Pacemaker current (If) in the human sinoatrial node

Verkerk, Arie O.; Wilders, Ronald; Borren, Marcel M. G. J. van; Peters, Ron J.G.; Broekhuis, Eli; Lam, Kayan; Coronel, Ruben; Bakker, Jacques M.T. de; Tan, Hanno L.

doi:10.1093/eurheartj/ehm339

Cited by 142 publications

(198 citation statements)

References 41 publications

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“…35,39 SAN dysfunction commonly occurs in the setting of heart failure and arterial hypertension but also is a genetic disease. Because HCN1 is expressed in the human SAN, 3,40,41 this channel may be added to the list of candidate genes associated with human SAN dysfunction. Mutations in HCN1 could be well tolerated and thus could be relevant for human disease.…”

Section: Discussionmentioning

confidence: 99%

Sick Sinus Syndrome in HCN1-Deficient Mice

et al. 2013

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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.)

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Section: Discussionmentioning

confidence: 99%

Sick Sinus Syndrome in HCN1-Deficient Mice

et al. 2013

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“…This modulation explains the stronger diastolic depolarization slope (DD slope) and the increase in pacing rhythm in response to adrenaline. By contrast, acetylcholine decreases the cAMP levels in the SAN, leading to a smaller current at the same voltage (left-shift of the activation curve), a weaker DD slope and bradycardia [42] . The β accessory subunit MiRP1 changes the activation kinetics of the current in opposite ways depending on the HCN isoform.…”

Section: Membrane or Voltage Clock Modelmentioning

confidence: 92%

“…These variations result from notable interspecies differences in the dynamics and contributions of the calcium handling proteins, in the density of each current, and their regulation. Very few studies, however, have reported data from single cells that were dissociated from an excised human SAN [42,110] . Each of the studies was performed with isolated cells from a single SAN, but it was possible to compare a few electrophysiological parameters with rabbit cells.…”

Section: Human Embryonic Stem Cell-derived Cardiomyocytes: a Model Fomentioning

confidence: 99%

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

et al. 2016

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The proper expression and function of the cardiac pacemaker is a critical feature of heart physiology. The sinoatrial node (SAN) in human right atrium generates an electrical stimulation approximately 70 times per minute, which propagates from a conductive network to the myocardium leading to chamber contractions during the systoles. Although the SAN and other nodal conductive structures were identified more than a century ago, the mechanisms involved in the generation of cardiac automaticity remain highly debated. In this short review, we survey the current data related to the development of the human cardiac conduction system and the various mechanisms that have been proposed to underlie the pacemaker activity. We also present the human embryonic stem cellderived cardiomyocyte system, which is used as a model for studying the pacemaker. Finally, we describe our latest characterization of the previously unrecognized role of the SK4 Ca 2+ -activated K + channel conductance in pacemaker cells. By exquisitely balancing the inward currents during the diastolic depolarization, the SK4 channels appear to play a crucial role in human cardiac automaticity.

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“…In analogy to rabbit SAN, the small (or absent) I K1 current may be the reason for the more positive resting membrane potential in human SAN cells. 8 Indirectly, this supports pacemaking. The HCN4 mRNA abundance was much lower in human compared with rabbit SAN, 4 and this is in good agreement with the 3 to 4 times smaller I f amplitude found in humans.…”

Section: Article P 1562mentioning

confidence: 92%