Administration of a human recombinant apyrase (AZD3366) limits myocardial tissue injury and improves cardiac function in a pig model of STEMI assessed by serial CMR

Abstract

Abstract Background Mitigating myocardial tissue injury (MTI) remains an unmet clinical need in the reperfusion era. Stimulating adenosine synthesis through the breakdown of adenosine triphosphate (ATP) by apyrase (CD39), an endothelial ADPase, has emerged as a potential new avenue in the reduction of MTI. Purpose In this study we examined whether the intravenous administration of a recombinant soluble form of human apyrase (AZD3366) prior to reperfusion limits MTI and improves cardiac function in a pig model of STEMI as assessed by serial cardiac magnetic resonance (CMR) imaging. Methods Pigs (n=16) were subjected to STEMI induction (1.5h closed-chest complete LAD coronary balloon occlusion). Immediately prior to reperfusion, pigs were randomized to intravenously receive one single dose of 3 mg/kg AZD3366 (n=8) or vehicle (n=8). Serial-CMR imaging was performed at baseline, 3 days, and 42 days post-MI for the assessment of structural and functional readouts at rest and during dobutamine stress. Light transmittance aggregometry (LTA; challenged by 5, 10 and 20 μM ADP) and ear bleeding time were monitored pre-MI, post-MI and at day 3. Results AZD3366 significantly reduced MTI by limiting (around 60%) oedema formation (21.3±6.7 vs. 12.3±6.7 g LV) and infarct size (14.3±6.1 vs. 8.4±3.4 g LV) and preventing microvascular obstruction (2.3±0.9 vs. 0.5±0.5 g LV) at 3 days post-MI, compared to vehicle-administered STEMI pigs (p<0.05). At a functional level, LVEDV and LVESV showed less deterioration in AZD3366 treated animal as compared to vehicle 3 days post-MI (p<0.05) and less numerical decrease of LVEF. Furthermore, AZD3366-treated animals showed no deterioration in LVEF upon dobutamine stress in contrast to vehicle-infused animals, (p<0.05). AZD3366 treatment nearly abolished LTA at all tested ADP doses early post-STEMI, an effect that remained up to 3 days post-infusion but did not affect ear bleeding time at any of the tested time points. No additional effects were seen at 42 days. Conclusion Infusion of one single dose of the soluble recombinant apyrase AZD3366 prior to reperfusion exerts cardioprotection by reducing oedema formation, microvascular obstruction and necrosis and improving cardiac performance at rest and after dobutamine stress during the acute post-MI period. Administration of AZD3366 as an adjunctive therapy to standard of care for STEMI patients undergoing primary PCI may reduce myocardial tissue injury. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): AstraZeneca, Gothenburg, Sweden