Asymptomatic and Symptomatic Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: Insights from a Japanese Registry

Background and Aims Immune checkpoint inhibitors (ICIs) are a cornerstone of cancer therapy; however, immune-related adverse events, including myocarditis, pose significant challenges. Furthermore, limited data exist on the pathology of mild or asymptomatic cases. This study aimed to characterize the clinical, biomarker, and pathological features of ICI-associated cardiac toxicity, comparing symptomatic and asymptomatic cases within a Japanese multicenter registry. Methods A nationwide, retrospective registry collected data from 90 patients across 23 hospitals between 2020 and 2022. Patients were classified according to the American Society of Clinical Oncology Clinical Practice Guidelines: Grade 1 (asymptomatic) and Grade 2–4 (symptomatic). Endomyocardial biopsy was performed in 24 patients (n=19 symptomatic, n=5 asymptomatic). Results Among the enrolled patients (mean age: 68 years; 76.7% male), 41.1% were classified as Grade 1, whereas 58.9% were symptomatic (Grade 2–4). Symptomatic cases exhibited significantly higher troponin I and creatine kinase levels at onset. Pathological analysis revealed more extensive lymphocytic infiltration (CD3+ T cells) in symptomatic cases, particularly with higher CD8+ and CD68+ cell counts. Continuation of ICI therapy was more frequent in the asymptomatic group, and only one patient experienced recurrence. In contrast, all seven myocarditis-related deaths occurred in symptomatic patients. Conclusions This study provides one of the largest pathological and biomarker-based comparisons of symptomatic and asymptomatic ICI-associated cardiac toxicity. Our findings suggest that asymptomatic cases may represent a distinct, less aggressive inflammatory phenotype, characterized by lower CD8+ infiltration and limited myocardial damage.