Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor‐associated lethal myocarditis in mice
Abstract 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 resu...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-04-01
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| Series: | ESC Heart Failure |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ehf2.14614 |
| _version_ | 1797242837282062336 |
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| author | Nestor Rubio‐Infante Elena Cristina Castillo Hugo Alves‐Figueiredo Martin Ramos‐González Felipe Salazar‐Ramírez Daniel Salas‐Treviño Adolfo Soto‐Domínguez Omar Lozano Gerardo García‐Rivas Guillermo Torre‐Amione |
| author_facet | Nestor Rubio‐Infante Elena Cristina Castillo Hugo Alves‐Figueiredo Martin Ramos‐González Felipe Salazar‐Ramírez Daniel Salas‐Treviño Adolfo Soto‐Domínguez Omar Lozano Gerardo García‐Rivas Guillermo Torre‐Amione |
| author_sort | Nestor Rubio‐Infante |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-24T18:45:34Z |
| format | Article |
| id | doaj.art-a73fc44d8437499999922c4692b270e3 |
| institution | Directory Open Access Journal |
| issn | 2055-5822 |
| language | English |
| last_indexed | 2024-04-24T18:45:34Z |
| publishDate | 2024-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | ESC Heart Failure |
| spelling | doaj.art-a73fc44d8437499999922c4692b270e32024-03-27T06:48:04ZengWileyESC Heart Failure2055-58222024-04-011121249125710.1002/ehf2.14614Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor‐associated lethal myocarditis in miceNestor Rubio‐Infante0Elena Cristina Castillo1Hugo Alves‐Figueiredo2Martin Ramos‐González3Felipe Salazar‐Ramírez4Daniel Salas‐Treviño5Adolfo Soto‐Domínguez6Omar Lozano7Gerardo García‐Rivas8Guillermo Torre‐Amione9Tecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud San Pedro Garza García MexicoTecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud San Pedro Garza García MexicoTecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud San Pedro Garza García MexicoTecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud San Pedro Garza García MexicoTecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud San Pedro Garza García MexicoDepartamento de Histología, Facultad de Medicina Universidad Autónoma de Nuevo León Monterrey MexicoDepartamento de Histología, Facultad de Medicina Universidad Autónoma de Nuevo León Monterrey MexicoTecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud San Pedro Garza García MexicoTecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud San Pedro Garza García MexicoTecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud San Pedro Garza García MexicoAbstract 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.https://doi.org/10.1002/ehf2.14614Heart damageHeart failureImmune checkpoint inhibitorsInflammationMyocarditis |
| spellingShingle | Nestor Rubio‐Infante Elena Cristina Castillo Hugo Alves‐Figueiredo Martin Ramos‐González Felipe Salazar‐Ramírez Daniel Salas‐Treviño Adolfo Soto‐Domínguez Omar Lozano Gerardo García‐Rivas Guillermo Torre‐Amione Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor‐associated lethal myocarditis in mice ESC Heart Failure Heart damage Heart failure Immune checkpoint inhibitors Inflammation Myocarditis |
| title | Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor‐associated lethal myocarditis in mice |
| title_full | Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor‐associated lethal myocarditis in mice |
| title_fullStr | Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor‐associated lethal myocarditis in mice |
| title_full_unstemmed | Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor‐associated lethal myocarditis in mice |
| title_short | Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor‐associated lethal myocarditis in mice |
| title_sort | previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor associated lethal myocarditis in mice |
| topic | Heart damage Heart failure Immune checkpoint inhibitors Inflammation Myocarditis |
| url | https://doi.org/10.1002/ehf2.14614 |
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