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Electrocardiographic Manifestations of Immune Checkpoint Inhibitor Myocarditis
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Abstract
Abstract Importance Immune-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. Objectives To describe ECG findings in ICI-myocarditis, compare them to ACR, and evaluate their prognostic significance. Design Cases 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. Setting 49 medical centers spanning 11 countries. Participants 147 adults with ICI-myocarditis, 50 adults with ACR. Exposure Myocarditis 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. Outcomes All-cause mortality, myocarditis-related mortality; and composite endpoint (defined as myocarditis-related mortality and life-threatening ventricular arrhythmia). Results Of 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). Conclusions ICI-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. NCT NCT04294771 Key Points Question What 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? Findings ICI-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. Meaning ICI-associated myocarditis is a highly arrhythmogenic cardiomyopathy. Ventricular arrhythmias, conduction disorders, low-voltage, and pathological Q-waves are associated with a poor prognosis.
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“Pathological Q waves, low QRS voltage, and a low Sokolow-Lyon index on ECG carry a poor prognosis for patients.”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [233]
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Metadata
- Authors
- Power, J. R., Alexandre, J., Choudhary, A., Ozbay, B., Hayek, S., Asnani, A., Tamura, Y., Aras, M., Cautela, J., Thuny, F., Gilstrap, L., Arangalage, D., Ewer, S., Huang, S., Deswal, A., Palaskas, N. L., Finke, D., Lehmann, L., Ederhy, S., Moslehi, J., Salem, J.-E., Abbar, B., Allenbach, Y., Azam, T. U., Baik, A., Baldassarre, L. A., Baroudjian, B., Blakley, P., Brodsky, S., Chahine, J., Chan, W.-T., Copeland, A., Crusz, S. M., Dy, G., Fenioux, C., Ghafourian, K., Ghosh, A. K., Gounant, V., Guha, A., Habib, M., Zadok, O. I. B., Lin, L. K., Laufer-Perl, M., Lenneman, C., Leong, D., Martini, M., Meheghan, T., Mervoyer, E., Monge, C., Morimoto, R., Narezkina, A., Nicol, M., Nowatzke, J., Orimoloye, O. A., Patel, M., Perry, D., Piriou, N., Piro, L., Moran, T., Stringer, B., Tajiri, K., Vachhani, P., Warner, E., & Zimmer, M.-C.
- Affiliations
- UC San Diego Health System (US)
- Université de Caen Normandie (FR)
- Beth Israel Deaconess Medical Center (US)
- Basaksehir Cam and Sakura State Hospital, Istanbul, Turkey (B.O.).
- University of Michigan (US)
- Mita Hospital (JP)
- University of California, San Francisco (US)
- Assistance Publique Hôpitaux de Marseille (FR)
- Dartmouth–Hitchcock Medical Center (US)
- Hôpital Bichat-Claude-Bernard (FR)
- University of Wisconsin–Madison (US)
- Vanderbilt University Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Université Paris Cité (FR)
- Heidelberg University (DE)
- Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France (S. Ederhy, J.-E.S.).
- Sorbonne Université (FR)
- ORCID
- Alexandre, Joachim
- Ozbay, Benay
- Hayek, Salim
- Asnani, Aarti
- Tamura, Yuichi
- Cautela, Jennifer
- Thuny, Franck
- Arangalage, Dimitri
- Deswal, Anita
- Palaskas, Nicolas L.
- Lehmann, Lorenz
- Ederhy, Stephane
- Salem, Joe-Elie
- Abbar, Baptiste
- Allenbach, Yves
- Baroudjian, Barouyr
- Crusz, Shanthini M.
- Fenioux, Charlotte
- Ghosh, Arjun K.
- Nicol, Martin
- Orimoloye, Olusola Ayodeji
- Piriou, Nicolas
- Venue
- Circulation
- Published
- 2021-11-02
- Volume
- 144
- Issue
- 18
- Pages
- 1521-1523
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC8567307
- OpenAlex
- W3134649264
- Cited by
- 136
- References
- 39
- Citations by year
- 2026: 23 · 2025: 33 · 2024: 25 · 2023: 31 · 2022: 24
- FWCI
- 7.29
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-12-06)
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- medRxiv (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL AMU (submittedVersion, other-oa)
- HAL (submittedVersion)
- Funders
- Bristol-Myers Squibb
- AstraZeneca
- Regeneron Pharmaceuticals
- Cytokinetics
- Audentes Therapeutics
- Servier
- Ipsen
- National Institutes of Health (UL1TR000445, TR000445)
- Japan Society for the Promotion of Science (18K08183)
- National Heart, Lung, and Blood Institute (R01HL153384, R01HL141466, R01HL156021, R01HL155990)
- National Center for Advancing Translational Sciences (TR-000445)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Infectious Diseases › Viral Infections and Immunology Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Chemotherapy-induced cardiotoxicity and mitigation
- Keywords
- immune checkpoint inhibitor-associated myocarditis, electrocardiographic findings, immune checkpoint inhibitors, cardiotoxicity, cardiac arrhythmias
- MeSH terms
- Immune Checkpoint Inhibitors, Aged, Electrocardiography, Female, Humans, Male, Middle Aged, Myocarditis, Retrospective Studies
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