title: Controlled Reperfusion Strategies Improve Cardiac Hemodynamic Recovery after Warm Global Ischemia in an Isolated, Working Rat Heart Model of Donation after Circulatory Death (DCD).
abstract: Aims:Donation after circulatory death (DCD) could improve cardiac graft availability, which is currently insufficient to meet transplant demand. However, DCD organs undergo an inevitable period of warm ischemia and most cardioprotective approaches can only be applied at reperfusion (procurement) for ethical reasons. We investigated whether modifying physical conditions at reperfusion, using four different strategies, effectively improves hemodynamic recovery after warm ischemia.Methods and Results:Isolated hearts of male Wistar rats were perfused in working-mode for 20 min, subjected to 27 min global ischemia (37°C), and 60 min reperfusion (n = 43). Mild hypothermia (30°C, 10 min), mechanical postconditioning (MPC; 2x 30 s reperfusion/30 s ischemia), hypoxia (no O2, 2 min), or low pH (pH 6.8-7.4, 3 min) was applied at reperfusion and compared with controls (i.e., no strategy). After 60 min reperfusion, recovery of left ventricular work (developed pressure*heart rate; expressed as percent of pre-ischemic value) was significantly greater for mild hypothermia (62 ± 7%), MPC (65 ± 8%) and hypoxia (61 ± 11%; p < 0.05 for all), but not for low pH (45 ± 13%), vs. controls (44 ± 7%). Increased hemodynamic recovery was associated with greater oxygen consumption (mild hypothermia, MPC) and coronary perfusion (mild hypothermia, MPC, hypoxia), and with reduced markers of necrosis (mild hypothermia, MPC, hypoxia) and mitochondrial damage (mild hypothermia, hypoxia).Conclusions:Brief modifications in physical conditions at reperfusion, such as hypothermia, mechanical postconditioning, and hypoxia, improve post-ischemic hemodynamic function in our model of DCD. Cardioprotective reperfusion strategies applied at graft procurement could improve DCD graft recovery and limit further injury; however, optimal clinical approaches remain to be characterized.
authors.affiliation: Clinic for Cardiovascular Surgery, Inselspital, Bern University HospitalBern, Switzerland; Department of Clinical Research, University of BernBern, Switzerland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Farine
authors.affiliation: Clinic for Cardiovascular Surgery, Inselspital, Bern University HospitalBern, Switzerland; Department of Clinical Research, University of BernBern, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Niederberger
authors.affiliation: Clinic for Cardiovascular Surgery, Inselspital, Bern University HospitalBern, Switzerland; Department of Clinical Research, University of BernBern, Switzerland.
authors.forename: Rahel K
authors.initials: RK
authors.lastname: Wyss
authors.affiliation: Clinic for Cardiovascular Surgery, Inselspital, Bern University HospitalBern, Switzerland; Department of Clinical Research, University of BernBern, Switzerland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Méndez-Carmona
authors.affiliation: Clinic for Cardiovascular Surgery, Inselspital, Bern University HospitalBern, Switzerland; Department of Clinical Research, University of BernBern, Switzerland.
authors.forename: Brigitta
authors.initials: B
authors.lastname: Gahl
authors.affiliation: Center of Laboratory Medicine, University Institute of Clinical Chemistry, University Hospital Inselspital, Bern, Switzerland.
authors.forename: Georg M
authors.initials: GM
authors.lastname: Fiedler
authors.affiliation: Clinic for Cardiovascular Surgery, Inselspital, Bern University HospitalBern, Switzerland; Department of Clinical Research, University of BernBern, Switzerland.
authors.forename: Thierry P
authors.initials: TP
authors.lastname: Carrel
authors.affiliation: Clinic for Cardiovascular Surgery, Inselspital, Bern University HospitalBern, Switzerland; Department of Clinical Research, University of BernBern, Switzerland.
authors.forename: Hendrik T
authors.initials: HT
authors.lastname: Tevaearai Stahel
authors.affiliation: Clinic for Cardiovascular Surgery, Inselspital, Bern University HospitalBern, Switzerland; Department of Clinical Research, University of BernBern, Switzerland.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Longnus
keywords: acidic reperfusion; cardioprotection; donation after circulatory death; heart transplantation; hypoxia; ischemia reperfusion injury; mechanical postconditioning; mild hypothermia