Intravenous Heme Arginate Induces HO-1 (Heme Oxygenase-1) in the Human Heart: Randomized, Placebo-Controlled, Safety, and Feasibility Pharmacokinetic StudyBrief Report

Objective HO-1 (heme oxygenase-1) induction may prevent or reduce ischemia-reperfusion injury. We previously evaluated its in vivo induction after a single systemic administration of heme arginate in peripheral blood mononuclear cells. The current trial was designed to assess the pharmacological tissue induction of HO-1 in the human heart with heme arginate in vivo. Approach and Results Patients planned for conventional aortic valve replacement received placebo (n=8), 1 mg/kg (n=7) or 3 mg/kg (n=9) heme arginate infused intravenously 24 hours before surgery. A biopsy of the right ventricle was performed directly before aortic cross-clamping and after cross-clamp release. In addition, the right atrial appendage was partially removed for analysis. HO-1 protein and mRNA concentrations were measured in tissue samples and in peripheral blood mononuclear cells before to and up to 72 hours after surgery. No study medication-related adverse events occurred. A strong, dose-dependent effect on myocardial HO-1 mRNA levels was observed (right ventricle: 7.95.0 versus 88.649.1 versus 203.6 +/- 148.7; P=0.002 and right atrium: 10.8 +/- 8.8 versus 229.8 +/- 173.1 versus 392.7 +/- 195.7; P=0.001). This was paralleled by a profound increase of HO-1 protein concentration in atrial tissue (8401 +/- 3889 versus 28585 +/- 10692 versus 29022 +/- 8583; P<0.001). Surgery and heme arginate infusion significantly increased HO-1 mRNA concentration in peripheral blood mononuclear cells (P<0.001). HO-1 induction led to a significant increase of postoperative carboxyhemoglobin (1.7% versus 1.4%; P=0.041). No effect on plasma HO-1 protein levels could be detected. Conclusions Myocardial HO-1 mRNA and protein can be dose-dependently induced by heme arginate. Protective effects of this therapeutic strategy should be evaluated in upcoming clinical trials. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02314780.