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.

Project Narrative (Public Health Relevance) Heart failure with preserved ejection fraction (HFpEF) is a highly morbid condition in which exercise capacity is significantly reduced. Our goal is to understand how functional iron deficiency relates to exercise capacity in HFpEF and in middle-aged adults at risk for HFpEF. We will then perform a trial to investigate how iron repletion influences mechanisms of exercise intolerance in patients with symptomatic HFpEF.