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Bloodless reperfusion with the oxygen carrier HBOC-201 in acute myocardial infarction: a novel platform for cardioprotective probes delivery

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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.

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Acknowledgements

This study was partially supported by a competitive grant from the Spanish Ministry of Economy and Competitiveness (MINECO) through the EXPLORA CIENCIA initiative of the Fondo Europeo de Desarrolo Regional (FEDER, RD: SAF2013-49663-EXP). José M García-Ruiz and Ana García-Alvarez were CNIC-Cardiojoven fellows. Rodrigo Fernández-Jiménez holds a FICNIC fellowship from the Fundació Jesús Serra, the Fundación Interhospitalaria de Investigación Cardiovascular (FIC), and the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC). Jaume Agüero is a FP7-PEOPLE-2013-ITN-Cardionext fellow. This study forms part of a Masters Research Agreement (MRA) between the CNIC and Philips healthcare. Borja Ibanez is supported by the Red de Investigación Cardiovascular (RIC) of the Spanish Ministry of Health (RD 12/0042/0054). The CNIC is supported by the MINECO and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). HBOC-201 was provided by HbO2 Therapeutics through an unrestricted MTA. Simon Bartlett (CNIC) provided English editing.

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Authors and Affiliations

  1. 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

    Jose M. García-Ruiz, Carlos Galán-Arriola, Rodrigo Fernández-Jiménez, Jaume Aguero, Ana García-Alvarez, Mario Nuno-Ayala, Gonzalo J. López-Martín, Juan A. Bernal, Enrique Lara-Pezzi, Valentín Fuster & Borja Ibáñez

  2. CIBER de Enfermedades CardioVasculares (CIBERCV), Madrid, Spain

    Jose M. García-Ruiz, Carlos Galán-Arriola, Rodrigo Fernández-Jiménez, Jaume Aguero, Enrique Lara-Pezzi & Borja Ibáñez

  3. Hospital Universitario Central de Asturias, Oviedo, Spain

    Jose M. García-Ruiz

  4. The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Rodrigo Fernández-Jiménez & Valentín Fuster

  5. Philips Healthcare Iberia, Madrid, Spain

    Javier Sánchez-González

  6. Hospital Clinic, Barcelona, Spain

    Ana García-Alvarez

  7. HbO2 Therapeutics, Souderton, PA, USA

    Gregory P. Dubé & Zafiris Zafirelis

  8. Department of Cardiology, Instituto de Investigación Sanitaria, Fundación Jiménez Díaz, Madrid, Spain

    Borja Ibáñez

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  1. Jose M. García-Ruiz
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  2. Carlos Galán-Arriola
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  3. Rodrigo Fernández-Jiménez
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  4. Jaume Aguero
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  6. Ana García-Alvarez
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  7. Mario Nuno-Ayala
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  8. Gregory P. Dubé
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  9. Zafiris Zafirelis
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  10. Gonzalo J. López-Martín
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  11. Juan A. Bernal
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  12. Enrique Lara-Pezzi
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  13. Valentín Fuster
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  14. Borja Ibáñez
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Correspondence to Borja Ibáñez.

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Javier Sánchez-González is a Philips employee. Gregory P. Dubé and Zafiris Zafirelis are employees of HbO2 Therapeutics, LLC. All other authors declare no conflicts of interest. B.I, JM.G-R, J.A, R.F-J, V.F, E.L-P, J.B, and C-G-A are in the process of submitting a patent for the use of oxygen carriers as a delivery system to the myocardium.

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García-Ruiz, J.M., Galán-Arriola, C., Fernández-Jiménez, R. et al. Bloodless reperfusion with the oxygen carrier HBOC-201 in acute myocardial infarction: a novel platform for cardioprotective probes delivery. Basic Res Cardiol 112, 17 (2017). https://doi.org/10.1007/s00395-017-0605-6

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  • DOI: https://doi.org/10.1007/s00395-017-0605-6

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