Blood Differential Gene Expression in Patients with Chronic Heart Failure and Systemic Iron Deficiency: Pathways Involved in Pathophysiology and Impact on Clinical Outcomes

Background: Iron deficiency is a common disorder in patients with heart failure and is related with adverse outcomes and poor quality of life. Previous experimental studies have shown biological connections between iron homeostasis, mitochondrial metabolism, and myocardial function. However, the mec...

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Autores principales:	Carles Díez-López, Marta Tajes Orduña, Cristina Enjuanes Grau, Pedro Moliner Borja, José González-Costello, Elena García-Romero, Josep Francesch Manzano, Sergi Yun Viladomat, Santiago Jiménez-Marrero, Raul Ramos-Polo, Maria del Mar Ras Jiménez, Josep Comín-Colet
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	heart failure iron deficiency cardiac metabolism mitochondria Medicine R
Acceso en línea:	https://doaj.org/article/80cbe2ece0304fa6b0ec7dae07f4d4ec
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spelling	oai:doaj.org-article:80cbe2ece0304fa6b0ec7dae07f4d4ec2021-11-11T17:34:28ZBlood Differential Gene Expression in Patients with Chronic Heart Failure and Systemic Iron Deficiency: Pathways Involved in Pathophysiology and Impact on Clinical Outcomes10.3390/jcm102149372077-0383https://doaj.org/article/80cbe2ece0304fa6b0ec7dae07f4d4ec2021-10-01T00:00:00Zhttps://www.mdpi.com/2077-0383/10/21/4937https://doaj.org/toc/2077-0383Background: Iron deficiency is a common disorder in patients with heart failure and is related with adverse outcomes and poor quality of life. Previous experimental studies have shown biological connections between iron homeostasis, mitochondrial metabolism, and myocardial function. However, the mechanisms involved in this crosstalk are yet to be unfolded. Methods: The present research attempts to investigate the intrinsic biological mechanisms between heart failure and iron deficiency and to identify potential prognostic biomarkers by determining the gene expression pattern in the blood of heart failure patients, using whole transcriptome and targeted TaqMan<sup>®</sup> low-density array analyses. Results: We performed a stepwise cross-sectional longitudinal study in a cohort of chronic heart failure patients with and without systemic iron deficiency. First, the full transcriptome was performed in a nested case-control exploratory cohort of 7 paired patients and underscored 1128 differentially expressed transcripts according to iron status (cohort1#). Later, we analyzed the messenger RNA levels of 22 genes selected by their statistical significance and pathophysiological relevance, in a validation cohort of 71 patients (cohort 2#). Patients with systemic iron deficiency presented lower mRNA levels of mitochondrial ferritin, sirtuin-7, small integral membrane protein 20, adrenomedullin and endothelin converting enzyme-1. An intermediate mitochondrial ferritin gene expression and an intermediate or low sirtuin7 and small integral membrane protein 20 mRNA levels were associated with an increased risk of all-cause mortality and heart failure admission ((HR 2.40, 95% CI 1.04–5.50, <i>p</i>-value = 0.039), (HR 5.49, 95% CI 1.78–16.92, <i>p</i>-value = 0.003), (HR 9.51, 95% CI 2.69–33.53, <i>p</i>-value < 0.001), respectively). Conclusions: Patients with chronic heart failure present different patterns of blood gene expression depending on systemic iron status that affect pivotal genes involved in iron regulation, mitochondrial metabolism, endothelial function and cardiovascular physiology, and correlate with adverse clinical outcomes.Carles Díez-LópezMarta Tajes OrduñaCristina Enjuanes GrauPedro Moliner BorjaJosé González-CostelloElena García-RomeroJosep Francesch ManzanoSergi Yun ViladomatSantiago Jiménez-MarreroRaul Ramos-PoloMaria del Mar Ras JiménezJosep Comín-ColetMDPI AGarticleheart failureiron deficiencycardiac metabolismmitochondriaMedicineRENJournal of Clinical Medicine, Vol 10, Iss 4937, p 4937 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	heart failure iron deficiency cardiac metabolism mitochondria Medicine R
spellingShingle	heart failure iron deficiency cardiac metabolism mitochondria Medicine R Carles Díez-López Marta Tajes Orduña Cristina Enjuanes Grau Pedro Moliner Borja José González-Costello Elena García-Romero Josep Francesch Manzano Sergi Yun Viladomat Santiago Jiménez-Marrero Raul Ramos-Polo Maria del Mar Ras Jiménez Josep Comín-Colet Blood Differential Gene Expression in Patients with Chronic Heart Failure and Systemic Iron Deficiency: Pathways Involved in Pathophysiology and Impact on Clinical Outcomes
