Immune Checkpoint Inhibitor Myocarditis Research Articles

Elevated IL-6 and Tumor Necrosis Factor-α in Immune Checkpoint Inhibitor Myocarditis

Introduction: The impact of peripheral cytokine levels on the prognosis and treatment of immune checkpoint inhibitor (ICI) myocarditis has not been well studied. Objectives: This study aimed to identify cytokines that can prognosticate and direct the treatment of ICI myocarditis. Methods: This was a single-center, retrospective cohort study of patients with ICI myocarditis who had available peripheral cytokine levels between January 2011 and May 2022. Major adverse cardiovascular events (MACEs) were defined as a composite of heart failure with/without cardiogenic shock, arterial thrombosis, life-threatening arrhythmias, pulmonary embolism, and sudden cardiac death. Results: In total, 65 patients with ICI myocarditis had cytokine data available. Patients were mostly males (70%), with a mean age of 67.8 ± 12.7 years. Interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) were the most common cytokines to be elevated with 48/65 (74%) of patients having a peak IL-6 above normal limits (>5 pg/mL) and 44/65 (68%) of patients with peak TNF-α above normal limits (>22 pg/mL). Patients with elevated peak IL-6 had similar 90-day mortality and MACE outcomes compared to those without (10.4% vs. 11.8%, p = 0.878 and 8.8% vs. 17.7%, p = 0.366, respectively). Similarly, those with elevated peak TNF-α had similar 90-day mortality and MACEs compared to those without (29.6% vs. 14.3%, p = 0.182 and 13.6% vs. 4.8%, p = 0.413, respectively). Kaplan–Meier survival analysis also showed that there was not a significant difference between MACE-free survival when comparing elevated and normal IL-6 and TNF-α levels (p = 0.182 and p = 0.118, respectively). MACEs and overall survival outcomes were similar between those who received infliximab and those who did not among all patients and those with elevated TNF-α (p-value 0.70 and 0.83, respectively). Conclusion: Peripheral blood levels of IL-6 and TNF-α are the most commonly elevated cytokines in patients with ICI myocarditis. However, their role in the prognostication and guidance of immunomodulatory treatment is currently limited.

Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy.

Myocarditis has emerged as an immune-related adverse event of immune checkpoint inhibitor (ICI) cancer therapy associated with significant mortality. To ensure patients continue to safely benefit from life-saving cancer therapy, an understanding of fundamental immunological phenomena underlying ICI myocarditis is essential. We recently developed the NOD-cMHCI/II-/-.DQ8 mouse model that spontaneously develops myocarditis with lower mortality than observed in previous HLA-DQ8 NOD mouse strains. Our strain was rendered murine MHC class I and II deficient using CRISPR/Cas9 technology, making it a genetically clean platform for dissecting CD4+ T cell-mediated myocarditis in the absence of classically selected CD8+ T cells. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, anti-PD-1 administration accelerates skeletal muscle myositis. Using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses, we performed a thorough characterization of cardiac and skeletal muscle T cells, identifying shared and unique characteristics of both populations. Taken together, this report details a mouse model with features of a rare, but highly lethal clinical presentation of overlapping myocarditis and myositis following ICI therapy. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies.

Immune Checkpoint Inhibitor-Associated Myocarditis: A Literature Review.

