Dataset Information

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

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.

SUBMITTER: Diez-Lopez C

PROVIDER: S-EPMC8585093 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background: a considerable numeer of patients with heart failure (HF) present systemic iron deficiency (ID), which is related with worse prognosis and a significant decline in quality of life. The mechanisms that underlay the crosstatlk between myocardial performance, neurohormonal activation and heart metabolism are still to be uncovered. Nonetheless, previous experimental studies have already revealed the potential links between iron, mitochondrial metabolism and heart function. Objectives: The present research attempts to investigate the mechanisms that link HF and ID and to identify potential biomarkers of disease prognosis by determning the gene expression pattern through mRNA transcriptome and PCR analyses. Results: The transcriptome of a first cohort of HF patients was analysed according to the presence of ID, underscoring 1128 overexpressed transcripts in patients with iron dysregulation, which permitted to identify 22 genes involved in biological pathways that could be related to HF and the cellular iron regulation and metabolism. From these 22 selected genes, 6 were found differentially expressed by PCR in a new wider cohort of patients, and comprehensive statistical studies identifying specific genetic patterns in three genes that correlate with prognostic outcomes. Briefly, a genetic expression pattern of the smal integral membrane protein 20 and the sirtuin 7 towards decreased expression (higher Δct) was significantly associated with an increased risk of death and the combined end-point of death and HF hospitalization and the composite. Similarly, the intermediate Δct gene expression pattern of mitochondrial ferritin was also associated of both of previous determined outcomes. Conclusions: Patients with HF present different standards of gene expression according to systemic iron status that involve paramount myocardial metabolic pathways implicated in myocardial function and correlate with prognosis. The study highlights the importance of iron regulation in the comprehensive approach to the treatment of myocardial disease.