title: Bloodless reperfusion with the oxygen carrier HBOC-201 in acute myocardial infarction: a novel platform for cardioprotective probes delivery.
abstract: Reperfusion, despite being required for myocardial salvage, is associated with additional injury. We hypothesize that infarct size (IS) will be reduced by a period of bloodless reperfusion with hemoglobin-based oxygen carriers (HBOC) before blood-flow restoration. In the pig model, we first characterized the impact of intracoronary perfusion with a fixed volume (600 ml) of a pre-oxygenated acellular HBOC, HBOC-201, on the healthy myocardium. HBOC-201 was administered through the lumen of the angioplasty balloon (i.e., distal to the occlusion site) immediately after onset of coronary occlusion at 1, 0.7, 0.4, or 0.2 ml/kg/min for 12, 17, 30, and 60 min, respectively, followed by blood-flow restoration. Outcome measures were systemic hemodynamics and LV performance assessed by the state-of-the-art cardiac magnetic resonance (CMR) imaging. The best performing HBOC-201 perfusion strategies were then tested for their impact on LV performance during myocardial infarction, in pigs subjected to 45 min mid-left anterior descending (LAD) coronary occlusion. At the end of the ischemia duration, pigs were randomized to regular reperfusion (blood-only reperfusion) vs. bloodless reperfusion (perfusion with pre-oxygenated HBOC-201 distal to the occlusion site), followed by blood-flow restoration. Hemodynamics and CMR-measured LV performance were assessed at 7- and 45-day follow-up. In modifications of the HBOC-201 procedure, glucose and insulin were included to support cardiac metabolism. A total of 66 pigs were included in this study. Twenty healthy pigs (5 per infusion protocol) were used in the study of healthy myocardium. Intracoronary administration of HBOC-201 (600 ml) at varying rates, including a flow of 0.4 ml/kg/min (corresponding to a maximum perfusion time of 30 min), did not damage the healthy myocardium. Slower perfusion (longer infusion time) was associated with permanent LV dysfunction and myocardial necrosis. A total of 46 pigs underwent MI induction. Compared with regular reperfusion, bloodless reperfusion with pre-oxygenated HBOC-201 alone increased IS. This effect was reversed by enrichment of pre-oxygenated HBOC-201 solution with glucose and insulin, resulting in no increase in IS or worsening of long-term ventricular function despite further delaying restoration of blood flow in the LAD. Bloodless reperfusion with a pre-oxygenated HBOC-201 solution supplemented with glucose and insulin is feasible and safe, but did not reduce infarct size. This strategy could be, however, used to deliver agents to the myocardium to treat or prevent ischemia/reperfusion injury before blood-flow restoration.
authors.affiliation: Myocardial Pathophysiology Area, Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain.|CIBER de Enfermedades CardioVasculares (CIBERCV), Madrid, Spain.|Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: García-Ruiz
authors.affiliation: Myocardial Pathophysiology Area, Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain.|CIBER de Enfermedades CardioVasculares (CIBERCV), Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Galán-Arriola
authors.affiliation: Myocardial Pathophysiology Area, Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain.|CIBER de Enfermedades CardioVasculares (CIBERCV), Madrid, Spain.|The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Fernández-Jiménez
authors.affiliation: Myocardial Pathophysiology Area, Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain.|CIBER de Enfermedades CardioVasculares (CIBERCV), Madrid, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Aguero
authors.affiliation: Philips Healthcare Iberia, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Sánchez-González
authors.affiliation: Myocardial Pathophysiology Area, Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain.|Hospital Clinic, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: García-Alvarez
authors.affiliation: Myocardial Pathophysiology Area, Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Nuno-Ayala
authors.affiliation: HbO2 Therapeutics, Souderton, PA, USA.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Dubé
authors.affiliation: HbO2 Therapeutics, Souderton, PA, USA.
authors.forename: Zafiris
authors.initials: Z
authors.lastname: Zafirelis
authors.affiliation: Myocardial Pathophysiology Area, Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain.
authors.forename: Gonzalo J
authors.initials: GJ
authors.lastname: López-Martín
authors.affiliation: Myocardial Pathophysiology Area, Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Bernal
authors.affiliation: Myocardial Pathophysiology Area, Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain.|CIBER de Enfermedades CardioVasculares (CIBERCV), Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Lara-Pezzi
authors.affiliation: Myocardial Pathophysiology Area, Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain.|The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Valentín
authors.initials: V
authors.lastname: Fuster
authors.affiliation: Myocardial Pathophysiology Area, Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain. bibanez@cnic.es.|CIBER de Enfermedades CardioVasculares (CIBERCV), Madrid, Spain. bibanez@cnic.es.|Department of Cardiology, Instituto de Investigación Sanitaria, Fundación Jiménez Díaz, Madrid, Spain. bibanez@cnic.es.
authors.forename: Borja
authors.initials: B
authors.lastname: Ibáñez
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006454:Hemoglobins / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000150:complications; D015425:Myocardial Reperfusion / Q000379:methods*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011897:Random Allocation; D013552:Swine
chemical_list: D006454:Hemoglobins; C096798:HBOC 201
keywords: Cardiac magnetic resonance; Cardioprotection; Delivery system; Hemoglobin-based oxygen carriers; Myocardial infarction; Reperfusion injury