Iron Overload Decreases CaV1.3-dependent L-type Ca2+ Currents Leading to Bradycardia, Altered Electrical Conduction, and Atrial Fibrillation

Overview

Journal Circ Arrhythm Electrophysiol

Specialty Cardiology & Vascular Diseases

Date 2011 Jul 13

PMID 21747058

Citations 38

Authors

Robert A Rose

Michael Sellan

Jeremy A Simpson

Farzad Izaddoustdar

Carlo Cifelli

Brian K Panama

Mark Davis

Dongling Zhao

Moniba Markhani

Geoffrey G Murphy

Joerg Striessnig

Peter P Liu

Scott P Heximer

Peter H Backx

Affiliations

Soon will be listed here.

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.

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