VISTA, a next-generation immune checkpoint: expression in heart failure and cardiovascular safety of inhibition

V-domain immunoglobulin suppressor of T cell activation (VISTA) is a next-generation immune checkpoint currently undergoing extensive clinical testing. However, data on cardiovascular safety are unavailable. Beyond T cells, VISTA influences innate immune responses and shows maximum inhibitory activity in acidic environments. This coincides with key characteristics of acutely ischemic myocardium, highlighting the importance of evaluating cardiovascular safety.

To characterize myocardial VISTA expression in human heart failure and to evaluate the cardiovascular safety of VISTA inhibition in healthy mice and in a model of acute ischemic cardiac injury.

Myocardial tissue was obtained at heart transplantation from patients with ischemic and non-ischemic heart failure. In a screening cohort, n = 7 samples per group were analysed, followed by validation in 80 failing hearts. Non-failing control myocardium (n = 6) was obtained from organ donors whose hearts were not transplanted for technical reasons. Myocardial expression of selected co-inhibitory immune checkpoints, with a focus on VISTA, was quantified by Western blot analysis and correlated with available clinical and functional parameters. In vivo safety was assessed in aged C57BL/6 mice and in an isoprenaline-induced type 2 myocardial infarction model. Healthy mice received anti-VISTA or isotype control antibody for 4 weeks. In the ischemia model, injury was induced by isoprenaline, with anti-VISTA or isotype control antibody administered before, during and after injury. Cardiac function was assessed by echocardiography, strain analysis, and electrocardiography, and myocardial injury was assessed by histology.

In failing human myocardium, PD-L1 expression was increased, and VISTA expression was uniformly reduced across both ischemic and non-ischemic heart failure. Myocardial PD-L1 correlated with cardiac function (vs LVEF: r = -0.403, p = 0.002), whereas VISTA expression showed no association with cardiac function, structure, or hemodynamic parameters (vs LVEF: r = 0.016, p = 0.904) in the overall cohort. In aged healthy mice, VISTA inhibition did not alter cardiac structure or systolic function compared with controls (LVEF: 61.52 ± 10.04 vs 61.14 ± 8.28 %, p = 0.994). Following pharmacological cardiac ischemia, VISTA inhibition did not exacerbate myocardial injury or functional impairment. Histological analysis demonstrated no increase in infarct extent or inflammatory cell infiltration compared with control animals.

Despite reduced myocardial VISTA expression in heart failure, this was not associated with cardiac dysfunction. VISTA inhibition did not induce adverse cardiac effects in healthy or acutely injured hearts in vivo. These findings address an important gap in cardio-oncology and support further evaluation of VISTA as a next-generation immune checkpoint target.