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

保留射血分数的心力衰竭功能性缺铁和补充铁的特征

• 批准号: 10468811
• 负责人: Gregory Dyer Lewis
• 金额: $ 62.41万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468811
• 关键词: Activities of Daily Living; Adult; Anemia; Animal Model; Biological Availability; Blood Tests; Blood Vessels; Cardiac Myocytes; Cardiac Output; Cardiopulmonary; Cardiovascular Models; Cardiovascular system; Catecholamines; Cell Respiration; Cells; Citric Acid Cycle; Communities; EFRAC; Enzymes; Erythropoiesis; Exercise; Exercise Test; Ferritin; Framingham Heart Study; Functional disorder; General Population; Generations; Genetic Determinism; Goals; Guidelines; HFE2 gene; Heart failure; Hemoglobin concentration result; High Prevalence; Homeostasis; Hormones; Human; Impairment; Individual; Inflammatory; Interleukin-1 beta; Interleukin-6; Intervention; Intravenous; Iron; Liver; Measures; Morbidity - disease rate; Muscle Fibers; Myoglobin; Nitric Oxide; Oral; Organ; Oxidative Phosphorylation; Oxygen; Patients; Peripheral; Pharmacotherapy; Phenotype; Physiological; Play; Population; Prevalence; Production; Proteins; Public Health; Pulmonary Vascular Resistance; Quality of life; Recommendation; Reporting; Risk; Risk Factors; Role; Serum; Signal Pathway; Skeletal Muscle; Study models; System; Therapeutic; Transferrin; United States National Institutes of Health; Work; base; cardiogenesis; cardioprotection; cardiorespiratory fitness; cohort; cost; exercise capacity; exercise intolerance; hemodynamics; hepcidin; improved; insight; iron deficiency; iron supplementation; middle age; mortality; pregnant; preservation; prospective; public health relevance; randomized trial; routine screening; ventricular hypertrophy

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.

项目概要/摘要 心力衰竭（HF）是世界范围内的一个主要公共卫生问题，一半的心力衰竭患者患有心力衰竭（HF）。 保留射血分数（HFpEF），而不是降低射血分数（HFrEF）。然而，HFpEF 仍然 鉴于目前对因果和影响因素的了解有限，这是一个治疗挑战。功能性铁 缺乏症（FID，定义为铁蛋白水平 < 100 ng/ml 或转铁蛋白饱和度 (Tsat) < 20%，铁蛋白 < 300 ng/ml) 存在于大约一半的 HFpEF 或 HFrEF 患者中。对于 HFrEF、FID 患者 与运动能力下降、生活质量较差和死亡率增加有关，无论 血红蛋白水平。然而，持续且持久地纠正 FID 可以提高 HFrEF 的运动能力 关于 FID 对 HFpEF 患者或一般人群的功能影响知之甚少。超过 由于其在红细胞生成中的作用，铁是肌红蛋白和参与细胞生成的酶的必需成分。 呼吸、氧化磷酸化、血管稳态、一氧化氮生成和柠檬酸循环， 这些都可能受到缺铁的负面影响。铁调素（Hepcidin）是一种由肝脏合成的激素， 被认为是铁稳态的主要调节剂。铁调素可降低铁的生物利用度，其水平为 受炎症信号通路（例如 IL-6、IL-1β）和血幼素蛋白调节，血幼素蛋白发挥着重要作用 在铁传感中发挥着关键作用。我们之前已经证明，较低的铁调素水平对心脏有保护作用。 动物模型研究表明，有症状的 HFrEF 患者铁调素水平升高阻碍了正常化 在 NIH 赞助的多中心 IRONOUT-HF 试验中，FID 与口服铁补充剂的结合。在我们的初步 对 HFpEF 患者进行综合心肺运动试验 (CPET) FID 的研究 Tsat/铁调素比值降低与运动心输出量、外周 O2 提取量、肺功能相关。 血管阻力和峰值摄氧量，表明 FID 是运动多个方面的重要决定因素 容量。我们现在建议测量一个大社区中的铁状况、铁调素和血幼素水平 - 基于队列（弗雷明汉心脏研究 Gen3/OMNI2，N=3,116）和疑似疑似患者的转诊队列 HFpEF（MGH ExS，N=450）了解 FID 在功能能力方面的作用，利用现有的 CPET 测量两组中低水平、中水平和峰值运动 O2 利用率。我们的首要任务 假设 FID 出现在明显 HFpEF 之前的促炎状态中，即 其特点是增加 O2 利用率的能力受损，如峰值 VO2 降低所反映。在目标 1A 中，我们 将确定功能性铁的患病率、风险因素、遗传决定因素和功能意义 社区中的缺陷（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 指示 MGH 运动研究中的 HFpEF 亚表型。在目标 2 中，我们将前瞻性地研究如何 在一项对 66 名 HFpEF 患者进行补铁的随机试验中，FID 治疗可改善运动能力和 影响运动不耐受的不同机制。