy. FK also played a role in screening fulltext articles and contributed to drafting and reviewing the discussion section. MT independently conducted the title and abstract screening using Rayyan software, ensuring the initial selection of studies. MT also wrote the conclusion section and participated in discussions regarding study inclusion and exclusion criteria. AO contributed to writing the discussion section and provided critical revisions to improve clarity and coherence. AO also participated in reviewing the final manuscript to ensure consistency and accuracy. AR played a role in the quality assessment of included studies and assisted in synthesizing the extracted data. AR also contributed to reviewing the discussion and conclusion sections to ensure alignment with the study objectives. All authors contributed to the conception and design of the study, provided input on data interpretation, and participated in manuscript revisions. All authors approved the final version before submission. Conflict of Interest No conflicts of interest were reported among the authors involved in this systematic review. References Moslehi J, Lichtman AH, Sharpe AH, Galluzzi L, Kitsis RN. Immune checkpoint inhibitor-associated myocarditis: manifestations and mechanisms. J Clin Invest. 2021;131(5):e145186. Lehmann LH, Heckmann MB, Bailly G, Finke D, Procureur A, Power JR, et al. Cardio-muscular biomarkers in the diagnosis and prognostication of immune checkpoint inhibitor myocarditis: Troponins as biomarkers in ICI-myocarditis. Circulation. 2023;148(6):473–86. Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol. 2018;71(16):1755–64. Michel L, Helfrich I, Hendgen-Cotta UB, Mincu RI, Korste S, Mrotzek SM, et al. Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy. Eur Heart J. 2021;43(4):316–29. Nguyen LS, Bretagne M, Arrondeau J, Zahr N, Ederhy S, Abbar B, et al. Reversal of immune-checkpoint inhibitor fulminant myocarditis using personalized-dose-adjusted abatacept and ruxolitinib: proof of concept. J Immunother Cancer. 2022;10:e004699. Salem JE, Allenbach Y, Kernels M, et al. Abatacept for Severe Immune Checkpoint Inhibitor–Associated Myocarditis. N Engl J Med. 2019;380(24):2377–9. Palaskas N, Lopez-Mattei J, Durand JB, Iliescu C, Deswal A. Immune Checkpoint Inhibitor Myocarditis: Pathophysiological Characteristics, Diagnosis, and Treatment. J Am Heart Assoc. 2020;9(2):e013757. 10.1161/JAHA.119.013757 . Awadalla M, Mahmood SS, Groarke JD, Hassan MZO, Nohria A, Rokicki A, et al. Global Longitudinal Strain and Cardiac Events in Patients with Immune Checkpoint Inhibitor-Related Myocarditis. J Am Coll Cardiol. 2020;75(5):467–78. Tanabe J, Watanabe N, Endo A, Nagami T, Inagaki S, Tanabe K. Asymptomatic Immune Checkpoint Inhibitor-associated Myocarditis. Intern Med. 2021;60(4):569–73. Lu Y, Gao J, Hou Y, Yang H, Wang D, Zhang G, et al. Targeting the NLRP3 inflammasome abrogates cardiotoxicity of immune checkpoint blockers. J Immunother Cancer. 2025;13:e010127. Dubey N, Wu C, Zubiri L, Fay M, Rouhani SJ, Merkin RD, et al. Predictors of Long-Term Survival in Patients With Immune Checkpoint Inhibitor–Associated Myocarditis. J Am Heart Assoc. 2025;14:e038719. Zheng Y, Chen Z, Song W, Xu Y, Zhao Z, Sun Y, et al. Cardiovascular adverse events associated with immune checkpoint inhibitors: A retrospective multicenter cohort study. Cancer Med. 2024;13:e7233. Ganatra S, Neilan TG. Immune Checkpoint Inhibitor-Associated Myocarditis. Oncologist. 2018;23(8):879–86. Liu YW, Chen YX, Zeng ZM, Liu AW. Research Progress of Immune Checkpoint Inhibitor-associated Myocarditis. Chin J Lung Cancer. 2021;24(9):668–72. Heemelaar JC, Antoni ML, Neilan TG, Review. Treatment of immune checkpoint inhibitor-associated myocarditis. J Cardiovasc Pharmacol. 2024;83(5):384–91. Todo M, Gatate Y, Nakano S, Kaneko G, Hagiwara M, Takahashi T, Umezawa Y, Ueda G, Ishikawa S, Makino Y, Oyama M, Shirotake S. Early detection of myocarditis caused by immune checkpoint inhibitor therapy with nivolumab and ipilimumab for advanced recurrent renal cell carcinoma. Cancer Immunol Immunother. 2025;74:97. Jensen G, Wang X, Kuempel J, Palaskas N, Chen Z, Yu W, et al. Immune checkpoint inhibitor-associated myocarditis. Am J Physiol Heart Circ Physiol. 2025;328(4):H734–51. Alexander G, Mortada I, Mhanna M, Byer S, Grewal US, Mansour S. Immune Checkpoint Inhibitor-Related Myocarditis: A Single Center Observational Registry. Clin Cardiol. 2025;48:e70154. Xu L, Chen Y, Xiong L, Shen Y, Zhou Z, Wang S, et al. A review of immune checkpoint inhibitor-associated myocarditis: Epidemiology, pathogenesis, and biomarkers. Hum Vaccin Immunother. 2025;21(1):2512645. Zhang JC, Chen WD, Bustamante Alvarez J, Jia K, Shi L, Wang Q, et al. Cancer immune checkpoint blockade therapy and its associated autoimmune cardiotoxicity. Acta Pharmacol Sin. 2018;39(11):1693–8. Turker I, Johnson DB. Immune Checkpoint Inhibitor-Related Myocarditis: Current Understanding and Potential Diagnostic and Therapeutic Strategies. Expert Opin Drug Saf. 2023;22(10):909–19. Cao W, Han S, Zhang P, Mi L, Wang Y, Nie J et al. Immune checkpoint inhibitor-related myocarditis in patients with lung cancer. BMC Cancer. 2025;25(685). Ke G, Chen P, Luo J, Huang J, Shang Y, Huang Y, et al. Plasma exchange plus glucocorticoids in the treatment of immune checkpoint inhibitor-induced myocarditis: a case series and review. Clin Cardiol. 2023;46(12):1481–7. Doms J, Prior JO, Peters S, Obeid M. Tocilizumab for refractory severe immune checkpoint inhibitor-associated myocarditis. Ann Oncol. 2020;31(9):1273–5. Zheng J, Yi Y, Tian T, Luo S, Liang X, Bai Y. ICI-induced cardiovascular toxicity: mechanisms and immune reprogramming therapeutic strategies. Front Immunol. 2025;16:1550400. Sessums M, Yararapu S, Guru PK, Sanghavi DK. Atezolizumab-induced myositis and myocarditis in a patient with metastatic urothelial carcinoma. BMJ Case Rep. 2020;13:e236357. Stein-Merlob AF, Hsu JJ, Colton B, Berg CJ, Ferreira A, Price MM, et al. Keeping immune checkpoint inhibitor myocarditis in check: advanced circulatory mechanical support as a bridge to recovery. ESC Heart Fail. 2021;8(5):4301–6. Wang C, Zhao G, Zhang Z, Yang L, Liu S, Li G, Wang H, Huang J, Wang S, Li N. Immune checkpoint inhibitor–associated myocarditis: a systematic analysis of case reports. Front Immunol. 2023;14:1275254. Qu S, Zhang J, Wang K, Zhou Y. Identification of key immune-related genes and potential therapeutic targets in immune checkpoint inhibitor-associated myocarditis. Postgrad Med J. 2025;101(1192):137–46. Tang X, Li Y, Huang H, Shi R, Shen L-T, Qian W-L, et al. Early evaluation of severe immune checkpoint inhibitor-associated myocarditis: a real-world clinical practice. J Cancer Res Clin Oncol. 2023;149(11):8345–57. Nishikawa T, Inoue T, Otsuka T, Kuno I, Kukita Y, Nakamura H, et al. Prevalence and characteristics of immune checkpoint inhibitor-related myocardial damage: A prospective observational study. PLoS ONE. 2022;17(11):e0275865. Atallah-Yunes SA, Kadado AJ, Kaufman GP, Hernandez-Montfort J. Immune checkpoint inhibitor therapy and myocarditis: a systematic review of reported cases. J Cancer Res Clin Oncol. 2019;145(7):1527–57. Liu X, Wu W, Fang L, Liu Y, Chen W. TNF-α inhibitors and other biologic agents for the treatment of immune checkpoint inhibitor-induced myocarditis. Front Immunol. 2022;13:922782. Moradi A, Kodali A, Okoye C, Klein DH, Mohamoud I, Olanisa OO, Parab P, Chaudhary P, Mukhtar S, Mohammed L. A Systematic Review of Myocarditis Induced by Immune Checkpoint Inhibitors: How Concerning Is the Most Common Cardiotoxicity of Immune Checkpoint Inhibitors? Cureus. 2023;15(7):e42071. Maetani T, Hamaguchi T, Nishimura T, Marumo S, Fukui M. Durvalumab-associated Late-onset Myocarditis Successfully Treated with Corticosteroid Therapy. Intern Med. 2022;61(4):527–31. Tay RY, Blackley E, McLean C, Moore M, Bergin P, Gill S, Haydon A. Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy. Br J Cancer. 2017;117(7):921–4. Puzanov I, Subramanian P, Yatsynovich YV, Jacobs DM, Chilbert MR, Sharma UC, et al. Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis. J Immunother Cancer. 2021;9:e002553. Cautela J, Zeriouh S, Gaubert M, Bonello L, Laine M, Peyrol M, Paganelli F, Lalevee N, Barlesi F, Thuny F. Intensified immunosuppressive therapy in patients with immune checkpoint inhibitor-induced myocarditis. J Immunother Cancer. 2020;8:e001887. Zhu H, Gaidos FX, Lee D, Wallany S, Huang YV, Ryan J, et al. Identification of Pathogenic Immune Cell Subsets Associated with Checkpoint Inhibitor-induced Myocarditis. Circulation. 2022;146(4):316–35. Matsumoto T, Fukuda K, Yoshida T, Shimazu K, Taguchi D, Shinozaki H, et al. Sudden and severe cardiotoxicity induced with pembrolizumab, its clinical course, therapeutic intervention, and outcome. Int Cancer Conf J. 2022;11(1):81–6. Jaber Chehayeb R, Singh J, Matute-Martinez C, Chen NW, Ferrigno Guajardo A, Lin D, et al. Clonal hematopoiesis of indeterminate potential is associated with increased risk of immune checkpoint inhibitor myocarditis in a prospective study of a cardio-oncology cohort. Cardio-Oncology. 2024;10:84. Thakker RA, Lee MA, Albaeini A, Elbadawi A, Suthar KH, Perez C, et al. Clinical Characteristics and Outcomes in Immune Checkpoint Inhibitor Therapy-Associated Myocarditis. Cardiol Res. 2021;12(5):270–8. Oikawa M, Haga F, Tani T, Yokokawa T, Miura S, Misaka T et al. Clinical Significance of Cardiac Troponin I Elevation in Detecting Immune Checkpoint Inhibitor-Induced Myocarditis. Circ Rep. 2025; (Epub ahead of print). Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9242293","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":613210908,"identity":"32a89686-2374-49d2-a8aa-ff1d1f43206d","order_by":0,"name":"Moontasir Ahmed","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYBADHgb25oMPQAw+otQfAGnhOZZsANLCRqwWBgaJHDMJEE1Qi25787HHH2rqZMwbEswqv+bYybAxMD98dAOPFrMzx9INDhw7zCNz4EDabdltyUCHsRkb5+DTcgPongNsB3gkGBuO3ZbcxgzUwsMmTVjLvzoeCWbGtmLJbfVEajnYxswjwcbMxvhx22EitJw5liZxtu8wjwQPG7M047bjQIqQX443H5Oo+FZnLyH//uPHn9uq7fnZmx8+xqcFBTDzgElilYMA4w9SVI+CUTAKRsGIAQCgo0RknPA0FgAAAABJRU5ErkJggg==","orcid":"","institution":"Tangail Medical College Hospital","correspondingAuthor":true,"prefix":"","firstName":"Moontasir","middleName":"","lastName":"Ahmed","suffix":""},{"id":613210910,"identity":"3cc36744-304e-4f33-8746-4d173d2f50bd","order_by":1,"name":"Jannatara Tina","email":"","orcid":"","institution":"Tangail Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jannatara","middleName":"","lastName":"Tina","suffix":""},{"id":613210911,"identity":"bad457b2-db43-4691-9f0b-c59d5b34e2a2","order_by":2,"name":"Shadman Newaz","email":"","orcid":"","institution":"Tangail Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shadman","middleName":"","lastName":"Newaz","suffix":""},{"id":613210912,"identity":"b3f5325b-b757-4ff5-a8d7-0179e16affb8","order_by":3,"name":"Rashid Shahriar Sazal","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Rashid","middleName":"Shahriar","lastName":"Sazal","suffix":""},{"id":613210913,"identity":"0096735a-78fe-4574-9e1d-036021e3fddd","order_by":4,"name":"Lamia Ashraf","email":"","orcid":"","institution":"Tangail Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lamia","middleName":"","lastName":"Ashraf","suffix":""},{"id":613210914,"identity":"65610b3f-5816-423d-a6ff-d19c35ac445a","order_by":5,"name":"Md Rubaiyat Tasfin Talukder","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Md","middleName":"Rubaiyat Tasfin","lastName":"Talukder","suffix":""},{"id":613210915,"identity":"4d8a0690-590e-4e26-8e20-c8394f3f8d9b","order_by":6,"name":"Faiyaz Saqif Khan","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Faiyaz","middleName":"Saqif","lastName":"Khan","suffix":""},{"id":613210916,"identity":"82e2b560-6d16-46ac-8ec0-153b505968c3","order_by":7,"name":"Arnika Tahsin Orpa","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Arnika","middleName":"Tahsin","lastName":"Orpa","suffix":""},{"id":613210920,"identity":"6a1535de-f855-49cb-b1c9-d3505e72b412","order_by":8,"name":"Arthi Roy","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Arthi","middleName":"","lastName":"Roy","suffix":""}],"badges":[],"createdAt":"2026-03-27 08:40:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9242293/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9242293/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105698944,"identity":"6e150e88-07fe-4466-acf5-2cabbae5b3ab","added_by":"auto","created_at":"2026-03-30 05:10:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":45529,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA Flow Diagram\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9242293/v1/e2d534125e4de431857be021.png"},{"id":105698948,"identity":"6d454c0a-bf4a-4162-b4a6-a5c533f7f670","added_by":"auto","created_at":"2026-03-30 05:10:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":202058,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRisk of bias assessment across included studies. Figure 2a shows the proportion of studies assessed for various domains of bias, including: selection of participants, confounding variables, measurement of exposure, blinding of outcome assessment, incomplete outcome data, and selective outcome reporting. Each domain is color-coded to represent the assessed level of bias: Low risk (green), Unclear risk (yellow), High risk (red), Critical risk (dark red), and No information (blue). Figure 2b provides a study-wise breakdown of risk of bias assessments, allowing a granular comparison across individual studies.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9242293/v1/b0bac5d7e3612bfa59a7d443.png"},{"id":106242471,"identity":"1c9c82cb-08a6-4dae-87ce-584f6f858170","added_by":"auto","created_at":"2026-04-06 15:12:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2156249,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9242293/v1/65b90dd5-75f1-46c9-afb6-7be3f4ee9ac9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eImmune Checkpoint Inhibitor–Associated Myocarditis in Cancer Patients: A Systematic Review of Clinical Presentation, Management, and Outcomes\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eImmune checkpoint inhibitors (ICIs) have revolutionized oncology by harnessing the immune system to fight cancer. However, this enhanced immunity can also lead to immune-related adverse events (irAEs), affecting various organs. Among these, ICI-associated myocarditis (ICI-M) is one of the most severe, with a fatality rate exceeding many other irAEs (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite its rarity, ICI-M presents a significant clinical challenge due to its non-specific presentation, rapid progression, and high mortality (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The clinical spectrum is broad, ranging from subclinical disease detected only by biomarker elevation to fulminant myocarditis and cardiogenic shock. Early diagnosis and intervention are paramount, yet standardized guidelines are still evolving based on accumulating evidence from cohort studies, registries, and case series.\u003c/p\u003e \u003cp\u003eOver the past decade, numerous studies have characterized the risk factors, clinical course, and outcomes of ICI-M. However, a comprehensive synthesis of this evidence is needed to consolidate our understanding and inform clinical decision-making. This systematic review aims to provide a detailed analysis of the global research landscape, patient characteristics, diagnostic findings, management strategies, and outcomes of ICI-M, integrating data from a wide range of published studies to offer a definitive overview for clinicians and researchers.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003eThis systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Search Strategy and Selection Criteria\u003c/h2\u003e \u003cp\u003eA systematic search was performed in PubMed from database inception to January, 2026. The search strategy combined terms related to (\"immune checkpoint inhibitor\" OR \"anti-PD-1\" OR \"anti-PD-L1\" OR \"anti-CTLA-4\") AND (\"myocarditis\" OR \"cardiotoxicity\" OR \"cardiovascular adverse event\"). Proceedings from key cardiology and oncology conferences were also screened.\u003c/p\u003e \u003cp\u003eStudies were included if they: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) reported on human cancer patients diagnosed with ICI-M; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) provided original data on epidemiology, clinical presentation, diagnosis, management, or outcomes; and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) were published in English. Case reports, cohort studies, registries, and clinical trials were eligible.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Data Extraction and Quality Assessment\u003c/h2\u003e \u003cp\u003eTwo reviewers independently screened titles, abstracts, and full-text articles. Data were extracted using a standardized form, capturing information on study design, patient demographics, cancer types, ICI regimens, diagnostic criteria, management, and outcomes. The risk of bias for RCTs was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Data Synthesis\u003c/h2\u003e \u003cp\u003eGiven the heterogeneity in study designs and reporting, a narrative synthesis was conducted. Data are presented in summary tables and descriptive text.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Study Selection and Characteristics\u003c/h2\u003e \u003cp\u003eThe initial search yielded 944 records. After removing duplicates and screening titles and abstracts, 104 full-text articles were assessed for eligibility. Ultimately, 43 studies were included in the final synthesis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Risk of Bias Assessment\u003c/h2\u003e \u003cp\u003eThe methodological quality of the included studies was assessed. The overall risk of bias was low to moderate. Common limitations included the retrospective nature of most studies and potential selection bias in single-center cohorts. The risk of bias summary and graph are presented in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Geographical Distribution and Research Output\u003c/h2\u003e \u003cp\u003eThe 43 included studies originated from a range of countries, with the United States (37.2%), China (20.9%), and Japan (14.0%) being the largest contributors (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This distribution highlights a significant geographical evidence gap, with vast regions like South America, Africa, and Eastern Europe unrepresented.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGeographical Distribution and Research Output of Included Studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of Studies\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePercentage of Total (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eStudy Types (Representative Examples)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnited States (USA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMulticenter registries, Single-center cohorts, Systematic Reviews, Case Reports, Preclinical/Translational\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective multicenter cohorts, Single-center cohorts, Case Series, Bioinformatics analysis, Review Articles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProspective observational studies, Retrospective cohort studies, Case Reports\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCase-Control Studies, Case Reports with novel therapeutics\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGermany\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProspective cohort, Preclinical/Clinical study\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMulti-National\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInternational retrospective cohort, International multicenter study\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAustralia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCase Report\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSwitzerland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCase Report\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe Netherlands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReview Article\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePart of a multicenter study\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnited Kingdom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCollaborator in a preclinical study\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAustria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCollaborator in a preclinical study\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003e \u003cem\u003e*Note: Studies where the country was a collaborator rather than the primary site.\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003eThis table provides a critical analysis of the global research landscape for ICI-associated myocarditis. The distribution is not uniform, revealing clear leaders and significant gaps. The dominance of the United States, contributing over a third of the studies, reflects its pioneering role in immuno-oncology, the high volume of patients treated at major cancer centers, and the early establishment of dedicated cardio-oncology research programs (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). This leadership is evidenced by a diverse output, from large, foundational multicenter registries to cutting-edge translational science. China's position as the second-largest contributor signals its rapidly expanding capacity and focus in this field, often characterized by large-scale retrospective clinical cohorts that leverage its vast patient population to generate significant real-world evidence (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Japan's significant output, while smaller in volume, is marked by high-quality, meticulous prospective and observational studies that have been instrumental in characterizing subclinical disease and detailed management (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe European contributions, particularly from France and Germany, are notable for their highly specialized and innovative nature, such as pioneering the use of novel therapeutic agents like abatacept (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) and producing key prospective biomarker studies (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The presence of multi-national collaborations (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) underscores the importance of pooling data to study this rare condition. Crucially, this map highlights a substantial evidence gap, with vast regions of the world (e.g., South America, Africa, Southeast Asia, Eastern Europe) unrepresented. This lack of geographical diversity may limit the generalizability of findings, as genetic backgrounds, regional cancer types, and healthcare delivery systems can influence the presentation and management of ICI-myocarditis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Baseline Patient Characteristics\u003c/h2\u003e \u003cp\u003eThe \"typical\" patient with ICI-M was an older adult (median age 65\u0026ndash;74 years) with metastatic cancer, most commonly melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Hypertension and diabetes were the most frequent comorbidities. A subset of patients had a pre-existing autoimmune condition.