title: Iron overload decreases CaV1.3-dependent L-type Ca2+ 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.
  
  
  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.
authors: Department of Physiology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: Robert A
authors: RA
authors: Rose
authors: Michael
authors: M
authors: Sellan
authors: Jeremy A
authors: JA
authors: Simpson
authors: Farzad
authors: F
authors: Izaddoustdar
authors: Carlo
authors: C
authors: Cifelli
authors: Brian K
authors: BK
authors: Panama
authors: Mark
authors: M
authors: Davis
authors: Dongling
authors: D
authors: Zhao
authors: Moniba
authors: M
authors: Markhani
authors: Geoffrey G
authors: GG
authors: Murphy
authors: Joerg
authors: J
authors: Striessnig
authors: Peter P
authors: PP
authors: Liu
authors: Scott P
authors: SP
authors: Heximer
authors: Peter H
authors: PH
authors: Backx
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology / Q000503:physiopathology*; D001919:Bradycardia / Q000209:etiology / Q000503:physiopathology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007501:Iron / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D012849:Sinoatrial Node / Q000187:drug effects / Q000503:physiopathology
chemical_list: C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; D007501:Iron