Among these channels, HCN (hyperpolarization-activated cyclic nucleotide-gated) channels, which are the molecular correlate of hyperpolarization-activated current (I f ), 14 are considered to be of particular importance. Three of the 4 members of the HCN channel family (HCN1, HCN2, and HCN4) have been identified in pacemaker cells. Quantitatively, in all vertebrates studied so far, HCN4 underlies the major fraction of SAN I f , amounting to ≈70% to 80% of the total I f . HCN4 is essential for the formation of mature pacemaker cells during embryogenesis.15 Moreover, analysis of human HCN4 channelopathies 16 and genetic mouse models 1,17,18 (see also the work by Herrmann et al 9 and Hoesl et al 10 ) suggests that this channel plays an important role in autonomic control of heart rate. Mice deficient in HCN2 display mild cardiac dysrhythmia, whereas autonomic control of heart rate is preserved in these mice. 11,19 In contrast to HCN4 and HCN2, the role of HCN1 in heart has not yet been examined. HCN1 was originally cloned from mouse brain. 20 Indeed, analysis of HCN1 knockout (KO) mice revealed that this channel is involved in the control of 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. (Circulation. 2013;128:2585-2594.)
Rationale:The hyperpolarization-activated current I h that is generated by hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) plays a key role in the control of pacemaker activity in sinoatrial node cells of the heart. By contrast, it is unclear whether I h is also relevant for normal function of cardiac ventricles.Objective: To study the role of the HCN3-mediated component of ventricular I h in normal ventricular function. Methods and Results:To test the hypothesis that HCN3 regulates the ventricular action potential waveform, we have generated and analyzed a HCN3-deficient mouse line. At basal heart rate, mice deficient for HCN3 displayed a profound increase in the T-wave amplitude in telemetric electrocardiographic measurements. Action potential recordings on isolated ventricular myocytes indicate that this effect was caused by an acceleration of the late repolarization phase in epicardial myocytes. Furthermore, the resting membrane potential was shifted to more hyperpolarized potentials in HCN3-deficient mice. Cardiomyocytes of HCN3-deficient mice displayed approximately 30% reduction of total I h . At physiological ionic conditions, the HCN3-mediated current had a reversal potential of approximately ؊35 mV and displayed ultraslow deactivation kinetics. Conclusions:
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