TY - JOUR
T1 - The transcriptional profile of iron deficiency in patients with heart failure
T2 - Heme-sparing and reduced immune processes
AU - Grote Beverborg, Niels
AU - Alnuwaysir, Ridha I.S.
AU - Markousis-Mavrogenis, George
AU - Hoes, Martijn F.
AU - van der Wal, Haye H.
AU - Romaine, Simon P.R.
AU - Nath, Mintu
AU - Koekoemoer, Andrea
AU - Cleland, John G.F.
AU - Lang, Chim C.
AU - Anker, Stefan D.
AU - Dickstein, Kenneth
AU - Metra, Marco
AU - Ng, Leong L.
AU - van Veldhuisen, Dirk J.
AU - Voors, Adriaan A.
AU - Samani, Nilesh J.
AU - van der Meer, Peter
N1 - Publisher Copyright:
© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
PY - 2024/12/26
Y1 - 2024/12/26
N2 - Aims: Iron deficiency (ID) is highly prevalent in patients with heart failure (HF) and associated with morbidity and poor prognosis, but pathophysiological mechanisms are unknown. We aimed to identify novel biological pathways affected by ID.Methods and results: We studied 881 patients with HF from the BIOSTAT-CHF cohort. ID was defined as a transferrin saturation <20%. Transcriptome profiling was performed in whole blood. Identified targets were validated in a human in vitro stem cell-derived cardiomyocyte ID model utilizing deferoxamine as iron chelator. ID was identified in 554 (62.9%) patients, and 89 differentially expressed genes between ID and non-ID were identified, of which 60 were up- and 29 were downregulated. Upregulated genes were overrepresented in pathways of erythrocyte development and homeostasis. Heme biosynthetic processes were confirmed as relatively upregulated in ID, while iron–sulfur cluster assembly was downregulated. Downregulated processes further included natural killer cell and lymphocyte mediated immunity. In agreement with patient data, cardiomyocyte iron depletion significantly induced the expression of two genes (SIAH2 and CLIC4), which could be normalized upon iron supplementation. Both SIAH2 and CLIC4 are associated with increased mortality in patients with HF (hazard ratio 2.40, 95% confidence interval 1.86–3.11, p < 0.001 hazard ratio 1.78, 95% confidence interval 1.53–2.07, p < 0.001, respectively).Conclusion: Iron deficiency is associated with the preservation of heme-related processes at the cost of iron–sulfur clusters. Immune processes are downregulated, uncovering another high energy demand system affected. SIAH2 and CLIC4 might be modifiable factors in the relation between ID and impaired prognosis.
AB - Aims: Iron deficiency (ID) is highly prevalent in patients with heart failure (HF) and associated with morbidity and poor prognosis, but pathophysiological mechanisms are unknown. We aimed to identify novel biological pathways affected by ID.Methods and results: We studied 881 patients with HF from the BIOSTAT-CHF cohort. ID was defined as a transferrin saturation <20%. Transcriptome profiling was performed in whole blood. Identified targets were validated in a human in vitro stem cell-derived cardiomyocyte ID model utilizing deferoxamine as iron chelator. ID was identified in 554 (62.9%) patients, and 89 differentially expressed genes between ID and non-ID were identified, of which 60 were up- and 29 were downregulated. Upregulated genes were overrepresented in pathways of erythrocyte development and homeostasis. Heme biosynthetic processes were confirmed as relatively upregulated in ID, while iron–sulfur cluster assembly was downregulated. Downregulated processes further included natural killer cell and lymphocyte mediated immunity. In agreement with patient data, cardiomyocyte iron depletion significantly induced the expression of two genes (SIAH2 and CLIC4), which could be normalized upon iron supplementation. Both SIAH2 and CLIC4 are associated with increased mortality in patients with HF (hazard ratio 2.40, 95% confidence interval 1.86–3.11, p < 0.001 hazard ratio 1.78, 95% confidence interval 1.53–2.07, p < 0.001, respectively).Conclusion: Iron deficiency is associated with the preservation of heme-related processes at the cost of iron–sulfur clusters. Immune processes are downregulated, uncovering another high energy demand system affected. SIAH2 and CLIC4 might be modifiable factors in the relation between ID and impaired prognosis.
KW - Heart failure
KW - Heme
KW - Iron deficiency
KW - Iron–sulfur
KW - Transcriptome profiling
UR - http://www.scopus.com/inward/record.url?scp=85213067185&partnerID=8YFLogxK
U2 - 10.1002/ejhf.3562
DO - 10.1002/ejhf.3562
M3 - Article
C2 - 39725571
AN - SCOPUS:85213067185
SN - 1388-9842
JO - European Journal of Heart Failure
JF - European Journal of Heart Failure
ER -