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Characteristics of Patients with Immune Checkpoint Inhibitor-Associated Myocarditis (ICI-M)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSummary Finding (Range or Most Frequent)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDetails / Specifics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eKey References\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Age\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65\u0026ndash;74 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThe patient population predominantly comprised older adults.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMahmood et al., 2018 (65\u0026thinsp;\u0026plusmn;\u0026thinsp;13) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eDubey et al., 2025 (74 IQR 68\u0026ndash;78) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e); Alexander et al., 2025 (74\u0026thinsp;\u0026plusmn;\u0026thinsp;9.4) (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePuzanov et al., 2021 (73 IQR 66\u0026ndash;79) (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCommon Cancer Types\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMelanoma, Lung Cancer, Renal Cell Carcinoma (RCC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMelanoma was the most frequently reported cancer.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLehmann et al., 2023 (Melanoma 20%, NSCLC 40%, RCC 10%) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eMahmood et al., 2018 (Melanoma 46%, NSCLC 11%) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eAwadalla et al., 2020 (Melanoma 41%, Lung 16%, RCC 8%) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eJensen et al., 2025 (Melanoma, NSCLC, RCC) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer Stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePredominantly Metastatic (Stage IV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThe vast majority of patients had advanced or metastatic disease.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDubey et al., 2025 (Majority Stage IV) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eTodo et al., 2025 (Metastatic) (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eCao et al., 2025 (Stage III-IV NSCLC) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eTang et al., 2023 (71.6% Stage IV) (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCommon Comorbidities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHypertension, Diabetes Mellitus, Coronary Artery Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHypertension was the most prevalent comorbidity.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMahmood et al., 2018 (Hypertension 34%, Diabetes 34%) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eAwadalla et al., 2020 (Hypertension 57%, Diabetes 24%) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eZheng et al., 2024 (Hypertension 38.6%, Diabetes 18.2%) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eAlexander et al., 2025 (Hypertension 78%, Diabetes 28%) (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-existing Autoimmune Condition\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePresent in a subset of patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNoted in several case reports and cohorts.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGanatra \u0026amp; Neilan, 2018 (Hashimoto's thyroiditis) (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eStein-Merlob et al., 2021 (Graves' disease) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThis table synthesizes the demographic and clinical foundation of the studied population, painting a picture of the \"typical\" patient at risk for this severe toxicity. The consistency across numerous international cohorts strongly suggests that ICI-M, while rare, does not occur randomly but is more likely in a specific patient profile. The predominance of older patients (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e) likely reflects both the higher incidence of cancers treated with ICIs in this age group and a potentially altered immune response. The recurrence of melanoma, NSCLC, and RCC (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) is expected, as these were among the first malignancies with approved ICI therapies, leading to extensive clinical experience and larger patient pools for observation. The overwhelming representation of metastatic disease (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) is a critical confounder; it is unclear whether advanced cancer stage is an independent risk factor or if the association is simply because these patients are the primary recipients of ICIs. The high prevalence of hypertension and other cardiovascular comorbidities (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) indicates that a compromised cardiovascular system may be more susceptible to immune-mediated injury, a key consideration for pre-therapy risk assessment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.5. Treatment-Related Factors\u003c/h2\u003e \u003cp\u003eCombination ICI therapy (e.g., ipilimumab\u0026thinsp;+\u0026thinsp;nivolumab) was the strongest risk factor for ICI-M (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The median time to onset was early, typically within the first 1\u0026ndash;4 cycles (17\u0026ndash;65 days). A significant proportion of patients received concurrent therapies like chemotherapy or radiotherapy.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTreatment-Related Factors Preceding ICI-Associated Myocarditis Onset\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSummary Finding\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDetails / Specifics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eKey References\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMost Common ICI Classes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnti-PD-1, Anti-PD-L1, Anti-CTLA-4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMyocarditis was reported with all major ICI classes.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMoslehi et al., 2021 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePalaskas et al., 2020 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eTurker \u0026amp; Johnson, 2023 (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHighest Risk Regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCombination ICI Therapy (e.g., Ipilimumab\u0026thinsp;+\u0026thinsp;Nivolumab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination therapy was consistently identified as the strongest risk factor.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMoslehi et al., 2021 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eMahmood et al., 2018 (34% on combination) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eGanatra \u0026amp; Neilan, 2018 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eJensen et al., 2025 (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Time to Onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u0026ndash;65 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOnset was often early in the treatment course.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMahmood et al., 2018 (34 days) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePalaskas et al., 2020 (27\u0026ndash;65 days) (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eTodo et al., 2025 (25 days) (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eTurker \u0026amp; Johnson, 2023 (27\u0026ndash;34 days) (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eAtallah-Yunes et al., 2019 (22.5 days) (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTypical Cycle of Onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWithin first 1\u0026ndash;4 cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMany cases occurred after the first or second dose.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAtallah-Yunes et al., 2019 (1\u0026ndash;2 doses in majority) (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eCao et al., 2025 (48.4% within first 2 cycles) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcurrent Therapies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChemotherapy, Targeted Therapy, Radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eA significant proportion received concurrent treatments.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCao et al., 2025 (84.8% ICI combo with chemo) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eTang et al., 2023 (54.3% concurrent chemo) (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eMatsumoto et al., 2022 (prior radiotherapy) (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThis table moves from \u003cem\u003ewho\u003c/em\u003e is at risk to \u003cem\u003ewhat\u003c/em\u003e precipitates the event, highlighting modifiable risk factors. The strong, consistent signal across nearly all studies that combination ICI therapy (most notably anti-PD-1\u0026thinsp;+\u0026thinsp;anti-CTLA-4) is the single greatest risk factor (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) is perhaps the most critical clinical finding. This makes biological sense, as dual checkpoint blockade induces a more potent and broader immune activation, inadvertently increasing the risk of breaking self-tolerance. The early median time to onset (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e) underscores the need for heightened vigilance during the initial treatment cycles, fundamentally shaping monitoring guidelines. However, the reports of late-onset cases (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e) remind clinicians that risk never completely dissipates. The data on concurrent therapies is more ambiguous, as many patients receive multi-modal treatment; while not definitively proven to be independent risk factors, chemotherapy and radiotherapy may create a pro-inflammatory environment that lowers the threshold for myocarditis (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.6. Clinical Presentation and Diagnostic Findings\u003c/h2\u003e \u003cp\u003eThe clinical presentation of ICI-M was highly variable (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Dyspnea was the most common symptom, but a significant proportion of patients were asymptomatic. Overlap with myositis and myasthenia gravis was frequent. Key diagnostic findings included elevated troponin, ECG abnormalities, and reduced global longitudinal strain (GLS) on echocardiography. Cardiac MRI and endomyocardial biopsy were crucial for confirmation.