Abstract 499: Ionic Remodeling and Sinoatrial Node Dysfunction Associated with Atrial Tachycardia: A Possible Molecular Basis for Tachy-Brady Syndrome
Background: Sinus node (SAN) dysfunction is frequently associated with atrial tachyarrhythmia (AT). Prolonged SAN pauses on termination of AT can cause syncope and require pacemaker implantation; the mechanism remains poorly understood. This study examined the hypothesis that AT induces ion channel remodeling in the SAN.
Methods: SAN tissues were obtained from 17 control dogs and 15 dogs with 7-day atrial tachypacing (ATP, 400 bpm). Real time RT-PCR was used to quantify mRNA. Ionic currents were measured from single SAN cells with whole cell patch clamp.
Results: ATP increased SAN recovery time in vivo by ~70% (P<0.01), reflecting impaired SAN function. In ATP dogs, SAN mRNA levels of hyperpolarization-activated cyclic nucleotide-gated subunits (HCN2 and 4) were reduced by 56% (P<0.01) and 59% (P<0.01) respectively. The mRNA expression of the α-subunit minK was reduced by 58% (P<0.05). Expression levels of the rapid delayed rectifier α-subunit ERG, the slow delayed rectifier (IKs) α-subunit KvLQT1, the transient outward α-subunit Kv4.3, the β-subunit MiRP1, the L-type Ca2+ current (ICaL) subunit Cav1.2 and T-type Ca2+ current (ICaT) subunit Cav3.1 were unaffected by ATP. ATP reduced densities of the HCN-related “funny” current (If) and IKs by 48% and 34% respectively (Figure⇓), with no change in voltage dependence or kinetics. ICaL and ICaT were unaffected.
Conclusions: ATP downregulates HCN2/4 and minK, along with the corresponding currents If and IKs. Remodeling of ion channel expression, particularly for the “pacemaker” subunit If, may contribute to the well-known and clinically important association between SAN dysfunction and supraventricular tachyarrhythmias.