Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis
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Published:2023-08-08
Issue:6
Volume:148
Page:473-486
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ISSN:0009-7322
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Container-title:Circulation
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language:en
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Short-container-title:Circulation
Author:
Lehmann Lorenz H.12ORCID, Heckmann Markus B.1ORCID, Bailly Guillaume3, Finke Daniel1ORCID, Procureur Adrien3ORCID, Power John R.4ORCID, Stein Frederic13, Bretagne Marie3, Ederhy Stephane5ORCID, Fenioux Charlotte3, Hamwy Omar3, Funck-Brentano Elisa6ORCID, Romano Emanuela7, Pieroni Laurence8ORCID, Münster Jan P.19ORCID, Allenbach Yves10ORCID, Anquetil Céline10, Leonard-Louis Sarah11, Palaskas Nicolas L.12ORCID, Hayek Salim S.13ORCID, Katus Hugo A.1, Giannitsis Evangelos1ORCID, Frey Norbert1, Kaya Ziya1ORCID, Moslehi JavidORCID, Prifti Edi1415ORCID, Salem Joe-Elie3ORCID, Thuny Franck, Crusz Shanthini, Asnani Aarti, Karlstaedt Anja, Rocher Fanny, Paven Elise, Obeid Michel, Chan Wei Ting, Flint Danette L, Arangalage Dimitri, Courand Pierre-Yves, Nicol Martin, Cariou Eve, Tamura Yuichi, Florido Roberta, Francis Sanjeev, Leong Darryl, Piriou Nicolas, Akhter Nausheen, Shahneen Sandhu, Itzhaki Ben Zadok Osnat, Habib Manhal, Vachhani Pankit, Peretto Giovanni, Zhu Han, Laufer Perl Michal, Aras Mandar, Alexandre Joachim, Lenneman Carrie, Levenson Joshua, Deswal Anita, Zaha Vlad G., Gaughan Elizabeth M, Ewer Steven, Johnson Douglas, Baldassarre Lauren A
Affiliation:
1. Department of Cardiology, Angiology, and Pneumology, Heidelberg University Hospital, German Centre for Cardiovascular Research DZHK, Heidelberg, Germany (L.H.L., M.B.H., D.F., F.S., J.P.M., H.A.K., E.G., N.F., Z.K.). 2. German Cancer Research Center (DKFZ), Heidelberg, Germany (L.H.L.). 3. Sorbonne Université, Assistance Publique-Hôpitaux de Paris, INSERM, Department of Pharmacology, UNICO-GRECO Cardio-oncology program, Pitié-salpétrière Hospital, Paris, France (G.B., A.P., F.S., M.B., C.F., O.H., J-E.S.). 4. University of California San Diego (J.R.P). 5. Sorbonne Université, Assistance Publique-Hôpitaux de Paris, INSERM, Department of Cardiology, UNICO-GRECO Cardio-oncology program, Saint-Antoine Hospital, Paris, France (S.E.). 6. Hopital Ambroise-Paré, Neuilly Sur Seine, France (E.F-B.). 7. Center for Cancer Immunotherapy, Department of Oncology, PSL Research University, Institut Curie, Paris, France (E.R.). 8. Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Biochimie- Hormonologie, Hôpital Tenon, Paris, France (L.P.). 9. Section of Cardio-Oncology and Immunology, Cardiovascular Research Institute, University of California San Francisco (J.P.M.). 10. Department of Internal Medicine (Y.A., C.A.), Sorbonne Université, Assistance Publique-Hôpitaux de Paris, INSERM, Hôpital Pitié-Salpêtrière, France. 11. Neuropathology (S.L-L.), Sorbonne Université, Assistance Publique-Hôpitaux de Paris, INSERM, Hôpital Pitié-Salpêtrière, France. 12. Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston (N.L.P.). 13. Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor (S.S.H.). 14. IRD, Sorbonne University, UMMISCO, Bondy, France (E.P.). 15. Sorbonne Université, INSERM NutriOmics, Paris, France (E.P.).
Abstract
BACKGROUND:
Immune checkpoint inhibitors (ICIs) are approved for multiple cancers but can result in ICI-associated myocarditis, an infrequent but life-threatening condition. Elevations in cardiac biomarkers, specifically troponin-I (cTnI), troponin-T (cTnT), and creatine kinase (CK), are used for diagnosis. However, the association between temporal elevations of these biomarkers with disease trajectory and outcomes has not been established.
METHODS:
We analyzed the diagnostic accuracy and prognostic performances of cTnI, cTnT, and CK in patients with ICI myocarditis (n=60) through 1-year follow-up in 2 cardio-oncology units (APHP Sorbonne, Paris, France and Heidelberg, Germany). A total of 1751 (1 cTnT assay type), 920 (4 cTnI assay types), and 1191 CK sampling time points were available. Major adverse cardiomyotoxic events (MACE) were defined as heart failure, ventricular arrhythmia, atrioventricular or sinus block requiring pacemaker, respiratory muscle failure requiring mechanical ventilation, and sudden cardiac death. Diagnostic performance of cTnI and cTnT was also assessed in an international ICI myocarditis registry.
RESULTS:
Within 72 hours of admission, cTnT, cTnI, and CK were increased compared with upper reference limits (URLs) in 56 of 57 (98%), 37 of 42 ([88%]
P
=0.03 versus cTnT), and 43 of 57 ([75%]
P
<0.001 versus cTnT), respectively. This increased rate of positivity for cTnT (93%) versus cTnI ([64%]
P
<0.001) on admission was confirmed in 87 independent cases from an international registry. In the Franco–German cohort, 24 of 60 (40%) patients developed ≥1 MACE (total, 52; median time to first MACE, 5 [interquartile range, 2–16] days). The highest value of cTnT:URL within the first 72 hours of admission performed best in terms of association with MACE within 90 days (area under the curve, 0.84) than CK:URL (area under the curve, 0.70). A cTnT:URL ≥32 within 72 hours of admission was the best cut-off associated with MACE within 90 days (hazard ratio, 11.1 [95% CI, 3.2–38.0];
P
<0.001), after adjustment for age and sex. cTnT was increased in all patients within 72 hours of the first MACE (23 of 23 [100%]), whereas cTnI and CK values were less than the URL in 2 of 19 (11%) and 6 of 22 (27%) of patients (
P
<0.001), respectively.
CONCLUSIONS:
cTnT is associated with MACE and is sensitive for diagnosis and surveillance in patients with ICI myocarditis. A cTnT:URL ratio <32 within 72 hours of diagnosis is associated with a subgroup at low risk for MACE. Potential differences in diagnostic and prognostic performances between cTnT and cTnI as a function of the assays used deserve further evaluation in ICI myocarditis.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
13 articles.
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