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical Presentation and Diagnostic Findings in ICI-Associated Myocarditis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFinding\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDetails / Specifics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eKey References\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCommon Symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDyspnea, Chest Pain, Fatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDyspnea was the most common symptom. A significant proportion were asymptomatic.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMahmood et al., 2018 (Dyspnea 71%) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eTanabe et al., 2021 (Asymptomatic) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eTodo et al., 2025 (Some asymptomatic) (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eCao et al., 2025 (45.5% symptomatic) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eNishikawa et al., 2022 (Mostly asymptomatic) (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverlap Syndromes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMyositis, Myasthenia Gravis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eConcomitant myositis was very common.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLehmann et al., 2023 (~\u0026thinsp;68% myositis) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eNguyen et al., 2022 (concurrent myositis) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eSalem et al., 2019 (myositis) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eKe et al., 2023 (myositis \u0026amp; MG) (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eSessums et al., 2020 (myositis) (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECG Abnormalities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eConduction Disorders, Arrhythmias\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAbnormal ECGs were found in 50\u0026ndash;89% of cases.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMahmood et al., 2018 (89% abnormal) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePalaskas et al., 2020 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eDubey et al., 2025 (34.3% conduction abnormalities) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKey Biomarkers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eElevated Troponin, Elevated CK, Elevated NT-proBNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTroponin was elevated in \u0026gt;\u0026thinsp;90% of cases.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMahmood et al., 2018 (Troponin elevated 94%) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePalaskas et al., 2020 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eAwadalla et al., 2020 (Troponin elevated 97%) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eDubey et al., 2025 (High TnT predicts mortality) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEchocardiography\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePreserved or Reduced LVEF, Reduced GLS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLVEF was preserved (\u0026gt;\u0026thinsp;50%) in approximately half of the patients. GLS was a more sensitive marker.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMahmood et al., 2018 (51% had normal LVEF) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eAwadalla et al., 2020 (60% had preserved EF; GLS predicted MACE) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eSessums et al., 2020 (Normal LVEF) (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac MRI (CMR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLate Gadolinium Enhancement (LGE), T2-Weighted Edema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCMR was a key diagnostic tool.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePalaskas et al., 2020 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eGanatra \u0026amp; Neilan, 2018 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eJensen et al., 2025 (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndomyocardial Biopsy (Gold Standard)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT-cell Lymphocytic Infiltration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBiopsy findings typically revealed a T-cell-predominant infiltrate.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMahmood et al., 2018 (T-cell infiltrate) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eNguyen et al., 2022 (CD3\u0026thinsp;+\u0026thinsp;T-cells) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eGanatra \u0026amp; Neilan, 2018 (CD8\u0026thinsp;+\u0026thinsp;T cells) (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThis table captures the clinical essence of the disease, revealing a spectrum from silent, biomarker-only disease to catastrophic failure. The high rate of asymptomatic or mildly symptomatic presentation (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) is a pivotal finding; it argues strongly for proactive biomarker screening rather than relying on symptom reporting alone. The frequent overlap with myositis and myasthenia gravis (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) is a unique and dangerous feature, suggesting a shared antigenicity between cardiac, skeletal muscle, and neuromuscular junctions that is unmasked by ICIs. The diagnostic pillars are clearly established: Troponin is the cornerstone biomarker (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), with its peak level being profoundly prognostic. Echocardiography often reveals preserved LVEF (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), but the superior sensitivity of GLS provides critical prognostic information even when LVEF appears normal (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Cardiac MRI is the best non-invasive tissue characterization tool (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), yet its false-negative rate confirms that it should complement, not replace, clinical judgment. The gold standard remains endomyocardial biopsy (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), which definitively reveals the T-cell-mediated pathology.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.7. Management Strategies\u003c/h2\u003e \u003cp\u003eManagement was stratified by severity (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The universal first step was ICI discontinuation. High-dose corticosteroids were the cornerstone of initial immunosuppression. For steroid-refractory cases, second-line agents (e.g., IVIG, mycophenolate, infliximab) and novel targeted agents (e.g., abatacept) were used. Fulminant cases required advanced supportive care, including mechanical circulatory support.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eManagement Strategies for ICI-Associated Myocarditis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eManagement Strategy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eApplication \u0026amp; Details\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNotes / Evidence\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eKey References\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICI Discontinuation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUniversal first step upon diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eICI therapy was permanently discontinued in the majority of severe cases.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMahmood et al., 2018 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePalaskas et al., 2020 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eGanatra \u0026amp; Neilan, 2018 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst-Line Immunosuppression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHigh-Dose Corticosteroids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIV methylprednisolone was the most common initial treatment.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMahmood et al., 2018 (89% received steroids) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePalaskas et al., 2020 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eHeemelaar et al., 2024 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePuzanov et al., 2021 (All severe patients received IV steroids) (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecond-Line Immunosuppression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFor steroid-refractory cases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eA variety of agents were used.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMahmood et al., 2018 (IVIG, Mycophenolate, Infliximab, ATG) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePalaskas et al., 2020 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eHeemelaar et al., 2024 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e); Liu et al., 2022 (Infliximab review) (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNovel / Targeted Agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFor severe, refractory cases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEmerging evidence from case reports.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNguyen et al., 2022 (Abatacept \u0026amp; Ruxolitinib) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eSalem et al., 2019 (Abatacept) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eDoms et al., 2020 (Tocilizumab) (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSupportive Care \u0026amp; Advanced Support\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFor fulminant cases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIncluded management in the Cardiac ICU and MCS.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNguyen et al., 2022 (ECLS) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eStein-Merlob et al., 2021 (Impella, VA-ECMO) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eMatsumoto et al., 2022 (IABP) (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThis table outlines the escalation of care, which is directly tied to disease severity (as defined in Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). The universal first step is ICI discontinuation (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), a high-stakes decision in a cancer patient that underscores the life-threatening nature of this toxicity. The cornerstone of medical management is high-dose corticosteroids (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e), with an emphasis on \u003cem\u003eearly initiation\u003c/em\u003e and \u003cem\u003ehigh dose\u003c/em\u003e (e.g., 1g methylprednisolone), as delays and lower doses are associated with worse outcomes (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). For steroid-refractory cases, a range of second-line agents are used empirically (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e), reflecting the lack of RCTs. The most compelling advances come from novel/targeted agents used in severe cases: Abatacept (a CTLA-4 agonist) to directly counter the ICI's mechanism (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), Ruxolitinib (a JAK inhibitor) to block inflammatory signaling (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), and Tocilizumab (an IL-6 blocker) (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), showing a shift towards pathophysiology-driven therapy. In fulminant cases, mechanical circulatory support (MCS) like VA-ECMO (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e) is a life-saving bridge to recovery, allowing time for immunosuppression to work.