IRON OVERLOAD IN HUMAN IPS CARDIOMYOCYTES

Stefan PEISCHARD ¹, Philipp KASTL², Ursula KLINGMUELLER ², Nathalie SEEBOHM ¹, Andrea STEINBICKER ³, Martina RAUNER ⁴, Guiscard SEEBOHM¹

¹Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany
²Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
³Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
⁴Department of Medicine III and Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany

Iron storage diseases, such as hemochromatosis, siderosis, and bronze diabetes, result in an excess accumulation of iron in the body. While the liver serves as the primary site for iron deposition in affected individuals, cardiac complications pose the predominant threat to morbidity and mortality. Prolonged iron overload leads to progressive cardiac dysfunction, culminating in heart failure. Additionally, hemochromatosis-related iron overload induces systemic oxidative stress, endothelial dysfunction, and inflammation, collectively contributing to the onset of atherosclerosis and an elevated risk of cardiovascular events, including arrhythmias typically manifesting in advanced disease progression (Jackson et al., 2022). These arrhythmias involve precarious ventricular arrhythmias, supraventricular arrhythmias, conduction disorders, ventricular arrhythmias, and cardiac arrest, raising the susceptibility to thromboembolic incidents and sudden cardiac death (Udani et al., 2021). Although iron deposition has been proposed as a factor disrupting electrical signals and causing abnormal heart rhythms, it may not comprehensively elucidate the complex electrical phenotype. Here, we demonstrate that elevated iron levels enhance rhythmic heterogeneity in human induced pluripotent stem cell-derived cardiomyocytes and cardiac pacemaker cells, representing a common pro-arrhythmic mechanism. To further elucidate these arrhythmic effects, we conducted an analysis of iron-altered protein expression in human induced pluripotent stem cell-derived cardiac cells via MS-MS and Western blot analyses. Finally, we show altered protein cleavage of key determinants of rhythmic activity). Our findings reveal that iron overload induces remodelling of the proteome with impact on cardiac cell rythmicity.