Preservation of myocardial contractility during acute hypoxia with OMX-CV, a novel oxygen delivery biotherapeutic

Abstract

The heart exhibits the highest basal oxygen (O2) consumption per tissue mass of any organ in the body and is uniquely dependent on aerobic metabolism to sustain contractile function. During acute hypoxic states, the body responds with a compensatory increase in cardiac output that further increases myocardial O2 demand, predisposing the heart to ischemic stress and myocardial dysfunction. Here, we test the utility of a novel engineered protein derived from the heme-based nitric oxide (NO)/oxygen (H-NOX) family of bacterial proteins as an O2 delivery biotherapeutic (Omniox-cardiovascular [OMX-CV]) for the hypoxic myocardium. Because of their unique binding characteristics, H-NOX–based variants effectively deliver O2 to hypoxic tissues, but not those at physiologic O2 tension. Additionally, H-NOX–based variants exhibit tunable binding that is specific for O2 with subphysiologic reactivity towards NO, circumventing a significant toxicity exhibited by hemoglobin (Hb)-based O2 carriers (HBOCs). Juvenile lambs were sedated, mechanically ventilated, and instrumented to measure cardiovascular parameters. Biventricular admittance catheters were inserted to perform pressure-volume (PV) analyses. Systemic hypoxia was induced by ventilation with 10% O2. Following 15 minutes of hypoxia, the lambs were treated with OMX-CV (200 mg/kg IV) or vehicle. Acute hypoxia induced significant increases in heart rate (HR), pulmonary blood flow (PBF), and pulmonary vascular resistance (PVR) (p < 0.05). At 1 hour, vehicle-treated lambs exhibited severe hypoxia and a significant decrease in biventricular contractile function. However, in OMX-CV–treated animals, myocardial oxygenation was improved without negatively impacting systemic or PVR, and both right ventricle (RV) and left ventricle (LV) contractile function were maintained at pre-hypoxic baseline levels. These data suggest that OMX-CV is a promising and safe O2 delivery biotherapeutic for the preservation of myocardial contractility in the setting of acute hypoxia.

Right Ventricular Response to Acute Hypoxia Exposure: A Systematic Review

“…The depressive effects of hypoxia on embryonic mouse cardiomyocytes may be related to hypoxia-inducible factor-1 mediated sarcoplasmic reticulum Ca 2+ -ATPase downregulation (Ronkainen et al, 2011). Direct negative inotropic effects of hypoxia were corroborated in a recent study that demonstrated preservation of the RV contractile function by improved oxygen delivery to the hypoxic myocardium in lambs exposed to acute hypoxia (Boehme et al, 2018).…”

“…Application of a carbon monoxide-saturated hemoglobin-based oxygen carrier significantly improved cardiac performance in mice exposed to high-altitude (Wang et al, 2017 ). Furthermore, in lambs exposed to acute hypoxia, administration of a novel oxygen delivery biotherapeutic Omniox-cardiovascular was associated with preserved RV contractile function despite elevated PVR (Boehme et al, 2018 ). Thus, artificial oxygen carriers might be useful in improving RV function in conditions of acute hypoxia exposure.…”

Supplemental Oxygen in the Newborn: Historical Perspective and Current Trends

“…Future therapies could target oxygen delivery specifically to the organs most in need. For example, a bio-engineered heme-containing protein, OMX-CV, has a 10-fold higher affinity for oxygen than hemoglobin does and has been shown to selectively deliver oxygen to hypoxic tissues but not to tissues at physiologic oxygen tension rates in juvenile lambs [ 121 ].…”

Fluids of the Future

“…It also has a lower affinity for nitric oxide, which theoretically will not present the same hypertensive complications observed with first-generation HBOC. Similar to other blood product substitutes, the molecule is polymerized and PEGylated to prolong half-life ( 42 ). Being smaller than a red blood cell, the compound travels more easily through the microcirculation.…”

“…Being smaller than a red blood cell, the compound travels more easily through the microcirculation. In an ovine model of myocardial injury, administration of Omniox® resulted in improved myocardial oxygenation and contractility compared to control ( 42 ).…”