Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor-associated lethal myocarditis in mice

Rubio-Infante, Nestor; Castillo, Elena Cristina; Alves-Figueiredo, Hugo; Ramos-Gonzalez, Martin; Salazar-Ramirez, Felipe; Salas-Trevino, Daniel; Soto-Dominguez, Adolfo; Lozano, Omar; Garcia-Rivas, Gerardo; Torre-Amione, Guillermo

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-alpha (<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.

Más información

Título según WOS: ID WOS:001113741800001 Not found in local WOS DB
Título de la Revista: ESC HEART FAILURE
Volumen: 11
Número: 2
Editorial: WILEY PERIODICALS, INC
Fecha de publicación: 2024
Página de inicio: 1249
Página final: 1257
DOI:

10.1002/ehf2.14614

Notas: ISI