Inhibition of the programmed death protein 1 immune checkpoint and the development of heart failure in the presence of prior cardiac ischaemia.

Gergely, Tamás G and Drobni, Zsófia D and Kovács, Tamás and Sayour, Nabil V and Tóth, Viktória E and Kocsis, Márton S and Onódi, Zsófia and Mórotz, Gábor M and Kovács, Andrea and Zlotoff, Daniel A and Gilman, Hannah K and Gong, Jingyi and Fekete, Nóra and Pállinger, Éva and Buzás, Edit I and Yousif, Laura I and Meijers, Wouter C and Merkely, Béla and Reynolds, Kerry L and Ferdinandy, Péter and Neilan, Tomas G and Varga, Zoltán V (2026) Inhibition of the programmed death protein 1 immune checkpoint and the development of heart failure in the presence of prior cardiac ischaemia. CARDIOVASCULAR RESEARCH, 122 (8). pp. 1055-1069. ISSN 0008-6363

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Abstract

AIMS Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, their use often leads to cardiovascular adverse effects, including cardiac dysfunction. Here, we hypothesized that a prior cardiac ischaemic injury could exacerbate cardiac dysfunction due to anti-programmed death protein 1 (PD-1) treatment. Furthermore, we investigated whether abatacept, a T-cell costimulation blocker, could ameliorate the ICI-induced cardiotoxicity in a pre-clinical model. METHODS AND RESULTS In a pre-clinical study, mice were treated with isoprenaline or control to induce reversible cardiac ischaemia. After 16 weeks of follow-up, recovery of cardiac function was confirmed via echocardiography, and mice from both groups were randomly treated with isotype control, anti-PD-1, or anti-PD-1 combined with abatacept, for 2 further weeks. Mice with prior ischaemic injury and anti-PD-1 treatment showed cardiac dysfunction with increased infiltration of T cells and macrophages and elevated expression of pro-inflammatory cytokines. Conversely, cardiac dysfunction and inflammation were less pronounced after anti-PD-1 treatment in mice without prior ischaemic injury. Mice with concomitant abatacept treatment exhibited normal cardiac function and alleviated pro-inflammatory response. In a parallel single-centre retrospective clinical cohort study, 1671 cancer patients receiving PD-1 inhibitors were analysed. Cases were defined as patients who developed incident heart failure (HF) after ICI initiation with a primary aim to test whether pre-existing ischaemic heart disease was associated with an increased risk for HF development post-ICI therapy. Sensitivity analyses included propensity score matching and comparison with non-ICI-treated cancer patients. Among ICI-treated patients, 109 (6.5%) developed HF over a median follow-up of 332 days. Multivariable logistic regression of the matched population showed increased odds of incident HF in patients with prior ischaemic cardiac events (odds ratio 2.11, 95% confidence interval 1.05-4.2, P = 0.033). CONCLUSION In mice, induction of cardiac inflammation and dysfunction by anti-PD-1 therapy was potentiated by prior transient ischaemic cardiac injury, which was ameliorated by abatacept cotreatment. Cancer patients with pre-existing ischaemic heart disease may be at greater risk for developing ICI-induced new-onset HF. Based on our findings, cardiac surveillance should be considered in patients starting ICI therapy with a prior history of ischaemic heart disease.

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