Recently in the field of oncology, immune checkpoint inhibitors (ICI) are being increasingly utilized both in clinical trials and in clinical practice. It is a form of biological therapy that targets tumors by activating the immune system, which in turn eliminates proliferating cancer cells. These have numerous immune-related adverse events (irAEs), one of which is myocarditis, which has high rates of mortality. This article was a narrative review of myocarditis related to ICI use. Studies from the PubMed, Cochrane, and American Society of Clinical Oncology (ASCO) databases were used in writing this review. The databases were searched for original publications for adverse effects related to ICI use and myocarditis specifically.There are numerous published instances of cancer immunotherapy causing myocarditis. ICI therapy has numerous benefits, as it upregulates the immune system to target cancer cells, utilizing the body's own defense mechanisms to target proliferating cells. Myocarditis is a serious side effect, however. Therefore, on balance, these monotherapies are worth using. While this literature review primarily identifies cross-reaction as the main mechanism of myocarditis, there are other possible mechanisms. One proposed mechanism involves a shared antigen between the myocardial tissue and the tumor. This mechanism is called molecular mimicry, where the monoclonal antibody attacks both the myocardial tissue and the tumor cell. Management of ICI-induced myocarditis has not been studied by randomized controlled trials or prospective studies, but based on previous case reports and case series it is mostly treated with steroids initially. An ICI rechallenge after temporary discontinuation appears conceivable in many cases, especially given its therapeutic effects, but only limited data are available on the safety of a rechallenge after an irAE. The lack of RCTs regarding rechallenge with an ICI after irAE, more so specifically about myocarditis, along with the overall results and the complexity involved in such cases once again emphasize the need to make decisions on an individual basis by a multidisciplinary expert working group. At the same time, the focus should also be on publishing more data as the need will grow along with the indications for ICI therapies.

T1 Mapping Enabled Detection and Follow-up of Rare Immune Checkpoint Inhibitor Myocarditis.

T1 Mapping Enabled Detection and Follow-up of Rare Immune Checkpoint Inhibitor Myocarditis.

Expansion of Pathogenic Cardiac Macrophages in Immune Checkpoint Inhibitor Myocarditis.

Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1) or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), have revolutionized cancer management but are associated with devastating immune-related adverse events including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI myocarditis is often fulminant and is pathologically characterized by myocardial infiltration of T lymphocytes and macrophages. Although much has been learned about the role of T-cells in ICI myocarditis, little is understood about the identity, transcriptional diversity, and functions of infiltrating macrophages. We used an established murine ICI myocarditis model (Ctla4+/-Pdcd1-/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, flow cytometry, in situ RNA hybridization, molecular imaging, and antibody neutralization studies. We observed marked increases in CCR2 (C-C chemokine receptor type 2)+ monocyte-derived macrophages and CD8+ T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2+ subpopulation highly expressing Cxcl9 (chemokine [C-X-C motif] ligand 9), Cxcl10 (chemokine [C-X-C motif] ligand 10), Gbp2b (interferon-induced guanylate-binding protein 2b), and Fcgr4 (Fc receptor, IgG, low affinity IV) that originated from CCR2+ monocytes. It is important that a similar macrophage population expressing CXCL9, CXCL10, and CD16α (human homologue of mouse FcgR4) was expanded in patients with ICI myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9+Cxcl10+ macrophages via IFN-γ (interferon gamma) and CXCR3 (CXC chemokine receptor 3) signaling pathways. Depleting CD8+ T-cells or macrophages and blockade of IFN-γ signaling blunted the expansion of Cxcl9+Cxcl10+ macrophages in the heart and attenuated myocarditis, suggesting that this interaction was necessary for disease pathogenesis. These data demonstrate that ICI myocarditis is associated with the expansion of a specific population of IFN-γ-induced inflammatory macrophages and suggest the possibility that IFN-γ blockade may be considered as a treatment option for this devastating condition.

Kiosk 5R-TA-01 - Left Atrial Evaluation in Immune Check Point Inhibitor Myocarditis Using Cardiac Magnetic Resonance Imaging and Correlations with Cardiovascular Outcomes

Kiosk 5R-TA-01 - Left Atrial Evaluation in Immune Check Point Inhibitor Myocarditis Using Cardiac Magnetic Resonance Imaging and Correlations with Cardiovascular Outcomes

Kiosk 5R-TB-01 - Prospective Evaluation of Immune Checkpoint Inhibitor Myocarditis with Serial Quantitative Cardiovascular Magnetic Resonance and Correlations with Cardiovascular Outcomes

Kiosk 5R-TB-01 - Prospective Evaluation of Immune Checkpoint Inhibitor Myocarditis with Serial Quantitative Cardiovascular Magnetic Resonance and Correlations with Cardiovascular Outcomes

Severe vs Nonsevere Immune Checkpoint Inhibitor-Induced Myocarditis: Contemporary 1-Year Outcomes

