Electrocardiographic features of immune checkpoint inhibitor-associated

: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events including myocarditis, whilst improving cancer-related outcomes. There is thus a clinical need to identify electrocardiographic manifestations of ICI-related myocarditis to guide clinical management. PubMed was searched for clinical studies and case reports describing electrocardiographic changes in patients with ICI-related myocarditis. A total of 6 clinical studies and 79 case reports were included. This revealed a range of presentations for patients on ICIs, including supraventricular arrhythmias, ventricular arrhythmias

Abstract: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events including myocarditis, whilst improving cancer-related outcomes.There is thus a clinical need to identify electrocardiographic manifestations of ICI-related myocarditis to guide clinical management.PubMed was searched for clinical studies and case reports describing electrocardiographic changes in patients with ICI-related myocarditis.A total of 6 clinical studies and 79 case reports were included.This revealed a range of presentations for patients on ICIs, including supraventricular arrhythmias, ventricular arrhythmias and heart block, and new changes of ST-T segment unrelated to coronary artery disease, ST-segment elevation or depression and T-wave abnormalities.Several patients showed low voltages in multiple leads and new onset Q-wave development.Patients with ICI-related myocarditis may develop new arrhythmia and ST-T changes, and infrequently low voltages in multiple leads.(Curr Probl Cardiol 2022;48:101478.)

Background
& T he development of immune checkpoint inhibitors (ICIs) repre- sents a significant breakthrough in tumor therapy.Despite showing better efficacy than traditional anticancer agents, the use of ICIs can lead to potentially life-threatening immune-related adverse events, including cardiovascular complications such as myocarditis. 7,70,72,103ICI-induced myocarditis is rare, with an estimated incidence ranging from 0.1% to 1%.Previous findings have showed that ICI-related myocarditis usually occurs in the early stage of ICI treatment and could deteriorate rapidly with a fatality rate up to 30-50%. 31Therefore, it is necessary to ensure early identification and diagnosis of myocarditis in patients receiving ICIs.
Recent reports have demonstrated the involvement of the cardiac conduction system, which can lead to cardiac arrhythmias 72 and have a negative impact on the prognosis of the patients.Since electrocardiogram (ECG) is a simple, noninvasive and cheap investigation, it could be used as a first line screen tool for cardiovascular abnormalities in ICI users.Therefore, in this systematic review, we will summarize the electrocardiographic characteristics of patients with ICI-related myocarditis and hope to provide early recognition to this potentially fatal complication.
comprehensive clinical manifestations and laboratory tests, etc.; (2) standard 12-lead electrocardiogram was provided; (3) for clinical studies, patients were identified as suffering from ICI-related myocarditis with the provision of ECG findings; (4) publication in English language.References which were in line with the criteria were also included.The following details were extracted from each study: age, sex, type of malignant tumor and ICIs.

Electrocardiographic evaluation
For clinical studies, the ECG findings and characteristic changes in patients with ICI myocarditis were extracted by 2 cardiologists, and cross-validated.Similarly, for case reports, the standard 12-lead ECG provided were analyzed by 2 cardiologists independently, with any disagreements resolved by a third cardiologist.

Statistical analysis
The baseline characteristics and ECG findings were expressed as frequency and proportion.Continuous variables were provided as median or mean values.
The electrocardiogram findings are shown in Table 2.A total of 86 patients had new changes in ECG compared to the baseline.The manifestations described were arrhythmias, conduction block, ST-T changes, Twave abnormalities, new onset Q-wave, and low voltages in multiple leads.Arrhythmias were more common in patients with ICI-related myocarditis and can be manifested as supraventricular and ventricular arrhythmias.For supraventricular arrhythmias, the commonest type was sinus tachycardia (12.09%), of which one patient had transient atrial fibrillation during hospitalization.In addition, there were 5 cases of atrial fibrillation or flutter and one case of sinus arrest followed by atrial fibrillation.It should be noted that among the case studies included, 6 patients developed ventricular tachycardia (Fig 2 ).Of these, one patient was in critical condition, developing atrial fibrillation and high-degree atrioventricular block.In addition, premature atrial contractions (n = 3) and In addition, new onset Q-wave was observed in one patient in an absence of coronary artery lesions from coronary angiography.Rarely, low voltages in multiple leads were observed (n = 3), which was infrequently associated with pericardial effusion.Only 5 patients showed no significant dynamic changes in their ECG when compared to their baseline ECG (Table 2).

