Faculty Opinions recommendation of Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker.

Introduction:Little is known about the clinical performance of single-chamber leadless pacemaker (LLPM) in patients without atrial fibrillation (AF) as pacing indication. The aim of this study was to describe the clinical characteristics of patients who underwent single chamber LLPM implantation at three tertiary referral centers and to compare the safety and effectiveness of the single-chamber LLPM among patients with or without AF.Materials and Methods:All the consecutive patients who underwent LLPM implantation at three referral centers were analyzed. The indications to LLPM in a real-world setting were described. The study population was divided into two groups according to AF as pacing indication. We assessed the procedure-related complications; moreover, we compared syncope, cardiac hospitalization, pacemaker syndrome, and all-cause death recurrence during the follow-up between patients with and without AF as pacing indication.Results:A total of 140 consecutive patients (mean age, 76.7 ± 11.24 years, men 64.3%) were included in the study. The indication to implantation of LLPM was permanent AF with slow ventricular response (n: 67; 47.8%), sinus node dysfunction (n: 25; 17.8%), third atrioventricular block (AVB) (n: 20; 14.2%), second-degree AVB (n: 18; 12.8%), and first degree AVB (n: 10; 7.1%). A total of 7 patients (5%) experienced perioperative complications with no differences between the AF vs. non-AF groups. During a mean follow-up of 606.5 ± 265.9 days, 10 patients (7.7%) died and 7 patients (5.4%) were reported for cardiac hospitalization; 5 patients (3.8%) experienced syncope; no patients showed pacemaker syndrome. No significant differences in the clinical events between the groups were shown. The Kaplan–Meier analysis for the combined endpoints did not show significant differences between the AF and non-AF groups [hazard ratio (HR): 0.94, 95% CI: 0.41–2.16; p = 0.88].Conclusion:Our real-world data suggest that LLPM may be considered a safe and reasonable treatment in patients without AF in need of pacing. Further studies are needed to confirm these preliminary results.

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GATA6 is a regulator of sinus node development and heart rhythm

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2007322118 ◽

2020 ◽

Vol 118 (1) ◽

pp. e2007322118

Author(s):

Lara Gharibeh ◽

Abir Yamak ◽

Jamieson Whitcomb ◽

Aizhu Lu ◽

Mathieu Joyal ◽

...

Keyword(s):

Molecular Basis ◽

Human Heart ◽

Sick Sinus Syndrome ◽

Sinus Node ◽

Pacemaker Implantation ◽

Cardiac Pacemaker ◽

Heart Rhythm ◽

Important Regulator ◽

Node Development ◽

Specific Deletion

The sinus node (SAN) is the primary pacemaker of the human heart, and abnormalities in its structure or function cause sick sinus syndrome, the most common reason for electronic pacemaker implantation. Here we report that transcription factor GATA6, whose mutations in humans are linked to arrhythmia, is highly expressed in the SAN and its haploinsufficiency in mice results in hypoplastic SANs and rhythm abnormalities. Cell-specific deletion reveals a requirement for GATA6 in various SAN lineages. Mechanistically, GATA6 directly activates key regulators of the SAN genetic program in conduction and nonconduction cells, such as TBX3 and EDN1, respectively. The data identify GATA6 as an important regulator of the SAN and provide a molecular basis for understanding the conduction abnormalities associated with GATA6 mutations in humans. They also suggest that GATA6 may be a potential modifier of the cardiac pacemaker.

