Interleukin-1 blockade in heart failure with preserved ejection fraction

描述(申请人提供)：心力衰竭(HF)是一种复杂的临床综合征，其特征是由于呼吸急促和疲劳而导致的运动不耐受。大约一半的心力衰竭患者心脏收缩能力降低(心力衰竭伴随射血分数降低[HFrEF])，而其余一半患者心脏收缩能力保持但心脏松弛功能受损(心力衰竭射血分数保留[HFpEF]或舒张性心力衰竭)。目前还没有确定的治疗HFpEF的方法，许多在HFrEF中被证明有效的治疗方法在HFpEF中没有好处。因此，迫切需要开发新的治疗方法来缓解症状，减缓疾病进展，并防止HFpEF患者住院。心力衰竭患者的身体损害与炎性细胞因子水平升高之间存在显著的相关性。在这些细胞因子中，白介素1(IL-1)是全身炎症的关键介质，在HFrEF和HFpEF中都会升高，并可能导致心功能受损和运动耐受。在最近的一项概念验证研究中，使用重组人IL-1受体拮抗剂(Anakinra)治疗2周后，HFrEF患者的有氧运动能力显著改善，这是通过峰值氧耗(VO2)和通风效率(VE/VCO2斜率)来衡量的。我们认为炎症增强(IL-1)也有助于HFpEF患者的病情严重程度，并建议在一项随机、双盲、先导性研究中(n=60)测量使用Anakinra的IL-1阻断对运动能力的影响，并评估IL-1阻断对HFpEF患者住院率的潜在益处。符合条件的患者将被随机(2：1)至12周的Anakinra治疗(n=40)或安慰剂治疗(n=20)。患者将接受心肺运动试验，以测量有氧运动表现，并进行负荷超声心动图，以测量充盈模式，舒张期功能，以及在休息和应激时的收缩能力。生物标志物将与临床变量进行相关性分析。这项先导性研究的结果将被用于优化治疗策略，并设计后续的III期临床试验，以评估IL-1阻断对HFpEF患者潜在的长期发病率和死亡率。

DESCRIPTION (provided by applicant): Heart failure (HF) is a complex clinical syndrome characterized by exercise intolerance due to shortness of breath and fatigue. Approximately half of HF patients have reduced cardiac contractility (HF with reduced ejection fraction [HFrEF]), whereas the remaining half has preserved contractility but impaired relaxation of the heart (HF with preserved ejection fraction [HFpEF] or diastolic heart failure). There are currently no established therapies for HFpEF and many of the treatments with demonstrated effectiveness in HFrEF provide no benefit in HFpEF. There is therefore an urgent need to develop novel treatments to alleviate symptoms, slow disease progression, and prevent hospitalizations in patients with HFpEF. A significant correlation exists between physical impairment and increasing levels of inflammatory cytokines in patients with HF. Among these cytokines, Interleukin-1 (IL-1) is a key mediator of systemic inflammation that becomes elevated in both HFrEF and HFpEF and may contribute to impaired cardiac function and exercise intolerance. In a recent proof-of-concept study, 2 weeks treatment with recombinant human IL-1 receptor antagonist (anakinra) produced a significant improvement in aerobic exercise performance as measured by peak oxygen consumption (VO2) and ventilatory efficiency (VE/VCO2 slope) in patients with HFrEF. We propose that enhanced inflammation (IL-1) also contributes to the severity of illness in patients with HFpEF and propose to measure the effect of IL-1 blockade with anakinra on exercise performance and to estimate the potential benefit of IL-1 blockade on hospital admission rates in a randomized, double-blind, pilot study (n=60) of patients with HFpEF. Eligible patients will be randomized (2:1) to 12 weeks treatment with anakinra (n=40) or placebo treatment (n=20). Patients will undergo cardiopulmonary exercise test to measure aerobic exercise performance and stress echocardiography to measure filling patterns, diastolic function, and contractility at rest and during stress. Biomarkers will be analyzed in correlation with the clinical variables. Results from this pilot study will be used to optimize the treatment strategy and design a subsequent phase III clinical trial to evaluate the potential long-term morbidity and mortality with IL-1 blockade in patients with HFpEF.