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.8. Outcomes and Prognostic Factors\u003c/h2\u003e \u003cp\u003eICI-M carried a high mortality rate (25\u0026ndash;50%) and a high incidence of major adverse cardiac events (MACE) (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Negative prognostic factors included combination ICI therapy, high troponin levels, low GLS, and conduction abnormalities. Early steroid administration and specific biomarker trends were associated with better outcomes.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOutcomes and Prognostic Factors in ICI-Associated Myocarditis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome / Factor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSummary Finding\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDetails / Specifics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eKey References\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall Mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25% \u0026minus;\u0026thinsp;50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eICI-associated myocarditis carried a high fatality rate.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMoslehi et al., 2021 (40\u0026ndash;50%) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eMahmood et al., 2018 (High fatality) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePalaskas et al., 2020 (25\u0026ndash;50%) (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eJensen et al., 2025 (~\u0026thinsp;40%) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eWang et al., 2023 (47.4% death) (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eMoradi et al., 2023 (up to 50%) (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMajor Adverse Cardiac Events (MACE)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCommon (up to 51%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMACE occurred in a significant proportion of patients.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMahmood et al., 2018 (46% MACE) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eAwadalla et al., 2020 (51% MACE) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eDubey et al., 2025 (62.9% died within 1 year) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eTang et al., 2023 (34.6% MACE) (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac Recovery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLeft ventricular function recovered in many survivors.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAwadalla et al., 2020 (GLS improvement) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eGanatra \u0026amp; Neilan, 2018 (LVEF improved to 54%) (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative Prognostic Factors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCombination ICI, High Troponin, Low GLS, Conduction Abnormalities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFactors consistently associated with worse outcomes.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMahmood et al., 2018 (High troponin, low steroid dose) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eAwadalla et al., 2020 (Low GLS predicts MACE) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eDubey et al., 2025 (High TnT, low LVEF, conduction abnormalities) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eAtallah-Yunes et al., 2019 (Complete heart block) (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive Prognostic Factors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEarly Steroid Administration, Specific Biomarker Trends\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEarly initiation of high-dose steroids was associated with improved survival.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDubey et al., 2025 (TnT decrement by day 8) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePuzanov et al., 2021 (Weekly troponin monitoring associated with better outcomes) (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThis table delivers the \"so what,\" quantifying the severe impact of ICI-M and identifying which patients are most vulnerable. The persistently high mortality rate (25\u0026ndash;50%) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) across a decade of literature highlights that despite increased awareness, this remains a very dangerous complication. The high incidence of MACE (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) clarifies that death is often preceded by discrete, catastrophic cardiovascular events. Prognostication is key, and robust factors have emerged: biomarker levels (peak and trend of troponin) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e), functional cardiac impairment (reduced GLS and LVEF) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), and electrical instability (heart block, VT) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e) are powerful predictors. The silver lining is that early, aggressive intervention can alter this trajectory, with rapid steroid initiation and a subsequent drop in troponin being associated with survival (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.9. Spectrum and Severity Grading\u003c/h2\u003e \u003cp\u003eThe severity of ICI-M spans a wide spectrum, from subclinical disease (Grade 1) to life-threatening fulminant myocarditis (Grade 4) (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). Management is directly tied to the severity grade.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEmerging Biomarkers, Mechanisms, and Future Directions\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKey Findings\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eImplications\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eKey References\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProposed Mechanisms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT-cell-mediated cytotoxicity, Shared Antigens, Macrophage Polarization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThe prevailing mechanism involves clonally expanded T cells.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZhu et al., 2022 (Clonal CD8+\u003c/p\u003e \u003cp\u003eTemra cells) (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eZhang et al., 2018 (Shared antigens) (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmerging Biomarkers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eImmune Cell Subsets, Cytokines, Genetic Markers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eResearch is exploring new predictive and diagnostic tools.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eJaber Chehayeb et al., 2024 (CHIP associated with 2.7x risk) (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eZhu et al., 2022 (CD8\u0026thinsp;+\u0026thinsp;Temra cells) (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eQu et al., 2025 (Gene signatures NKG7, GZMH) (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNovel Therapeutic Targets\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNLRP3 Inflammasome, JAK/STAT Pathway, T-cell Metabolism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePreclinical studies suggest potential for new treatments.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLu et al., 2025 (NLRP3 inhibition with MCC950) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eNguyen et al., 2022 (Ruxolitinib) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eZheng et al., 2025 (Immune reprogramming) (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIdentified Research Gaps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLack of RCTs, Standardized Diagnostics, Predictive Biomarkers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThe literature consistently highlights the need for more research.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMoslehi et al., 2021 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eJensen et al., 2025 (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eZheng et al., 2025 (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThis table looks forward, summarizing the science that is shaping the future of ICI-M management. The proposed mechanisms move from observation to molecular understanding, with evidence of clonally expanded T-cells (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e) and shared antigens explaining the overlap syndromes. Emerging biomarkers aim to shift from reaction to prediction; the association of Clonal Hematopoiesis (CHIP) with a 2.7x increased risk (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e) is a paradigm-shifting finding, suggesting a pre-existing immune dysregulation that predisposes patients. The identification of specific cytotoxic CD8\u0026thinsp;+\u0026thinsp;Temra cells and their chemokine signature in blood (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e) offers a potential non-invasive diagnostic and monitoring tool. Novel therapeutic targets like the NLRP3 inflammasome (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) and JAK/STAT pathway (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) are promising because they aim to dissociate cardiotoxicity from antitumor efficacy. The consensus on research gaps (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) provides a clear roadmap for the field, emphasizing the critical need for RCTs, standardized definitions, and predictive biomarkers.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.10. ICI Rechallenge After Myocarditis\u003c/h2\u003e \u003cp\u003eThe decision to rechallenge with ICIs after an episode of myocarditis is high-risk (Table\u0026nbsp;\u003cspan refid=\"Tab8\" class=\"InternalRef\"\u003e8\u003c/span\u003e). Rechallenge after severe (G3/G4) myocarditis is generally contraindicated due to a very high risk of recurrence. The evidence for rechallenge after mild (G1/G2) disease is limited and suggests a moderate to high risk.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab8\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 8\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSpectrum and Severity Grading of ICI-Associated Myocarditis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeverity Grade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClinical Presentation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDiagnostic Findings\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTypical Management Approach\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKey References\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubclinical / Grade 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAsymptomatic. Discovered via routine biomarker screening.