BackgroundThe long-term contemporary outcomes of patients with immune checkpoint inhibitor (ICI) myocarditis, spanning the spectrum of clinical severity, are undetermined. ObjectivesWe sought to investigate the characteristics and cardiovascular outcomes of patients with severe and nonsevere ICI myocarditis. MethodsThis was a retrospective cohort study of patients with suspected ICI myocarditis at Massachusetts General Brigham Health System conducted between 2015 and 2022. Cases were classified as severe, nonsevere, and negative based on the International Cardio-Oncology Society criteria. One-year cardiovascular mortality, all-cause mortality, and cardiovascular readmissions were evaluated. We also evaluated 1-year ICI resumption and left ventricular ejection fraction over a median follow-up of 18 (Q1-Q3: 8-67) weeks. ResultsThe study included 160 patients: 28 severe, 96 nonsevere, and 36 negative cases. Patients with severe myocarditis had an increased risk of 1-year cardiovascular mortality, particularly in the early post-myocarditis period (29% vs 5%; HR: 6.52; 95% CI: 2.2-19.6; P < 0.001). Patients with nonsevere myocarditis had a cardiovascular mortality rate similar to negative cases (HR: 0.61; 95% CI: 0.14-2.54). One-year all-cause mortality did not differ between severe, nonsevere, and negative cases (P = 0.74). Rates of 1-year cardiovascular readmissions and long-term left ventricular ejection fraction were also similar among the 3 groups. ICI resumption was low, even in negative cases. ConclusionsIn a contemporary analysis of patients with suspected ICI myocarditis, severe ICI myocarditis was associated with increased 1-year cardiovascular mortality, which was lower than previously reported. Patients with nonsevere ICI myocarditis had outcomes similar to negative cases. The optimal management strategies for nonsevere ICI myocarditis need to be re-evaluated.

Abstract 16013: Non-Bacterial Thrombotic Endocarditis and Recurrent Cerebrovascular Accidents in Immune Checkpoint Inhibitor Myocarditis

Background: Nonbacterial thrombotic endocarditis (NBTE) is a rare condition associated with cancer, hypercoagulable state, and systemic emboli including stroke. This report presents a case of NBTE associated with metastatic lung adenocarcinoma and recurrent strokes despite anticoagulation for prior pulmonary embolism (PE) and highlights the challenges in management of NBTE. Case: 66-year-old man with stage IV non-small cell lung adenocarcinoma treated with pembrolizumab complicated by immune checkpoint inhibitor (ICI) myocarditis treated with high dose steroids and PE treated with rivaroxaban, presented with diplopia and gait instability. MRI brain revealed a left corona radiata infarct and rivaroxaban was switched to apixaban. Three weeks later, the patient developed left internal carotid artery (ICA) occlusion, and underwent emergent thrombectomy. A transesophageal echocardiogram revealed a new 1.8 cm mass on the mitral valve with negative blood cultures. Anticoagulation was switched to therapeutic enoxaparin. Cardiothoracic surgery was consulted, though patient opted for palliative care. Decision making: Patient presented with recurrent multifocal strokes despite treatment with multiple direct oral anticoagulants (DOACs), just weeks after ICI myocarditis. The challenges here were approach to anticoagulation in a patient with recurrent strokes despite anticoagulation, the risk of hemorrhagic conversion of stroke, and the mechanism of stroke. The mitral valve mass was presumed to be NBTE, due to his metastatic malignancy and negative blood cultures. However, a recent history of ICI-myocarditis raised the possibility of an immune mediated mechanism of NBTE, given the growing association of auto-immune diseases and NBTE. Conclusion: NBTE is a rare complication of metastatic disease that can commonly lead to stroke and is treated with optimal anticoagulation and addressing the underlying malignancy. However, this case highlights the failure of multiple oral anticoagulants to treat NBTE and raises the question of additional mechanisms of NBTE beyond malignancy and hypercoagulable state. Further studies are required to elucidate a common immune mediated mechanism of NBTE and ICI myocarditis.

