Systemic iron deficiency does not affect the cardiac iron content and progression of heart failure
Graphical abstract
Introduction
Chronic heart failure (HF) is accompanied by systemic iron deficiency (ID) in as many as 50% of all patients [1,2]. However, whether iron deficiency is just a marker of HF severity or whether it mediates heart failure progression and outcomes and therefore should be treated is not entirely clear.
Several studies demonstrated that ID was associated with increased mortality [3], reduced exercise capacity and VO2max [4] and impaired quality of life [5] of HF patients independently of other prognostic factors. However, it is unknown whether ID affects progression of HF or is merely an ominous sign of other contributing comorbidities. Small human studies were unable to solve this dilemma [6,7]. This is an important question from the therapeutic point of view: intravenous iron therapy was shown to improve quality of life, functional NYHA class and exercise capacity, but not the hard endpoints such as mortality [1]. Furthermore, no study examined effects of intravenous iron on cardiac remodeling.
The second crucial question is whether and how systemic ID affects cardiac iron status in HF, i.e. whether the failing heart is really iron deficient under conditions of systemic ID. Healthy mouse heart is remarkably resistant to iron deficiency under ID conditions [8]. Human studies revealed either reduced [[9], [10], [11], [12]], unchanged [13] or even increased [14] cardiac iron content in cardiac samples from HF patients. Recently Hirsch et al [15] demonstrated that cardiac iron was unrelated to systemic iron parameters. So currently it is unknown if cardiac ID results from HF or is an independent abnormality, presumably contributing to HF.
Since providing answers to these questions in the clinical setting is difficult or even impossible, therefore we used an established rat model of HF to investigate whether moderate ID without anemia or severe ID with anemia (IDA) affects (1) cardiac function and progression of HF at the organ and cardiomyocyte level, (2) cardiac iron status and function of cardiomyocyte iron handling proteins.
Section snippets
Methods
All animal procedures conformed to the guidelines from Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes. The study was approved by the local ethics committee (Second Warsaw Local Ethics Committee for Animal Experimentation, WAW2/031/2018).
Morphological parameters, hemodynamic function
Three weeks after induction of myocardial infarction (MI) or sham operation (Sh) ID and IDA were induced by a combination of phlebotomy and low iron diet for 5 weeks. Eight weeks after surgery rats underwent echocardiography imaging and LV catheterization (Supplementary Fig. S1). Mean infarct size did not differ between the HF groups (Table 1). Eight weeks after MI induction the following were found: (i) LV systolic dysfunction: reduced ejection fraction (LVEF) (Fig. 1A), contractility
Discussion
Here we show that (1) the cardiac iron status in both failing and normal hearts is remarkably resistant to systemic ID and that (2) systemic ID leads to an increase in circulating catecholamine levels and enhances cardiomyocyte Ca2+ signaling and contractility and at least temporarily prevents HF progression (Fig. 6).
Conclusion
We show here that the failing heart is remarkably resistant to systemic ID and that systemic ID does not have detrimental effects on cardiac remodeling, function, HF severity or function of isolated cardiomyocytes in the rat model of MI-induced HF. This is an important argument in the quest to discover the role of abnormalities of iron handling in HF. However, it should be stressed that observed lack of HF progression under systemic ID due to enhanced cardiomyocytes function results from the
Limitations
Short duration of the study (8 weeks in total, 5 weeks of ID) is the main limitation of our study. We cannot exclude the possibility that longer duration of HF or ID would unmask some other effects.
The following are the supplementary data related to this article.
Author contributions
UM and MM conceived the original idea; MM, UM and AP designed research; AP, MO, EC, HPM, MM and UM conducting experiments; AP, MM and UM analyzed data; AP, MM and UM wrote the paper; all authors discussed the results and reviewed the manuscript.
Declaration of Competing Interest
The authors have declared that no conflict of interest exists.
Acknowledgements
This work was supported by grant from National Science Centre (2015/17/B/NZ5/00292), (AP, MO, MM, UM) and statutory funding to Institute of Nuclear Chemistry and Technology (EC, HPM).
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Both authors equally contributed to the study.