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eElevated troponin with normal other tests.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClose monitoring.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTanabe et al., 2021 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eNishikawa et al., 2022 (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePuzanov et al., 2021 (Subclinical group) (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild / Grade 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMild symptoms (e.g., fatigue, palpitations).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eElevated troponin, possible minor ECG/echo changes.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHold ICI. Initiate oral corticosteroids.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePuzanov et al., 2021 (Managed with steroids) (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere / Grade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSignificant symptoms (chest pain, dyspnea at rest). Evidence of heart failure or arrhythmias.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMarkedly elevated troponin, ECG abnormalities, reduced LVEF.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePermanently discontinue ICI. Hospitalization. High-dose IV corticosteroids.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMahmood et al., 2018 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePalaskas et al., 2020 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLife-Threatening / Grade 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFulminant myocarditis. Cardiogenic shock, cardiac arrest.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eProfoundly elevated biomarkers. Severe LV dysfunction.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePermanent ICI discontinuation. ICU. High-dose IV steroids\u0026thinsp;+\u0026thinsp;second-line immunosuppression. MCS.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNguyen et al., 2022 (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e); Stein-\u003c/p\u003e \u003cp\u003eMerlob et al., 2021 (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDeath.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThis table provides a crucial framework for standardizing the description of ICI-M, which is essential for comparing studies and guiding therapy. The inclusion of subclinical (Grade 1) disease (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e) is a modern concept driven by proactive screening; its natural history and management are still being defined. The distinction between Grade 2 and 3 is a critical decision point, often hinging on the presence of heart failure or significant arrhythmias, which mandates hospitalization and IV steroids (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Grade 4 (fulminant) myocarditis represents a medical emergency characterized by cardiogenic shock, requiring a dual approach: maximal immunosuppression and advanced MCS to sustain life (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). This grading system directly correlates with the management strategies outlined in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, creating a clear clinical pathway.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e3.11. Comparison with Other Cardiovascular Toxicities\u003c/h2\u003e \u003cp\u003eThis diagnostic decision-tree table is invaluable for clinicians facing a cardiac complication in an ICI-treated patient. It emphasizes that not all cardiac irAEs are myocarditis and provides key differentiators to guide diagnosis and management.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab9\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 9\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of ICI-Myocarditis with Other ICI-Related Cardiovascular Toxicities\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFeature\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMyocarditis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePericarditis / Pericardial Effusion\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTakotsubo Syndrome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNon-Inflammatory LV Dysfunction\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary Pathology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInflammatory cell infiltration.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eInflammation of the pericardium.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eStress-induced, transient myocardial stunning.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMyocardial injury without prominent lymphocytic infiltration.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKey Symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChest pain, dyspnea, fatigue, arrhythmias.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePleuritic chest pain, dyspnea.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eChest pain, dyspnea, often post-stress.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eInsidious onset of heart failure symptoms.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiagnostic Biomarkers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTroponin (highly elevated), CK.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTroponin usually normal or mildly elevated.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eModerate troponin elevation.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTroponin may be mildly elevated. BNP/NT-proBNP is key.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECG Findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eConduction delays, heart block, VT.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDiffuse ST elevation, PR depression.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eST elevation, T-wave inversions.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOften non-specific.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEchocardiography\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRegional or global LV dysfunction, reduced GLS.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePericardial effusion.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eApical ballooning with basal hyperkinesis.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGlobal LV dysfunction, reduced GLS.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac MRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLGE (non-ischemic pattern), T2 edema.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePericardial enhancement, edema.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAbsence of LGE, reversible dysfunction.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAbsence of LGE/T2 edema.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst-Line Treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHigh-dose corticosteroids.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNSAIDs/colchicine.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSupportive care; heart failure management.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHold ICI; standard heart failure therapy.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKey References\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThis diagnostic decision-tree table is invaluable for clinicians facing a cardiac complication in an ICI-treated patient. It emphasizes that not all cardiac irAEs are myocarditis. Key differentiators include: the pattern of biomarker elevation (massive troponin in myocarditis vs. mild or BNP-predominant in others), electrical findings (conduction blocks are classic for myocarditis), and most importantly, tissue characterization on CMR (LGE and edema in myocarditis vs. its absence in Takotsubo and non-inflammatory dysfunction). This directs appropriate management: immunosuppression for inflammatory conditions vs. standard heart failure care or NSAIDs for others.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e3.12. Emerging Biomarkers, Mechanisms, and Future Directions\u003c/h2\u003e \u003cp\u003eThis table looks forward, summarizing the science that is shaping the future of ICI-M management, from understanding its causes to developing new treatments and identifying critical research gaps.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab10\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 10\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDetailed Analysis of ICI Rechallenge After Myocarditis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRechallenge Scenario\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReported Outcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRisk of Recurrence\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eContributing Factors \u0026amp; Recommendations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKey References\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRechallenge after Severe (G3/G4) Myocarditis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExtremely limited data; generally, not recommended.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVery High.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePermanent discontinuation is the standard.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eWang et al., 2023 (recurrence in 1 of 11) (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRechallenge after Mild/Subclinical (G1/G2) Myocarditis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePossible but risky. Some success, but also recurrence.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModerate to High.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMay be considered if no alternatives. Ensure complete resolution.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eWang et al., 2023 (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePuzanov et al., 2021 (recurrence in 1 subclinical patient) (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall Evidence Quality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVery Low (based on case reports and small series).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eConclusion: A high-stakes decision without robust safety data.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThis table addresses one of the most challenging dilemmas in cardio-oncology. The evidence is clear: rechallenge after severe (G3/G4) myocarditis is contra-indicated due to the unacceptably high risk of recurrence and fatal outcome (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). The data on mild (G1/G2) cases is sparse and conflicting, but suggests a non-negligible risk (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). The proposed strategies for a potential rechallenge in this scenario\u0026mdash;such as ensuring complete resolution, switching ICI class, and using prophylactic steroids\u0026mdash;are based on theoretical reasoning and anecdote rather than evidence. This table effectively communicates that any decision to rechallenge must be a shared, multidisciplinary decision made with the understanding that it constitutes an uncontrolled experiment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e3.13. Summary of Clinical Recommendations\u003c/h2\u003e \u003cp\u003eThis table serves as a concise clinical practice guideline distilled from the entire body of evidence, creating a logical patient journey from pre-therapy risk assessment to long-term follow-up.