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: 10290015
• 负责人: Gregory Dyer Lewis
• 金额: $ 64.36万
• 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/10290015
• 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.

项目总结/摘要 心力衰竭（HF）是世界范围内的主要公共卫生问题，并且呈现HF的患者中有一半患有心力衰竭。 射血分数保留（HFpEF），而不是射血分数降低（HFrEF）。然而，HFpEF仍然 鉴于目前对因果关系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， 血红蛋白水平然而，FID的纠正持续且持久地改善了HFrEF的运动能力， 关于FID对HFpEF患者或普通人群的功能影响，我们知之甚少。超出 由于铁在红细胞生成中作用，铁是肌红蛋白和参与细胞增殖的酶的专性组分。 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。铁调素是一种由肝脏合成的激素， 被认为是铁稳态的主要调节者。铁调素降低铁的生物利用度， 受炎症信号通路（如IL-6、IL-1β）和蛋白质hemojuvelin调节， 在铁传感中的关键作用。我们以前已经证明，较低的铁调素水平对心脏有保护作用， 动物模型研究和有症状的HFrEF患者中升高的铁调素水平排除了正常化 在NIH申办的多中心IRONOUT-HF试验中，在我们的初步调查中 HFpEF患者接受综合心肺运动试验（CPET）FID的研究， Tsat/hepcidin比值的降低与运动心输出量、外周氧摄取、肺动脉压、肺 血管阻力和峰值VO 2，暗示FID是运动多个方面的重要决定因素 容量我们现在建议在一个大的社区中测量铁状态，铁调素和血幼素水平- 基于队列（Frachial Heart Study Gen 3/OMNI 2，N= 3，116）和疑似 HFpEF（MGH ExS，N=450），以了解FID在功能能力方面的作用，利用现有的 CPET测量两个队列中的低水平、中等水平和峰值运动O2利用率。我们的总体 一种假设是FID出现在明显HFpEF之前的促炎状态， 其特征在于增加O2利用的能力受损，如通过降低的峰值VO 2所反映的。在目标1A中，我们 将确定功能性铁的患病率、危险因素、遗传决定因素和功能意义。 社区缺乏（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 表明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66例HFpEF患者的铁补充随机试验中，FID治疗可改善运动能力， 影响运动不耐症的不同机制。