Prevention of heart failure with IL-1 blockade: a mechanistic study

项目摘要 本申请是针对一项名为“IL-1阻滞剂预防HF： 由Antonio Abbate MD，PhD和Benjamin货车Tassell，PharmD提交。尽管 随着早期诊断和治疗的改善，ST段抬高型心肌梗死（STEMI）仍然是一种 是美国发病率和死亡率的主要原因。STEMI患者的风险显著增加， 发展成心力衰竭虽然许多研究已经确定炎症是心力衰竭的危险因素， 目前还没有抗炎疗法在STEMI患者中具有记录的益处。中 白细胞介素-1（IL-1）是一种重要的炎症介质， 全身性炎症（即发热），但也因为IL-1足以引起心脏的显著抑制， 急性心肌梗死患者的心功能、心脏储备受损和心脏重构恶化。在最近的一 一项研究表明，在STEMI患者中使用阿那白滞素（重组IL-1受体拮抗剂）治疗可显著减弱 急性全身性炎症反应和较少的阿那白滞素治疗患者发生心力衰竭 在接下来的一年里。本申请将通过以下方式研究其机制来证实和扩展这些发现： 用阿那白滞素阻断IL-1可以预防心力衰竭。我们建议用阿那白滞素阻断IL-1 通过心脏舒张/收缩储备保持心肺功能，影响生活质量， STEMI患者心力衰竭的发生率。我们建议进行一项随机双盲安慰剂试验- 对照、II期临床试验（n=84），在以下患者中以1：1分配至阿那白滞素或安慰剂组，持续14天 急性STEMI和最先进的心肺运动试验，多普勒心脏成像 超声心动图和心脏磁共振、生物标志物和长达12个月的生活质量评估。

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.