Inhibition of the PD-1 immune checkpoint and the development of heart failure in the presence of prior cardiac ischemia

AIMS: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment. However, their use often leads to cardiovascular adverse effects, including cardiac dysfunction. Here, we hypothesized that a prior cardiac ischemic injury could exacerbate cardiac dysfunction due to anti-PD-1 treatment. Furthermore, we investigated whether abatacept, a T-cell co-stimulation blocker, could ameliorate the ICI-induced cardiotoxicity in a preclinical model. METHODS AND RESULTS: In a preclinical study, mice were treated with isoprenaline or control to induce reversible cardiac ischemia. 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 two further weeks. Mice with prior ischemic 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 ischemic injury. Mice with concomitant abatacept treatment exhibited normal cardiac function and alleviated pro-inflammatory response.In a parallel single-center retrospective clinical cohort study, 1,671 cancer patients receiving PD-1 inhibitors were analyzed. Cases were defined as patients who developed incident HF after ICI initiation with a primary aim to test whether pre-existing ischemic 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 ischemic cardiac events (OR 2.11 95%, CI 1.05-4.2, p=0.033). CONCLUSION: In mice, induction of cardiac inflammation and dysfunction by anti-PD1 therapy was potentiated by prior transient ischemic cardiac injury, which was ameliorated by abatacept co-treatment. Cancer patients with pre-existing ischemic 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 ischemic heart disease.