Preoxygenated hemoglobin-based oxygen carrier HBOC-201 annihilates myocardial ischemia during brief coronary artery occlusion in pigs

Hekkert, Maaike te Lintel; Dubé, Gregory P.; Regar, Evelyn; Boer, Martine de; Vranckx, Pascal; Giessen, Wim J. van der; Serruys, Patrick W.; Duncker, Dirk J.

doi:10.1152/ajpheart.00667.2009

Cited by 25 publications

(8 citation statements)

References 28 publications

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“…Hemoglobin-based oxygen carriers (HBOCs) are red blood cell substitutes under development for more than three decades [ 3 ]. Our previous work and other studies indicated that HBOCs are promising candidates to prevent many organs from I/R injury [ 4 – 7 ]. Functionally, they allow delivery of more oxygen (O 2 ) to hypoxic tissues due to their higher O 2 affinity, lower viscosity, and smaller mean diameter than human erythrocytes.…”

Section: Introductionmentioning

confidence: 99%

High-Dose Polymerized Hemoglobin Fails to Alleviate Cardiac Ischemia/Reperfusion Injury due to Induction of Oxidative Damage in Coronary Artery

Yang

et al. 2015

Oxidative Medicine and Cellular Longevity

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Objective. Ischemia/reperfusion (I/R) injury is an unavoidable event for patients in cardiac surgery under cardiopulmonary bypass (CPB). This study was designed to investigate whether glutaraldehyde-polymerized human placenta hemoglobin (PolyPHb), a hemoglobin-based oxygen carrier (HBOC), can protect heart against CPB-induced I/R injury or not and to elucidate the underlying mechanism. Methods and Results. A standard dog CPB model with 2-hour cardiac arrest and 2-hour reperfusion was established. The results demonstrated that a low-dose PolyPHb (0.1%, w/v) provided a significant protection on the I/R heart, whereas the high-dose PolyPHb (3%, w/v) did not exhibit cardioprotective effect, as evidenced by the impaired cardiac function, decreased myocardial oxygen utilization, and elevated enzymes release and pathological changes. Further study indicated that exposure of isolated coronary arteries or human umbilical vein endothelial cells (HUVECs) to a high-dose PolyPHb caused impaired endothelium-dependent relaxation, which was companied with increased reactive oxygen species (ROS) production, reduced superoxide dismutase (SOD) activity, and elevated malonaldehyde (MDA) formation. Consistent with the increased oxidative stress, the NAD(P)H oxidase activity and subunits expression, including gp91phox, p47phox, p67phox, and Nox1, were greatly upregulated. Conclusion. The high-dose PolyPHb fails to protect heart from CPB-induced I/R injury, which was due to overproduction of NAD(P)H oxidase-induced ROS and resultant endothelial dysfunction.

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Section: Introductionmentioning

confidence: 99%

High-Dose Polymerized Hemoglobin Fails to Alleviate Cardiac Ischemia/Reperfusion Injury due to Induction of Oxidative Damage in Coronary Artery

Yang

et al. 2015

Oxidative Medicine and Cellular Longevity

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“…One study has demonstrated that intracoronary infusion of preoxygenated HBOC-201 preserved myocardial metabolism, regional oxygen delivery and left ventricular function produced by a three minute coronary artery occlusion. 36 Importantly, intracoronary infusion of nonoxygenated HBOC-201, Ringers solution or no treatment resulted in immediate loss of ventricular function in the ischemic region and evidence for anaerobic metabolism. 36 These findings have important clinical implications regarding the potential benefits of HBOC-201 as an organ preservation fluid and require further investigation.…”

Section: Discussionmentioning

confidence: 99%

Vital Organ Tissue Oxygenation After Serial Normovolemic Exchange Transfusion with HBOC-201 in Anesthetized Swine

