Abstract Body (Do not enter title and authors here): BACKGROUND:
Although immune checkpoint inhibitor (ICI) myocarditis typically occurs soon after initiating checkpoint therapy (<90 days), it can also arise as a delayed complication even after discontinuation of ICI therapy. However, the clinical and histopathological characteristics between early- and late-onset ICI myocarditis have not been fully understood.

METHODS:
We conducted a retrospective national cohort study by collecting endomyocardial biopsy samples and clinical information from patients with a clinical diagnosis of myocarditis after ICI initiation. Biopsy samples were analyzed to assess myocyte injury, fibrosis, fat replacement, and inflammatory cell migration.

RESULTS:
Among 35 patients (mean age, 66 yrs; 25 males) who underwent endomyocardial biopsy, 26 (74%) had early-onset (<90 days) ICI myocarditis. These cases showed more severe cardiomyocyte injury, higher levels of CD3+T cells (median 432 vs. 121 cells/mm², p=0.03), CD8+T cells (289 vs. 86 cells/mm², p=0.02), and CD 68+ macrophages (307 vs. 57 cells/mm², p=0.008), and a trend towards higher CD4+T cells expression (p=0.05), contrasting with 9 (26%) patients with late-onset (≥90 days) ICI myocarditis. There were no significant differences in regulatory T cells, collagen volume, and fat replacement. Early-onset ICI myocarditis was clinically characterized by higher cardiac biomarkers, lower QRS voltage, and a trend toward older age and lower BMI, compared to late-onset cases. However, left ventricular ejection fraction was similar in both groups. Two (8%) of the 26 patients with early-onset myocarditis died, in contrast to none in those with late-onset myocarditis. ICI therapy was re-initiated in only 2 (6%) patients overall. Notably, cancer-related mortality following myocarditis was more frequent in the late-onset group (33%) than in the early-onset group (8%). The ASCO clinical grading scale correlated with cardiomyocyte injury, but did not accurately reflect the severity of inflammatory cell invasion.

CONCLUSIONS:
Our analysis of endomyocardial biopsy specimens revealed distinct differences in the severity of myocardial injury and inflammatory cell profiles between early- and late-onset ICI myocarditis, underscoring the need for time-of-onset-specific management strategies. The late-onset group demonstrated milder inflammation yet experienced higher cancer-related mortality, suggesting that cautious ICI re-initiation may be a viable and potentially beneficial option for this subgroup.