Introduction

The use of immune checkpoint inhibitors (ICIs) in cancer management has significantly increased in recent years. The remarkable efficacy of these agents as anti-neoplastic therapies is shadowed by their potential for inducing autoimmune or inflammatory side effects, collectively termed immune-related adverse events. Cardiovascular immune-related adverse events, particularly myocarditis, are increasingly recognized. The prevalence of myocarditis has been reported between 0.06% and 2.4%, with a higher risk in combination immunotherapy.^1-3 Based on recent data, ICI-induced myocarditis can no longer be considered a rare immune-related adverse event.⁴ Other manifestations include pericardial disease,⁶ vasculitis,⁵ Takotsubo syndrome,⁷ destabilization of atherosclerotic lesions,8 venous thromboembolism,⁹ or conduction abnormalities,⁴ but epidemiological data are sparse. Here we summarize the current approach to the diagnosis and management of ICI-associated myocarditis.

Mechanism of ICI Cardiotoxicity

The therapeutic mechanisms of the most commonly used ICIs are based on blocking either the cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) or programmed cell death protein-1 (PD-1) pathways. CTLA-4 and PD-1 serve as immune response inhibitors by normally suppressing the T-cell response in order to prevent autoimmunity and maintain T-cell tolerance.^10,11 Concomitant use of CTLA-4 and PD-1 antagonists leads to a synergistic effect, providing a dual blockade of T-lymphocyte inhibition.¹¹ Cardiac immune-related adverse events appear more frequently in patients treated with CTLA-4 antagonists compared with PD-1 inhibitors,¹² and the risk increases with combination therapy.^3,13,14 The development of cardiac immune-related adverse events in patients treated with combination therapy leads to ICI discontinuation in up to 50% of patients.^13,14

CTLA-4 is expressed predominantly on T-cells, and PD-1 may also be expressed on human hearts.¹⁵ CTLA-4 and PD-1-deficient mice develop autoimmune myocarditis or dilated cardiomyopathy, eventually leading to death due to heart failure.^15,16 However, the mechanism of ICI-induced myocarditis is still unclear. It has been hypothesized that it occurs due to a loss of the inhibitors of T-cell inactivation, leading to an autoimmune reaction secondary to the release of cardiac antigens (e.g., troponin)¹⁷ and T-cell infiltration of the myocardium. Similar T-cell clones were identified in other tissues and organs of patients treated with ICIs, generating a shared antigen hypothesis.³ As such, patients with comorbid autoimmune diseases are at increased risk,^18,19 as are those with diabetes mellitus or pre-existing cardiovascular disease.^2,18

Diagnosis of ICI-Associated Myocarditis

The onset of ICI-associated myocarditis is within 3 months of treatment initiation in 81% of cases,^2,3 with a median time of 17-65 days after the first dose of ICI.²⁰ Symptoms are non-specific and may include dyspnea, chest pain, fatigue, myalgia, palpitations, syncope, dizziness, or altered mental status. Subclinical myocarditis has also been described, posing management challenges.²¹ It is unclear whether screening for myocarditis is warranted because currently available imaging modalities are normal in the majority of patients.¹² Almost all patients will have increased serum troponin, which should immediately prompt suspicion of ICI-associated myocarditis. An electrocardiogram (ECG) should be performed to rule out an acute coronary syndrome, but findings are non-specific. It is unclear whether baseline ECG or troponins predict ICI-associated myocarditis or modify management/outcomes. Echocardiography is useful for determining cardiac function, but the definitive imaging modality is cardiac magnetic resonance (CMR), which allows for better tissue characterization. T1- and T2-weighted sequences, as well as late gadolinium enhancement sequence, may reveal myocardial inflammation or necrosis. Endomyocardial biopsy (EMB) remains the gold standard for diagnosing myocarditis. The false-negative rate for EMB remains high due to the patchy infiltration of T-cells within the myocardium; at least six samples should be collected from different endomyocardial regions, and results should be interpreted in conjunction with the results from CMR. Various T-cell phenotypes have been observed on EMB in cases of ICI-associated myocarditis. It is unclear whether outcomes differ based on these phenotypes. Further research in immune profiling may identify certain inflammation patterns and pave the way toward individualized management.

