Ferrokinetics Impacts Physical Therapy Responses in HFpEF

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Compared to the usual care, patients with HFpEF in the active arms demonstrated less improvement in peakVO2 when they had iron deficiency and lower values of ferritin and transferrin saturation, according to a new study.

A new study found ferrokinetics plays a vital role in modifying the response to physical therapies in patients with heart failure preserved ejection fraction (HFpEF).1

Led by Patricia Palau, from the department of cardiology at Hospital Clínico Universitario, INCLIVA, Universitat de València in Valencia, Spain, investigators sought to evaluate the effect of baseline ferrokenetics on peak oxygen consumption (peakVO2) improvement following a 12-week physical therapy program for patients with stable HFpEF.

“We found that baseline ferrokinetic was associated with maximal aerobic capacity response to exercise training by showing that patients with surrogates of [iron deficiency] showed lower improvement in aerobic capacity in response to physical therapies,” wrote investigators.

A common issue in patients with heart failure, management of iron deficiency has been a major topic of discussion for the cardiology community in recent years.2 Much of this comes as the result of major trials, including HEART-FID, that have spurred new guideline recommendations from major organizations, including the European Society of Cardiology.

Despite its prevalence, little is known about the effect of baseline ferrokinetics status on response to exercise-based cardiac rehabilitation programs.1 Therefore, the investigators wanted to see how physical therapy impacted the condition in their post-hoc sub-analysis of the TRAINING-HF trial.

The TRAINING-HF trial was a randomized clinical trial where 59 stable patients with HFpEF were randomized into 1 of the 3 study arms: inspiratory muscle training, functional electrical stimulation, a combination of inspiratory muscle training and functioning electrical stimulation (usual care). All arms but usual care, which served as a control arm, received a 12-week physical therapy.

The inspiratory muscle training arm had physical therapies focusing on improving muscle strength with weekly monitoring by a physiotherapist. The functional electrical stimulation arm had leg muscle training sessions with functional electrical stimulation twice a week.

The study was conducted at Hospital Clínic Universitari de València from September 2015 – December 2016. To be included in the study, individuals had to have a New York Heart Association functional class ≥ II, a left ventricular ejection fraction >50% and end-diastolic diameter < 60 mm, a structural heart disease (left ventricle hypertrophy/ left atrial enlargement), diastolic dysfunction calculated by a 2-dimensional echocardiography according to the 2012 European Society of Cardiology Guidelines, and clinical stability, meaning no HF decompensations in the past 3 months.

In total, 52 patients completed the trial. The mean age of the cohort was 74 ± 9 years, and 58% (n = 43) were female.

Serum ferritin and transferrin saturation were both assessed at baseline. Iron deficiency was characterized as ferritin < 100 ng/mL or a transferrin saturation <20% if ferritin was within the 100 – 299 ng/mL. Hemoglobin concentration was defined as a hemoglobin level of <12 g/dL in women and < 13 g/dL in men, as per the World Health Organization definition.

The investigators evaluated maximal functional capacity with cardiopulmonary exercise testing on a bicycle ergometer, starting with a workload of 10 W and gradually increasing 10 W increments every minute. The maximal functional capacity was when the patient stopped pedaling due to symptoms, and the respiratory exchange ratio was ≥ 1.

The investigators found 61% (n = 36) of participants had iron deficiency. The team used a linear mixed regression model to evaluate treatment changes in peakVO2 across ferrokinetics status at weeks 12 and 24 and found the mean of peakVO2 was 9.9 ± 2.5 mL/kg/min. Additionally, the median of ferritin was 91 (50 – 181) ng/mL, and the median for transferrin saturation was 23% (16–30).

Compared to patients with usual care, patients randomized to the active arms demonstrated less improvement in peak VO2 when they had iron deficiency (P < .001), as well as lower values of ferritin (P < .001) and transferrin saturation (P < .001).

“The association between ferrokinetic status and functional response to therapy was greater at 3 months, a fact that may be attributable to the restriction of physical intervention to a period of 3-month,” investigators wrote.

The investigators highlighted several limitations, such as it not being able to be generalized to other populations with it being a single-center study and only evaluating patients with symptomatic stable HFpEF—and thus the findings may not apply to individuals with milder syndrome forms. Other limitations they pointed out were not evaluating the nutritional and inflammatory status that could impact therapy response, as well as acknowledging the fact this was a post-hoc analysis, and the study was not designed to assess peakVO2 following physical therapy for patients with HFpEF.

“In this post hoc analysis of the TRAINING-HF trial on patients with symptomatic HFpEF, ID was associated with poorer aerobic capacity improvement after a 12-week programme of physical therapies,” investigators wrote. “Further studies are needed to confirm these results and evaluate their clinical implications.”


  1. Palau P, López L, Domínguez E, et al. Exercise training response according to baseline ferrokinetics in heart failure with preserved ejection fraction: A substudy of the TRAINING-HF trial. J Cachexia Sarcopenia Muscle. Published online January 15, 2024. doi:10.1002/jcsm.13419
  2. Campbell P. Interpreting new IV iron guidelines, with muthiah vaduganathan, MD, MPH. HCP Live. October 9, 2023. Accessed January 24, 2024.