Abstract 16004: Natural IgM Blockade Mitigates Myocardial Ischemia-Reperfusion Injury in Miniature Swine
Background: Acute coronary syndrome is the leading cause of mortality worldwide. However, treatment of acute coronary occlusion inevitably results in ischemia-reperfusion injury. Circulating pathogenic natural IgM has been shown to play a significant role in reperfusion injury in mouse models of myocardial, hind-limb, and intestinal ischemia. A specific self-antigen, non-muscle myosin heavy chain II (NMHC-II), has been identified as a target of pathogenic IgM. Therefore, we hypothesized that a mouse monoclonal antibody (m21G6) directed against NMHC-II inhibits IgM binding and reduces injury in a pre-clinical model of myocardial ischemia-reperfusion.
Methods: Thirty swine underwent occlusion of the mid left anterior descending coronary artery for 60 minutes using a fluoroscopically-guided balloon catheter. Thirty minutes prior to reperfusion, 2 mg/kg of m21G6 mAb (n = 9) vs. saline (n = 14) was injected centrally in a blinded fashion. Animals were then followed for either 5 or 21 days. Primary endpoints for the 5d study were troponin levels and infarct size, while the primary endpoints for the 21d study also included left ventricular ejection fraction measured weekly by 2D and 3D echocardiography.
Results: There was no significant difference in the area at risk of the left ventricle between the saline and m21G6 treated groups (42% vs. 45%). Specificity and localization of m21G6 to injured myocardium of the left ventricle were confirmed by injecting fluorescently-labeled m21G6. Treatment with m21G6 resulted in a 49% reduction in infarct size as a function of the area at risk of the left ventricle (p = 0.0002). Furthermore, peak and integrated troponin levels were reduced by 61% and 47%, respectively in m21G6 vs. saline treated animals (p = 0.02, p = 0.0078). During the 21d functional study, m21G6 treated animals recovered 99% of their baseline cardiac function, as compared to 75% in saline treated controls (p = 0.013).
Conclusion: Treatment with m21G6 monoclonal antibody significantly reduced infarct size and troponin release, and led to a greater recovery of cardiac function in comparison to saline treated controls. Overall, these findings demonstrate that IgM blockade is a valid therapeutic strategy in mitigating myocardial ischemia-reperfusion injury.
- © 2013 by American Heart Association, Inc.