Altered HCN4 channel C-linker interaction is associated with familial tachycardia–bradycardia syndrome and atrial fibrillation

Duhme, Nana; Schweizer, Patrick; Thomas, Dierk; Becker, Rüdiger; Schröter, Julian; Barends, Thomas R. M.; Schlichting, Ilme; Draguhn, Andreas; Bruehl, Claus; Katus, Hugo A.; Koenen, Michael

doi:10.1093/eurheartj/ehs391

Cited by 86 publications

(58 citation statements)

References 28 publications

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“…1 Familial HCN4 mutations have been identified in patients with sinus bradycardia that result in a lack of channel responsiveness to cAMP (and therefore sympathetic stimulation) 68 or a change in the channel voltage dependence leading to a reduction of If. [69][70][71][72] As might be expected, these mutations can cause pre-syncope, 72 chronotropic incompetence 68 and AF. 71 However, given the importance of If in normal SAN pacemaking, the phenotype of these may be more benign than would be predicted, manifesting primarily as asymptomatic sinus bradycardia.…”

Section: Snd In Endurance Athletesmentioning

confidence: 69%

“…[69][70][71][72] As might be expected, these mutations can cause pre-syncope, 72 chronotropic incompetence 68 and AF. 71 However, given the importance of If in normal SAN pacemaking, the phenotype of these may be more benign than would be predicted, manifesting primarily as asymptomatic sinus bradycardia. 69, 70 Furthermore, transgenic mice with a conditional HCN4 There is widespread electrical remodeling at the cellular level, including downregulation of HCN4 and If.…”

Section: Snd In Endurance Athletesmentioning

confidence: 69%

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Fibrosis, Electrics and Genetics

Morris

Kalman

2014

Circ J

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The sinoatrial node (SAN) is the normal pacemaker of the heart. During a human lifetime it must initiate approximately 2 billion heartbeats and coordinate the cardiovascular response to our physiological and emotional demands. Disease of the SAN is common, and one of the leading indications for electronic pacemaker implantation. Advances in understanding the genetics and molecular mechanisms determining normal SAN function, and of the pathways controlling remodeling are revealing SAN disease to be heterogeneous. We review the contemporary concepts of SAN function, heart rate adaptation and SAN disease from the molecular level to clinical application. (Circ J 2014; 78: 1272 -1282

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Section: Snd In Endurance Athletesmentioning

confidence: 69%

Section: Snd In Endurance Athletesmentioning

confidence: 69%

Fibrosis, Electrics and Genetics

Morris

Kalman

2014

Circ J

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“…Several point mutations or deletions within the HCN4 gene have been found to be associated with bradycardia or paroxysmal AF. [58][59][60][61][62] One study screened a patient with idiopathic SND, detecting a heterozygous single base deletion leading to a truncated C-terminus. 58 When this mutant HCN4 gene was expressed in vitro in single cells, patch clamp experiments demonstrated I f insensitive to increased cAMP levels.…”

Section: Sinoatrial Node Dysfunction and Atrial Tachyarrhythmiasmentioning

confidence: 99%

“…58 Three other studies focused on related patients each detecting three different mutations, all of which expressed mutant HCN4 channels in vitro that only activated at more negative voltages. [59][60][61] Another study focused on patients with the same Moroccan-Jewish ethnic background, which revealed a novel point mutation that also led to HCN4 channels activating at more negative voltages. 62 The studies looking at family or ethnic ties all suggested an autosomal-dominant inheritance pattern.…”

