Effect of iron deficiency on skeletal muscle metabolism in heart failure with preserved ejection fraction
Authors: Weerts J , Barandiaran Aizpurua M A , Brouwers J H M , Mevenkamp J , Schroen B L M , Knackstedt C , Houben A J H M , Schrauwen-Hinderling V B , Van Empel V P M 
Published: October 2022

Abstract

Background
Iron deficiency (ID) is suggested to be one of the key comorbidities contributing to heart failure with preserved ejection fraction (HFpEF) and concomitant exercise intolerance, possibly by inducing systemic inflammation and microvascular dysfunction (MVD). ID is associated with poorer prognosis in HFpEF, but its exact impact on exercise capacity in HFpEF patients remains to be further investigated.

Purpose
To evaluate the effect of ID on exercise capacity in HFpEF patients by assessing skeletal muscle metabolism. Additionally, to assess the association between ID and MVD in HFpEF patients.

Methods
This prospective study included patients diagnosed with HFpEF according to the ESC Heart Failure 2016 guidelines between January 2018 and May 2021. Patients were excluded if they were of childbearing potential, had any iron supplementation 6 months or chemotherapy 1 year prior to inclusion, were known with significant peripheral artery disease, or had any contraindication for phosphorus-magnetic resonance spectroscopy (31P-MRS). Iron status was defined as absolute ID (serum ferritin &lt;100μg/L), relative ID (serum ferritin 100–299μg/L and transferrin saturation &lt;20%), and no ID. Skeletal muscle oxidative capacity of the upper leg was evaluated by determining phosphocreatine (PCr) recovery kinetics with 31P-MRS in the vastus lateralis muscle after isometric knee extension exercise. Microvascular function was assessed as heat-induced skin hyperemia using laser-Doppler flowmetry. Clinical data up to 6 months prior to or after inclusion was used.

Results
Twenty-four HFpEF patients without ID and 18 with ID were included, including 14 patients with absolute ID. Clinical characteristics of patients without ID and with ID were comparable: median age 74 [69–79] vs. 77 [69–81] years, 13 (54%) vs. 14 (78%) were females, and 20 (83%) vs. 16 (89%) had a history of hypertension (Table 1). Both groups showed similar halftime of PCr recovery after exercise (29.2 [22.8–33.2] vs. 27.0 [21.1–31.4] seconds, p=0.416), and similar skin hyperaemic flow increase (1142 [576–2247] vs. 1023 [574–1511] %, p=0.554). These measures of skeletal muscle metabolism and microvascular function were not correlated. In a subset of patients (11 without ID and 13 with ID), elevated high-sensitive C-reactive protein (hsCRP) was correlated with PCr recovery halftime in those with ID (R2 0.565, p=0.003). This correlation was not found in patients without ID (R2 0.119, p=0.300) in the original data (Figure 1), but was found after removal of a prominent outlier (R2 0.654, p=0.005).

Conclusion
HFpEF patients without ID showed comparable skeletal muscle oxidative capacity and microvascular skin hyperaemia compared to HFpEF patients with ID. Post-hoc analysis suggests that inflammation affects skeletal muscle metabolism in HFpEF patients, possibly regardless of ID. Future studies on the effects of ID and inflammation on cellular metabolism could suggest therapeutic targets in HFpEF.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): This study was funded by Vifor Pharma. The funder had no influence on the study results.