Systemic iron deficiency does not affect the cardiac iron content and progression of heart failure

https://doi.org/10.1016/j.yjmcc.2021.06.005Get rights and content

Highlights

  • Systemic iron deficiency does not result in cardiac iron deficiency.

  • Iron deficiency in HF is accompanied by an increase of serum catecholamine level.

  • Iron deficiency temporarily improve cardiomyocyte contractile function.

  • Iron therapy may prevent the increase of catecholaminergic drive in HF.

  • Iron therapy should be considered as an additional therapeutic option in HF.

Abstract

Chronic heart failure (HF) is often accompanied by systemic iron deficiency (ID). However, effects of ID on cardiac iron status and progression of HF are unknown. To investigate these effects rats underwent LAD ligation to induce post-myocardial infarction HF or sham operation. After 3 weeks the animals from both groups were randomized into three subgroups: control, moderate ID and severe ID+anemia (IDA) by a combination of phlebotomy and low iron diet for 5 weeks. Serum and hepatic iron content were reduced by 55% and 70% (ID) and by 80% and 77% (IDA), respectively, while cardiac iron content was unchanged in HF rats. Changes in expression of all cardiomyocyte iron handling proteins indicating preserved cardiomyocytes iron status in HF and ID/IDA. Contractile function of LV cardiomyocytes, Ca2+ transient amplitude, sarcoplasmic reticulum Ca2+ release and SERCA2a function was augmented by ID and IDA and it was accompanied by an increase in serum catecholamines. Neither ID nor IDA affected left ventricular (LV) systolic or diastolic function or dimensions. To sum up, systemic ID does not result in cardiac ID and does not affect progression of HF and even improves contractile function and Ca2+ handling of isolated LV cardiomyocytes, however, at the cost of increased catecholamine level. This suggests that intravenous iron therapy should be considered as an additional therapeutic option in HF, preventing the increase of catecholaminergic drive with its well-known long-term adverse effects.

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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  • 1

    Both authors equally contributed to the study.

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