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2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS).

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Immune-checkpoint inhibitors (ICI) have revolutionized cancer therapy but are associated with infrequent but lethal myocarditis, for which management remains uncertain. Abatacept, a CTLA-4 fusion protein targeting CD86 on antigen presenting cells and leading to global T-cell anergy, has been described as a potential treatment in individual reports. Yet, abatacept treatment dosage, schedule and optimal combination with other immunosuppressive therapies are unclear. We describe a 25-year-old man who developed pembrolizumab (anti-PD1)-induced myocarditis 14 days after first injection for thymoma treatment, which deteriorated into cardiogenic shock, with sustained ventricular arrhythmia, requiring urgent extracorporeal life support implantation, despite prompt initiation of corticosteroids and mycophenolate-mofetil. Using a strategy of serial measurement ensuring with a target of >80% CD86 receptor occupancy on circulating monocytes, abatacept dose was adjusted and combined with ruxolitinib and methylprednisolone. This strategy resulted in high-dose of abatacept: 60 mg/kg in three doses (20 mg/kg each) within the first 10 days, followed by two doses. Clinical improvement occurred within 7 days, with resolution of systolic cardiac dysfunction, and ventricular arrhythmias resulting in successful discharge from hospital. We reversed a case of nearly lethal ICI-myocarditis, using specific patient-dose adjusted abatacept, which may serve as basis for personalized treatment of patients with severe ICI-adverse events. Trial registration number: NCT04294771.

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Reversal of immune-checkpoint inhibitor fulminant myocarditis using personalized-dose-adjusted abatacept and ruxolitinib: proof of concept

Over the last decade or so, there has been a paradigm shift in the oncologic care of patients with a range of solid tumour and haematologic malignancies, away from traditional cytotoxic chemotherapy and towards personalized cancer treatments, using both targeted therapy and immunotherapy. This shift has contributed to the remarkable and sustained increase in the number of cancer survivors and the longevity of patients with a cancer diagnosis. This review will focus on the cardiovascular effects of immune checkpoint inhibitors and will present a background on immune checkpoint inhibition for cancer, the epidemiology, potential mechanisms, the potential insights into cardiovascular biology, and a diagnostic and therapeutic approach to potential cases. Our understanding of the cardiovascular effects of immune checkpoint inhibitors needs to improve. However, the evolution necessarily needs to be rapid. Initial observations noted that immune checkpoint inhibitor therapy can lead to a fulminant myocarditis. Recent reports have expanded the effect of immune checkpoint inhibitor therapy on the cardiovascular system to include an increase in cardiac dysfunction without myocarditis, arrhythmias, venous thromboembolic disease, accelerated atherosclerosis, and atherosclerosis-related cardiovascular events. The association between immune checkpoint inhibitor therapy and an increase in these cardiovascular events is not only limited to events occurring within the first few weeks after starting therapy but can also include events that occur months to years after therapy. The latter observation is especially of relevance in those treated with adjuvant or neoadjuvant therapy. There needs to be a shift from recognition of an increase in cardiovascular events to currently approved immune checkpoint inhibitor therapies to understanding the mechanisms that lead to adverse cardiovascular effects, understanding who is at risk, and understanding what we can do about it.

Cardiovascular complications of immune checkpoint inhibitors for cancer.

The field of inflammatory disease of the heart or “cardio-immunology” is rapidly evolving due to the wider use of non-invasive diagnostic tools able to detect and monitor myocardial inflammation. In acute myocarditis, recent data on the use of immunomodulating therapies have been reported both in the setting of systemic autoimmune disorders and in the setting of isolated forms, especially in patients with specific histology (e.g., eosinophilic myocarditis) or with an arrhythmicburden. A role for immunosuppressive therapies has been also shown in severe cases of coronavirus disease 2019 (COVID-19), a condition that can be associated with cardiac injury and acute myocarditis. Furthermore, ongoing clinical trials are assessing the role of high dosage methylprednisolone in the context of acute myocarditis complicated by heart failure or fulminant presentation or the role of anakinra to treat patients with acute myocarditis excluding patients with hemodynamically unstable conditions. In addition, the explosion of immune-mediated therapies in oncology has introduced new pathophysiological entities, such as immune-checkpoint inhibitor-associated myocarditis and new basic research models to understand the interaction between the cardiac and immune systems. Here we provide a broad overview of evolving areas in cardio-immunology. We summarize the use of new imaging tools in combination with endomyocardial biopsy and laboratory parameters such as high sensitivity troponin to monitor the response to immunomodulating therapies based on recent evidence and clinical experience. Concerning pericarditis, the normal composition of pericardial fluid has been recently elucidated, allowing to assess the actual presence of inflammation; indeed, normal pericardial fluid is rich in nucleated cells, protein, albumin, LDH, at levels consistent with inflammatory exudates in other biological fluids. Importantly, recent findings showed how innate immunity plays a pivotal role in the pathogenesis of recurrent pericarditis with raised C-reactive protein, with inflammasome and IL-1 overproduction as drivers for systemic inflammatory response. In the era of tailored medicine, anti-IL-1 agents such as anakinra and rilonacept have been demonstrated highly effective in patients with recurrent pericarditis associated with an inflammatory phenotype.

