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To cite: Dai et al. Evaluation of the efficacy of medications for heart failure: a systematic review and network metaanalysis. Inplasy protocol 2020110004.

Introduction: Cardiac transplantation following circulatory death (DCD) and normothermic regional perfusion (NRP) is a new strategy that allows assessment of cardiac function and therapeutical interventions before cardiac transplantation. Sodium-3-hydroxybutyric acid (3-OHB) increases cardiac output by 40% in heart failure patients and diminishes ischemia and reperfusion (IR) injury, presumably by improving mitochondrial energy metabolism. Hypothesis: We hypothesize that infusion with 3-OHB during NRP improves cardiac hemodynamic function after NRP and mitochondrial function after cardiac transplantation. Methods: Pigs ~80 kg underwent a 15-minute anoxic cardiac arrest followed by NRP on a heart-lung cardiac bypass machine. During NRP pigs received 3-OHB or Ringer Acetate infusion. We measured hemodynamic function invasively using pressure-volume catheters and mitochondrial function by high resolution respirometry. Results: Infusion with 3-OHB (360mg/kg/h) increased plasma levels of 3-OHB from 0.05±0.06mM to 3.95±1.13mM (P=0.006) following NRP. 3-OHB increased cardiac output by 5.18±0.97 L min -1 (P<0.0001) driven by a 60% reduction in afterload (3-OHB vs. control: 1.4±0.2 vs. 2.2±0.7 mmHg*mL -1 , P=0.02) and an increase in stroke volume of 36±11mL (P=0.006). Following transplantation and 3-OHB infusion, maximally coupled mitochondrial respiration returned to baseline levels corresponding to a 50% improvement compared with control (3-OHB vs. control: 135±25 vs. 78±26 ρmol O 2 *s -1 mg -1 , P=0.0008). The increment was associated with uncoupling of the inner mitochondrial membrane (3-OHB vs. control: 122±19 vs. 70±34 ρmol O 2 *s -1 mg -1 , P=0.018). Transplantation caused a shift in mitochondrial substrate efficiency measured as the respiratory control ratio, favoring 3-OHB over glucose linked substrates (3-OHB vs. glucose: 22±12 vs. 8±4, p=0.0008). Conclusions: Infusion with 3-OHB improved cardiac hemodynamic recovery following NRP. The improvement was driven predominantly by afterload reduction and was associated with an improvement in mitochondrial respiratory capacity.