Korean Journal of Radiology

The Korean Society of Radiology (대한영상의학회)
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Human Recombinant Apyrase Therapy Protects Against Myocardial Ischemia/Reperfusion Injury and Preserves Left Ventricular Systolic Function in Rats, as Evaluated by 7T Cardiovascular Magnetic Resonance Imaging

  • Ziqian Xu (Department of Radiology, West China Hospital, Sichuan University) ;
  • Wei Chen (Department of Radiology, The First Affiliated Hospital of Kunming Medical College) ;
  • Ruzhi Zhang (Department of Radiology, West China Hospital, Sichuan University) ;
  • Lei Wang (Department of Radiology, West China Hospital, Sichuan University) ;
  • Ridong Chen (APT Therapeutics Inc.) ;
  • Jie Zheng (Mallinckrodt Institute of Radiology, Washington University School of Medicine) ;
  • Fabao Gao (Department of Radiology, West China Hospital, Sichuan University)
  • Received : 2019.11.12
  • Accepted : 2020.02.05
  • Published : 2020.06.01
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Abstract

Objective: The occurrence of intramyocardial hemorrhage (IMH) and microvascular obstruction (MVO) in myocardial infarction (MI), known as severe ischemia/reperfusion injury (IRI), has been associated with adverse remodeling. APT102, a soluble human recombinant ecto-nucleoside triphosphate diphosphohydrolase-1, can hydrolyze extracellular nucleotides to attenuate their prothrombotic and proinflammatory effects. The purpose of this study was to temporally evaluate the therapeutic effect of APT102 on IRI in rats and to elucidate the evolution of IRI in the acute stage using cardiovascular magnetic resonance imaging (CMRI). Materials and Methods: Fifty-four rats with MI, induced by ligation of the origin of the left anterior descending coronary artery for 60 minutes, were randomly divided into the APT102 (n = 27) or control (n = 27) group. Intravenous infusion of APT102 (0.3 mg/kg) or placebo was administered 15 minutes before reperfusion, and then 24 hours, 48 hours, 72 hours, and on day 4 after reperfusion. CMRI was performed at 24 hours, 48 hours, 72 hours, and on day 5 post-reperfusion using a 7T system and the hearts were collected for histopathological examination. Cardiac function was quantified using cine imaging and IMH/edema using T2 mapping, and infarct/MVO using late gadolinium enhancement. Results: The extent of infarction (p < 0.001), edema (p < 0.001), IMH (p = 0.013), and MVO (p = 0.049) was less severe in the APT102 group than in the control group. IMH size at 48 hours was significantly greater than that at 24 hours, 72 hours, and 5 days after reperfusion (all p < 0.001). The left ventricular ejection fraction (LVEF) was significantly greater in the APT102 group than in the control group (p = 0.006). There was a negative correlation between LVEF and IMH (r = -0.294, p = 0.010) and a positive correlation between IMH and MVO (r = 0.392, p < 0.001). Conclusion: APT102 can significantly alleviate damage to the ischemic myocardium and microvasculature. IMH size peaked at 48 hours post reperfusion and IMH is a downstream consequence of MVO. IMH may be a potential therapeutic target to prevent adverse remodeling in MI.

Keywords

Acknowledgement

This study was supported by the National Natural Science Foundation of China (81930046, 81829003, 81520108014, and 81771800), the State's Key Project of Research and Development Plan of China (2016YFA0201402), and the international cooperation project of science and technology program of Sichuan (2017HH0045).

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