Sick Sinus Syndrome in HCN1-Deficient Mice
Background—Sinus node dysfunction (SND) is a major clinically relevant disease which is associated with sudden cardiac death and requires surgical implantation of electrical pacemaker devices. Frequently, SND occurs in heart failure and hypertension, conditions that lead to electrical instability of the heart. While the pathologies of acquired SND have been extensively studied, little is known about the molecular and cellular mechanisms that cause congenital SND.
Methods and Results—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. Based on 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.
Conclusions—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.
- Received May 16, 2013.
- Revision received September 25, 2013.
- Accepted September 27, 2013.