PubMed 24218458

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: HCN1 , HCN3 , HCN4

Title: Sick Sinus Syndrome in HCN1-Deficient Mice.

Authors: Stefanie Fenske, Stefanie C Krause, Sami I H Hassan, Elvir Becirovic, Franziska Auer, Rebekka Bernard, Christian Kupatt, Philipp Lange, Tilman Ziegler, Carsten T Wotjak, Henggui Zhang, Verena Hammelmann, Christos Paparizos, Martin Biel, Christian A Wahl-Schott

Journal, date & volume: Circulation, 2013 Dec 17 , 128, 2585-94

PubMed link:

Sinus node dysfunction (SND) is a major clinically relevant disease that is associated with sudden cardiac death and requires surgical implantation of electric pacemaker devices. Frequently, SND occurs in heart failure and hypertension, conditions that lead to electric instability of the heart. Although the pathologies of acquired SND have been studied extensively, little is known about the molecular and cellular mechanisms that cause congenital SND.Here, we show that the HCN1 protein is highly expressed in the sinoatrial node and is colocalized with HCN4, the main sinoatrial pacemaker channel isoform. To characterize the cardiac phenotype of HCN1-deficient mice, a detailed functional characterization of pacemaker mechanisms in single isolated sinoatrial node cells, explanted beating sinoatrial node preparation, telemetric in vivo electrocardiography, echocardiography, and in vivo electrophysiology was performed. On the basis of these experiments we demonstrate that mice lacking the pacemaker channel HCN1 display congenital SND characterized by bradycardia, sinus dysrhythmia, prolonged sinoatrial node recovery time, increased sinoatrial conduction time, and recurrent sinus pauses. As a consequence of SND, HCN1-deficient mice display a severely reduced cardiac output.We propose that HCN1 stabilizes the leading pacemaker region within the sinoatrial node and hence is crucial for stable heart rate and regular beat-to-beat variation. Furthermore, we suggest that HCN1-deficient mice may be a valuable genetic disease model for human SND.