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Peer-reviewedCC BY-NC-ND 4.0JACC: CardioOncology

Inflammatory Cell Profiles in Early- and Late-Manifestation Immune Checkpoint Inhibitor Myocarditis

  • Kazuaki Maruyama1
  • Yudai Tamura2
  • Shiro Nakamori3
  • Kazuko Tajiri4,5
  • Hirofumi Tomita6
  • Koichiro Kinugawa7
  • Ryota Morimoto8
  • Hiroshi Akazawa9
  • Toshihiro Tsuruda10
  • Michiro Maruyama11
  • Yuichi Miyake12
  • Hiroaki Kawano13
5 more authors
  • Michiaki Hiroe1,14
  • Kaoru Dohi3
  • Kyoko Imanaka-Yoshida1,3
  • Issei Komuro15,16
  • Yuichi Tamura2,15
16 affiliations
  1. 1Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan
  2. 2Pulmonary Hypertension Center, International University of Health and Welfare Mita Hospital, Tokyo, Japan
  3. 3Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan
  4. 4Department of Cardiology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan
  5. 5Department of Cardiology, National Cancer Center Hospital East, Kashiwa, Japan
  6. 6Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
  7. 7The Second Department of Internal Medicine, University of Toyama, Toyama, Japan
  8. 8Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
  9. 9Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  10. 10Department of Hemo-Vascular Advanced Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
  11. 11Department of Cardiology, Toyama Prefectural Central Hospital, Toyama, Japan
  12. 12Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine Kagawa University, Kagawa, Japan
  13. 13Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  14. 14Department of Cardiology, National Center for Global Health and Medicine, Tokyo, Japan
  15. 15International University of Health and Welfare School of Medicine, Tokyo, Japan
  16. 16Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Abstract

Background: Immune checkpoint inhibitor (ICI) myocarditis typically develops soon after treatment initiation (<90 days) but may also occur as a delayed complication after discontinuation of ICI therapy. The clinical and histopathologic differences between early- and late-manifestation ICI myocarditis remain unclear.

Objectives: This study sought to compare the clinical features and myocardial histopathology of early- versus late-manifestation ICI myocarditis.

Methods: We conducted a retrospective national cohort study of patients diagnosed with myocarditis after ICI initiation who underwent endomyocardial biopsy. Biopsy samples were analyzed for inflammatory cell infiltration, severity of myocardial inflammation, and collagen volume fraction.

Results: Among 35 patients (mean age: 66 ± 13 years; 71.4% male), 26 (74.3%) developed early-manifestation myocarditis (<90 days), whereas 9 (25.7%) had late-manifestation myocarditis (≥90 days). Early-manifestation cases showed significantly more severe myocardial inflammation; higher levels (median [Q1-Q3]) of CD3+ T cells (432 [173-1,381] vs 121 [43-400] cells/mm2; P = 0.036), CD8+ T cells (289 [73-994] vs 86 [21-168] cells/mm2; P = 0.019), and CD 68+ macrophages (307 [116-841] vs 57 [36-200] cells/mm2; P = 0.008); and higher CD4+ T-cell levels that did not reach statistical significance (P = 0.054). There were no significant differences in regulatory T cells or collagen volume. Clinically, early-manifestation myocarditis was characterized by higher cardiac biomarker levels and older age, whereas left ventricular ejection fraction was similar between groups. Mortality due to myocarditis occurred in 2 early-manifestation cases and in no late-manifestation cases. Conversely, cancer-related mortality was more frequent in the late-manifestation group (n = 3) than in the early-manifestation group (n = 2). ICI therapy was reinitiated in only 2 patients overall.

Conclusions: Late-manifestation ICI myocarditis may represent a temporally distinct or partially attenuated inflammatory phase. Despite a milder inflammatory profile, higher cancer-related mortality was observed, suggesting that cautious ICI reinitiation may warrant consideration in selected patients within this subgroup.

