Recurrent Myocardial Injury Leads to Disease Tolerance in a Murine Model of Stress-Induced Cardiomyopathy

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

“…Supporting our hypothesis that previous damage is a prerequisite for developing myocarditis, we tested it in immunocompetent conditions. In line with our hypothesis, a recent study conducted in PD‐1 knockout mice found that repetitive neurohormonal stress increased mortality, hypertrophy, left ventricular dysfunction, and T‐cell infiltration 20 . On the other hand, the A/J mice strain, which possesses an MHC haplotype susceptible to myocarditis 21 and complement C5 deficiency, developed myocarditis after ICI treatment without any additional stimulus 11 .…”

Recurrent Adrenergic Stress Provokes Persistent Myocarditis in PD-1–Deficient Mice

“…As shown by the Kaplan Meier curves in Figure 1B , there were no deaths in the ISO primed /ISO injury WT mice, consistent with our prior observations with ISO-induced preconditioning in WT mice. 9 In sharp contrast, there was a statistically significant ( P = 0.008) decrease in survival in the ISO primed /ISO injury PD-1 −/− mice when compared with ISO primed /ISO injury WT mice. Similar findings with respect to ISO-induced lethality were observed in male PD-1 −/− mice ( Supplemental Figure 3A ).…”

“…Relative to baseline values, there were no significant differences in the number of influxing neutrophils in the WT ( P = 0.37) and PD-1 −/− mice ( P = 0.071) on day 1 after the high-dose ISO injection, consistent with our prior observations with ISO-induced preconditioning ( Figure 3A ). 9 However, on day 35, the number of Ly6G + neutrophils in the ISO primed /ISO injury PD-1 −/− mice was significantly increased ( P = 0.002) relative to ISO primed /ISO injury WT mice ( Figure 3A ). In contrast, there were no significant differences between ISO primed /ISO injury WT and PD-1 −/− mice with respect to the number of Ly6C high CD64 low monocytes ( P = 0.11 by 2-way ANOVA) ( Figure 3B ), CD64 + Ly6C low/− macrophages ( P = 0.12 by 2-way ANOVA) ( Figure 3C ), CD4 + T cells ( P = 0.76 by 2-way ANOVA) ( Figure 3D ), or CD19 + B cells ( P = 0.19 by 2-way ANOVA) ( Figure 3F ), in accordance with our prior observations with ISO-induced preconditioning.…”

“…There were no changes in the heart weight-to-tibia length ratio in the ISO primed /ISO injury WT mice compared with baseline, in agreement with our prior observations with ISO-induced preconditioning in WT mice. 9

Figure 2 Characterization of ISO primed /ISO injury WT and PD-1 −/− Mice (A) Representative photographs of ISO primed /ISO injury whole hearts at baseline and on days 1, 3, 7, 14, and 35 (scale bar = 1 cm) after high-dose ISO injury. (B) Heart weight-to-tibia length ratios at baseline and on days 1, 3, 7, 14, and 35 (n = 8-17 mice per group per time).

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“… 8 In subsequent studies, we demonstrated that ISO-mediated tissue injury and inflammation protected the heart from the myopathic effects of a recurrent challenge with ISO in WT mice, including decreased cardiac myocyte necrosis, reduced myocardial inflammation, preserved LV structure and function, and increased survival. 9 Intriguingly, the ISO-mediated cytoprotective effects were abolished by depleting macrophages and dendritic cells using clodronate, 9 suggesting that repetitive tissue injury leads to nonspecific innate immune cell–mediated protection against recurrent tissue injury (ie, trained innate immunity). 10 To further explore the role of the PD-1 signaling axis in the context of recurrent myocardial tissue injury, we performed repetitive ISO-mediated neurohormonal stress in PD-1–deficient (PD-1 −/− ) mice.…”