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

项目摘要 本申请适用于一项名为“使用IL-1阻断预防心衰：A”的机械性临床研究(R01) 由Antonio Abbate医学博士和Benjamin Van Tassell药学博士提交的《机械研究》。尽管 ST段抬高心肌梗死(STEMI)早期诊断和治疗的改进 是美国发病率和死亡率的主要原因。患有STEMI的患者显著增加了 发展为心力衰竭。虽然许多研究已经确定炎症是心力衰竭的风险因素， 目前还没有抗炎疗法对STEMI患者有明确的益处。在这些人中 不同的炎症介质，白介素1(IL-1)占据着核心作用，不仅因为它是一个关键的介质 全身炎症(即发烧)，但也因为IL-1足以导致心脏显著抑制 急性心肌梗死患者心脏功能受损，心脏储备受损，心脏重构恶化。在最近一次 研究表明，阿纳金拉(重组IL-1受体拮抗剂)对STEMI患者的治疗作用明显减弱 急性全身炎症反应和较少接受Anakinra治疗的患者发生心力衰竭 在下一年。这个应用程序将通过研究以下机制来确认和扩展这些发现 用Anakinra阻断IL-1可以预防心力衰竭。我们建议用Anakinra阻断IL-1 通过心脏舒张期/收缩期储备来保持心肺健康，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- 对照II期临床试验(n=84)，在患有以下疾病的患者中，1：1分配给阿纳金拉或安慰剂，疗程14天 急性STEMI和最新的心肺运动试验、心脏成像和多普勒 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.