Abstract 16450: Increased Monocyte Count and Neutrophil-to-Lymphocyte Ratio With ICI Myocarditis

Introduction: Diagnosing immune checkpoint inhibitor (ICI) myocarditis remains complex in practice, often requiring advanced imaging or invasive endomyocardial biopsy. We constructed an institutional cohort of patients who received at least 1 dose of ICI and developed probable or definite ICI myocarditis. Hypothesis: We hypothesized that routine serum biomarkers, including troponin I, neutrophil-to-lymphocyte ratio (NLR), monocytes, and AST/ALT, would be elevated and peak at diagnosis. Methods: This retrospective cohort study used EHR data from patients on ICI at a single academic institution who developed probable or definite myocarditis from 7/2015 - 1/2023. Inclusion criteria and diagnosis date were defined using Bonaca criteria and/or documented clinical consensus, e.g. initiation of steroids for presumed myocarditis. Primary outcomes were levels of troponin I/high sensitivity troponin I, monocytes, NLR, and AST/ALT. LOESS regression with default smoothing parameter α = 0.75 was used to evaluate biomarker patterns 7 days pre- and post- diagnosis. Results: We included 16 cases of myocarditis. At diagnosis, most patients had at least 1 significant elevation in troponin I (100%), AST (81%), ALT (63%), or monocytes (69%) while on ICI (Figure 1). After diagnosis, absolute monocyte and lymphocyte count initially decreased before rebounding. Serum NLR rose prior to and briefly after diagnosis (Figure 2). Conclusions: Peripheral cardiac and non-cardiac biomarkers change with ICI myocarditis. Further research on routine non-cardiac biomarkers associated with myocarditis and other ICI toxicities may help prevent high-grade adverse events.

Abstract 16577: Unraveling T-cell and Macrophage Chemokine Crosstalk in Immunotherapy-Induced Myocarditis

Introduction: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate immunity against tumor cells but can cause immune related adverse events such as myocarditis, a rare but serious side effect with up to 40% mortality. Hypothesis: Macrophages contribute to recruitment of cytotoxic T-cell subsets to the heart in the setting of ICI, causing myocarditis. Methods: To study the role of macrophage depletion on ICI myocarditis, we treated MRL/Pdcd1-/- mice with liposomal clodronate. To identify timing of immune infiltration, we performed serial single cell T-cell receptor and RNA sequencing of CD45+ cells from the hearts/blood of MRL/Pdcd1-/- myocarditis mice at 1, 2, and 4 weeks of age. We treated MRL mice with anti-PD1/CTLA4 to induce myocarditis and assessed if anti-CXCR3 could decrease effector CD8+ T-cell cardiac infiltration and mitigate myocarditis. We studied the effects of in vitro CXCR3 blockade on CXCR3+ T-cell migration in a transwell assay. Results: Serial single-cell TCR sequencing/scRNA-seq of immune cells from MRL/ Pdcd1-/- vs. MRL control hearts showed infiltration of CXCL9/10+ macrophages ( Fig. 1, A ) along with progressive clonal expansion of CXCR3+ effector CD8+ T-cells in the heart starting at 2 weeks of age, prior to clinical onset of myocarditis. Macrophage depletion with liposomal clodronate reduced myocarditis and improved survival in MRL/ Pdcd1-/- mice ( Fig. 1, B-C) . CXCR3 blockade with anti-CXCR3 antibody reduced myocarditis, decreased CXCR3+ CD8+ T-cell infiltration, and improved survival in mice treated with anti-CTLA4/anti-PD1 antibodies (Fig. 1, D-E) . CXCR3 blockade in transwell assay also reduced migration of CD8+CXCR3+ T-cells towards the macrophage compartment (Fig. 1, F) . Conclusions: CXCL9/10+ macrophages likely play a critical role in development of ICI myocarditis through the recruitment of CXCR3+ effector T-cells into the heart, making this pathway an attractive therapeutic target.

