Electrocardiographic Manifestations of Immune Checkpoint Inhibitor Myocarditis
Authors: Power John R , Alexandre Joachim , Choudhary Arrush , Ozbay Benay , Hayek Salim , Asnani Aarti , Tamura Yuichi , Aras Mandar , Cautela Jennifer , Thuny Franck , Gilstrap Lauren , Arangalage Dimitri , Ewer Steven , Huang Shi , Deswal Anita , Palaskas Nicolas L. , Finke Daniel , Lehman Lorenz , Ederhy Stephane , Moslehi Javid , Salem Joe-Elie 
Published: March 2021

AbstractImportanceImmune-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.ObjectivesTo describe ECG findings in ICI-myocarditis, compare them to ACR, and evaluate their prognostic significance.DesignCases 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.Setting49 medical centers spanning 11 countries.Participants147 adults with ICI-myocarditis, 50 adults with ACR.ExposureMyocarditis 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.OutcomesAll-cause mortality, myocarditis-related mortality; and composite endpoint (defined as myocarditis-related mortality and life-threatening ventricular arrhythmia).ResultsOf 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<.001; 3.40[1.38-8.33],p=0.008; 2.20[0.95-5.12],p=0.07; respectively) but inversely associated with Sokolow-Lyon Index (HR(sh)/mV=0.57[0.34-0.94],p=0.03; HR(sh)=0.54[0.30-0.97],p=0.04; 0.50[0.30-0.85],p=0.01; respectively). The composite outcome was also associated with conduction disorders on presenting ECG (HR(sh)=3.27[1.29-8.34],p=0.01).ConclusionsICI-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.NCTNCT04294771Key PointsQuestionWhat 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?FindingsICI-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.MeaningICI-associated myocarditis is a highly arrhythmogenic cardiomyopathy. Ventricular arrhythmias, conduction disorders, low-voltage, and pathological Q-waves are associated with a poor prognosis.