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. 2023 Aug 19;119(10):1969-1980.
doi: 10.1093/cvr/cvad092.

Pre-emptive iron supplementation prevents myocardial iron deficiency and attenuates adverse remodelling after myocardial infarction

Bomee Chung  1   2 , Yong Wang  1   2 , Marleen Thiel  1   2 , Fatemeh Rostami  1   2 , Anika Rogoll  3 , Valentin G Hirsch  1   2 , Zulaikha Malik  1   2 , Anne Bührke  4 , Christian Bär  4 , Michael Klintschar  5 , Jan D Schmitto  6 , Carla Vogt  3 , Christopher Werlein  7 , Danny Jonigk  7 , Johann Bauersachs  1 , Kai C Wollert  1   2 , Tibor Kempf  1   2
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Pre-emptive iron supplementation prevents myocardial iron deficiency and attenuates adverse remodelling after myocardial infarction

Bomee Chung et al. Cardiovasc Res. .

Abstract

Aims: Heart failure (HF) after myocardial infarction (MI) is a major cause of morbidity and mortality. We sought to investigate the functional importance of cardiac iron status after MI and the potential of pre-emptive iron supplementation in preventing cardiac iron deficiency (ID) and attenuating left ventricular (LV) remodelling.

Methods and results: MI was induced in C57BL/6J male mice by left anterior descending coronary artery ligation. Cardiac iron status in the non-infarcted LV myocardium was dynamically regulated after MI: non-haem iron and ferritin increased at 4 weeks but decreased at 24 weeks after MI. Cardiac ID at 24 weeks was associated with reduced expression of iron-dependent electron transport chain (ETC) Complex I compared with sham-operated mice. Hepcidin expression in the non-infarcted LV myocardium was elevated at 4 weeks and suppressed at 24 weeks. Hepcidin suppression at 24 weeks was accompanied by more abundant expression of membrane-localized ferroportin, the iron exporter, in the non-infarcted LV myocardium. Notably, similarly dysregulated iron homeostasis was observed in LV myocardium from failing human hearts, which displayed lower iron content, reduced hepcidin expression, and increased membrane-bound ferroportin. Injecting ferric carboxymaltose (15 µg/g body weight) intravenously at 12, 16, and 20 weeks after MI preserved cardiac iron content and attenuated LV remodelling and dysfunction at 24 weeks compared with saline-injected mice.

Conclusion: We demonstrate, for the first time, that dynamic changes in cardiac iron status after MI are associated with local hepcidin suppression, leading to cardiac ID long term after MI. Pre-emptive iron supplementation maintained cardiac iron content and attenuated adverse remodelling after MI. Our results identify the spontaneous development of cardiac ID as a novel disease mechanism and therapeutic target in post-infarction LV remodelling and HF.

Keywords: Ferric carboxymaltose; Hepcidin; Iron deficiency; Myocardial infarction; Remodelling.

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Conflict of interest statement

Conflict of interest: T.K. has received an unrestricted research grant and advisory board and speaker fees from Vifor Pharma Ltd and advisory board fees from Pharmocosmos Ltd and Norgine B.V. J.B. has received consulting and speaker fees from Vifor Pharma Ltd and Norgine B.V. All other authors report no relationships relevant to this paper. Vifor Pharma Ltd did not have any role in study design and conduct; data collection, management, analysis, and interpretation; or manuscript preparation and approval. This manuscript was handled by Consulting Editor Ajay M. Shah.

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