Chronic Iron-overload Causes Sinus Bradycardia By Altering Electrical Activity In Sinoatrial Node Myocytes

Abstract

Treatment of blood disorders such as thalassemias require constant blood transfusions that cause iron-overload leading to iron-mediated cardiomyopathy, which is characterized by contractile dysfunction and electrical disturbances, especially bradyarrhythmias. In this study we explored the cellular mechanisms underlying iron-mediated bradycardia by examining the effects of chronic iron-overload (CIO; 0.6 mg/g iron-dextran 3 days/week for 4 weeks by IP injection) on heart rate and sinoatrial node (SAN) function in mice. As expected, heart rate (assessed with telemetry electrocardiograms), was lower (p<0.001) in CIO mice (509 ± 21 beats/min; n = 5) compared to controls (601 ± 12 beats/min; n = 6, dextrose injected). To examine intrinsic SAN function, heart rate was further studied in anesthetized mice following autonomic nervous system blockade with propranolol (10 mg/kg IP) and atropine (1 mg/kg IP), as well as in isolated Langendorff-perfused hearts. In both cases heart rate was ∼22% lower (p<0.05) in CIO mice suggesting iron-overload impairs SAN electrical activity. Indeed, spontaneous action potential (AP) frequency was reduced by 34% (p<0.05) in isolated SAN myocytes from CIO mice along with a reduction (p<0.05) in slope of the diastolic depolarization from 35.1 ± 3.6 V/s in controls to 18.8 ± 2.2 V/s in CIO. The maximum diastolic potential was unaltered in CIO myocytes. Voltage-clamp experiments showed that the reduction in SAN firing frequency was linked to a reduction (p<0.05) in L-type Ca2+ current (ICa,L) density from -4.8 ± 0.8 pA/pF to -2.6 ± 0.2 pA/pF along with a right shift (p<0.05) in the V1/2 for activation from -20.2 ± 3.7 mV in control to -6.2 ± 2.6 mV in CIO SAN myocytes. In conclusion, the severe bradycardia caused by iron-overload originates from impaired intrinsic electrical activity and reduced ICa,L in SAN pacemaker myocytes.