Acute myocardial infarction (AMI) remains a major cause of morbidity and mortality. Many patients die early during the course, and those who survive are at risk for dying late from adverse cardiac remodeling and heart failure. The initial ischemic damage to the myocardium initiates an intense inflammatory response in promoting further cardiac dysfunction and heart failure. Interleukin-1 (IL-1) is the prototypical inflammatory cytokine involved in the tissue response to injury. In the experimental model of large anterior wall AMI in the mouse, IL-1 blockade using anakinra, a recombinant human IL-1 receptor antagonist ameliorates cardiac remodeling and improves survival following AMI. Although the mouse AMI model is helpful in understanding the events leading to adverse post-infarction cardiac remodeling and heart failure, the exact role of IL-1 in patients with AMI has not been completely characterized. We propose to address this question by studying patients presenting with ST-segment elevation AMI (STEMI). Such patients are at high risk for in-hospital and long-term mortality and display several markers of inflammation. We hypothesize that IL-1 blockade in patients STEMI with will limit the acute inflammatory response and prevent adverse cardiac remodeling, heart failure, and related morbidity.We plan to study the individual response in biomarkers, cardiac dimensions and systolic and diastolic function, and exercise capacity in patients admitted with STEMI and randomized to treatment with anakinra or matching placebo for 14 days. We anticipate that patients with STEMI will have increased CRP levels, reflecting leukocyte activation and enhanced response to specific and non-specific stimuli, and that CRP peak levels will predict adverse cardiac remodeling. We hypothesize that anakinra will blunt the inflammatory response during STEMI compared with placebo.We also hypothesize that treatment with anakinra will lead to more favorable cardiac remodeling. Left ventricular end-systolic volume index (LVESVi) is the preferred clinical marker of adverse cardiac remodeling and a strong predictor of heart failure-related mortality in patients with STEMI, and will be used as primary endpoint of the study. We propose that anakinra will reduce the change in LVESVi from baseline to 10-14 weeks after STEMI, and will prevent, at least in part, other changes in cardiac function and exercise tolerance associated with adverse cardiac remodeling and heart failure.
|Program type||Scientist Development Grant|
|Effective start/end date||07/01/2010 → 06/30/2014|