Project Summary This application is for a Mechanistic Clinical Study (R01) entitled “Prevention of HF with IL-1 blockade: a mechanistic study” submitted by Antonio Abbate MD, PhD and Benjamin Van Tassell, PharmD. Despite improvements in early diagnosis and treatment, ST-segment elevation myocardial infarction (STEMI) remains a leading cause of morbidity and mortality in the US. Patients with STEMI are significantly increased risk for developing heart failure. While numerous studies have identified inflammation as a risk factor for heart failure, there are currently no anti-inflammatory therapies with a documented benefit in patients with STEMI. Among the different inflammatory mediators, Interleukin-1 (IL-1) occupies a central role, not only because it is a key mediator of systemic inflammation (i.e. fever) but also because IL-1 is sufficient to cause significant depression of cardiac function, impaired cardiac reserve, and worsened cardiac remodeling in acute myocardial infarction. In a recent study, treatment with anakinra (recombinant IL-1 receptor antagonist) in patients with STEMI significantly blunted the acute systemic inflammatory response and fewer patients treated with anakinra developed heart failure during the following year. This application will confirm and expand these findings by studying the mechanism by which IL-1 blockade with anakinra may prevent heart failure. We propose the IL-1 blockade with anakinra preserves cardiorespiratory fitness through cardiac diastolic/systolic reserve, affecting quality of life, and incidence of heart failure in patients with STEMI. We propose to conduct a randomized, double-blind, placebo- controlled, phase II clinical trial (n=84) with 1:1 allocation to anakinra or placebo for 14 days among patients with acute STEMI and state-of-the-art cardiopulmonary exercise testing, cardiac imaging with Doppler echocardiography and cardiac magnetic resonance, biomarkers and quality of life assessments up to 12 months.