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(Circulation. 2009;119:1576-1585.)
© 2009 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Funny Current Downregulation and Sinus Node Dysfunction Associated With Atrial Tachyarrhythmia

A Molecular Basis for Tachycardia-Bradycardia Syndrome

Yung-Hsin Yeh, MD^*; Brett Burstein, PhD^*; Xiao Yan Qi, PhD^*; Masao Sakabe, MD, PhD; Denis Chartier, MSc; Philippe Comtois, PhD; Zhiguo Wang, PhD; Chi-Tai Kuo, MD; Stanley Nattel, MD

From the Department of Medicine (Y.-H.Y., B.B., X.Y.Q., M.S., D.C., P.C., Z.W., S.N.), Department of Physiology and Institute of Biomedical Engineering (P.C.), Montreal Heart Institute Research Center and Université de Montréal, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics (B.B., S.N.), McGill University, Montreal, Quebec, Canada; and the First Cardiovascular Division, Chang-Gung Memorial Hospital and Chang-Gung University (Y.-H.Y., C.-T.K.) Tao-Yuan, Taiwan.

Correspondence to Stanley Nattel, 5000 Belanger St E, Montreal, H1T 1C8, Quebec, Canada. E-mail stanley.nattel{at}icm-mhi.org

Received April 30, 2008; accepted October 17, 2008.

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 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 β-subunit minK by 42% (P<0.05). SAN transcript expression for the rapid delayed-rectifier (I_Kr) -subunit ERG, the slow delayed-rectifier (I_Ks) -subunit KvLQT1, the β-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 (I_f) and I_Ks by 48% (P<0.001) and 34% (P<0.01), respectively, with no change in voltage dependence or kinetics. I_Kr, I_CaL, and I_CaT were unaffected. SAN cells lacked Ba²⁺-sensitive inward-rectifier currents, irrespective of AT. SAN action potential simulations that incorporated AT-induced alterations in I_f accounted for slowing of periodicity, with no additional contribution from changes in I_Ks.

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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
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