Muir¹,

Ilangovan²,

Zweíer³

et al. 2011

Shock

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This study determined the effects of serial, normovolemic, stepwise exchange transfusions with either 6% human serum albumin (HSA) or the hemoglobin-based oxygen carrier, HBOC-201, on tissue oxygenation of the heart, brain and kidney in intact anaesthetized pigs. Exchange transfusions to 10%, 30% and 50% of the pigs total blood volume were completed at a withdrawal rate of 1.0 ml/kg/min followed by an infusion rate of 0.5 ml/kg/min of HBOC-201 or iso-oncotically matched 6% HSA. Measurements included invasive systemic hemodynamic (blood pressures, left ventricular end diastolic pressure [LVEDP]), hematolic (hemoglobin, hematocrit, methemoglobin), acid-base (pH, pCO2) and biochemistry (serum lactate) measurements. Brain and kidney tissue oxygenation (tPO2) were determined by electron paramagnetic resonance (EPR) and heart tPO2 by O2 sensitive fiber optic probe. The main results demonstrated that tPO2 after HBOC-201 remained stable despite significant decreases in hematocrit and changing hemodynamics. In vivo tPO2 measurements (heart tPO2 average ≥ 22 mm Hg; brain tPO2 average ≥ 8 mmHg; and kidney tPO2 average ≥10 mmHg) were maintained in all groups at all times. Blood pressures were 20–30 mm Hg higher after HBOC-201 compared to HSA controls. Heart rate and LVEDP were not different among treatment groups. In conclusion, the administration of HBOC-201 maintained tPO2 in three vital organs after profound hemodilution.

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“…), anesthetized with pentobarbital (15 mg/kg i.v. ), intubated and mechanically ventilated with O 2 and N 2 (1:3 v/v), and instrumented as previously described [ 26 , 44 ]. Catheters were placed in the external jugular vein for maintenance of anesthesia (pentobarbital, 10–15 mg/kg/h) and infusion of physiological saline, and the left femoral artery for measurement of arterial blood pressure.…”

Section: Methodsmentioning

confidence: 99%

Vagal nerve stimulation started just prior to reperfusion limits infarct size and no-reflow

et al. 2015

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Vagal nerve stimulation (VNS) started prior to, or during, ischemia has been shown to reduce infarct size. Here, we investigated the effect of VNS when started just prior to, and continued during early, reperfusion on infarct size and no-reflow and studied the underlying mechanisms. For this purpose, swine (13 VNS, 10 sham) underwent 45 min mid-LAD occlusion followed by 120 min of reperfusion. VNS was started 5 min prior to reperfusion and continued until 15 min of reperfusion. Area at risk, area of no-reflow (% of infarct area) and infarct size (% of area at risk), circulating cytokines, and regional myocardial leukocyte influx were assessed after 120 min of reperfusion. VNS significantly reduced infarct size from 67 ± 2 % in sham to 54 ± 5 % and area of no-reflow from 54 ± 6 % in sham to 32 ± 6 %. These effects were accompanied by reductions in neutrophil (~40 %) and macrophage (~60 %) infiltration in the infarct area (all p < 0.05), whereas systemic circulating plasma levels of TNFα and IL6 were not affected. The degree of cardioprotection could not be explained by the VNS-induced bradycardia or the VNS-induced decrease in the double product of heart rate and left ventricular systolic pressure. In the presence of NO-synthase inhibitor LNNA, VNS no longer attenuated infarct size and area of no-reflow, which was paralleled by similarly unaffected regional leukocyte infiltration. In conclusion, VNS is a promising novel adjunctive therapy that limits reperfusion injury in a large animal model of acute myocardial infarction.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-015-0508-3) contains supplementary material, which is available to authorized users.

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Preoxygenated hemoglobin-based oxygen carrier HBOC-201 annihilates myocardial ischemia during brief coronary artery occlusion in pigs

Cited by 25 publications

References 28 publications

High-Dose Polymerized Hemoglobin Fails to Alleviate Cardiac Ischemia/Reperfusion Injury due to Induction of Oxidative Damage in Coronary Artery

High-Dose Polymerized Hemoglobin Fails to Alleviate Cardiac Ischemia/Reperfusion Injury due to Induction of Oxidative Damage in Coronary Artery

Vital Organ Tissue Oxygenation After Serial Normovolemic Exchange Transfusion with HBOC-201 in Anesthetized Swine

Vagal nerve stimulation started just prior to reperfusion limits infarct size and no-reflow

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