Natural IgM Blockade Limits Infarct Expansion and Left Ventricular Dysfunction in a Swine Myocardial Infarct Model

Circ Cardiovasc Interv. 2016 Jan;9(1):e002547. doi: 10.1161/CIRCINTERVENTIONS.115.002547.

Abstract

Background: Acute coronary syndrome is the leading cause of mortality worldwide. However, treatment of acute coronary occlusion inevitably results in ischemia-reperfusion injury. Circulating natural IgM has been shown to play a significant role in mouse models of ischemia-reperfusion injury. A highly conserved self-antigen, nonmuscle myosin heavy chain II, has been identified as a target of pathogenic IgM. We hypothesized that a monoclonal antibody (m21G6) directed against nonmuscle myosin heavy chain II may inhibit IgM binding and reduce injury in a preclinical model of myocardial infarction. Thus, our objective was to evaluate the efficacy of intravenous m21G6 treatment in limiting infarct expansion, troponin release, and left ventricular dysfunction in a swine myocardial infarction model.

Methods and results: Massachusetts General Hospital miniature swine underwent occlusion of the midleft anterior descending coronary artery for 60 minutes, followed by 1 hour, 5-day, or 21-day reperfusion. Specificity and localization of m21G6 to injured myocardium were confirmed using fluorescently labeled m21G6. Treatment with m21G6 before reperfusion resulted in a 49% reduction in infarct size (P<0.005) and a 61% reduction in troponin-T levels (P<0.05) in comparison with saline controls at 5-day reperfusion. Furthermore, m21G6-treated animals recovered 85.4% of their baseline left ventricular function as measured by 2-dimensional transthoracic echocardiography in contrast to 67.1% in controls at 21-day reperfusion (P<0.05).

Conclusions: Treatment with m21G6 significantly reduced infarct size and troponin-T release, and led to marked preservation of cardiac function in our study. Overall, these findings suggest that pathogenic IgM blockade represents a valid therapeutic strategy in mitigating myocardial ischemia-reperfusion injury.

Keywords: immunology; inflammation; left ventricular function; myocardial infarction; troponin T.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Anti-Idiotypic / pharmacology*
  • Antibodies, Monoclonal / pharmacology*
  • Coronary Vessels
  • Disease Models, Animal
  • Disease Progression
  • Echocardiography
  • Follow-Up Studies
  • Immunoglobulin M / immunology*
  • Myocardial Infarction / complications
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / physiopathology
  • Myocardium / metabolism
  • Myocardium / pathology*
  • Myosin Heavy Chains / immunology
  • Swine
  • Swine, Miniature
  • Troponin T / metabolism
  • Ventricular Dysfunction, Left / etiology
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Dysfunction, Left / prevention & control*
  • Ventricular Function, Left / drug effects
  • Ventricular Function, Left / physiology*

Substances

  • Antibodies, Anti-Idiotypic
  • Antibodies, Monoclonal
  • Immunoglobulin M
  • Troponin T
  • Myosin Heavy Chains