Clinical studies
A total of 6 clinical studies were included, all of which were retrospective studies.No prospective clinical studies were identified.One study was published in 2018, two studies in 2020 and three studies in 2021.Two studies were retrospectively analyzed and reported by a single center, with a relatively small sample size.Of the other four studies, the largest consisted of 140 patients with ICI-related myocarditis matched with 179 ICI users without myocarditis.In this study, the type of tumor was not limited, and it was found that the duration of QRS was closely related to MACE development.Another study suggests that patients with ICIrelated myocarditis had a faster heart rate, longer QRS and QTc durations on the ECG compared to those without myocarditis.One case-control study including patients with ICI-related myocarditis explored the effects of intensified immunosuppressive therapy (IIST) on the clinical outcome of patients.Previous studies have found that patients who need IIST tend  ECG, electrocardiography.ICI, immune checkpoint inhibitor.MACE, major adverse cardiac events.
Curr Probl Cardiol, 2022 to have worse overall condition and higher incidence of arrhythmias and malignant cardiovascular events (Table 3).

Discussion
ICIs restore the immune response of CD8+ and CD4+T cells to cancerous tissues by blocking the inhibitory effects of ligand-receptor interactions and have improved the quality of life and survival of patients with many different cancers.However, their immune-related adverse events (IrAEs) affecting different organ systems cannot be neglected. 19,76,90,101ICI-related cardiovascular toxicity includes myocarditis, pericarditis, arrhythmia, heart failure, vasculitis and venous thromboembolism. 14,24,43,51,55,87,99,102ICI-associated myocarditis is characterized by acute inflammation of the myocardium and may show electrophysiological abnormalities such as ventricular arrhythmias, pulseless electrical activity or complete atrioventricular block, which can progress to acute heart failure or sudden death. 50,72he underlying mechanism may be related to T-cell-mediated cytotoxicity involving the cardiac conduction system.Histological studies have shown that ICI-mediated cardiomyocyte necrosis is characterized by infiltration of CD4+ and CD8+T cells, similar to the development of acute cardiac rejection after transplantation. 31,46Lymphocyte infiltration can involve sinoatrial node and atrioventricular node, especially in patients with new-onset bifascicular block and first degree heart block during ICI treatment, reflecting conduction abnormalities across the atrioventricular node or at more distal parts of the conduction system, with a high risk of progression into complete atrioventricular block. 92Clinically, patients with complete atrioventricular block and ventricular arrhythmias are often in critical condition with increased mortality.Indeed, ICIrelated myocarditis is associated with a fatality rate of 30%-50%, 31 and thus continuous monitoring of vital signs, cardiac status and ECGs for such patients is needed.
In this study, previously reported cases of ICI-related myocarditis were systematically searched and the ECG findings were summarized.Amongst the 91 patients included, sinus arrhythmias (mostly sinus tachycardia, about 12.09%), atrial fibrillation/atrial flutter, ventricular arrhythmias (including ventricular extrasystole and ventricular tachycardia), heart conduction block, new ST-T abnormalities, T-wave changes, low voltages and new onset Q-waves were detected.Previous clinical studies have reported that ICI-related myocarditis may be associated with ECG changes, mostly arrhythmias.The incidence of ICI-related atrial arrhythmias is about 1%-3%, of which atrial fibrillation is more common; the incidence of ventricular arrhythmias is about 5%-10%, and is associated with 40% mortality. 40,57However, the incidence of complete atrioventricular block is unclear.Power et al. found that nearly 7.5% of patients with ICI-related myocarditis have second degree atrioventricular block and 17% have complete atrioventricular block. 67Of the above ECG changes, the incidence of heart block was the highest (about 58.24%),where complete atrioventricular block accounted for 20.88%, followed by right bundle branch block (19.78%).
In addition, we found that ICI-related myocarditis may present with ST-T segment changes unrelated related to coronary artery disease.In this study, 32.97% of the patients had new ST-T changes, excluding vascular lesions after coronary angiography, which could return to normal after high-dose hormone immunosuppressive therapy.Furthermore, some nonspecific changes can also be seen in patients with ICI myocarditis, such as multilead low voltage, which may be associated with large pericardial effusion or cardiomyopathy; In addition, there was another patient whose electrocardiogram showed new Q-waves, which ruled out coronary artery disease after coronary angiography.Maybe the appearance of Q-waves was also related to the involvement of ICI related conduction system.
Finally, it is reported that ICI myocarditis usually occurs in the early stage of ICI treatment.Moslehi et al. retrospectively analyzed 101 cases of ICI-associated myocarditis in Vigibase, a pharmacovigilance database by WHO designed to identify drug-associated adverse events.64% of the patients developed myocarditis after the first or second administration of ICI.The average onset time of myocarditis was 27 days (5-155 days), and 76% occurred in the first six weeks of treatment.Another prospective study of 35 cases of ICI-associated myocarditis from eight centers found that 81% of ICI-associated myocarditis occurred within the first 4 cycles (from the median of 34 days at the beginning of treatment). 50,59In their study, the median time from when the first initiation of ICI to myocarditis occurred was 21 days, which was consistent with the previous findings.Patients may have asymptomatic or develop nonspecific symptoms such as progressive fatigue, muscle soreness or weakness, palpitations, chest pain, presyncope, or syncope, shortness of breath and edema.In severe cases, cardiogenic shock or sudden death may occur.Cardiovascular symptoms may be masked or co-present by other irAEs (such as myositis, pneumonia, and hypothyroidism) or lung symptoms associated with malignant tumors or complications.

