Human platelet‐mediated transfer of cardioprotection by remote ischemic conditioning is abrogated by aspirin, but not by ticagrelor

Background Repeated ischemia/reperfusion in a tissue/organ remote from the heart (remote ischemic conditioning, RIC) protects against injury from sustained myocardial ischemia/reperfusion (I/R). Platelets are considered as mediators/targets of RIC´s protection. We have recently reported that infusion of washed platelets, taken from healthy volunteers after RIC, reduced infarct size (IS) in isolated rat hearts (FASEB Journal 2021; 35; S1; DOI: 10.1096/fasebj.2021.35.S1.03444). Anti‐platelet drugs are potential confounders of RIC. Aim To study the impact of anti‐platelet drugs, the cyclooxygenase inhibitor aspirin and the P2Y 12 inhibitor ticagrelor, on the platelet‐mediated transfer of cardioprotection. Methods We included 18 healthy volunteers. As a contemporary control, volunteers were subjected to RIC through 3 x 5 min blood pressure cuff inflation at 200 mmHg on the left upper arm/ 5 min deflation. After at least 2 weeks, these volunteers were again subjected to RIC 3 hours after pretreatment with oral aspirin (500‐1000 mg) and again at least another 2 weeks later 2 hours after pretreatment with oral ticagrelor (180 mg). Venous blood samples were taken before RIC and 60 min after RIC, respectively. Washed platelets were prepared using apyrase, prostaglandin E 1 and citrated Tyrode‐buffer. The platelet count was adjusted to 2.5 x 10 5 platelets/µL. The functionality of washed platelets was tested in response to thrombin (1U/ml), aggregation measured with turbodimetric light transmission aggregometry and expressed as the increase in light transmission in percent of control. Platelet preparations with an aggregation <60% were discarded. Male Lewis rats were sacrificed, their hearts isolated and perfused at constant pressure with buffer. Washed platelets before and after RIC, respectively, were infused for 8 min (2.5 x 10 4 platelets/µL) into rat hearts before global 30 min/ 120 min I/R. IS was demarcated by triphenyl tetrazolium chloride staining and calculated in percent of ventricular mass. Results We confirm, that infusion of platelets after RIC reduces IS in isolated hearts with global I/R (Figure). This platelet‐mediated transfer of cardioprotection was abrogated by aspirin‐pretreatment of the volunteers (Figure). Platelets before RIC from ticagrelor‐pretreated volunteers reduced IS per se; nevertheless, platelets after RIC further reduced IS (Figure). Conclusion Human platelets serve as carriers for RIC’s cardioprotective signal through an aspirin‐sensitive and thus cyclooxygenase‐dependent mechanism. The P2Y 12 inhibitor ticagrelor per se induces a cardioprotective platelet‐dependent signal, which is further enhanced by RIC. The precise signal transfer from the platelets to the myocardium and the nature of the platelet‐derived factors remain to be further identified.