Section: Sinoatrial Node Dysfunction and Atrial Tachyarrhythmiasmentioning

confidence: 99%

Biology of the Sinus Node and its Disease

Choudhury

Boyett

Morris

2015

Arrhythmia &Amp; Electrophysiology Review

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The sinoatrial or sinus node (SAN) is the heart's natural pacemaker.Located in the superior right atrium, it automatically produces cyclical electrical activity to initiate each heartbeat in normal sinus rhythm. SAN dysfunction (SND) in humans, also known as 'sick sinus syndrome', can manifest as pathological bradycardia and asystolic pauses. As a result, SND can lead to symptoms of reduced cerebral perfusion such as dizziness and syncope.However, early SND may be latent and individuals may remain asymptomatic. Implantable electronic pacemakers are currently the only effective treatment. SND is the most common reason to have a pacemaker implanted, the indication for 27.5 % of all pacemakers implanted in the UK. 1 The prevalence of SND in the UK is around 0.03 % affecting all ages, but it is much more common in the elderly population. The aetiology of SND can be intrinsic, extrinsic or often a mixture of the two. One retrospective study of 277 patients presenting to the emergency department with compromising bradycardia showed that 51 % of cases were attributable to a treatable extrinsic cause such as an adverse drug reaction, electrolyte imbalance or acute myocardial infarction. The other 49 % were assumed to be intrinsic or 'idiopathic'. The pathophysiology of 'idiopathic' SND is still not clearly understood.Historically it is attributed to fibrosis and cell senescence and this is often still quoted today. 4,5 However, contemporary evidence suggests that electrical remodelling of molecular pacemaking mechanisms such as membrane ion channels and intracellular Ca 2+ cycling are important factors in SND. 6 In this article we summarise the mechanisms of SAN function and review the current evidence surrounding the pathophysiology of SND. Development of the Sinoatrial NodeThe SAN is the uppermost part of the cardiac conduction system (CCS), a chain of specialised tissue that directs electrical impulses through the heart and thus co-ordinates the way it contracts. The CCS is defined by a specific pattern of gene expression, differing to the surrounding 'working myocardium'. During early embryogenesis as the heart tube forms, mesodermal cells quickly multiply and differentiate into working cardiomyocytes capable of contraction and fast conduction.7 However, the CCS is derived from primary myocardium that is instead led down a different lineage directed by specific transcription factors (Figure 1). 7Tbx3 is a T-box transcription factor found selectively within the CCS.Transgenic mice have been used to demonstrate its role in repressing working myocardial development and promoting a pacemaker programme of genes.8 These include key pacemaker genes, such as those encoding the low conductance gap junction connexin (Cx)45 and the hyperpolarisation-activated cyclic nucleotide-gated (HCN) membrane ion channel. 8,9 The function of HCN channels within the SAN is discussed below.The SAN is derived from an area of the developing CCS called the sinus venosus. The sinus venosus expresses a homeobox regulatory gene named Shox2.10 Sho...

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“…Dysfunction of pacemaker ion channels, including altered HCN4 channels, are associated with familial tachycardia-bradycardia syndrome and atrial fibrillation (Duhme et al, 2013). While it is clear that cardiac arrhythmias, including SAN dysfunction and atrial fibrillation (AF), are multifactorial there is increasing experimental evidence for abnormal Ca 2+ handling being a key factor (Dobrev and Nattel, 2008;Yeh et al, 2008) and is the focus of this paper.…”

Section: Introduction the Role Of Intracellular Ca 2+ In Sinoatrial Amentioning

confidence: 99%

Ca2+ Signaling and Heart Rhythm

Lei¹,

Huang²,

Solaro³

et al. 2016

Frontiers Research Topics

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms Citation: Lee BH, Trajanovska S, Hao G, Allen DG, Lei M and Cannell MB (2015) The involvement of TRPC3 channels in sinoatrial arrhythmias. Front. Physiol. 6:86. doi: 10.3389/fphys.2015.00086 The involvement of TRPC3 channels in sinoatrial arrhythmias Atrial fibrillation (AF) is a significant contributor to cardiovascular morbidity and mortality. The currently available treatments are limited and AF continues to be a major clinical challenge. Clinical studies have shown that AF is frequently associated with dysfunction in the sino-atrial node (SAN). The association between AF and SAN dysfunction is probably related to the communication between the SAN and the surrounding atrial cells that form the SAN-atrial pacemaker complex and/or pathological processes that affect both the SAN and atrial simultaneously. Recent evidence suggests that Ca 2+ entry through TRPC3 (Transient Receptor Potential Canonical-3) channels may underlie several pathophysiological conditions -including cardiac arrhythmias. However, it is still not known if atrial and sinoatrial node cells are also involved. In this article we will first briefly review TRPC3 and IP 3 R signaling that relate to store/receptor-operated Ca 2+ entry (SOCE/ROCE) mechanisms and cardiac arrhythmias. We will then present some of our recent research progress in this field. Our experiments results suggest that pacing-induced AF in angiotensin II (Ang II) treated mice are significantly reduced in mice lacking the TRPC3 gene (TRPC3 −/− mice) compared to wild type controls. We also show that pacemaker cells express TRPC3 and several other molecular components related to SOCE/ROCE signaling, including STIM1 and IP 3 R. Activation of G-protein coupled receptors (GPCRs) signaling that is able to modulate SOCE/ROCE and Ang II induced Ca 2+ homeostasis changes in sinoatrial complex being linked to TRPC3. The results provide new evidence that TRPC3 may play a role in sinoatrial and atrial arrhythmias that are caused by GPCRs activation.

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Altered HCN4 channel C-linker interaction is associated with familial tachycardia–bradycardia syndrome and atrial fibrillation

Abstract: Altered C-linker oligomerization in heteromeric channels is considered to promote familial tachycardia-bradycardia syndrome and persistent AF, indicating that f-channel dysfunction contributes to the development of atrial tachyarrhythmias.

Cited by 86 publications

References 28 publications

Fibrosis, Electrics and Genetics

Fibrosis, Electrics and Genetics

Biology of the Sinus Node and its Disease

Ca2+ Signaling and Heart Rhythm

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