Liposome-Encapsulated Hemoglobin Attenuates Cardiac Dysfunction and Sympathetic Activity During Hypohemoglobinemic Shock

Abstract

The use of liposome-encapsulated hemoglobin (LHb), which is a cellular Hb, has been demonstrated to be beneficial in the treatment of hypohemoglobinemic shock. As a molecule of appropriate size (220 nm) that can carry oxygen, LHb may ameliorate cardiac dysfunction during lethal hemodilation. The purpose of this study was to determine the efficacy of LHb transfusion in relieving cardiovascular dysfunction in a rat model of lethal progressive hemodilution. Over the course of 150 min, rats were subjected to blood withdrawal (0.2 mL/min) and simultaneously transfused with LHb, washed rat red blood cells, or 5% albumin. Temporal changes in cardiac function, heart-type fatty acid-binding protein levels, plasma levels of catecholamines, heart rate variability, and hypoxia-inducible factor 1α expression were measured during lethal progressive hemodilution. More than 80% of the rats transfused with either LHb or washed rat red blood cells survived for 8 days. Liposome-encapsulated hemoglobin transfusion suppressed hypoxia-inducible factor 1α expression in the heart, maintained low levels of heart-type fatty acid-binding protein, and attenuated sympathetic nerve activity as reflected by changes in heart rate variability and plasma levels of epinephrine and norepinephrine. The results indicate that LHb attenuates cardiac dysfunction and sympathetic overactivity during lethal hemorrhage.

Liposome‐encapsulated hemoglobin (HbV) transfusion rescues rats undergoing progressive lethal 85% hemorrhage as a result of an anti‐arrhythmogenic effect on the myocardium

“…The results of the present study are in agreement with those of our previous reports 23,29,30 and other reports of prototypic cellular Hbs and acellular Hbs. 23,30 In our previous reports that used the same 85% hemodilution lethal massive hemorrhagic shock model, the prototype cellular Hb, which is similar to HbV, improved the prognosis and ameliorated organ damage comparably to wRBC, 23 and showed a significant salutary effect on cardiac autonomic function and the condition of the heart. 30 However, this previous study did not investigate the mechanism of this favorable effect on the heart, especially arrhythmogenesis.…”

“…Third, to investigate the protective effect of HbV on myocardium in severe hemorrhage, the measurements of the blood levels of troponin and/or CK‐MB are important, but we could not measure these parameters. We previously measured heart‐type fatty acid‐binding protein which is a similar biomarker to troponin and CK‐MB in a severe hemorrhagic model and we showed that prototypic cellular Hbs prevented the leakage of heart‐type fatty acid‐binding protein from the heart 30 . We speculate that HbV has the same effects on the troponin and CK‐MB.…”

“…We previously measured heart-type fatty acid-binding protein which is a similar biomarker to troponin and CK-MB in a severe hemorrhagic model and we showed that prototypic cellular Hbs prevented the leakage of heart-type fatty acidbinding protein from the heart. 30 We speculate that HbV has the same effects on the troponin and CK-MB. Last, it is well known that hypoxia in the heart produces life-threatening arrhythmias through voltage-dependent sodium (NaV1.5) channel.…”

“…23,30 In our previous reports that used the same 85% hemodilution lethal massive hemorrhagic shock model, the prototype cellular Hb, which is similar to HbV, improved the prognosis and ameliorated organ damage comparably to wRBC, 23 and showed a significant salutary effect on cardiac autonomic function and the condition of the heart. 30 However, this previous study did not investigate the mechanism of this favorable effect on the heart, especially arrhythmogenesis. In the present study, we examined the effect of HbV on electrophysiological properties in the heart subjected to 85% hemodilution, and it was found that HbV significantly preserved electrophysiological features such as the conduction pattern and APDd.…”

Intraosseous infusion of liposome‐encapsulated hemoglobin (HbV) acutely prevents hemorrhagic anemia‐induced lethal arrhythmias, and its efficacy persists with preventing proarrhythmic side effects in the subacute phase of severe hemodilution model

“…However, according to a clinical study, 18 relatively longer periods after the occurrence of prolonged cardiac ischemia are required before these abnormal levels are detected; therefore, these parameters were not measured in this study. However, we previously measured heart‐type fatty acid–binding protein, which is detected much earlier than troponin or CK‐MB, and demonstrated that prototypic cellular Hb ameliorated the blood levels of heart‐type fatty acid–binding protein 19 …”