Review of Hemoglobin-Induced Myocardial Lesions

Abstract

Over 100 preclinical studies in several small and large animal species were performed to evaluate the safety and efficacy of diaspirin cross-linked hemoglobin (DCLHb; Baxter Healthcare Corp.) as an oxygen therapeutic. During the preclinical evaluation of DCLHb, myocardial lesions were observed following the administration of DCLHb to certain species. These lesions were characterized as minimal to moderate, focal-to-multifocal myocardial degeneration and/or necrosis that were scored using a severity scale of minimal to marked in relative severity. The lesions were typically observed 24-48 h after single topload infusions of DCLHb into rhesus monkeys or pigs at doses as low as 200 or 700 mg/kg, respectively. Dogs, sheep, and rats did not develop these lesions after single-dose administrations of DCLHb. The left ventricular myocardium, typically near the base of or including the papillary muscles, was the most severely affected region, followed by the intraventricular septum and the right ventricle. The left and right atria were usually not affected. In a study in rhesus monkeys, morphometric analysis revealed that these lesions comprised less than 3% of the total myocardium. Although increases in serum enzyme activities (AST, CK, LDH) were observed after infusion of DCLHb, myocardial-related isoenzymes did not increase. ECG analysis and echocardiography were not altered by these lesions, and there was no observable adverse effect on myocardial function. Polymerization of DCLHb reduced, but did not eliminate, the incidence and severity of the lesions. However, infusion of hemoglobin solutions with reduced reaction rates with nitric oxide (NO) resulted in a significant decrease in lesion incidence and severity, while administration of L-NAME, an NO synthase inhibitor, resulted in the appearance of lesions that were indistinguishable from those induced by hemoglobin, suggesting that reduction in normal NO levels is an important mechanistic factor. Overall, the presence of myocardial lesions represents a histopathologic finding that must be considered during the preclinical testing and development of new HBOCs.

Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy

“…Cardiovascular effects of extracellular Hb have been extensively studied in the context of hemolytic diseases and Hb-based oxygen carrier administration and are reported in the literature with regard to (transient, but occasionally severe) hypertension and myocardial injury (20,26,27). In agreement with these data, our studies demonstrate an acute and transient rise in systemic blood pressure after transfusion of old blood.…”

“…Exposure to free Hb is known to elicit an increase in blood pressure (20,26). Hb exposures have also been associated with cardiovascular toxicity in certain species, manifested as early-onset (within 24 hours) myocardial lesions (27). Therefore, we examined the vascular effects of new and older storage blood transfusion with or without Hp.…”

Repeated Injection of High Doses of Hemoglobin-Encapsulated Liposomes (Hemoglobin Vesicles) Induces Accelerated Blood Clearance in a Hemorrhagic Shock Rat Model

“…However, Natanson et al (2008) recently performed a meta-analysis based on data from randomized controlled trials of five different acellulartype HBOCs and concluded that acellular-type HBOCs are associated with a significantly increased risk of death and myocardial infarction. This risk would be induced by the scavenging of nitric oxide (NO) by cell-free Hb, because it was reported that a reduction in NO levels in myocardial lesions is an important factor in inducing histological damage in cases of myocardial lesions (Burhop et al, 2004).…”

Polynitroxylated-Pegylated Hemoglobin Attenuates Fluid Requirements and Brain Edema in Combined Traumatic Brain Injury Plus Hemorrhagic Shock in Mice

“…The recombinant human Hb rHb2.0 (Baxter, Boulder, CO, USA) had a 20-to 30-fold reduced NO affinity, 22 but animal models still showed myocardial injury. 23 These attempts to reduce NO scavenging were unsuccessful, possibly because they fail to address the pro-oxidant effect of Hb. 24 Hemoglobin is an oxygen carrier and a pro-oxidant, and participates in complex redox processes involving the heme iron center.…”