Association of early electrical changes with cardiovascular outcomes in immune checkpoint inhibitor myocarditis

Power, John R.; Alexandre, Jonas; Choudhary, Arrush; Özbay, Benay; Hayek, Salim S.; Asnani, Aarti; Tamura, Yuichi; Aras, Mandar A.; Cautela, Jennifer; Thuny, Franck; Gilstrap, Lauren; Arangalage, Dimitri; Ewer, Steven M.; Huang, Shi; Deswal, Anita; Palaskas, Nicolas; Finke, Daniel; Lehmann, Lorenz; Éderhy, Stéphane; Moslehi, Javid; Salem, Joe‐Elie

doi:10.1016/j.acvd.2022.03.003

Cited by 12 publications

(19 citation statements)

References 34 publications

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“…4,5 ICI myocarditis often presents concurrently with other myotoxicities, including symptomatic myositis (≈30% to 35% of the time), and may lead to fatal respiratory muscle failure. [4][5][6][7][8][9] Mechanistically, ICI myocarditis is associated with macrophage and T-cell infiltration into muscles and associated myocyte death. [10][11][12][13] Diagnosing ICI myocarditis is challenging, and a combination of biomarkers, cardiac imaging, and endomyocardial biopsy is needed to confirm the diagnosis.…”

Section: Lehmann Et Almentioning

confidence: 99%

“…In the index Franco-German cohort, cTnT was measured in 1751 samples (n=60 patients with ≥1 measurement), cTnI in 920 samples (n=55 [7][8][9][10][11][12][13][14][15][16][17][18][19][20], and 21 (IQR, 14-39), respectively. For a detailed outline of the different assays used and their individual characteristics, including limit of detection, 10% coefficient of variation, 99th and 95th percentiles (for troponins and CK, respectively), and upper reference limit (URL) of normal population values, refer to Table S2.…”

Section: Measurement Of Cardiac and Muscular Circulating Biomarkersmentioning

confidence: 99%

“…We assessed (as previously described in other cardiac prevalent diseases) [23][24][25][26][27][28][29] whether ICI myocarditis was associated with the presence of anti-cTnI antibodies, potentially interfering with cTnI assays. Sera samples (242 in total; n=7 per patient [IQR,[4][5][6][7][8][9][10][11]) from all patients prospectively included at APHP Sorbonne (n=29 patients) 15 were used to detect circulating anti-cTnI immunoglobulin M (IgM) or immunoglobulin G (IgG) during the course of their care. Ninety-six well plates were coated with anti-cTnI diluted in coating buffer (0.1 M NaHCO 3 :34 mM Na 2 CO 3 ; pH, 9.5) and then incubated overnight at 4 °C.…”

Section: Determination Of Ctni Circulating Auto-antibody Titersmentioning

confidence: 99%

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Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis

Lehmann,

Heckmann,

Bailly

et al. 2023

Circulation

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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 comprising 13 countries. 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.

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Section: Lehmann Et Almentioning

confidence: 99%

Section: Measurement Of Cardiac and Muscular Circulating Biomarkersmentioning

confidence: 99%

Section: Determination Of Ctni Circulating Auto-antibody Titersmentioning

confidence: 99%

See 1 more Smart Citation

Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis

Lehmann,

Heckmann,

Bailly

et al. 2023

Circulation

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“…(3)(4)(5)(6)(7) Clinical suspicion for ICI-myocarditis often arises after associated symptoms and increases in cardiac biomarkers (troponins) or electrocardiographic alterations. (3,(8)(9)(10) Endomyocardial biopsy is the gold-standard for establishing the diagnosis, (10,11) while cardiac magnetic resonance imaging (cMRI) and echocardiography may be misleadingly normal especially early in the clinical course. (10,12,13) Other forms of myotoxicity often accompany myocarditis and these include peripheral myositis, which can affect respiratory muscles or mimic myastheniagravis-like syndrome.…”

Section: Introductionmentioning

confidence: 99%

Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis

et al. 2023

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Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and is highly fatal. We report the results of a strategy that included identification of individuals with severe ICI-myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with CTLA4-fusion protein abatacept and the Janus-kinase inhibitor ruxolitinib. Forty cases with definite ICI-myocarditis were included with pathological confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. Abatacept dose was adjusted using CD86-receptor occupancy on circulating monocytes. Myotoxicity-related fatality rate was 3.4%(1/30) in these 30 patients vs.60% in 1st quartile(p<0.0001). These clinical results are hypothesis-generating and need further evaluation.

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“…This prompted our further examining the concomitance of coronary artery disease (CAD) with ICB-myocarditis and the implications of revascularization and outcomes for such patients; data are currently lacking with this question. We utilised an international ICBmyocarditis registry, previously described [9,10], to better understand the outcomes of patients presenting with clinically suspected ICB-myocarditis and the effect of undergoing acute coronary revascularization on outcomes.…”

Section: Introductionmentioning

confidence: 99%

Coronary artery disease and revascularization associated with immune checkpoint blocker myocarditis: Report from an international registry

Nowatzke¹,

Guedeney²,

Palaskas³

et al. 2022

European Journal of Cancer

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Association of early electrical changes with cardiovascular outcomes in immune checkpoint inhibitor myocarditis

Cited by 12 publications

References 34 publications

Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis

Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis

Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis

Coronary artery disease and revascularization associated with immune checkpoint blocker myocarditis: Report from an international registry

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