Abstract 17127: Rapid Progression of Conduction System Disease in Suspected Fulminant Nivolumab Myocarditis

Background: Immune checkpoint inhibitors (ICI) have shown efficacy in treating a wide spectrum of malignancies, but have a known risk of cancer therapy related cardiac toxicity. We present a case that demonstrates how conduction system disease can rapidly progress in a patient with suspected nivolumab (PD1) induced fulminant myocarditis. Case: An 82-year-old male with a history of esophageal carcinoma presented with agonal breathing and altered mental status. He had received his second dose of PD1 therapy three days prior. He was intubated and admitted for hypoxic respiratory failure and elevated troponin. His initial EKG demonstrated new marked 1st degree AV block with right bundle branch block (RBBB) morphology. A stat echocardiogram noted an EF of 60-65% with no wall motion abnormalities. Decision-making: On Day 2, Mobitz Type I block was appreciated on telemetry. The patient met criteria for acute myocarditis with his clinical presentation, new conduction system disease, and high sensitivity troponin of 13,000. Given recent PD1 therapy, lack of infectious prodrome, and lack of prior heart disease, suspicion for ICI induced myocarditis was high. High dose steroid therapy was initiated. On Day 3, the patient was noted to have alternating left bundle branch block and RBBB. On Day 4, he progressed to complete heart block, prompting transvenous pacemaker (PM) placement with subsequent permanent PM placement. A repeat echo showed global hypokinesis with an EF of 40-45% and reduced RV function. He also required vasopressor support meeting criteria for fulminant myocarditis. Due to his hemodynamic instability and low clinical suspicion, he did not receive cardiac catheterization. Cardiac MRI and cardiac biopsy were not readily available in this institution. Conclusion: The clinical findings, lack of infectious prodrome, and worsening arrhythmia requiring pacing and vasopressor support, in patient with recent PD1 treatment suggests nivolumab induced fulminant myocarditis. In institutions without advanced testing infrastructure, rapid recognition of progressive conduction system disease may be used as an early marker for diagnosis, treatment initiation, and referral to tertiary care centers for advanced management of fulminant ICI myocarditis.

Abstract 15756: To Close or Not to Close: A Case of Multisystem Immune Checkpoint Inhibitor Toxicity and PFO

Introduction: Recent emergence of immune checkpoint inhibitors (ICIs) in oncologic treatments has led to increasing research on their side effect profile. Myocarditis occurs in roughly 0.04-1.14% of patients treated with ICIs and is associated with up to 50% mortality. We present a case of multisystem ICI toxicity requiring comprehensive evaluation to ultimately reveal a PFO shunt as the cause of persistent hypoxemia. Case: A 67-year-old male with Stage IIIC cutaneous melanoma presented with non-radiating pleuritic chest pain, diplopia, dyspnea and syncope. ECG showed high grade AV block and right bundle branch block. Labs showed elevated troponin, creatinine kinase and inflammatory markers. An echocardiogram showed edematous myocardium, a small pericardial effusion, and akinetic apical/inferior septal segments. Despite diuresis, 5g of methylprednisolone, IV immunoglobulin plus mycophenolate and resolution of AV block, the patient had hypoxemia on 100% FiO2. He underwent a CTA (which ruled out PE and ICI-induced pneumonitis) and fluoroscopic sniff test (revealing bilateral moderate diaphragm paresis). A recent cardiac catheterization on prior admission showed no obstructive coronary disease. Arterial blood gas showed pO2 120 mmHg without hypercapnia on 100% FiO2. We suspected a shunt as the underlying cause and obtained a bubble study disclosing a large (&gt; 25 bubble) PFO with right-to-left shunt. Results: Given the timing of symptoms, it was determined that pembrolizumab administration caused myocarditis and myositis with diaphragmatic paresis. In patients with pulmonary disease or diaphragmatic paresis, elevated intrathoracic and pulmonary artery pressures have been a proposed mechanism of acute worsening of right-to-left shunt resulting in hypoxemia. The patient underwent right heart catheterization and PFO closure using Gore Cardioform septal occluder with resolution of hypoxemia. A repeat echocardiogram obtained 1 month later was normal. Conclusion: All concerning clinical symptoms in the setting of ICI use require a thorough evaluation. In this case, persistent hypoxemia despite treatment for ICI toxicity unmasked a large PFO requiring closure. A multisystem approach should be used to assess suspected ICI myocarditis.

Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis.

Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris-Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities.

Cardiac Troponins for Diagnosis and Prognostic Assessment of Immune Checkpoint Inhibitor Myocarditis and Myositis: The Emerging Importance of Peripheral Vision.

Cardiac Troponins for Diagnosis and Prognostic Assessment of Immune Checkpoint Inhibitor Myocarditis and Myositis: The Emerging Importance of Peripheral Vision.

Complete heart block is a significant predictor of mortality in immune checkpoint inhibitor myocarditis

BackgroundImmune checkpoint inhibitor (ICI) myocarditis is associated with significant mortality risk. Electrocardiogram (ECG) changes in ICI myocarditis have strong prognostic value. However the impact of complete heart block (CHB) is not well defined. This study sought to evaluate the impact of CHB on mortality in ICI myocarditis, and to identify clinical predictors of mortality and CHB incidence.MethodsWe conducted a retrospective cohort study of patients with ICI myocarditis at three Mayo Clinic sites from 1st January 2010 to 31st September 2022 to evaluate mortality rates at 180 days. Clinical, laboratory, ECG, echocardiographic, and cardiac magnetic resonance imaging (CMR) characteristics were assessed. Cox and logistic regression were performed for associations with mortality and CHB respectively.ResultsOf 34 identified cases of ICI myocarditis, 7 (20.6%) had CHB. CHB was associated with higher mortality (HR 7.41, p = 0.03, attributable fraction 86.5%). Among those with CHB, troponin T (TnT) < 1000 ng/dL, low white blood cell count and high ventricular rate at admission were protective. There was trend towards increased survival among patients who underwent permanent pacemaker insertion (p = 0.051), although most experienced device lead complications. Factors associated with development of CHB included prolonged PR and QRS intervals and low Sokolow Lyon Index. Where these were normal and TnT was < 1000 ng/dL, no deaths occurred. Impaired myocardial longitudinal strain was sensitive for ICI myocarditis but was not prognostically significant.ConclusionThere is a strong temporal association between CHB and early mortality in people with ICI myocarditis. Focusing on arrhythmogenic complications can be helpful in predicting outcomes for this group of critically ill individuals.

Slow bidirectional ventricular tachycardia associated with immune checkpoint inhibitor myocarditis.

Slow bidirectional ventricular tachycardia associated with immune checkpoint inhibitor myocarditis.

Abstract P2174: Transcriptomic Profiling Of Immune Checkpoint Inhibitor Myocarditis Reveals Novel Therapeutic Targets

Introduction: Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of advanced cancers. However, the increased use of ICI has also resulted in a higher incidence of ICI-related cardiovascular side effects, including myocarditis, which has a high mortality rate of nearly 50%. Understanding the mechanisms underlying ICI-related cardiotoxicity is essential for identifying new therapeutic targets and improving patient survival. Hypothesis: We hypothesized that ICI-myocarditis has a unique transcriptomic profile that could be used to identify new drug targets. Methods: To test our hypothesis, we isolated RNA from our ICI-myocarditis mouse hearts and performed RNA-seq using the Illumina NovaSeq 6000. We also reanalyzed a human IC-myocarditis dataset downloaded from the Gene Expression Omnibus database. Results: Our results demonstrated that in both our animal models and patients, the upregulated pathways in ICI myocarditis heart tissues were enriched for regulation of T cell activation, leukocyte adhesion, and multiple cytokine signaling pathways. Conversely, downregulated pathways included those involved in cellular respiration, oxidative phosphorylation, and cardiac conduction. The most significantly upregulated genes were involved in innate and adaptive immune responses, including the CD8-dependent gene program and response to interferon-gamma of macrophages. By querying the Drug Gene Interaction Database, we identified several novel biologically plausible therapeutic targets. Correspondingly, a number of FDA-approved drugs were revealed, including monoclonal or chimeric antibodies such as Tocilizumab and Alemtuzumab, recombinant proteins like Abatacept and Anakinra, as well as small molecules such as Ruxolitinib and Imiquimod. Conclusions: Our study is the first to use the entire transcriptomic profile of ICI myocarditis in both preclinical models and patients for drug discovery. Our results demonstrate that ICI myocarditis has a distinct gene expression profile compared to healthy and other cardiac diseases. By querying a drug-gene interaction database, we identified several novel drug targets and possible treatments for ICI-related cardiotoxicity.

