Soluble transferrin receptor as a marker of tissue iron deficiency: impact on exercise capacity and functional class in patients with heart failure without systemic iron deficiency or anaemia
Authors: Ramos Polo R , Ras Jimenez M , Jimenez Marrero S , Jose Bazan N , Corbella M , Calero Molina E , Alcoberro L , Quiros Hidalgo E , Enjuanes Grau C , Yun Viladomat S , Ruiz Munoz M , Garay Melero A , Moliner Borja P , Comin Colet J 
Published: November 2023

Abstract

Background
Soluble receptor of transferrin (sTfR) is a marker of tissue iron status and may help to inform on subtle iron depletion and increased iron demand at tissular level even in the absence of overt systemic iron deficiency or anaemia. In this regard, the impact of raised sTfR levels as a marker of subtle tissue ID on functional limitation and submaximal exercise capacity in non-anaemic HF patients with normal systemic iron status has not been evaluated.

Purpose
To describe the association between sTfR as a marker of increased iron demand and tissue iron deficiency on submaximal exercise capacity, estimated with the distance walked in the 6-minutes walking test (6MWT), and symptoms of functional limitation (evaluated with the NYHA functional class) in non-anaemic patients with HF and normal systemic iron status.

Methods
We conducted an observational, prospective, cohort study of 1120 consecutive patients with chronic HF regardless the level of LVEF (DAMOCLES study). Patients included had a normal haemoglobin levels (≥12 g/dL), a normal systemic iron status (serum iron &gt;33 µg/dL, ferritin &gt;100ng/mL and % transferrin saturation &gt;20%) and an available 6-minute walking test data. Tissue ID was defined as levels of sTfR &gt;75th percentile (1.63mg/L). The primary endpoint was the distance walked in the 6MWT at inclusion in the study.
The unadjusted associations between sTfR and the distance walked in the 6MWT were explored using General Additive Models (GAM), uni/multivariate linear regression models and also uni/multivariate binary regression models. All models were adjusted by age, sex, and prognostic factors such as LVEF, NYHA, NT-proBNP levels and iron status parameters among other well-known determinants of HF severity.

Results
The final study cohort consisted in 202 patients from the DAMOCLES study. Mean age was 70±12 years, mean LVEF was 43±15% and 57 (28%) were women. Mean sTfR values were 1.42±0.66 mg/L. Tissue ID was present in 54 patients (25%). In the whole cohort, mean 6MWT distance was 287±168 m. 6MWT distance was significantly worse in patients with tissue ID compared to patients without tissue ID (206±179m vs. 314±155, p-value&lt;0.0001, respectively). Likewise, impaired submaximal exercise capacity was more common in patients with tissue ID (32, 64%) compared to patients without tissue ID (59, 39%, p-value=0.003). In unadjusted GAM models (Figure 1) we observed a significant association between increased iron demand (higher levels of sTfR) and lower distance achieved in the 6MWT.
As shown in Table 1, higher sTfR levels were associated with lower distance in the 6MWT in unadjusted linear regression and binary logistic regression models.

Conclusions
In a cohort of HF patients without iron deficiency or anaemia, higher levels of sTfR indicating increased iron demand and tissue ID were associated with worse submaximal exercise capacity and tended to experience more functional limitations according to NYHA functional class.