New pathophysiological pathways connecting heart failure and iron deficiency

Abstract

[eng] INTRODUCTION: Heart failure (HF) remains a global challenge, affecting millions of individuals and it is characterized by myocardial dysfunction, congestion, and multi-organ failure. It typically starts with an either episodic or persistent insult, affecting the heart’s structure or function. Patients with HF experience a declining clinical trajectory, marked by diminished quality of life and adverse prognosis. Current research underscores the relevance of metabolism and myocardial energetics to understand HF syndrome. Iron deficiency (ID) affects 40- 50% of patients with HF and has emerged as an important pathophysiological factor in disease onset and progression, independent from anemia. Iron is intimately related with metabolism and ID is associated with decreased contractility and myocardial remodeling, but the mechanisms that lead to ID and the specific consequences into the cardiovascular function and disease progression are broadly unknown. We sought to investigate novel regulatory pathways influencing iron homeostasis and define the relationship between iron regulation, neurohormonal activation, metabolism, and oxidative stress both at a myocardial and systemic levels. HYPOTHESIS AND OBJECTIVES:

1. The high prevalence of ID in HF patients suggests that it might be an intrinsic component of the HF syndrome rather than a consequence of it. 2. HF may induce changes in the expression of genes involved in myocardial iron regulation, leading to ID and promoting disease progression. 3. Neurohormonal activation in HF may be a key factor responsible for the disruption of intramyocardial iron regulation. 4. The effect of ID on myocardial function might be mediated through mitochondrial dysfunction and increased oxidative stress.

5. ID might induce changes in the expression of specific genes involved in systemic metabolism, iron regulation, and cardiovascular function, independent of anemia. 6. Alterations in myocardial and systemic metabolism due to ID might play a significant role in the progression of HF. To test our hypothesis, we developed the following research plan and objectives: 1. Analyze the impact of HF on iron status and regulation in the myocardium. 2. Investigate the impact of neurohormonal stimuli in HF on cardiac cell iron levels and regulatory pathways. 3. Evaluate the influence of HF neurohormonal stimuli on cardiac cell mitochondrial function and iron regulation. 4. Study alterations in mitochondrial iron regulation under neurohormonal stimuli intracellular ID. 5. Examine the systemic transcriptomic profile in HF patients with systemic ID but without anemia and identify systemic biological pathways linking HF and ID, in the absence of anemia 6. Discover candidate genes associated with iron regulation, cardiovascular function, and metabolism within these shared pathways and analyze the gene expression patterns of the identified genes related to cardiovascular disease and metabolism in the context of ID without anemia. 7. Correlate biological pathways observed in mice and cellular models with gene expression patterns in transcriptomic analyses of patient blood samples. 8. Evaluate the clinical implications of variations in genetic expression profiles of selected biological pathways and candidate genes in blood samples from HF patients.