Liposome-encapsulated hemoglobin rescues hemorrhagic shock heart through anti-ischemic and anti-arrhythmogenic effects on myocardium in repetitive 65% bleeding rat model

Artif Organs. 2025 Jan;49(1):39-51. doi: 10.1111/aor.14858. Epub 2024 Sep 21.

Abstract

Background: Phase I clinical trial of an artificial oxygen carrier (liposome-encapsulated hemoglobin vesicles [HbVs]) is safely completed, considering the other clinical application. Herein, we aimed to investigate the resuscitation effects of HbVs in cases of lethal hemorrhage, including the mechanisms involved.

Methods: Optical mapping analysis (OMP) and electrophysiological studies (EPS), immunostaining pathological examination for hypoxia-inducible factor-1α (HIF1-alpha) in the heart tissue, and blood troponin I (TnI) level measurements were performed in rats that underwent five rounds of spontaneous arterial bleeding with up to 65% hemorrhage.

Results: Ten rats in each group were resuscitated by a transvenous infusion of 5% albumin (ALB), washed erythrocytes (wRBC), HbVs (HbV), 50% HbV diluted by 5% albumin (50% HbV), and 66% HbV diluted by 5% albumin (66% HbV). The rats in the ALB and 50% HbV groups died, whereas those in the other groups survived. OMP showed impaired action potential duration dispersion (APDd) in the left ventricle in the ALB and 50% HbV groups, which was attenuated in the other groups. Lethal arrhythmias were provoked by EPS in the ALB and 50% HbV groups but not in the other groups. HIF1-alpha was positively stained only in the ALB and 50% HbV groups. TnI levels were elevated in the ALB and 50% HbV groups.

Conclusions: Acute lethal hemorrhage causes myocardial ischemia with hypoxia and arrhythmias, which may be induced by impaired APDd and myocardial damage, reflected in the increased levels of HIF1-alpha and TnI. HbVs could be useful for resuscitation and may help save patients with injuries such as gunshot wounds.

Keywords: HIF1‐alpha; arterial bleeding; artificial oxygen carrier; lethal arrhythmia.

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / etiology
  • Blood Substitutes* / administration & dosage
  • Blood Substitutes* / pharmacology
  • Disease Models, Animal*
  • Hemoglobins* / administration & dosage
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Liposomes
  • Male
  • Myocardial Ischemia / complications
  • Myocardium / metabolism
  • Myocardium / pathology
  • Rats
  • Rats, Sprague-Dawley*
  • Resuscitation / methods
  • Shock, Hemorrhagic* / therapy
  • Troponin I / blood

Substances

  • Hemoglobins
  • Blood Substitutes
  • liposome-encapsulated hemoglobin
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Liposomes
  • Troponin I