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Immunomodulating Therapies in Acute Myocarditis and Recurrent/Acute Pericarditis

Importance Immune-checkpoint inhibitor (ICI)-myocarditis often presents with arrhythmias, but electrocardiographic (ECG) findings have not been well described. ICI-myocarditis and acute cellular rejection (ACR) following cardiac transplantation share similarities on histopathology; however, whether they differ in arrhythmogenicity is unclear. Objectives To describe ECG findings in ICI-myocarditis, compare them to ACR, and evaluate their prognostic significance. Design Cases of ICI-myocarditis were retrospectively identified through a multicenter network. Grade 2R or 3R ACR was retrospectively identified within one center. Two blinded cardiologists interpreted ECGs. Setting 49 medical centers spanning 11 countries. Participants 147 adults with ICI-myocarditis, 50 adults with ACR. Exposure Myocarditis after ICI exposure per European Society of Cardiology criteria for clinically suspected myocarditis, grade 2R or 3R ACR per the International Society for Heart and Lung Transplantation working formulation for biopsy diagnosis of rejection. Outcomes All-cause mortality, myocarditis-related mortality; and composite endpoint (defined as myocarditis-related mortality and life-threatening ventricular arrhythmia). Results Of 147 patients, the median age was 67 years (58-77) with 92 (62.6%) men. At 30 days, ICI-myocarditis had an all-cause mortality of 39/146(26.7%), myocarditis-related mortality of 24/146(16.4%), and composite endpoint of 37/146(25.3%). All-cause mortality was more common in patients who developed complete heart block (12/25[48%] vs 27/121[22.3%], hazard ratio (HR)=2.62, 95% confidence interval [1.33-5.18],p=0.01) or life-threatening ventricular arrhythmias (12/22[55%] vs 27/124[21.8%], HR=3.10 [1.57-6.12],p=0.001) within 30 days after presentation. Compared to ACR, patients with ICI-myocarditis were more likely to experience life-threatening ventricular arrhythmias (22/147 [16.3%] vs 1/50 [2%];p=0.01) or third-degree heart block (25/147 [17.0%] vs 0/50 [0%];p=0.002). In ICI-myocarditis, overall mortality, myocarditis-related mortality, and composite outcome adjusted for age and sex were associated with pathological Q-waves on presenting ECG (hazard ratio by subdistribution model [HR(sh)]=5.98[2.8-12.79],p Conclusions ICI-myocarditis has more life-threatening arrhythmias than ACR and manifests as decreased voltage, conduction disorders, and repolarization abnormalities. Ventricular tachycardias, complete heart block, low-voltage, and pathological Q-waves were associated with adverse outcomes. NCT NCT04294771 Key Points Question What are the electrocardiographic manifestations of immune checkpoint inhibitor (ICI)-associated myocarditis? How do they compare to acute cellular rejection (ACR), which is resembling pathophysiologically to ICI-myocarditis? Which electrocardiographic features are associated with adverse outcomes? Findings ICI-myocarditis results in more frequent ventricular arrhythmias and high-degree atrioventricular blocks compared to ACR. Prolonged QRS intervals, decreased voltage, conduction disorders, and pathological Q-waves are predictors of adverse outcomes in ICI-associated myocarditis. Meaning ICI-associated myocarditis is a highly arrhythmogenic cardiomyopathy. Ventricular arrhythmias, conduction disorders, low-voltage, and pathological Q-waves are associated with a poor prognosis.

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Electrocardiographic Manifestations of Immune Checkpoint Inhibitor Myocarditis

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Benay Ozbay

Papers

Electrocardiographic Manifestations of Immune Checkpoint Inhibitor Myocarditis

Electrocardiographic Manifestations of Immune Checkpoint Inhibitor Myocarditis.