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.

项目摘要/摘要 心力衰竭（HF）是全球一个主要的公共卫生问题，有一半的HF患者有 保留的射血分数（HFPEF），而不是减少射血分数（HFREF）。但是，HFPEF仍然存在 鉴于当前对因果关系和促成因素的了解有限，治疗挑战。功能铁 缺陷（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）大约有HFPEF或HFREF患者中的一半。在HFREF患者中 与降低的运动能力，较差的生活质量和死亡率有关 血红蛋白水平。但是 关于FID对HFPEF患者或普通人群患者的功能影响知之甚少。超过 铁在红细胞生成中的作用，铁是肌红蛋白和酶的强制性成分 呼吸，氧化磷酸化，血管稳态，一氧化氮的产生和柠檬酸循环， 所有这些都会受到铁缺乏症的负面影响。肝脏是由肝脏合成的马匹肝素的，是 被认为是铁稳态的主要调节剂。肝素降低了铁生物利用度，水平为 受炎症信号通路（例如，IL-6，IL-1β）和蛋白质血二素的调节 在铁敏感性中的关键作用。我们以前已经证明，在 动物模型研究以及有症状的HFREF患者的肝素水平升高排除了归一化 在NIH赞助的多中心Ironout-HF试验中，添加口服铁的FID。在我们的初步中 HFPEF患者接受全面心肺运动测试（CPET）FID的研究 降低的TSAT/肝素比与运动心输出量，外周O2提取，肺相关 血管抗性和峰值Vo2，隐含的fid是锻炼多个方面的重要决定因素 容量。现在，我们建议在一个大型社区中衡量铁状态，肝素和血果素水平 - 基于基于的队列（Framingham心脏研究GEN3/OMNI2，n = 3,116），在带有可疑的转诊队列中 HFPEF（MGH EXS，n = 450）了解FID在功能能力方面的作用，利用现有 CPET在两个队列中的低水平，中级和峰值运动O2利用率的量度。我们的总体 假设是FID在公开HFPEF之前的促炎状态下产生 峰值VO2的峰值反映，其特征在于增加O2利用的能力。在AIM 1A中，我们 将确定功能铁的患病率，危险因素，遗传确定剂和功能意义 社区中的不足（FID）。在AIM 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亚表征。在AIM 2中，我们可能会调查如何 在66名HFPEF患者的铁补充的随机试验中，FID的治疗提高了运动能力和 影响运动肠道的不同机制。