Limitations and future directions
Some limitations of this study should be recognized.First of all, the case reports included in this study are all from PubMed, and the clinical information available is limited, and the ECG quality of some cases was variable.Second, this study is a retrospective collection of published case reports and clinical studies, there is a specific selection bias.Finally, publication time and attending institutions are different, especially the case reports, diagnosis and treatment programs are different.
By searching the previously published case reports and clinical studies on the changes of ECG in patients with ICI myocarditis, this study emphasizes the feasibility of early identification of ICI-myocarditis using the ECG, which may allow early treatment to improve prognosis.However, the specific physiological mechanism of the disease is not clear and needs to be further explored.Second, most of the clinical reports published are retrospective, and the sample size is relatively small.In the future, clinical studies with a larger sample size are needed to further clarify the ECG manifestations of patients with ICI-related myocarditis.

Conclusion
Myocarditis is a common cardiovascular complication in patients treated with ICIs.The electrocardiogram of patients with ICI-related myocarditis may show new arrhythmias and ST-T changes, and a few patients may show low voltages on multiple leads.A small number of patients had no symptoms and no apparent ECG abnormalities.Monitoring is essential because of its high mortality, with early identification potentially allowing prompt treatment to improve patients' prognosis.

Sources of funding
The work was funded by Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-029A).

FIG 1 .
FIG 1. Flow diagram of the study selection process.

FIG 3 .
FIG 3. ECG reproduced from Bukamur et al. with permission. 11An 88-year-old woman with squamous cell carcinoma of the lung admitted to hospital 2 cycles after treatment with nivolumab, and during her hospital stay, she developed complete atrioventricular block as seen in the electrocardiogram.

TABLE 1 .
Clinical characteristics of the patients included in this meta-analysis ICI, immune checkpoint inhibitor; ICD, implantable cardioverter defibrillator; IABP, intra-aortic balloon pump; ECMO, extracorporeal membrane oxygenation; NA, not available.*Two cases did not report the time from the administration of ICI to the date of diagnosis of ICI myocarditis, n = 89.

TABLE 2 .
Electrocardiographic findings of patients included in this meta-analysis ), or complete atrioventricular block (n = 1).Interestingly, one patient had a first electrocardiogram showed left bundle branch block, followed by right bundle branch block several days later.Finally, ST-T changes unrelated to coronary artery disease were reported in ICI-related myocarditis, with ST segment elevation found in 19 cases, ST segment depression in five patients and T-wave inversion in 6 patients.
FIG 2. ECG reproduced from Yogasundaram et al. with permission. 95A 69-year-old man with metastatic castration-resistant prostate cancer admitted to hospital 74 days after treatment with pembrolizumab, and the electrocardiogram demonstrated bidirectional accelerated idioventricular rhythm with the alternating QRS axis.Retrograde p waves are best visualized in lead V1.

TABLE 3 .
Summary of clinical studies included in this review