1Universitätsklinikum Halle (Saale) Universitätsklinik und Poliklinik für Herzchirurgie Halle (Saale), Deutschland
Purpose: Ischemia/reperfusion (I/R) leads to increased levels of proinflammatory mediators and promotes coronary endothelial dysfunction and an impaired microvascular reflow after transplantation. Hearts donated after circulatory death (DCD) are exposed to ischemia, predominantly followed by ex-vivo blood perfusion (EVBP). Old donor hearts are less tolerant of I/R injury. However, they could further increase the number of DCD organs. Accumulating senescent cells secrete the senescence-associated secretory phenotype (SASP), including proinflammatory cytokines. Senomorphic agents block the SASP. Therefore, we investigated the effect of the senomorphic agent ruxolitinib during EVBP on microvascular coronary flow after transportation.
Methods: In a rat model, DCD hearts were maintained by EVBP with (DCD-BP+Ruxo group) or without (DCD-BP group) ruxolitinib (500 nM). After EVBP, we mounted the hearts on an evaluation apparatus, which was primed with fresh blood of another rat, reperfused the heart for 1 h, and assessed the microvascular flow according to perfusion pressures from 20 to 100 mmHg. In two other groups, DCD hearts (DCD group) and native control hearts (Control group), were mounted on the evaluation apparatus without prior EVBP. All experiments were performed in male and female, 6- and 18-month-old rats (N=4-6/group). Myocardial microcirculation was measured by Laser-Doppler-Perfusion(LDP) and expressed as relative LDP (RLDP).
Results: RLDP was reduced in the DCD group compared to Control in all subpopulations except young male donors (male young: 2±0.3 vs. 1.8±0.3; female young: 1.7±0.3 vs. 3±1.6; male old: 1.3±0.4 vs. 2.1±0.5; female old: 1.6±0.4 vs. 2.2±0.5). In the DCD-BP group, RLDP was higher than in the DCD group in female old donors (2.7±0.5 vs. 1.6±0.4). In the DCD-BP+Ruxo group, RLDP was higher compared to DCD-BP in young female (3.4±1 vs. 2.8±0.5) and old male (1.9±0.4 vs. 1.4±0.3) donors.
Conclusion: The myocardial microvascular circulation is impaired by circulatory death in hearts from female young and male or female old donors. EVBP reconditions the myocardial microcirculation only in DCD hearts from female old donors. Ruxolitinib during EVBP reconditions the myocardial microcirculation in the hearts of young female and male old donors.