Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor-associated lethal myocarditis in mice
© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology..
AIMS: Immune checkpoint inhibitors (ICIs) are antineoplastic drugs designed to activate the immune system's response against cancer cells. Evidence suggests that they may lead to immune-related adverse events, particularly when combined (e.g., anti-CTLA-4 plus anti-PD-1), sometimes resulting in severe conditions such as myocarditis. We aimed to investigate whether a previously sustained cardiac injury, such as pathological remodelling due to hypertension, is a prerequisite for ICI therapy-induced myocarditis.
METHODS: We evaluated the cardiotoxicity of ICIs in a hypertension (HTN) mouse model (C57BL/6). Weekly doses were administered up to day 21 after the first administration. Our analysis encompassed the following parameters: (i) survival and cardiac pathological remodelling, (ii) cardiac function assessed using pressure-volume (PV)-loops, with brain natriuretic peptide (BNP) serving as a marker of haemodynamic dysfunction and (iii) cardiac inflammation (cytokine levels, infiltration, and cardiac antigen autoantibodies).
RESULTS: After the first administration of ICI combined therapy, the treated HTN group showed a 30% increased mortality (P = 0.0002) and earlier signs of hypertrophy and pathological remodelling compared with the untreated HTN group. BNP (P = 0.01) and TNF-α (<0.0001) increased 2.5- and 1.7-fold, respectively, in the treated group, while IL-6 (P = 0.8336) remained unchanged. Myocarditis only developed in the HTN group treated with ICIs on day 21 (score >3), characterised by T cell infiltration and increased cardiac antigen antibodies (86% showed a titre of 1:160). The control group treated with ICI was unaffected in any evaluated feature.
CONCLUSIONS: Our findings indicate that pre-existing sustained cardiac damage is a necessary condition for ICI-induced myocarditis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
ESC heart failure - 11(2024), 2 vom: 01. März, Seite 1249-1257 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rubio-Infante, Nestor [VerfasserIn] |
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| Links: |
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| Themen: |
Heart damage |
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| Anmerkungen: |
Date Completed 28.03.2024 Date Revised 29.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/ehf2.14614 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM365403393 |
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| 245 | 1 | 0 | |a Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor-associated lethal myocarditis in mice |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. | ||
| 520 | |a AIMS: Immune checkpoint inhibitors (ICIs) are antineoplastic drugs designed to activate the immune system's response against cancer cells. Evidence suggests that they may lead to immune-related adverse events, particularly when combined (e.g., anti-CTLA-4 plus anti-PD-1), sometimes resulting in severe conditions such as myocarditis. We aimed to investigate whether a previously sustained cardiac injury, such as pathological remodelling due to hypertension, is a prerequisite for ICI therapy-induced myocarditis | ||
| 520 | |a METHODS: We evaluated the cardiotoxicity of ICIs in a hypertension (HTN) mouse model (C57BL/6). Weekly doses were administered up to day 21 after the first administration. Our analysis encompassed the following parameters: (i) survival and cardiac pathological remodelling, (ii) cardiac function assessed using pressure-volume (PV)-loops, with brain natriuretic peptide (BNP) serving as a marker of haemodynamic dysfunction and (iii) cardiac inflammation (cytokine levels, infiltration, and cardiac antigen autoantibodies) | ||
| 520 | |a RESULTS: After the first administration of ICI combined therapy, the treated HTN group showed a 30% increased mortality (P = 0.0002) and earlier signs of hypertrophy and pathological remodelling compared with the untreated HTN group. BNP (P = 0.01) and TNF-α (<0.0001) increased 2.5- and 1.7-fold, respectively, in the treated group, while IL-6 (P = 0.8336) remained unchanged. Myocarditis only developed in the HTN group treated with ICIs on day 21 (score >3), characterised by T cell infiltration and increased cardiac antigen antibodies (86% showed a titre of 1:160). The control group treated with ICI was unaffected in any evaluated feature | ||
| 520 | |a CONCLUSIONS: Our findings indicate that pre-existing sustained cardiac damage is a necessary condition for ICI-induced myocarditis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Heart damage | |
| 650 | 4 | |a Heart failure | |
| 650 | 4 | |a Immune checkpoint inhibitors | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a Myocarditis | |
| 650 | 7 | |a Immune Checkpoint Inhibitors |2 NLM | |
| 700 | 1 | |a Castillo, Elena Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Alves-Figueiredo, Hugo |e verfasserin |4 aut | |
| 700 | 1 | |a Ramos-González, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Salazar-Ramírez, Felipe |e verfasserin |4 aut | |
| 700 | 1 | |a Salas-Treviño, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Soto-Domínguez, Adolfo |e verfasserin |4 aut | |
| 700 | 1 | |a Lozano, Omar |e verfasserin |4 aut | |
| 700 | 1 | |a García-Rivas, Gerardo |e verfasserin |4 aut | |
| 700 | 1 | |a Torre-Amione, Guillermo |e verfasserin |4 aut | |
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