description	Background: Iron deficiency is a common disorder in patients with heart failure and is related with adverse outcomes and poor quality of life. Previous experimental studies have shown biological connections between iron homeostasis, mitochondrial metabolism, and myocardial function. However, the mechanisms involved in this crosstalk are yet to be unfolded. Methods: The present research attempts to investigate the intrinsic biological mechanisms between heart failure and iron deficiency and to identify potential prognostic biomarkers by determining the gene expression pattern in the blood of heart failure patients, using whole transcriptome and targeted TaqMan<sup>®</sup> low-density array analyses. Results: We performed a stepwise cross-sectional longitudinal study in a cohort of chronic heart failure patients with and without systemic iron deficiency. First, the full transcriptome was performed in a nested case-control exploratory cohort of 7 paired patients and underscored 1128 differentially expressed transcripts according to iron status (cohort1#). Later, we analyzed the messenger RNA levels of 22 genes selected by their statistical significance and pathophysiological relevance, in a validation cohort of 71 patients (cohort 2#). Patients with systemic iron deficiency presented lower mRNA levels of mitochondrial ferritin, sirtuin-7, small integral membrane protein 20, adrenomedullin and endothelin converting enzyme-1. An intermediate mitochondrial ferritin gene expression and an intermediate or low sirtuin7 and small integral membrane protein 20 mRNA levels were associated with an increased risk of all-cause mortality and heart failure admission ((HR 2.40, 95% CI 1.04–5.50, <i>p</i>-value = 0.039), (HR 5.49, 95% CI 1.78–16.92, <i>p</i>-value = 0.003), (HR 9.51, 95% CI 2.69–33.53, <i>p</i>-value < 0.001), respectively). Conclusions: Patients with chronic heart failure present different patterns of blood gene expression depending on systemic iron status that affect pivotal genes involved in iron regulation, mitochondrial metabolism, endothelial function and cardiovascular physiology, and correlate with adverse clinical outcomes.
format	article
author	Carles Díez-López Marta Tajes Orduña Cristina Enjuanes Grau Pedro Moliner Borja José González-Costello Elena García-Romero Josep Francesch Manzano Sergi Yun Viladomat Santiago Jiménez-Marrero Raul Ramos-Polo Maria del Mar Ras Jiménez Josep Comín-Colet
author_facet	Carles Díez-López Marta Tajes Orduña Cristina Enjuanes Grau Pedro Moliner Borja José González-Costello Elena García-Romero Josep Francesch Manzano Sergi Yun Viladomat Santiago Jiménez-Marrero Raul Ramos-Polo Maria del Mar Ras Jiménez Josep Comín-Colet
author_sort	Carles Díez-López
title	Blood Differential Gene Expression in Patients with Chronic Heart Failure and Systemic Iron Deficiency: Pathways Involved in Pathophysiology and Impact on Clinical Outcomes
title_short	Blood Differential Gene Expression in Patients with Chronic Heart Failure and Systemic Iron Deficiency: Pathways Involved in Pathophysiology and Impact on Clinical Outcomes
title_full	Blood Differential Gene Expression in Patients with Chronic Heart Failure and Systemic Iron Deficiency: Pathways Involved in Pathophysiology and Impact on Clinical Outcomes
title_fullStr	Blood Differential Gene Expression in Patients with Chronic Heart Failure and Systemic Iron Deficiency: Pathways Involved in Pathophysiology and Impact on Clinical Outcomes
title_full_unstemmed	Blood Differential Gene Expression in Patients with Chronic Heart Failure and Systemic Iron Deficiency: Pathways Involved in Pathophysiology and Impact on Clinical Outcomes
title_sort	blood differential gene expression in patients with chronic heart failure and systemic iron deficiency: pathways involved in pathophysiology and impact on clinical outcomes
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/80cbe2ece0304fa6b0ec7dae07f4d4ec
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Blood Differential Gene Expression in Patients with Chronic Heart Failure and Systemic Iron Deficiency: Pathways Involved in Pathophysiology and Impact on Clinical Outcomes

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