Characterization of Functional Iron Deficiency and Repletion in Heart Failure with Preserved Ejection Fraction

项目摘要/摘要 心力衰竭(HF)是世界范围内的一个主要公共健康问题，有一半的心衰患者患有 保留射血分数(HFpEF)，而不是减少射血分数(HFrEF)。然而，HFpEF仍然 鉴于目前对病因和致病因素的了解有限，这是一项治疗挑战。功能铁 缺乏(FID，定义为铁蛋白水平100 ng/ml或转铁蛋白饱和度(TSAT)20%伴铁蛋白300 Ng/ml)存在于大约一半的HFpEF或HFrEF患者中。在HFrEF、FID患者中 与运动能力降低、生活质量下降和死亡率增加有关，无论 血红蛋白水平。然而，FID的纠正持续和持久地改善了HFrEF的运动能力 对于FID在HFpEF患者或普通人群中的功能影响，我们知之甚少。超越 铁在红血球生成中的作用，是肌红蛋白和细胞内相关酶的必需成分。 呼吸作用、氧化磷酸化、血管动态平衡、一氧化氮生成和柠檬酸循环， 这一切都会受到缺铁的负面影响。海普西丁，一种由肝脏合成的激素，是 被认为是铁稳态的主要调节者。海普西丁降低铁的生物利用度和水平 受炎症信号通路(如IL-6、IL-1β)和发挥作用的蛋白血红蛋白的调节 在铁感应中的关键作用。我们以前已经证明，较低的海普西丁水平对心脏有保护作用 动物模型研究和有症状的HFrEF患者海普西丁水平升高排除了正常化 在NIH赞助的多中心IRONOUT-HF试验中，口服补铁对FID的影响。在我们的预赛中 HFpEF患者进行综合心肺运动试验FID的研究 TSAT/海普西丁比率降低与运动心输出量、外周血氧摄取、肺功能 血管阻力和最大VO2，暗示FID是运动多方面的重要决定因素 容量。我们现在建议在一个大型社区中测量铁状态、海普西丁和血凝素水平- 基于队列(Framingham心脏研究第三代/OMNI2，N=3,116)和转诊队列中疑似 HFpEF(MGH EXS，N=450)，以了解FID与功能容量的关系，利用现有 CPET测量两个队列中的低水平、中等水平和高峰运动的氧气利用率。我们最重要的是 假设FID发生在显性HFpEF之前的促炎状态，这是 以增加氧气利用率的能力受损为特征的，表现为峰值VO2降低。在目标1A中，我们 将决定功能性铁的患病率、风险因素、遗传决定因素和功能意义 社区中的缺乏(FID)。在目标1B中，我们将确定FID与器官特异性功能障碍的关系 在MGH运动研究中指示HFpEF亚型。在目标2中，我们将前瞻性地调查 在一项对66名HFpEF患者进行的随机铁补充试验中，FID的治疗改善了运动能力和 影响运动不耐受的不同机制。

Project Summary/Abstract Heart failure (HF) is a major public health problem worldwide, and half of patients presenting with HF have preserved ejection fraction (HFpEF), rather than reduced ejection fraction (HFrEF). However, HFpEF remains a therapeutic challenge, given current limited understanding of causal and contributing factors. Functional iron deficiency (FID, defined as a ferritin level < 100 ng/ml or transferrin saturation (Tsat) < 20% with ferritin < 300 ng/ml) is present in approximately half of all patients with either HFpEF or HFrEF. In patients with HFrEF, FID is associated with reduced exercise capacity, poorer quality of life, and increased mortality regardless of hemoglobin level. Correction of FID consistently and durably improves exercise capacity in HFrEF, however less is known about the functional impact of FID in patients with HFpEF or in the general population. Beyond its role in erythropoiesis, iron is an obligate component of myoglobin and enzymes involved in cellular respiration, oxidative phosphorylation, vascular homeostasis, nitric oxide generation, and the citric acid cycle, which all can be negatively impacted by iron deficiency. Hepcidin, a hormone synthesized by the liver, is considered the master regulator of iron homeostasis. Hepcidin reduces iron bioavailability and levels are regulated by inflammatory signaling pathways (eg, IL-6, IL-1β) and by the protein hemojuvelin which plays a critical role in iron sensing. We have previously demonstrated that lower hepcidin levels are cardioprotective in animal model studies and that elevated hepcidin levels in symptomatic HFrEF patients precluded normalization of FID with oral iron supplementation in the NIH-sponsored multi-center IRONOUT-HF Trial. In our preliminary studies of HFpEF patients undergoing comprehensive cardiopulmonary exercise testing (CPET) FID with reduced Tsat/hepcidin ratio was associated with exercise cardiac output, peripheral O2 extraction, pulmonary vascular resistance and peak VO2, implicating FID as an important determinant of multiple aspects of exercise capacity. We now propose to measure iron status, hepcidin and hemojuvelin levels in a large community- based cohort (Framingham Heart Study Gen3/OMNI2, N=3,116) and in a referral cohort with suspected HFpEF (MGH ExS, N=450) to understand the role of FID in relation to functional capacity, leveraging existing CPET measures of low-level, intermediate and peak exercise O2 utilization in both cohorts. Our overarching hypothesis is that FID arises in the setting of pro-inflammatory states that precede overt HFpEF, which is characterized by impaired ability to augment O2 utilization, as reflected by reduced peak VO2. In Aim 1A, we will determine the prevalence, risk factors, genetic determinants, and functional significance of functional iron deficiency (FID) in the community. In Aim 1B, we will determine how FID relates to organ-specific dysfunction indicative of HFpEF subphenotypes in the MGH Exercise Study. In Aim 2, we will prospectively investigate how treatment of FID in a randomized trial of iron repletion in 66 HFpEF patients improves exercise capacity and influences distinct mechanisms of exercise intolerance.