Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy.

AIMS: Cardiac immune-related adverse events (irAEs) from immune checkpoint inhibition (ICI) targeting programmed death 1 (PD1) are of growing concern. Once cardiac irAEs become clinically manifest, fatality rates are high. Cardio-oncology aims to prevent detrimental effects before manifestation of severe complications by targeting early pathological changes. We therefore aimed to investigate early consequences of PD1 inhibition for cardiac integrity to prevent the development of overt cardiac disease. METHODS AND RESULTS: We investigated cardiac-specific consequences from anti-PD1 therapy in a combined biochemical and in vivo phenotyping approach. Mouse hearts showed broad expression of the ligand PDL1 on cardiac endothelial cells as a main mediator of immune-crosstalk. Using a novel melanoma mouse model, we assessed that anti-PD1 therapy promoted myocardial infiltration with CD4+ and CD8+ T cells, the latter being markedly activated. Left ventricular (LV) function was impaired during pharmacological stress, as shown by pressure-volume catheterization. This was associated with a dysregulated myocardial metabolism, including the proteome and the lipidome. Analogous to the experimental approach, in patients with metastatic melanoma (n = 7) receiving anti-PD1 therapy, LV function in response to stress was impaired under therapy. Finally, we identified that blockade of tumour necrosis factor alpha (TNFα) preserved LV function without attenuating the anti-cancer efficacy of anti-PD1 therapy. CONCLUSIONS: Anti-PD1 therapy induces a disruption of cardiac immune homeostasis leading to early impairment of myocardial functional integrity, with potential prognostic effects on the growing number of treated patients. Blockade of TNFα may serve as an approach to prevent the manifestation of ICI-related cardiotoxicity.

PD1 Deficiency Modifies Cardiac Immunity during Baseline Conditions and in Reperfused Acute Myocardial Infarction.

The programmed cell death protein 1 (PD1) immune checkpoint prevents inflammatory tissue damage by inhibiting immune reactions. Understanding the relevance of cardiac PD1 signaling may provide new insights into the inflammatory events under baseline conditions and disease. Here, we demonstrate distinct immunological changes upon PD1 deficiency in healthy hearts and during reperfused acute myocardial infarction (repAMI). In PD1-deficient mice, upregulated inflammatory cytokines were identified under baseline conditions including cardiac interleukins and extracellular signal-related kinase 1/2 (ERK1/2). A murine in vivo repAMI model to determine inflammatory changes in the early phase showed downregulation of the ligand PDL1, paralleled by an endothelial injury, indicated by loss of the CD31 signal. Immunofluorescence imaging showed decreased PDL1 expression specifically in the infarct zone, highlighting an involvement in PDL1 in myocardial injury response. Pharmacological depletion of PD1 prior to repAMI did not alter the area of infarction but led to increased numbers of CD8+ T cells in treated mice. We conclude that PD1/PDL1 signaling plays a significant role in healthy hearts and repAMI, emphasizing the relevance of adaptive immunity during myocardial injury. The findings highlight the risk for adverse outcomes from acute myocardial infarction in the growing group of patients receiving immune checkpoint inhibitor therapy.

Sublingual microcirculatory assessment on admission independently predicts the outcome of old intensive care patients suffering from shock.

Shock is a life-threatening condition. This study evaluated if sublingual microcirculatory perfusion on admission is associated with 30-day mortality in older intensive care unit (ICU) shock patients. This trial prospectively recruited ICU patients (≥ 80 years old) with arterial lactate above 2 mmol/L, requiring vasopressors despite adequate fluid resuscitation, regardless of shock cause. All patients received sequential sublingual measurements on ICU admission (± 4 h) and 24 (± 4) hours later. The primary endpoint was 30-day mortality. From September 4th, 2022, to May 30th, 2023, 271 patients were screened, and 44 included. Patients were categorized based on the median percentage of perfused small vessels (sPPV) into those with impaired and sustained microcirculation. 71% of videos were of good or acceptable quality without safety issues. Patients with impaired microcirculation had significantly shorter ICU and hospital stays (p = 0.015 and p = 0.019) and higher 30-day mortality (90.0% vs. 62.5%, p = 0.036). Cox regression confirmed the independent association of impaired microcirculation with 30-day mortality (adjusted hazard ratio 3.245 (95% CI 1.178 to 8.943, p = 0.023). Measuring sublingual microcirculation in critically ill older patients with shock on ICU admission is safe, feasible, and provides independent prognostic information about outcomes.Trial registration NCT04169204.