Iron Overload Decreases Ca V 1.3-Dependent L-Type Ca 2+ Currents Leading to Bradycardia, Altered Electrical Conduction, and Atrial Fibrillation

Abstract

Background— Chronic iron overload (CIO) is associated with blood disorders such as thalassemias and hemochromatosis. A major prognostic indicator of survival in patients with CIO is iron-mediated cardiomyopathy characterized by contractile dysfunction and electrical disturbances, including slow heart rate (bradycardia) and heart block. Methods and Results— We used a mouse model of CIO to investigate the effects of iron on sinoatrial node (SAN) function. As in humans, CIO reduced heart rate (≈20%) in conscious mice as well as in anesthetized mice with autonomic nervous system blockade and in isolated Langendorff-perfused mouse hearts, suggesting that bradycardia originates from altered intrinsic SAN pacemaker function. Indeed, spontaneous action potential frequencies in SAN myocytes with CIO were reduced in association with decreased L-type Ca 2+ current (I Ca,L ) densities and positive (rightward) voltage shifts in I Ca,L activation. Pacemaker current (I f ) was not affected by CIO. Because I Ca,L in SAN myocytes (as well as in atrial and conducting system myocytes) activates at relatively negative potentials due to the presence of Ca V 1.3 channels (in addition to Ca V 1.2 channels), our data suggest that elevated iron preferentially suppresses Ca V 1.3 channel function. Consistent with this suggestion, CIO reduced Ca V 1.3 mRNA levels by ≈40% in atrial tissue (containing SAN) and did not lower heart rate in Ca V 1.3 knockout mice. CIO also induced PR-interval prolongation, heart block, and atrial fibrillation, conditions also seen in Ca V 1.3 knockout mice. Conclusions— Our results demonstrate that CIO selectively reduces Ca V 1.3-mediated I Ca,L , leading to bradycardia, slowing of electrical conduction, and atrial fibrillation as seen in patients with iron overload.