Role of Biomarkers in the Management of Immune-Checkpoint Inhibitor-Related Myocarditis.

Immune checkpoint inhibitor (ICI)-related myocarditis poses a major clinical challenge given its non-specific presentation, rapid progression, and high mortality rate. Here, we review the role of blood-based biomarkers in the clinical management of patients with ICI-related myocarditis. Myocardial injury, its unique pattern, and the co-occurrence with myositis are defining features of ICI-related myocarditis. Non-cardiac biomarkers, specifically creatinine phosphokinase, precedes the symptomatic presentation and is highly sensitive for diagnosing ICI-related myocarditis, making them useful screening biomarkers. Combined elevations in cardiac troponins and non-cardiac biomarkers improve the confidence of an ICI myocarditis diagnosis. High troponin and creatinine phosphokinase levels are strongly associated with severe outcomes. We propose biomarker-based algorithms for the monitoring and diagnosis of ICI-related myocarditis. Biomarkers, such as cardiac troponins and creatine phosphokinase, can be used in combination in the monitoring, diagnosis, and prognostication of patients with ICI-related myocarditis.

Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis.

Immune checkpoint inhibitors (ICIs) are approved for multiple cancers but can result in ICI-associated myocarditis, an infrequent but life-threatening condition. Elevations in cardiac biomarkers, specifically troponin-I (cTnI), troponin-T (cTnT), and creatine kinase (CK), are used for diagnosis. However, the association between temporal elevations of these biomarkers with disease trajectory and outcomes has not been established. We analyzed the diagnostic accuracy and prognostic performances of cTnI, cTnT, and CK in patients with ICI myocarditis (n=60) through 1-year follow-up in 2 cardio-oncology units (APHP Sorbonne, Paris, France and Heidelberg, Germany). A total of 1751 (1 cTnT assay type), 920 (4 cTnI assay types), and 1191 CK sampling time points were available. Major adverse cardiomyotoxic events (MACE) were defined as heart failure, ventricular arrhythmia, atrioventricular or sinus block requiring pacemaker, respiratory muscle failure requiring mechanical ventilation, and sudden cardiac death. Diagnostic performance of cTnI and cTnT was also assessed in an international ICI myocarditis registry. Within 72 hours of admission, cTnT, cTnI, and CK were increased compared with upper reference limits (URLs) in 56 of 57 (98%), 37 of 42 ([88%] P=0.03 versus cTnT), and 43 of 57 ([75%] P<0.001 versus cTnT), respectively. This increased rate of positivity for cTnT (93%) versus cTnI ([64%] P<0.001) on admission was confirmed in 87 independent cases from an international registry. In the Franco-German cohort, 24 of 60 (40%) patients developed ≥1 MACE (total, 52; median time to first MACE, 5 [interquartile range, 2-16] days). The highest value of cTnT:URL within the first 72 hours of admission performed best in terms of association with MACE within 90 days (area under the curve, 0.84) than CK:URL (area under the curve, 0.70). A cTnT:URL ≥32 within 72 hours of admission was the best cut-off associated with MACE within 90 days (hazard ratio, 11.1 [95% CI, 3.2-38.0]; P<0.001), after adjustment for age and sex. cTnT was increased in all patients within 72 hours of the first MACE (23 of 23 [100%]), whereas cTnI and CK values were less than the URL in 2 of 19 (11%) and 6 of 22 (27%) of patients (P<0.001), respectively. cTnT is associated with MACE and is sensitive for diagnosis and surveillance in patients with ICI myocarditis. A cTnT:URL ratio <32 within 72 hours of diagnosis is associated with a subgroup at low risk for MACE. Potential differences in diagnostic and prognostic performances between cTnT and cTnI as a function of the assays used deserve further evaluation in ICI myocarditis.