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

Carles Díez-López,Sergi Yun Viladomat,Maria Del Mar Ras Jiménez,Josep Francesch Manzano,Marta Tajes Orduña,Josep Comín-Colet,Santiago Jiménez-Marrero,Raul Ramos-Polo,Elena García-Romero,Cristina Enjuanes Grau,José González-Costello,Pedro Moliner Borja

doi:10.3390/jcm10214937

Abstract

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® 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, p-value = 0.039), (HR 5.49, 95% CI 1.78–16.92, p-value = 0.003), (HR 9.51, 95% CI 2.69–33.53, p-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.

Highlights

Heart failure (HF) is a world-wide epidemic caused by functional and structural myocardial abnormalities that result in congestion, functional impairment and eventually, multiorgan dysfunction [1]
Systemic and myocardial iron homeostasis have emerged as relevant factors that participate in the HF syndrome given that: (1) a significant number of HF patients have systemic iron deficiency (ID) [4], (2) patients with ID have a worse clinical course when compared with non-ID patients [5,6,8,25], and
We have previously demonstrated that patients with ID presented higher noradrenaline levels and that this increased neurohormonal activation was related with impaired iron homeostasis [15]

Summary

Introduction

Heart failure (HF) is a world-wide epidemic caused by functional and structural myocardial abnormalities that result in congestion, functional impairment and eventually, multiorgan dysfunction [1]. Contemporary medical treatment is based on the prevention of disease progression by extensive pharmacological neurohormonal blockade and device therapies [2]. Despite the recent advances in the understanding of the pathophysiology of HF and the advent of new pharmacologic and device-based treatments, these patients present progressive clinical deterioration, limited life expectancy and great limitations in quality of life [3]. Derangements in iron homeostasis are frequent in HF patients [4] and come along with a negative clinical impact regarding functional capacity, disease progression and mortality, independent of the hemoglobin levels [5,6,7,8]. Patients with impaired iron transport capacity (functional ID), have worse prognosis, independent of the presence of absolute ID [9,10]. The treatment with intravenous iron has demonstrated to have a positive impact in functional capacity, quality of life and HF-related hospitalizations [11,12,13]

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