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab11\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 11\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of Key Recommendations from Included Studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDomain\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKey Recommendations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eKey References\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-Treatment Screening \u0026amp; Risk Assessment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Obtain ECG, baseline troponin, and echocardiogram prior to ICI initiation.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLehmann et al., 2023 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eJaber Chehayeb et al., 2024 (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonitoring During Therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Be most vigilant during the first 6\u0026ndash;12 weeks.\u003c/p\u003e \u003cp\u003e\u0026bull; Implement serial troponin measurements.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePuzanov et al., 2021 (Weekly x 6 weeks) (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eOikawa et al., 2025 (Serial cTnI) (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiagnostic Workup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Any clinical suspicion should trigger an immediate ECG and troponin.\u003c/p\u003e \u003cp\u003e\u0026bull; Use echocardiography (with GLS) and Cardiac MRI.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMahmood et al., 2018 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eAwadalla et al., 2020 (GLS) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eManagement Principles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Permanently discontinue ICI in severe myocarditis.\u003c/p\u003e \u003cp\u003e\u0026bull; Initiate high-dose intravenous corticosteroids immediately.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMahmood et al., 2018 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e);\u003c/p\u003e \u003cp\u003ePalaskas et al., 2020 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eHeemelaar et al., 2024 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrognostication \u0026amp; Follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Use high troponin levels, low GLS, and conduction abnormalities to identify high-risk patients.\u003c/p\u003e \u003cp\u003e\u0026bull; Refer survivors to cardio-oncology for long-term follow-up.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDubey et al., 2025 (Prognostic factors) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e);\u003c/p\u003e \u003cp\u003eAwadalla et al., 2020 (GLS predicts MACE) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThis table serves as a concise clinical practice guideline distilled from the entire body of evidence. It creates a logical patient journey from pre-therapy risk assessment to long-term follow-up. The emphasis on baseline and serial troponin monitoring (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e) is a central, evidence-based recommendation that can enable early diagnosis. The command to \"hold ICI and start high-dose steroids immediately\" is the universal refrain for managing confirmed cases (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The call for multidisciplinary care is not just a formality but a necessity, integrating oncology, cardiology, and often neurology and immunology expertise to manage these complex patients.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e4.1. Summary of Evidence\u003c/h2\u003e \u003cp\u003eThis systematic review of 43 studies provides a comprehensive overview of ICI-associated myocarditis. The evidence paints a clear picture of a severe toxicity that typically affects older patients with metastatic cancer, particularly those on combination ICI therapy. The clinical presentation is heterogeneous, necessitating a high index of suspicion and a low threshold for investigation with troponin, ECG, and echocardiography. Management hinges on immediate ICI discontinuation and rapid initiation of high-dose corticosteroids, with escalation to second-line agents in refractory cases. Despite these measures, mortality remains high, underscoring the critical need for early detection and intervention.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003e4.2. Interpretation in the Context of Existing Literature\u003c/h2\u003e \u003cp\u003eOur findings consolidate and confirm the key observations from major registries and cohort studies published over the last several years (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The strong association with combination ICI therapy is a consistent and critical theme, reinforcing the importance of weighing the enhanced anti-tumor efficacy of these regimens against their increased toxicity profile. The high rate of asymptomatic presentation argues compellingly for the implementation of proactive monitoring strategies, such as serial troponin measurements during the initial treatment cycles, as suggested by several studies (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe dramatic efficacy of novel agents like abatacept in severe cases (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) represents a shift towards mechanism-driven therapy, targeting the specific immunopathology of ICI-M. Furthermore, the poor prognosis associated with specific factors like high troponin and low GLS provides clinicians with a framework for risk stratification, enabling more intensive monitoring and treatment for the most vulnerable patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003ch2\u003e4.3. Limitations\u003c/h2\u003e \u003cp\u003eThis review has limitations. The included studies are predominantly retrospective and observational, subject to potential selection and reporting biases. The rarity of ICI-M means that even large studies have limited sample sizes, and no randomized controlled trials exist to guide management. The geographical concentration of research in North America, East Asia, and Western Europe limits the generalizability of findings to other populations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003e4.4. Clinical Implications\u003c/h2\u003e \u003cp\u003eThe findings from this review have immediate implications for practice:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eVigilance and Screening: High vigilance is required, especially during the first 6\u0026ndash;12 weeks of treatment and for patients on combination therapy. Consider baseline and serial monitoring with troponin and ECG.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eRapid Diagnosis and Grading: Any clinical suspicion should trigger an immediate and structured diagnostic workup. The severity grading system (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e) should be used to standardize assessment and guide therapy.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAggressive and Escalating Management: The cornerstone of management is prompt ICI hold/discontinuation and initiation of high-dose corticosteroids. Have a low threshold for escalating to second-line immunosuppression in severe or refractory cases and involving a multidisciplinary team.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCautious Rechallenge: Rechallenge with ICIs after myocarditis is fraught with risk and should only be considered in select cases of mild, fully resolved toxicity when there are no other treatment options, following a thorough multidisciplinary discussion.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eImmune checkpoint inhibitor-associated myocarditis is a severe, potentially fatal complication that requires a high index of suspicion, prompt diagnosis, and immediate, aggressive management. A structured approach involving risk stratification, proactive monitoring, and a graded treatment algorithm is essential to improve outcomes. Future research should focus on validating predictive biomarkers, understanding underlying mechanisms, and conducting prospective trials to optimize immunosuppressive strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding Resource\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any external funding or support from external entities. All aspects of this work were conducted independently, and there are no financial or material conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026apos;s Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMA\u003c/strong\u003e developed the methodology and wrote the methodology section. MA also conducted data extraction using a predesigned Excel spreadsheet, capturing key study details. Additionally, MA oversaw the entire review process and coordinated the writing of the manuscript. \u003cstrong\u003eJT\u003c/strong\u003e independently verified 50% of the extracted data to ensure accuracy and consistency. JT also wrote the results section, contributed to the final review of the manuscript, played a role in developing the study design, and assisted in refining the methodology section. \u003cstrong\u003eSN\u003c/strong\u003e contributed to refining the search strategy, participated in the full-text review process, and assisted in synthesizing the extracted data. SN also built the tables and diagrams for the manuscript and helped review the methodology section. \u003cstrong\u003eRS\u003c/strong\u003e independently conducted the title and abstract screening using Rayyan software, ensuring the initial selection of studies. RS also conducted the full-text review for studies meeting the inclusion criteria and wrote the discussion section. \u003cstrong\u003eLA\u003c/strong\u003e independently verified 50% of the extracted data alongside JT to enhance data accuracy. LA also contributed to refining the study methodology and participated in manuscript revisions. \u003cstrong\u003eFK\u003c/strong\u003e wrote the introduction section and assisted in optimizing the search strategy. FK also played a role in screening fulltext articles and contributed to drafting and reviewing the discussion section. \u003cstrong\u003eMT\u003c/strong\u003e independently conducted the title and abstract screening using Rayyan software, ensuring the initial selection of studies. MT also wrote the conclusion section and participated in discussions regarding study inclusion and exclusion criteria. \u003cstrong\u003eAO\u003c/strong\u003e contributed to writing the discussion section and provided critical revisions to improve clarity and coherence. AO also participated in reviewing the final manuscript to ensure consistency and accuracy. \u003cstrong\u003eAR\u003c/strong\u003e played a role in the quality assessment of included studies and assisted in synthesizing the extracted data. AR also contributed to reviewing the discussion and conclusion sections to ensure alignment with the study objectives. All authors contributed to the conception and design of the study, provided input on data interpretation, and participated in manuscript revisions. All authors approved the final version before submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo conflicts of interest were reported among the authors involved in this systematic review.