Interleukin-1 blockade in heart failure with preserved ejection fraction

描述（由申请人提供）：心力衰竭（HF）是一种复杂的临床综合征，以呼吸短促和疲劳引起的运动不耐受为特征。大约一半的HF患者心脏收缩力降低（HF伴射血分数降低[HFrEF]），而其余一半的患者心脏收缩力保持不变，但心脏舒张功能受损（HF伴射血分数保持[HFpEF]或舒张性心力衰竭）。目前尚无针对HFpEF的既定治疗方法，许多已证明对HFpEF有效的治疗方法对HFpEF没有任何益处。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。HF患者身体损伤与炎症细胞因子水平升高之间存在显著相关性。在这些细胞因子中，白细胞介素-1 （IL-1）是全身性炎症的关键介质，在HFrEF和HFpEF中都会升高，并可能导致心功能受损和运动不耐受。在最近的一项概念验证研究中，用重组人IL-1受体拮抗剂（anakinra）治疗2周，通过测量HFrEF患者的峰值耗氧量（VO2）和通气效率（VE/VCO2斜率），可以显著改善有氧运动表现。我们提出，炎症增强（IL-1）也有助于HFpEF患者疾病的严重程度，并建议在一项随机、双盲、试点研究（n=60）中，测量阿那白拉阻断IL-1对运动表现的影响，并估计IL-1阻断对HFpEF患者住院率的潜在益处。符合条件的患者将随机（2:1）接受12周的阿那真拉治疗（n=40）或安慰剂治疗（n=20）。患者将进行心肺运动试验以测量有氧运动表现，并进行应激超声心动图以测量静息和应激时的充盈模式、舒张功能和收缩力。将分析生物标志物与临床变量的相关性。该试点研究的结果将用于优化治疗策略，并设计后续的III期临床试验，以评估IL-1阻断对HFpEF患者的潜在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.