Funny Current Downregulation and Sinus Node Dysfunction Associated With Atrial Tachyarrhythmia A Molecular Basis for Tachycardia-Bradycardia Syndrome

Background-Sinoatrial node (SAN) dysfunction is frequently associated with atrial tachyarrhythmias (ATs). Abnormalities in SAN pacemaker function after termination of ATs can cause syncope and require pacemaker implantation, but underlying mechanisms remain poorly understood. This study examined the hypothesis that ATs impair SAN function by altering ion channel expression. Methods and Results-SAN tissues were obtained from 28 control dogs and 31 dogs with 7-day atrial tachypacing (400 bpm). Ionic currents were measured from single SAN cells with whole-cell patch-clamp techniques. Atrial tachypacing increased SAN recovery time in vivo by approximate to 70% (P < 0.01), a change which reflects impaired SAN function. In dogs that underwent atrial tachypacing, SAN mRNA expression (real-time reverse-transcription polymerase chain reaction) was reduced for hyperpolarization-activated cyclic nucleotide-gated subunits (HCN2 and HCN4) by >50% (P < 0.01) and for the beta-subunit minK by approximate to 42% (P < 0.05). SAN transcript expression for the rapid delayed-rectifier (I-Kr) alpha-subunit ERG, the slow delayed-rectifier (I-Ks) alpha-subunit KvLQT1, the beta-subunit MiRP1, the L-type (I-CaL) and T-type (I-CaT) Ca2+-current subunits Cav1.2 and Cav3.1, and the gap-junction subunit connexin 43 (were unaffected by atrial tachypacing. Atrial tachypacing reduced densities of the HCN-related funny current (If) and IKs by approximate to 48% (P < 0.001) and approximate to 34% (P < 0.01), respectively, with no change in voltage dependence or kinetics. IKr, ICaL, and ICaT were unaffected. SAN cells lacked Ba2+-sensitive inward-rectifier currents, irrespective of AT. SAN action potential simulations that incorporated AT-induced alterations in If accounted for slowing of periodicity, with no additional contribution from changes in IKs. Conclusions-AT downregulates SAN HCN2/4 and minK subunit expression, along with the corresponding currents I-f and I-Ks. Tachycardia-induced remodeling of SAN ion channel expression, particularly for the pacemaker subunit I-f, may contribute to the clinically significant association between SAN dysfunction and supraventricular tachyarrhythmias. ( Circulation. 2009; 119: 1576-1585.)