The sinus node function: normal and pathological

Marneffe, Michel De; Grégoire, Jean‐Marie; Waterschoot, Patrick; Kestemont, Marie‐Paule

doi:10.1093/eurheartj/14.5.649

Cited by 36 publications

(27 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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.…”

Section: Discussionmentioning

confidence: 99%

Sick Sinus Syndrome in HCN1-Deficient Mice

et al. 2013

View full text Add to dashboard Cite

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.)

show abstract

Section: Discussionmentioning

confidence: 99%

Sick Sinus Syndrome in HCN1-Deficient Mice

et al. 2013

View full text Add to dashboard Cite

show abstract

“…It accounts for approximately ∼ 50% of one million permanent pacemaker implants every year worldwide [22]. Although it may accompany underlying cardiac disease, it can occur at any age, but most commonly occurs in the elderly without apparent heart disease [23]. Patients with SSS may experience syncope, pre-syncope, palpitations, or vertigo; however, they often are asymptomatic or have subtle or nonspecific symptoms related to the decreased cardiac output that occurs with the bradyarrhythmias or tachyarrhythmias.…”

Section: Scn5a Mutation and Sinus Node Dysfunctionmentioning

confidence: 99%

SCN5A and sinoatrial node pacemaker function

Lei¹,

Zhang²,

Grace³

et al. 2007

Cardiovascular Research

View full text Add to dashboard Cite

The SCN5A gene encodes specific voltage-dependent Na+ channels abundant in cardiac muscle that open and close at specific stages of cardiac activity in response to voltage change, thereby controlling the magnitude and timecourse of voltage-dependent Na+ currents (iNa) in cardiac muscle cells. Although iNa has been recorded from sinoatrial (SA) node pacemaker cells, its precise role in SA node pacemaker function remains uncertain. This review summarizes recent findings bearing upon: (i) Sinus node dysfunction resulting from genetic mutations in SCN5A; (ii) Sinus node function in the murine cardiac model with targeted disruptions of the SCN5A gene; (iii) Experimental and computational evaluations of the functional roles of iNa in SA node pacemaker function. Taken together, these new observations suggest strong correlations between SCN5A-encoded Na+ channel and SA node pacemaker function.

show abstract

“…However, in a number of patients, no specific cause can be identified [1,2]. Recent reports describing families with hereditary SND have suggested a genetic cause or susceptibility in its pathogenesis [3].…”

Section: Introductionmentioning

confidence: 99%

Genetic Variation in the Inwardly Rectifying K+ Channel Subunits KCNJ3 (GIRK1) and KCNJ5 (GIRK4) in Patients with Sinus Node Dysfunction

et al. 2010

View full text Add to dashboard Cite

Background: Sinus node dysfunction (SND) is a heterogeneous disorder of unknown etiology characterized by a variety of supraventricular arrhythmias with symptoms of syncope, palpitations, and dizziness. The mechanism underlying the abnormal rhythm is incompletely understood. Objective: Because vagal stimulation and acetylcholine (ACh) affect the function of pacemaker cells, we hypothesized that genetic variation in the genes encoding the ACh-activated K⁺ channels, the KACh channels, could be involved in the pathogenesis of SND. Methods and Results: We screened 184 patients listed in the pacemaker registry of the Copenhagen University Hospital aged <60 years at pacemaker implantation for SND in the period 1982–2005. Forty-three patients fulfilled the following inclusion criteria: documented sinus arrest, asystole, or extreme sinus bradycardia. The coding sequences of KCNJ3 and KCNJ5, encoding the main subunits of the KACh channels, were re-sequenced. We identified several known single nucleotide polymorphisms in KCNJ3 and KCNJ5, but no mutations in either of the genes. Conclusions: Genetic variation in KCNJ3 and KCNJ5 encoding the subunits of the KACh channels is apparently not involved in the pathogenesis of SND.

show abstract

The sinus node function: normal and pathological

Cited by 36 publications

References 0 publications

Sick Sinus Syndrome in HCN1-Deficient Mice

Sick Sinus Syndrome in HCN1-Deficient Mice

SCN5A and sinoatrial node pacemaker function

Genetic Variation in the Inwardly Rectifying K<sup>+</sup> Channel Subunits <i>KCNJ3</i> (<i>GIRK1</i>) and <i>KCNJ5</i> (<i>GIRK4</i>) in Patients with Sinus Node Dysfunction

Contact Info

Product

Resources

About