Management of ICI-Associated Myocarditis

The American Society of Clinical Oncology recently issued a practice guideline for the management of ICI-associated myocarditis.⁹ Baseline ECG and serum troponins are recommended. In all cases suspected of ICI-induced cardiotoxicity, ICI therapy should be withheld. Serum high-sensitivity cardiac troponin T (hs-cTnT) and brain natriuretic peptide should be measured. An ECG and a transthoracic echocardiogram should be performed. Further management is guided by symptoms and serum troponin levels, but patients should be admitted. In symptomatic cases, CMR and cardiac catheterization with EMB are warranted. In asymptomatic cases, we recommend CMR if hs-cTnT is >100 ng/L with no other identifiable cause; cardiac catheterization with EMB should be added if hs-cTnT is >250 ng/L based on the institutional agreed practice at The University of Texas MD Anderson Cancer Center. Ongoing research is validating this approach. If myocarditis is confirmed, serum erythrocyte sedimentation rate, C-reactive protein, C3, and C4 should be measured to guide immunosuppressive therapy going forward.²²

The severity of the myocarditis may be broadly classified into four grades with independent treatment strategies.⁹ G1 is defined as subclinical myocarditis based on an abnormal test; it is unclear whether this grade warrants specific treatments. Symptomatic but clinically stable cases with abnormal tests may be classified as G2 and G3; treatment should be attempted with 1-2 mg/kg prednisone or methylprednisolone. Decompensated cases are classified as G4 and require more aggressive immunosuppressive regimens, such as 1-2 mg/kg prednisone + mycophenolate, anti-thymocyte globulin, or infliximab (to be avoided in cases of heart failure). These cases may also require advanced heart failure support. For most immune-related adverse events, cessation of therapy is recommended for only G2 or higher, but for cardiac immune-related adverse events, the consensus statements recommend stopping at G1 due to the high mortality observed in cardiac immune-related adverse events.⁹

Conclusion

Several important challenges in the management of ICI-associated cardiotoxicity exist. The rates of mortality and major adverse cardiovascular events remain high with current treatment strategies.² Reports have emerged of therapeutic success with various immunosuppressive regimens, such as with intravenous immunoglobulins, but no clinical trials comparing the efficiency of these regimens currently exist.² Further research is warranted to evaluate response to increased doses of glucocorticoids and varying immunosuppression regimens. The benefit of EMB on all patients with suspicion of ICI-associated cardiotoxicity in cases with negative CMR is not currently well-established. Furthermore, the risks versus benefits of cardiac catheterization and EMB in high-risk patients (e.g., with thrombocytopenia) are also unclear. The possibility of ICI resumption after resolution of the myocarditis is currently based on the severity of this immune-related adverse event and perceived risks versus benefits from an oncologic perspective. These challenges highlight the compelling need for clinical vigilance for immune-related adverse events, the collaboration of oncologists and cardiologists when managing these cases, and further research.

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Keywords: Cardiotoxicity, Cardiotoxins, Acute Coronary Syndrome, Antilymphocyte Serum, Autoimmunity, Cardiac Catheterization, Biopsy, Blood Sedimentation, Cardiomyopathy, Dilated, Apoptosis Regulatory Proteins, Chest Pain, Consensus, C-Reactive Protein, CTLA-4 Antigen, Diabetes Mellitus, Dizziness, Echocardiography, Dyspnea, Electrocardiography, Gadolinium, Glucocorticoids, Heart Failure, Immunoglobulins, Intravenous, Immunosuppression, Immunosuppressive Agents, Immunotherapy, Inflammation, Magnetic Resonance Spectroscopy, Medical Oncology, Methylprednisolone, Myalgia, Myocardium, Myocarditis, Natriuretic Peptide, Brain, Neoplasms, Phenotype, Prednisone, Syncope, Takotsubo Cardiomyopathy, Thrombocytopenia, T-Lymphocytes, Cytotoxic, Troponin, Troponin T, Vasculitis, Venous Thromboembolism

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