Anemia Contributes to Exercise Intolerance in Heart Failure with Preserved Ejection Fraction, Study Finds


An analysis of data from nearly 500 patients provides insight into the contributions of anemia to reduced exercise tolerance observed in patients with heart failure with preserved ejection fraction.

Hideki Ishii, MD, PhD Credit: European Society of Cardiology

Hideki Ishii, MD, PhD
Credit: European Society of Cardiology

New research from investigators in Japan are shedding light on the contributions of anemia to exercise tolerance in heart failure with preserved ejection fraction (HFpEF).

An exercise stress echocardiographic study of nearly 500 patients with and without HFpEF, results of the study suggest those with anemia and HFpEF had similar cardiac output during exercise, but had a lower exercise capacity, exercise intensity, and duration than their counterparts in other groups.

“These data provide new insights into the pathophysiology of anemia in patients with HFpEF,” wrote investigators.1

In 2023, the cardiology community, and advanced heart failure specialists specifically, has witnessed a renewed emphasis on addressing the impact of anemia and iron deficiency in patients with heart failure. Use of intravenous iron was centerstage at the European Society of Cardiology (ESC) 2023 Congress, where Robert Mentz, MD, of the Duke University School of Medicine, presented data from the HEART-FID trial, which was billed by investigators as the largest study to assess the long-term safety and efficacy of intravenous ferric carboxymaltose in heart failure with reduced ejection fraction and iron deficiency. During the same session, Piotr Ponikowski, MD, PhD, of Wroclaw Medical University, presented what he described as the largest and most up-to-date analysis of the effect of ferric carboxymaltose in iron deficient heart failure patients with reduced or mildly reduced ejection fraction in a pooled analysis of data from the CONFIRM-HF, AFFIRM-AHF, and HEART-FID trials.2

In addition to these presentations, the ESC updated their heart failure guidelines to include a pair of new recommendations related to intravenous iron supplementation. These updates recommended iron supplementation in symptomatic patients with reduced or mildly reduced ejection fraction, and iron deficiency, to alleviate heart failure symptoms and improve quality of life as well as recommending intravenous iron supplementation with ferric carboxymaltose or ferrite derisomaltose should be considered in symptomatic patients with reduced or mildly reduced and ejection fraction, and iron deficiency, to reduce the risk of heart failure hospitalization.2

The current study, which was led by led by Hideki Ishii, MD, PhD, and a team from Gunma University Graduate School of Medicine and the Nihon University School of Medicine, sought to develop a greater understanding of exercise capacity, cardiovascular and ventilatory reserve, and the O2 pathway in anemic patients with HFpEF. To do so, the study was designed as a retrospective analysis of consecutive patients referred for exercise stress echocardiography for exertion dyspnea at Gunma University Hospital in Japan from October 2019 though January 2023.1

For the purpose of analysis, HFpEF was defined using Heart Failure Association criteria and anemia was defined as a hemoglobin level less than 13 g/dL and less than 12 g/dL in men and women, respectively.1

A total of 486 participants were identified for inclusion in the study, including 248 controls and 238 patients with HFpEF.Investigators pointed out the prevalence of anemia in patients with HFpEF was 47% (n=112), with mean hemoglobin levels of 13.5 (Standard deviation [SD], 1.5) g/dL in controls, 13.7 (SD, 1.2) g/dL in HFpEF patients without anemia, and 10.9 (SD, 1.2) g/dL in anemic HFpEF patients.1

Upon analysis, results indicated patients with HFpEF and anemia had worse nutritional status and renal function, lower iron levels, and greater left ventricular (LV) remodeling and plasma volume expansion than those with HFpEF without anemia. Further analysis suggested peak VO2, exercise intensity, and exercise duration was reduced among those with anemia and HFpEF group than in the other groups, with these differences remaining significant after adjustment for age and sex (all P <.01).1

Investigators called attention to limitations within their study to consider when interpreting the findings from their study. These limitations included possibility of selection and referral bias as a result of being conducted at a tertiary referral center, inability to exclude the possibility some HFpEF patients may have been missed, and use of resting hemoglobin levels to estimate arterial O2 content during peak exercise.1

“We demonstrated that anemic HFpEF patients were characterized by worse nutritional status, lower renal function, and greater left heart remodeling and plasma volume expansion than those without anemia,” investigators wrote.1 “Anemia was associated with impaired arterial O2 delivery, which limited the augmentation of peripheral O2 extraction and utilization, contributing to poor exercise capacity.”


  1. Naito A, Obokata M, Kagami K, et al. Contributions of anemia to exercise intolerance in heart failure with preserved ejection fraction-An exercise stress echocardiographic study. Int J Cardiol Heart Vasc. 2023;48:101255. Published 2023 Aug 20. doi:10.1016/j.ijcha.2023.101255
  2. Campbell P. Role of intravenous iron in spotlight at ESC congress 2023. HCP Live. August 27, 2023. Accessed October 23, 2023.
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