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Cite

BibTeXRIS
BibTeX
@article{maruyama2026inflammatory,
  title = {{Inflammatory Cell Profiles in Early- and Late-Manifestation Immune Checkpoint Inhibitor Myocarditis}},
  author = {Kazuaki Maruyama and Yudai Tamura and Shiro Nakamori and Kazuko Tajiri and Hirofumi Tomita and Koichiro Kinugawa and Ryota Morimoto and Hiroshi Akazawa and Toshihiro Tsuruda and Michiro Maruyama and Yuichi Miyake and Hiroaki Kawano and Michiaki Hiroe and Kaoru Dohi and Kyoko Imanaka-Yoshida and Issei Komuro and Yuichi Tamura},
  journal = {JACC: CardioOncology},
  year = {2026},
  month = aug,
  doi = {10.1016/j.jaccao.2026.07.008},
  url = {https://doi.org/10.1016/j.jaccao.2026.07.008},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Inflammatory Cell Profiles in Early- and Late-Manifestation Immune Checkpoint Inhibitor Myocarditis
AU  - Kazuaki Maruyama
AU  - Yudai Tamura
AU  - Shiro Nakamori
AU  - Kazuko Tajiri
AU  - Hirofumi Tomita
AU  - Koichiro Kinugawa
AU  - Ryota Morimoto
AU  - Hiroshi Akazawa
AU  - Toshihiro Tsuruda
AU  - Michiro Maruyama
AU  - Yuichi Miyake
AU  - Hiroaki Kawano
AU  - Michiaki Hiroe
AU  - Kaoru Dohi
AU  - Kyoko Imanaka-Yoshida
AU  - Issei Komuro
AU  - Yuichi Tamura
PY  - 2026
DA  - 2026/08/05
JO  - JACC: CardioOncology
DO  - 10.1016/j.jaccao.2026.07.008
UR  - https://doi.org/10.1016/j.jaccao.2026.07.008
AB  - Background: Immune checkpoint inhibitor (ICI) myocarditis typically develops soon after treatment initiation (<90 days) but may also occur as a delayed complication after discontinuation of ICI therapy. The clinical and histopathologic differences between early- and late-manifestation ICI myocarditis remain unclear.  Objectives: This study sought to compare the clinical features and myocardial histopathology of early- versus late-manifestation ICI myocarditis.  Methods: We conducted a retrospective national cohort study of patients diagnosed with myocarditis after ICI initiation who underwent endomyocardial biopsy. Biopsy samples were analyzed for inflammatory cell infiltration, severity of myocardial inflammation, and collagen volume fraction.  Results: Among 35 patients (mean age: 66 ± 13 years; 71.4% male), 26 (74.3%) developed early-manifestation myocarditis (<90 days), whereas 9 (25.7%) had late-manifestation myocarditis (≥90 days). Early-manifestation cases showed significantly more severe myocardial inflammation; higher levels (median [Q1-Q3]) of CD3+ T cells (432 [173-1,381] vs 121 [43-400] cells/mm2; P = 0.036), CD8+ T cells (289 [73-994] vs 86 [21-168] cells/mm2; P = 0.019), and CD 68+ macrophages (307 [116-841] vs 57 [36-200] cells/mm2; P = 0.008); and higher CD4+ T-cell levels that did not reach statistical significance (P = 0.054). There were no significant differences in regulatory T cells or collagen volume. Clinically, early-manifestation myocarditis was characterized by higher cardiac biomarker levels and older age, whereas left ventricular ejection fraction was similar between groups. Mortality due to myocarditis occurred in 2 early-manifestation cases and in no late-manifestation cases. Conversely, cancer-related mortality was more frequent in the late-manifestation group (n = 3) than in the early-manifestation group (n = 2). ICI therapy was reinitiated in only 2 patients overall.  Conclusions: Late-manifestation ICI myocarditis may represent a temporally distinct or partially attenuated inflammatory phase. Despite a milder inflammatory profile, higher cancer-related mortality was observed, suggesting that cautious ICI reinitiation may warrant consideration in selected patients within this subgroup.
SN  - 2666-0873
ER  -