Key result
In vitro iron overload decreases force production via sarcomeric oxidative damage and myosin inhibition.
Why the study?
Isolating the cardiac-specific cellular and molecular mechanisms driving iron overload cardiomyopathy has been challenging because it affects multiple interconnected organ systems.
Does iron overload cause cardiac dysfunction and arrhythmogenesis in human engineered heart tissues?
Does iron overload cause cardiac dysfunction and arrhythmogenesis in human engineered heart tissues?
In vitro models of human iron overload cardiomyopathy demonstrate that iron overload impairs contractile function and relaxation, and increases arrhythmogenesis through altered calcium kinetics and oxidative damage to sarcomeric proteins.
Stem cell-derived cardiac tissues model iron overload cardiomyopathy in vitro; leaves open whether identified mechanisms inform targeted therapies.
Iron overload cardiomyopathy (IOC) is caused by elevated systemic iron, and it is characterized by systolic and diastolic dysfunction as well as arrhythmias. Isolating the cardiac-specific cellular and molecular mechanisms driving IOC has been challenging because it affects multiple interconnected organ systems. Here, we leverage stem cells, cardiac tissue engineering, and protein reconstitution to model key contractile aspects of human IOC in vitro and probe the cellular and molecular mechanisms driving cardiac dysfunction. Human engineered heart tissues consisting of both cardiomyocytes and cardiac fibroblasts faithfully recapitulate key aspects of the human disease, including reduced contractile function, impaired relaxation, and increased prevalence of arrhythmogenic events. While both cardiomyocytes and cardiac fibroblasts show increased intracellular iron levels, cardiomyocytes show higher iron accumulation and reactive oxygen species production. Moreover, iron overload has little effect on the action potential kinetics in engineered heart tissues; however, it impacts the kinetics of the calcium transient, potentially driving arrhythmogenesis. Finally, iron overload decreases force production, in part, through oxidative damage of sarcomeric proteins and iron-based inhibition of myosin. Our results reveal insights into the cellular and molecular mechanisms of human IOC pathogenesis and establish in vitro models that can be harnessed for mechanistic and translational studies.
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Modak et al. (2026) studied Iron overload cardiomyopathy. In vitro iron overload model was evaluated on Cellular and molecular mechanisms of cardiac dysfunction (contractile function, relaxation, arrhythmogenesis). In vitro models of human iron overload cardiomyopathy showed that iron overload decreases force production via oxidative damage of sarcomeric proteins and iron-based inhibition of myosin.
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