Iron-deficiency anemia reduces cardiac contraction by downregulating RyR2 channels and suppressing SERCA pump activity

Abstract

Iron deficiency is present in ~50% of heart failure (HF) patients. Large multicenter trials have shown that treatment of iron deficiency with i.v. iron benefits HF patients, but the underlying mechanisms are not known. To investigate the actions of iron deficiency on the heart, mice were fed an iron-depleted diet, and some received i.v. ferric carboxymaltose (FCM), an iron supplementation used clinically. Iron-deficient animals became anemic and had reduced ventricular ejection fraction measured by magnetic resonance imaging. Ca 2+ signaling, a pathway linked to the contractile deficit in failing hearts, was also significantly affected. Ventricular myocytes isolated from iron-deficient animals produced smaller Ca 2+ transients from an elevated diastolic baseline but had unchanged sarcoplasmic reticulum (SR) Ca 2+ load, trigger L-type Ca 2+ current, or cytoplasmic Ca 2+ buffering. Reduced fractional release from the SR was due to downregulated RyR2 channels, detected at protein and message levels. The constancy of diastolic SR Ca 2+ load is explained by reduced RyR2 permeability in combination with right-shifted SERCA activity due to dephosphorylation of its regulator phospholamban. Supplementing iron levels with FCM restored normal Ca 2+ signaling and ejection fraction. Thus, 2 Ca 2+ -handling proteins previously implicated in HF become functionally impaired in iron-deficiency anemia, but their activity is rescued by i.v. iron supplementation.

A genetic mouse model of severe iron deficiency anemia reveals tissue-specific transcriptional stress responses and cardiac remodeling

“…Previous models that give rise to IDA in mice have utilized strategies of dietary iron manipulation or genetic deletion of iron handling in the embryo (6,11,17,18). However, mice are extremely resistant to IDA when placed on iron-deficient diets (9,11).…”

“…IRIDA patients require intravenous iron supplementation. If uncorrected, IDA can result in severe fatigue, weakness, and pathological cardiac complications (6,7).…”

Systematic review and meta-analysis of prolactin and iron deficiency in peripartum cardiomyopathy

“…Emerging evidence suggests that iron deficiency itself may contribute to the development of cardiomyopathy even in the absence of anaemia. [10][11][12] Interestingly, there is a significant drain in maternal iron that occurs during the latter part of pregnancy, which coincides with the unique onset of PPCM and hints at a possible role of maternal iron status in the pathophysiology of the disease. Therefore, it would be important to determine whether mothers who develop PPCM present with significantly different iron profiles than those who do not.…”

Keeping heart homeostasis in check through the balance of iron metabolism

“…Inotropic reserve in animal models with IRP deletion is restored with intravenous (IV) iron supplementation . Recent data with animal models suggest that ID in HF impairs calcium currents in cardiomyocytes by reducing the activity of calcium‐related channels involved in excitation‐contraction coupling . This defect is ameliorated with iron supplementation, which results in improved ejection fraction …”