Currents Leading to Bradycardia, Altered Electrical Conduction, and Atrial Fibrillation

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 current (ICa,L) densities and positive (rightward) voltage shifts in ICa,L activation. Pacemaker current (If) was not affected by CIO. Because ICa,L in SAN myocytes (as well as in atrial and conducting system myocytes) activates at relatively negative potentials due to the presence of CaV1.3 channels (in addition to CaV1.2 channels), our data suggest that elevated iron preferentially suppresses CaV1.3 channel function. Consistent with this suggestion, CIO reduced CaV1.3 mRNA levels by 40% in atrial tissue (containing SAN) and did not lower heart rate in CaV1.3 knockout mice. CIO also induced PR-interval prolongation, heart block, and atrial fibrillation, conditions also seen in CaV1.3 knockout mice. Conclusions—Our results demonstrate that CIO selectively reduces CaV1.3-mediated ICa,L, leading to bradycardia, slowing of electrical conduction, and atrial fibrillation as seen in patients with iron overload. (Circ Arrhythm Electrophysiol.