https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Essen Institut für Pathophysiologie Essen, Deutschland
Background:
Microvascular injury impairs myocardial perfusion after interventional reperfusion therapy for acute myocardial infarction and determines the prognosis of patients - independent of the infarct size. Currently, however, no therapies are available that specifically target microvascular injury during acute myocardial ischemia/reperfusion injury. While red blood cells (RBCs) contribute to microvascular obstruction and thrombus formation, experimental studies suggest they may also mediate cardioprotection. Repeated blood flow restriction and reperfusion in a tissue/organ remote from the heart (remote ischemic conditioning, RIC) reduce myocardial I/R injury. RIC induces a release of cardioprotective humoral factors, i.e., cardioprotection is transferable from one species to an isolated perfused heart of another species via plasma-dialysates or isolated platelets. Whether or not RBCs, as integral players in microvascular physiology, also mediate RIC’s cardioprotective effects and target the microvascular injury during I/R remains unknown.
Methods:
Healthy volunteers (3 females, 10 males, 27±5 years) underwent RIC, induced by 3 cycles of 5-minute blood pressure cuff inflations (200 mmHg) and 5-minute deflations on the left upper arm. Venous blood samples (30 mL each) were taken before and 60 minutes after RIC. Plasma-dialysates (12-14 kDa cut-off, 1:10 saline buffer dialysis for 24 h) were prepared to control for RIC’s humoral cardioprotective transfer. RBCs were isolated and washed 5 times with saline buffer. Undiluted plasma-dialysates or RBCs (5x10⁴/mL) before/after RIC were infused into isolated, perfused rat hearts for 8 minutes, followed by a 2-minute washout, then subjected to 30 minutes of left anterior descending coronary artery occlusion and 120 minutes of reperfusion. Saline infusion before I/R served as control. Thioflavin-S was infused to demarcate microvascular obstruction (Thioflavin-S negative areas, no-reflow) before demarcating the area at risk via patent blue infusion. Infarct size and microvascular obstruction were calculated as a percentage of the area at risk (means±standard deviations).
Results:
Infarct size was 45±9%, and no-reflow was 9±4% with saline infusion. Plasma-dialysate infusion before RIC (43±5%, 9±3%) resulted in a comparable infarct size. Plasma-dialysate after RIC reduced infarct size to 34±8%, confirming prior studies. Plasma-dialysate after RIC, however, had no impact on no-reflow (9±4%). Compared to saline and dialysate-plasma before RIC, RBCs before RIC reduced infarct size per se to 34±11%, confirming prior studies. RBCs before RIC had also no impact on no-reflow (12±6%). The infusion of RBCs after RIC reduced infarct size to 20±9% and reduced also no-reflow to 5±2% (see Figure).
Conclusion:
RBCs from healthy young volunteers reduce infarct size in isolated saline-perfused rat hearts compared to saline or plasma-dialysate infusion. In the present study, however, we further demonstrate that this unique property of RBCs is amplified by the cardioprotective effects of remote ischemic conditioning (RIC) in healthy volunteers: RBCs carry -similar to platelets- an additional cardioprotective signal in response to RIC. Unlike humoral factors in plasma-dialysate, RBCs from volunteers with RIC protect not only cardiomyocytes but also the coronary microcirculation, indicating a dual cardioprotective mechanism.