Iron Metabolism Disorders in Cardiovascular Health

Iron is indispensable for oxygen transport, mitochondrial respiration and enzymatic processes in the heart. Yet both iron deficiency and iron overload contribute to cardiac dysfunction. Deficiency impairs haem synthesis and energy production, leading to reduced contractility and exacerbation of heart failure symptoms, while iron excess promotes oxidative damage, fibrosis and arrhythmias. Key regulatory proteins—such as hepcidin, transferrin receptor and ferritin—maintain systemic and cellular iron homeostasis, but inflammation, genetic mutations and dietary factors can disrupt their expression. In the myocardium, dysregulated iron uptake via divalent metal transporter 1 and calcium‐permeable channels, coupled with impaired efflux through ferroportin, culminates in labile iron accumulation. This catalyses reactive oxygen species (ROS) generation, damages mitochondrial DNA and proteins, alters calcium handling and provokes cell death pathways. Globally, iron‐related cardiomyopathies—from thalassaemia major to acquired hemosiderosis—remain a major cause of morbidity and mortality. Improved diagnostics, including non‐invasive imaging and biomarkers, alongside targeted therapies, are essential to mitigate this growing burden.

Research from Nature Portfolio

Recent studies have elucidated novel interventions for iron‐related cardiac injury. In models of obesity‐induced hypertrophy, caloric restriction was shown to normalise myocardial expression of transferrin receptor, ferritin and ferroportin, reducing oxidative stress, inflammation and left ventricular remodelling. Preclinical work on cardiomyocyte insulin resistance revealed that iron fosters ROS production via mitochondrial oxidases, dampens autophagic flux and impairs Akt signalling; treatment with an adiponectin receptor agonist restored autophagy and insulin sensitivity. Seminal investigations using resveratrol demonstrated that activation of SIRT1 reverses iron‐overload cardiomyopathy by reducing oxidative damage, restoring SERCA2a levels and correcting calcium homeostasis, thereby improving both diastolic and systolic function in animal models.

Iron Metabolism Disorders in Cardiovascular Health publication trend

The graph below shows the total number of articles in iron metabolism disorders in cardiovascular health across all publications each year (not limited to Nature Index journals).

Technical terms

Hepcidin: Liver‐derived peptide that inhibits iron export by binding to ferroportin.
Non‐transferrin bound iron (NTBI): Redox‐active iron species circulating when transferrin capacity is exceeded.
Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that can damage lipids, proteins and DNA.
Autophagy: Intracellular process for degradation and recycling of damaged organelles and proteins.
Mitochondrial permeability transition pore (mPTP): Channel whose opening disrupts mitochondrial membrane potential and can trigger cell death.
Sarcoplasmic reticulum Ca2+ ATPase (SERCA): Enzyme that pumps cytosolic Ca2+ back into the sarcoplasmic reticulum during muscle relaxation.
Divalent metal transporter 1 (DMT1): Membrane protein that mediates cellular uptake of ferrous iron.

References

1. Inflammation, dysregulated iron metabolism, and cardiovascular disease. Frontiers in Aging (2023).
2. Iron-overload injury and cardiomyopathy in acquired and genetic models is attenuated by resveratrol therapy. Scientific Reports (2015).
3. Mitochondrial DNA Damage in Iron Overload*. Journal of Biological Chemistry (2008).
4. Iron induces insulin resistance in cardiomyocytes via regulation of oxidative stress. Scientific Reports (2019).
5. Iron Overload, Oxidative Stress and Calcium Mishandling in Cardiomyocytes: Role of the Mitochondrial Permeability Transition Pore. Antioxidants (2020).
6. Modeling Secondary Iron Overload Cardiomyopathy with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Cell Reports (2020).
7. Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in impaired leptin signaling mice. Scientific Reports (2020).
8. Role of Mitochondrial Iron Overload in Mediating Cell Death in H9c2 Cells. Cells (2022).