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

IL-1 阻断预防心力衰竭：机制研究

基本信息

批准号：
10577771
负责人：
Antonio Abbate
金额：
$ 62.08万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577771
关键词：
Acute Acute myocardial infarction Affect Anti-Inflammatory Agents Biological Markers Boston C-reactive protein Cardiac Cardiac Output Cardiopulmonary Cessation of life Clinical Clinical Data Clinical Research Clinical Trials Coupled Doctor of Pharmacy Doctor of Philosophy Doppler Echocardiography Double-Blind Method Early Diagnosis Early treatment Echocardiography Event Exercise Exercise Test Fever Functional disorder Heart failure Hospitalization Hospitals Image Impairment Incidence Infarction Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-1 Intervention Ischemia Left Left Ventricular Ejection Fraction Link Magnetic Resonance Measures Mediator Morbidity - disease rate Muscle Myocardial Infarction Myocardial dysfunction Myocardium Outcome Oxygen Consumption Patients Phase II Clinical Trials Placebo Control Placebos Prevention Prevention approach Process Quality of Life Assessment Quality of life ROC Curve Randomized Recombinant Interleukin-1 Reperfusion Therapy Risk Risk Factors Role Sensitivity and Specificity Testing Time Tissues Translating Ventricular Woman adjudication anakinra cardiac depression cardiorespiratory fitness cytokine healing heart function heart imaging heart preservation improved insight mortality multidisciplinary myocardial damage novel novel strategies phase 2 study preservation prevent primary endpoint response to injury systemic inflammatory response

项目摘要

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.

项目摘要该应用是用于机械临床研究（R01），名为“使用IL-1盖blocade预防HF：A 机械研究”由Antonio Abbate MD，博士和Benjamin van Tassell提交。早期诊断和治疗的改善，ST段海拔心肌梗塞（STEMI）仍然是一个美国发病和死亡率的主要原因。 STEMI患者的风险显着增加发展心力衰竭。尽管许多研究都将炎症确定为心力衰竭的危险因素，但目前尚无抗炎疗法对STEMI患者的益处。在不同的炎症介质，白介素-1（IL-1）占据了核心角色，不仅是因为它是关键的介体系统性炎症（即发烧）的功能，心脏储备受损，并在急性心肌梗塞中恶化心脏重塑。在最近的一个研究，用Anakinra（重组IL-1受体拮抗剂）治疗STEMI患者急性全身性炎症反应和用Anakinra治疗的患者较少出现心力衰竭在第二年。该应用程序将通过研究机制来确认和扩展这些发现 IL-1用Anakinra阻断可以防止心力衰竭。我们建议用anakinra进行IL-1封锁通过心脏舒张/收缩期储备保护心肺健康，影响生活质量，并且 STEMI患者心力衰竭的发生率。我们建议进行随机的双盲，安慰剂 - 受控的，II期临床试验（n = 84），分配给Anakinra或安慰剂1：1的患者14天急性STEMI和最新的心肺运动测试，多普勒的心脏成像超声心动图和心脏磁共振，生物标志物和生活质量评估长达12个月。