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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

基本信息

批准号：
10664960
负责人：
Gregory Dyer Lewis
金额：
$ 61.43万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/10664960
关键词：
Activities of Daily Living Adult Anemia Animal Model Biological Availability Blood Tests Blood Vessels Cardiac Myocytes Cardiac Output Cardiopulmonary Cardiovascular Diseases Cardiovascular system Catecholamines Cell Respiration Cells Citric Acid Cycle Communities Development 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 Therapeutic Transferrin United States National Institutes of Health Work body system 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

项目摘要

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/文摘

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction: The METEORIC-HF Randomized Clinical Trial.

Omecamtiv Mecarbil 对射血分数降低的慢性心力衰竭运动能力的影响：METEORIC-HF 随机临床试验。

DOI：
10.1001/jama.2022.11016
发表时间：
2022
期刊：
JAMA
影响因子：
0
作者：
Lewis,GregoryD;Voors,AdriaanA;Cohen-Solal,Alain;Metra,Marco;Whellan,DavidJ;Ezekowitz,JustinA;Böhm,Michael;Teerlink,JohnR;Docherty,KieranF;Lopes,RenatoD;Divanji,PunagH;Heitner,StephenB;Kupfer,Stuart;Malik,FadyI;Meng,L
通讯作者：
Meng,L

Integrative single-cell meta-analysis reveals disease-relevant vascular cell states and markers in human atherosclerosis.

综合单细胞荟萃分析揭示了人类动脉粥样硬化中与疾病相关的血管细胞状态和标志物。

DOI：
10.1016/j.celrep.2023.113380
发表时间：
2023
期刊：
Cell reports
影响因子：
8.8
作者：
Mosquera,JoseVerdezoto;Auguste,Gaëlle;Wong,Doris;Turner,AdamW;Hodonsky,ChaniJ;Alvarez-Yela,AstridCatalina;Song,Yipei;Cheng,Qi;LinoCardenas,ChristianL;Theofilatos,Konstantinos;Bos,Maxime;Kavousi,Maryam;Peyser,PatriciaA;Mayr
通讯作者：
Mayr

Invasive exercise haemodynamics: an oracle in heart failure with preserved ejection fraction diagnosis and prognostication.

侵入性运动血流动力学：心力衰竭的神谕，具有保留的射血分数诊断和预测。