摘要

BACKGROUND: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.
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. 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.
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.

译文

背景: 窦房结功能障碍 (SND) 是一种主要的临床相关疾病，与心脏性猝死相关，需要手术植入电动起搏器。经常，SND 发生在心力衰竭和高血压，导致心脏电不稳定的情况下。尽管获得性 SND 的病理已经被广泛研究，但对导致先天性 SND 的分子和细胞机制知之甚少。
方法和结果: 在这里，我们表明 HCN1 蛋白在窦房结中高表达，并与主要窦房结起搏器通道亚型 HCN4 共定位。为了描述 HCN1-deficient 小鼠的心脏表型，对单个孤立的窦房结细胞的起搏器机制的详细功能描述，假定窦房结跳动准备，体内遥测心电图，超声心动图, 并进行了体内电生理学。在这些实验的基础上，我们证明缺乏起搏器通道 HCN1 的小鼠表现出先天性 SND，其特征是心动过缓、窦性心律失常、窦房结恢复时间延长、窦房结传导时间增加。和复发性鼻窦停顿。作为 SND 的结果，HCN1-deficient 小鼠显示出严重的心输出量减少。
结论: 我们认为 HCN1 稳定了窦房结内的前导起搏器区域，因此对稳定的心率和规律的搏动变化至关重要。此外，我们认为 HCN1-deficient 小鼠可能是人类 SND 的一个有价值的遗传病模型。