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.

Development of a cardiac loading device to monitor cardiac function during ex vivo graft perfusion

“…All balloons were designed and produced in our laboratory. Two LV ellipsoid Plexiglas positives for VBs were designed with volumes of 240 or 280 μL, estimated using previously obtained data[ 4 ]. RBs were designed with a spherical shape and a larger volume of 4.2 mL, to limit pressure in the device with the maximal volume increase of 280 μL (occurs only if VB empties completely).…”

“…However, with marginal donation and DCD, evaluation of graft suitability for transplantation takes on an even greater importance. For example, DCD organs undergo an inevitable period of warm, global ischemia, which requires specialized strategies to limit ischemia-reperfusion injury and ensure adequate post-transplant functional recovery[ 4 ].…”

Mechanical Postconditioning Promotes Glucose Metabolism and AMPK Activity in Parallel with Improved Post-Ischemic Recovery in an Isolated Rat Heart Model of Donation after Circulatory Death

“…An isolated heart model of DCD heart transplantation was used, as previously reported [26,45,47,53,54], with male Wistar rats (Janvier Labs, Le Genest-Saint-Isle, France) of 10 to 11 weeks of age to ensure mature cardiac metabolism [55] and to represent young, adult human DCD donors. Rats were housed under standard conditions at a controlled room temperature with a 12-h light-dark cycle and access to water and food ad libitum.…”

“…To obtain data for cardiac function, a micro-tip pressure catheter (Millar, Houston, TX, USA) placed in the left ventricle was used to continuously measure heart rate (HR), peak systolic pressure, developed pressure (DP), minimum and maximum first derivatives of left ventricular pressure (dP/dt min and dP/dt max). Left ventricular work (LV work) was calculated as previously described [45,47,53,54]: DP × HR.…”

Olanzapine-mediated cardiotoxicity is associated with altered energy metabolism in isolated rat hearts

“…injection of 100 mg/kg ketamine and 10 mg/kg xylazine, and, in the first series, anticoagulated with heparin (500 IU i.p.). Hearts were explanted and perfused via the aorta at 80 mm Hg with a modified Krebs-Henseleit solution (Farine et al, 2016;Knezl et al, 2017) and gassed with 95% O 2 and 5% CO 2 .…”