Treating Acute Myocardial Infarctions With Anti-Inflammatory Agents.

There is an unmet need to further reduce the size of acute myocardial infarctions above and beyond the current standard of care of early reperfusion therapy with primary percutaneous coronary intervention (angioplasty/stenting) and anti-platelet agents to keep the infarct related artery patent. Even a 5% reduction in myocardial infarct size may be clinically meaningful. It is known that the inflammatory process occurs early after coronary artery occlusion/reperfusion with very early influx of neutrophils. There has been concern that if the inflammatory response is too severe it could contribute to additional myocardial cells dying and lead to infarct extension with a larger infarct size. On the other hand, the early inflammatory response is the first step in the healing phase of myocardial infarction. Experimental studies from the 1980s suggested that certain anti-inflammatory medicines, such as steroids and non-steroidal anti-inflammatory agents, such as ibuprofen, administered early during infarction would reduce the size of myocardial infarction. There was considerable excitement about this possibility and clinical studies were planned and some were carried out. However, there was underlying concern that inhibiting the inflammatory cascade early after occlusion might then inhibit the healing phase of acute myocardial infarction. In a series of studies from the early 1980s our research group assessed the effects of methylprednisolone, ibuprofen, and indomethacin on the healing phase of myocardial infarctions. Methylprednisolone was shown to enhance “mummification” of the myocardium whereby large sheets of necrotic, but architecturally preserved muscle fibers remained in the center of the myocardial infarction during the healing phase. Steroids clearly suppressed the process whereby necrotic debris is removed from the infarct and delayed the shrinkage of the scar. Short term administration of methylprednisolone resulted in thinner scars and reduced left ventricular function. Nonsteroidal anti-inflammatory drugs including ibuprofen and indomethacin when administered early and acutely after myocardial infarction contributed to an increase in myocardial infarct expansion, that phenomenon whereby necrotic myocytes thin, stretch, slip by each other resulting in a thin and elongated infarct, thinned scar, regional ventricular dilatation and then global dilatation. This phenomenon of adverse left ventricular remodeling is known to occur in patients, especially those with large infarcts and can contribute to heart failure, myocardial rupture and death. There were a few clinical studies that examined the effect of steroids on myocardial infarct size in which the results were negative; although one meta-analysis suggested corticosteroids did no harm and perhaps improved survival. Clinical trials that tried to impede the function of neutrophils, including their ability to adhere to the walls of blood vessels and trials of anticomplement strategies were negative. Thus, after pre-clinical studies showing concern about inhibiting the healing phase of infarction coupled with negative clinical trials, the enthusiasm for treating myocardial infarctions with anti-inflammatory drugs faded . . . . . . until recently. Work by investigators including Ridker and Libby and others clearly showed that inflammation played a crucial aspect of the pathogenesis of atherosclerosis and its sequelae. Studies in patients with chronic coronary artery disease showed that colchicine and some very specific anti-inflammatory agents such as interleukin-1 (IL-1) receptor antagonist canakinumab, were capable of reducing major adverse cardiovascular events. Recent studies are now exploring a more focused approach on inhibiting the interleukin 1 or 6 pathway for reducing inflammation in the setting of acute myocardial infarction with some early promising results. Abbate et al reported on the effects of an interleukin-1 blocker, anakinra, given once daily or twice daily over 2 weeks in patients with acute ST segment elevation myocardial infarction. Anakinra did not reduce enzymatic estimates of myocardial infarction, but it did decrease the high-sensitivity C Reactive Protein (high sensitivity-CRP) area under the curve, verifying an anti-inflammatory action. Over the course of 1 year, anakinra reduced the composite endpoint of all-cause death and new-onset of worsening heart failure. The change in LV volumes and ejection fraction