학술논문
Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor-associated lethal myocarditis in mice.
Document Type
Academic Journal
Author
Rubio-Infante N; Tecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud, San Pedro Garza García, Mexico.; Castillo EC; Tecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud, San Pedro Garza García, Mexico.; Tecnologico de Monterrey, Institute for Obesity Research, Hospital Zambrano Hellion, TecSalud, San Pedro Garza García, Mexico.; Alves-Figueiredo H; Tecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud, San Pedro Garza García, Mexico.; Ramos-González M; Tecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud, San Pedro Garza García, Mexico.; Salazar-Ramírez F; Tecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud, San Pedro Garza García, Mexico.; Salas-Treviño D; Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, Mexico.; Soto-Domínguez A; Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, Mexico.; Lozano O; Tecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud, San Pedro Garza García, Mexico.; Tecnologico de Monterrey, Institute for Obesity Research, Hospital Zambrano Hellion, TecSalud, San Pedro Garza García, Mexico.; García-Rivas G; Tecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud, San Pedro Garza García, Mexico.; Tecnologico de Monterrey, Institute for Obesity Research, Hospital Zambrano Hellion, TecSalud, San Pedro Garza García, Mexico.; Torre-Amione G; Tecnologico de Monterrey, Cátedra de Cardiología y Medicina Vasular, Escuela de Medicina y Ciencias de la Salud, San Pedro Garza García, Mexico.; The Methodist Hospital, Cornell University, Houston, Texas, USA.
Source
Publisher: John Wiley & Sons Ltd on behalf of the European Society of Cardiology Country of Publication: England NLM ID: 101669191 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2055-5822 (Electronic) Linking ISSN: 20555822 NLM ISO Abbreviation: ESC Heart Fail Subsets: MEDLINE
Subject
Language
English
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.
(© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)
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.
(© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)