Diazoxide protects myocardial mitochondria, metabolism, and function during cardiac surgery: A double-blind randomized feasibility study of diazoxide-supplemented cardioplegia

ObjectivesThe study was designed to assess whether diazoxide-mediated cardioprotection might be used in human subjects during cardiac surgery.MethodsForty patients undergoing coronary artery bypass grafting were randomized to receive intermittent warm blood antegrade cardioplegia supplemented with either diazoxide (100 μmol/L) or placebo (n = 20 in each group). Mitochondria were assessed before and after ischemia and reperfusion in myocardial biopsy specimens. Myocardial oxygen and glucose and lactic acid extraction ratios were measured before ischemia and in the first 20 minutes of reperfusion. Hemodynamic data were collected, and troponin I, creatine kinase–MB, and N-terminal prohormone brain natriuretic peptide levels were measured. All outcomes were analyzed by using mixed-effects modeling for repeated measures.ResultsNo deaths, strokes, or infarcts were observed. Patients received, on average, 36.2 ± 1.2 mg of diazoxide and 37.3 ± 1.9 mg of placebo (P = .6). Diazoxide added to cardioplegia prevented mitochondrial swelling (8899 ± 474 vs 9273 ± 688 pixels before and after the procedure, respectively; P = .6) compared with that seen in the placebo group (8474 ± 163 vs 11,357 ± 759 pixels, P = .004). No oxygen debt was observed in the diazoxide group. Glucose consumption and lactic acid production returned to preischemic values faster in the diazoxide group. The following hemodynamic parameters differed between the diazoxide and placebo groups, respectively, in the postoperative period: cardiac index, 3.0 ± 0.09 versus 2.6 ± 0.09 L · min−1 · m−2 (P = .002); left cardiac work index, 2.81 ± 0.07 versus 2.31 ± 0.07 kg/m2 (P < .001); oxygen delivery index, 420 ± 14 versus 377 ± 13 mL · min−1 · m−2 (P = .03); and oxygen extraction ratio, 29.3% ± 1.1% versus 32.6% ± 1.1% (P = .02). Postoperative myocardial enzyme levels did not differ, but N-terminal prohormone brain natriuretic peptide levels were lower in the diazoxide group (120 ± 27 vs 192 ± 29 pg/mL, P = .04).ConclusionsSupplementing blood cardioplegia with diazoxide is safe and improves myocardial protection during cardiac surgery, possibly through its influence on the mitochondria