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European Heart Journal Advance Access originally published online on September 6, 2007
European Heart Journal 2007 28(20):2472-2478; doi:10.1093/eurheartj/ehm339
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Pacemaker current (If) in the human sinoatrial node

Arie O. Verkerk1, Ronald Wilders1, Marcel M.G.J. van Borren1, Ron J.G. Peters2, Eli Broekhuis3, Kayan Lam3, Ruben Coronel1, Jacques M.T. de Bakker1,4 and Hanno L. Tan1,2,*

1 Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2 Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
3 Department of Cardiothoracic Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
4 Interuniversity Cardiology Institute the Netherlands, Utrecht, The Netherlands

Received 15 February 2007; revised 1 June 2007; accepted 17 July 2007; online publish-ahead-of-print 6 September 2007.

* Corresponding author: Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel: +31 20 5663264; fax: +31 20 6975458. E-mail address: h.l.tan{at}amc.uva.nl

Aims: Animal studies revealed that the hyperpolarization-activated pacemaker current, If, contributes to action potential (AP) generation in sinoatrial node (SAN) and significantly determines heart rate. If is becoming a novel therapy target to modulate heart rate. Yet, no studies have demonstrated that If is functionally present and contributes to pacemaking in human SAN. We aimed to study If properties in human SAN.

Methods and results: In a patient undergoing SAN excision, we identified SAN using epicardial activation mapping. From here, we isolated myocytes and recorded APs and If using patch-clamp techniques. Pacemaker cells generated spontaneous APs (cycle length 828 ± 15 ms) following slow diastolic depolarization, maximal diastolic potential – 61.7 ± 4.3 mV, and maximal AP upstroke velocity 4.6 ± 1.2 V/s. They exhibited an hyperpolarization-activated inward current, blocked by external Cs+ (2 mmol/L), characterizing it as If. Fully-activated conductance was 75.2 ± 3.8 pS/pF, reversal potential – 22.1 ± 2.4 mV, and half-maximal activation voltage and slope factor of steady-state activation – 96.9 ± 2.7 and – 8.8 ± 0.5 mV. Activation time constant ranged from ~350 ms (–130 mV) to ~1 s (–100 mV), deactivation time constant 156 ± 45 ms (–40 mV). The role of If in pacemaker activity was demonstrated by slowing of pacemaker cell diastolic depolarization and beating rate by Cs+.

Conclusion: If is functionally expressed in human SAN and probably contributes to pacemaking in human SAN.

Key Words: Electrophysiology • Ion channels • Pacing • Sinoatrial node • Action potentials


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