Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function

Abstract

AimsIron deficiency is common in patients with heart failure and associated with a poor cardiac function and higher mortality. How iron deficiency impairs cardiac function on a cellular level in the human setting is unknown. This study aims to determine the direct effects of iron deficiency and iron repletion on human cardiomyocytes.Methods and resultsHuman embryonic stem cell‐derived cardiomyocytes were depleted of iron by incubation with the iron chelator deferoxamine (DFO). Mitochondrial respiration was determined by Seahorse Mito Stress test, and contractility was directly quantified using video analyses according to the BASiC method. The activity of the mitochondrial respiratory chain complexes was examined using spectrophotometric enzyme assays. Four days of iron depletion resulted in an 84% decrease in ferritin (P < 0.0001) and significantly increased gene expression of transferrin receptor 1 and divalent metal transporter 1 (both P < 0.001). Mitochondrial function was reduced in iron‐deficient cardiomyocytes, in particular ATP‐linked respiration and respiratory reserve were impaired (both P < 0.0001). Iron depletion affected mitochondrial function through reduced activity of the iron–sulfur cluster containing complexes I, II and III, but not complexes IV and V. Iron deficiency reduced cellular ATP levels by 74% (P < 0.0001) and reduced contractile force by 43% (P < 0.05). The maximum velocities during both systole and diastole were reduced by 64% and 85%, respectively (both P < 0.001). Supplementation of transferrin‐bound iron recovered functional and morphological abnormalities within 3 days.ConclusionIron deficiency directly affects human cardiomyocyte function, impairing mitochondrial respiration, and reducing contractility and relaxation. Restoration of intracellular iron levels can reverse these effects.

Rationale and design of the IRON‐CRT trial: effect of intravenous ferric carboxymaltose on reverse remodelling following cardiac resynchronization therapy

“…It is unclear if treatment in these patients will result in the attainment of incremental reverse remodelling. 5 In both cell-based and animal studies, iron deprivation resulted in a diminished activity of the electron transport chain, resulting in an energetic crisis (decrease in the amount of phosphocreatine and ATP), which probably contributes to the observed decreased cardiac contractility and relaxation. 22 The IRON-CRT trial will learn whether treatment with intravenous iron will result in incremental reverse remodelling, which is an important surrogate endpoint in heart failure.…”

“…Importantly, further therapeutic options that could lead to functional improvement and reverse remodelling in CRT patients with incomplete reverse remodelling are limited, as patients by selection are on maximal tolerable doses of neurohormonal blockers. 5,18 Nevertheless, these artificially induced iron deficiency cell-based and animal models exhibit extreme iron depletion, limiting the clinical relevance towards real-world patients. Indeed, most therapies that improve outcome such as angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, beta-blockers, mineralocorticoid receptor antagonists, and CRT all induce reverse remodelling.…”

“…1,2 Iron deficiency is associated with a reduced functional status, poor exercise performance, and increased risk for heart failure hospitalization and cardiovascular mortality. 5,6 Therefore, iron deficiency is involved in the process of progressive cardiac remodelling and failing cardiac energetics. 5,6 Therefore, iron deficiency is involved in the process of progressive cardiac remodelling and failing cardiac energetics.…”

“…Not surprisingly, the presence of iron deficiency at the time of CRT implant is associated with diminished cardiac reverse remodelling and limited functional improvement. 5,18 The effect of intravenous ferric carboxymaltose on reverse remodelling following cardiac resynchronization therapy (IRON-CRT) trial was specifically designed to answer two important questions: (i) if treatment with ferric carboxymaltose induces incremental reverse remodelling in CRT patients with iron deficiency and a persistently reduced left ventricular ejection fraction and (ii) if treatment with ferric carboxymaltose is capable of improving cardiac contractility (force-frequency relationship) in vivo. 15 Normally, when heart rate increases, cardiac contractility increases disproportionally, a process termed 'positive force-frequency relationship or Treppe phenomenon'.…”

Highlights in heart failure

“…[58][59][60] Ferric carboxymaltose improves functional capacity, symptoms, and quality of life of HF patients with iron deficiency. Its deficiency may be also a cause of impaired contractility.…”