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMoslehi J, Lichtman AH, Sharpe AH, Galluzzi L, Kitsis RN. Immune checkpoint inhibitor-associated myocarditis: manifestations and mechanisms. J Clin Invest. 2021;131(5):e145186.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLehmann LH, Heckmann MB, Bailly G, Finke D, Procureur A, Power JR, et al. Cardio-muscular biomarkers in the diagnosis and prognostication of immune checkpoint inhibitor myocarditis: Troponins as biomarkers in ICI-myocarditis. 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Early detection of myocarditis caused by immune checkpoint inhibitor therapy with nivolumab and ipilimumab for advanced recurrent renal cell carcinoma. Cancer Immunol Immunother. 2025;74:97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJensen G, Wang X, Kuempel J, Palaskas N, Chen Z, Yu W, et al. Immune checkpoint inhibitor-associated myocarditis. Am J Physiol Heart Circ Physiol. 2025;328(4):H734\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlexander G, Mortada I, Mhanna M, Byer S, Grewal US, Mansour S. Immune Checkpoint Inhibitor-Related Myocarditis: A Single Center Observational Registry. Clin Cardiol. 2025;48:e70154.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu L, Chen Y, Xiong L, Shen Y, Zhou Z, Wang S, et al. A review of immune checkpoint inhibitor-associated myocarditis: Epidemiology, pathogenesis, and biomarkers. Hum Vaccin Immunother. 2025;21(1):2512645.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang JC, Chen WD, Bustamante Alvarez J, Jia K, Shi L, Wang Q, et al. Cancer immune checkpoint blockade therapy and its associated autoimmune cardiotoxicity. Acta Pharmacol Sin. 2018;39(11):1693\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTurker I, Johnson DB. Immune Checkpoint Inhibitor-Related Myocarditis: Current Understanding and Potential Diagnostic and Therapeutic Strategies. Expert Opin Drug Saf. 2023;22(10):909\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCao W, Han S, Zhang P, Mi L, Wang Y, Nie J et al. Immune checkpoint inhibitor-related myocarditis in patients with lung cancer. BMC Cancer. 2025;25(685).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKe G, Chen P, Luo J, Huang J, Shang Y, Huang Y, et al. Plasma exchange plus glucocorticoids in the treatment of immune checkpoint inhibitor-induced myocarditis: a case series and review. Clin Cardiol. 2023;46(12):1481\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDoms J, Prior JO, Peters S, Obeid M. Tocilizumab for refractory severe immune checkpoint inhibitor-associated myocarditis. Ann Oncol. 2020;31(9):1273\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZheng J, Yi Y, Tian T, Luo S, Liang X, Bai Y. ICI-induced cardiovascular toxicity: mechanisms and immune reprogramming therapeutic strategies. Front Immunol. 2025;16:1550400.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSessums M, Yararapu S, Guru PK, Sanghavi DK. Atezolizumab-induced myositis and myocarditis in a patient with metastatic urothelial carcinoma. BMJ Case Rep. 2020;13:e236357.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStein-Merlob AF, Hsu JJ, Colton B, Berg CJ, Ferreira A, Price MM, et al. Keeping immune checkpoint inhibitor myocarditis in check: advanced circulatory mechanical support as a bridge to recovery. ESC Heart Fail. 2021;8(5):4301\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang C, Zhao G, Zhang Z, Yang L, Liu S, Li G, Wang H, Huang J, Wang S, Li N. Immune checkpoint inhibitor\u0026ndash;associated myocarditis: a systematic analysis of case reports. Front Immunol. 2023;14:1275254.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQu S, Zhang J, Wang K, Zhou Y. Identification of key immune-related genes and potential therapeutic targets in immune checkpoint inhibitor-associated myocarditis. Postgrad Med J. 2025;101(1192):137\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTang X, Li Y, Huang H, Shi R, Shen L-T, Qian W-L, et al. Early evaluation of severe immune checkpoint inhibitor-associated myocarditis: a real-world clinical practice. J Cancer Res Clin Oncol. 2023;149(11):8345\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNishikawa T, Inoue T, Otsuka T, Kuno I, Kukita Y, Nakamura H, et al. Prevalence and characteristics of immune checkpoint inhibitor-related myocardial damage: A prospective observational study. PLoS ONE. 2022;17(11):e0275865.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAtallah-Yunes SA, Kadado AJ, Kaufman GP, Hernandez-Montfort J. Immune checkpoint inhibitor therapy and myocarditis: a systematic review of reported cases. J Cancer Res Clin Oncol. 2019;145(7):1527\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu X, Wu W, Fang L, Liu Y, Chen W. TNF-α inhibitors and other biologic agents for the treatment of immune checkpoint inhibitor-induced myocarditis. Front Immunol. 2022;13:922782.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoradi A, Kodali A, Okoye C, Klein DH, Mohamoud I, Olanisa OO, Parab P, Chaudhary P, Mukhtar S, Mohammed L. A Systematic Review of Myocarditis Induced by Immune Checkpoint Inhibitors: How Concerning Is the Most Common Cardiotoxicity of Immune Checkpoint Inhibitors? Cureus. 2023;15(7):e42071.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaetani T, Hamaguchi T, Nishimura T, Marumo S, Fukui M. Durvalumab-associated Late-onset Myocarditis Successfully Treated with Corticosteroid Therapy. Intern Med. 2022;61(4):527\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTay RY, Blackley E, McLean C, Moore M, Bergin P, Gill S, Haydon A. Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy. Br J Cancer. 2017;117(7):921\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePuzanov I, Subramanian P, Yatsynovich YV, Jacobs DM, Chilbert MR, Sharma UC, et al. Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis. J Immunother Cancer. 2021;9:e002553.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCautela J, Zeriouh S, Gaubert M, Bonello L, Laine M, Peyrol M, Paganelli F, Lalevee N, Barlesi F, Thuny F. Intensified immunosuppressive therapy in patients with immune checkpoint inhibitor-induced myocarditis. J Immunother Cancer. 2020;8:e001887.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhu H, Gaidos FX, Lee D, Wallany S, Huang YV, Ryan J, et al. Identification of Pathogenic Immune Cell Subsets Associated with Checkpoint Inhibitor-induced Myocarditis. Circulation. 2022;146(4):316\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsumoto T, Fukuda K, Yoshida T, Shimazu K, Taguchi D, Shinozaki H, et al. Sudden and severe cardiotoxicity induced with pembrolizumab, its clinical course, therapeutic intervention, and outcome. Int Cancer Conf J. 2022;11(1):81\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJaber Chehayeb R, Singh J, Matute-Martinez C, Chen NW, Ferrigno Guajardo A, Lin D, et al. Clonal hematopoiesis of indeterminate potential is associated with increased risk of immune checkpoint inhibitor myocarditis in a prospective study of a cardio-oncology cohort. Cardio-Oncology. 2024;10:84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThakker RA, Lee MA, Albaeini A, Elbadawi A, Suthar KH, Perez C, et al. Clinical Characteristics and Outcomes in Immune Checkpoint Inhibitor Therapy-Associated Myocarditis. Cardiol Res. 2021;12(5):270\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOikawa M, Haga F, Tani T, Yokokawa T, Miura S, Misaka T et al. Clinical Significance of Cardiac Troponin I Elevation in Detecting Immune Checkpoint Inhibitor-Induced Myocarditis. Circ Rep. 2025; (Epub ahead of print).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Immune checkpoint inhibitors, Myocarditis, Cardio-oncology, Immunotherapy, Immune-related adverse events, Systematic review","lastPublishedDoi":"10.21203/rs.3.rs-9242293/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9242293/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eImmune checkpoint inhibitor-associated myocarditis (ICI-M) is a rare but life-threatening toxicity. This systematic review synthesizes the current evidence on the epidemiology, clinical presentation, diagnostic approaches, management strategies, and outcomes of ICI-M to guide clinical practice.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe systematically searched PubMed from inception to January, 2026 for studies reporting on ICI-M in cancer patients. Data on patient demographics, clinical features, diagnostic findings, treatment, and outcomes were extracted. The risk of bias was assessed using appropriate tools.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e43 studies were included. ICI-M predominantly affected older adults (median age 65\u0026ndash;74 years) with metastatic melanoma, non-small cell lung cancer, or renal cell carcinoma. The highest risk was associated with combination ICI therapy (anti-PD-1/PD-L1\u0026thinsp;+\u0026thinsp;anti-CTLA-4). Clinical presentation ranged from asymptomatic biomarker elevation to fulminant heart failure, with a high frequency of concurrent myositis. Key diagnostic findings included elevated troponin (\u0026gt;\u0026thinsp;90% of cases), ECG abnormalities, and reduced global longitudinal strain on echocardiography. Management universally involved ICI discontinuation and high-dose corticosteroids. Second-line immunosuppression (e.g., IVIG, infliximab, abatacept) was used in refractory cases. Despite treatment, mortality remained high (25\u0026ndash;50%). Poor prognostic factors included high troponin levels, reduced left ventricular ejection fraction, and conduction abnormalities.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eICI-M is a severe complication with high mortality. Early recognition via proactive monitoring, prompt diagnosis using a multi-modal approach, and immediate, aggressive immunosuppression are critical. Future research should focus on predictive biomarkers and randomized trials to optimize management.\u003c/p\u003e","manuscriptTitle":"Immune Checkpoint Inhibitor–Associated Myocarditis in Cancer Patients: A Systematic Review of Clinical Presentation, Management, and Outcomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-30 05:08:50","doi":"10.21203/rs.3.rs-9242293/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f3ed58b4-e9b2-49ba-9f8f-d5c86486d086","owner":[],"postedDate":"March 30th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-06T15:11:05+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-30 05:08:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9242293","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9242293","identity":"rs-9242293","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}