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Effects of repetitive vagal stimulation on heart rate and on cardiac vasoactive intestinal polypeptide efflux

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.268.5.h1939 ◽

1995 ◽

Vol 268 (5) ◽

pp. H1939-H1946 ◽

Cited By ~ 3

Author(s):

M. R. Hill ◽

D. W. Wallick ◽

P. J. Martin ◽

M. N. Levy

Keyword(s):

Vasoactive Intestinal Polypeptide ◽

Vagal Stimulation ◽

Sinus Node ◽

Cardiac Pacemaker ◽

Close Correlation ◽

Right Atrial ◽

Chronotropic Response ◽

Sinus Node Artery ◽

Stimulation Regimen ◽

Intestinal Polypeptide

In dogs anesthetized with alpha-chloralose, we assessed the "vagally induced tachycardia" elicited by successive 2-min periods of intense vagal stimulation (0.5 ms, 10 mA, 20 Hz) after we had blocked the animals' muscarinic and beta-adrenergic receptors with atropine and propranolol, respectively. We found that the tachycardia produced by the successive vagal stimulations progressively decreased to < 20% of the initial tachycardia response within 84 min. We also observed that the chronotropic response to vasoactive intestinal polypeptide (VIP) injected into the sinus node artery after the vagal stimulation regimen did not differ significantly from the response to the same dose of VIP injected prior to vagal stimulation. This finding indicates that the postjunctional responsiveness of the cardiac pacemaker cells had not diminished over the course of the vagal stimulation regimen. In isolated, perfused right atrial preparations, we observed a close correlation between the efflux of VIP from the atrial tissues and the chronotropic responses to vagal stimulation. Our results support the hypotheses that 1) VIP is a mediator of vagally induced tachycardia, 2) the reduction in VIP efflux is associated with a diminished vagally induced tachycardia, and 3) the reduced efflux of VIP probably reflects a diminution in neuronal release, perhaps by depletion of this peptide from the vagus nerve endings consequent to the prolonged neural stimulation.

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Vasoactive intestinal polypeptide enhances automaticity of supraventricular pacemakers in anesthetized dogs

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1991.261.2.h463 ◽

1991 ◽

Vol 261 (2) ◽

pp. H463-H468 ◽

Cited By ~ 2

Author(s):

D. F. Rigel ◽

D. A. Lathrop

Keyword(s):

Vasoactive Intestinal Polypeptide ◽

Sinus Node ◽

Cardiac Pacemaker ◽

Autonomic Nerve ◽

Beta Adrenergic ◽

Pentobarbital Sodium ◽

Sinus Node Artery ◽

Anesthetized Dogs ◽

Muscarinic Cholinergic ◽

Intestinal Polypeptide

Effects of the cardiac neuropeptide vasoactive intestinal polypeptide (VIP) and isoproterenol (ISO) were compared on sinus nodal, subsidiary atrial, and atrioventricular junctional pacemaker automaticity in pentobarbital sodium-anesthetized dogs (n = 14). Autonomic cardiac nerves were decentralized by bilateral vagotomy and stellectomy. VIP and ISO (30, 100, and 300 pmol/kg iv) were administered during sinus rhythm and either after crushing the sinus node to unmask a latent subsidiary atrial pacemaker (n = 7 dogs) or after injecting pentobarbital sodium into the sinus node artery to elicit an atrioventricular junctional pacemaker (n = 7). Spontaneous sinus nodal, subsidiary atrial, and atrioventricular junctional pacemaker rates (after autonomic nerve decentralization) were 142 +/- 4, 114 +/- 3, and 79 +/- 4 beats/min (means +/- SE), respectively. Both VIP and ISO dose dependently increased the rates of all three pacemaker sites. Combined muscarinic-cholinergic (atropine; 0.11 mg/kg iv) and beta-adrenergic receptor blockade (nadolol; 0.5 mg/kg iv) abolished the stimulatory effects of ISO on subsidiary atrial and atrioventricular junctional pacemakers but did not affect the responses to VIP. We conclude that exogenous VIP enhances the automaticity of sinus nodal, subsidiary atrial, and atrioventricular junctional pacemakers independently of muscarinic-cholinergic and beta-adrenergic receptors. Based on the previous demonstration of VIP-immunoreactive nerves throughout the heart, our findings also suggest that endogenous VIP may be involved in cardiac pacemaker regulation.

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Molecular Architecture of the Human Sinus Node

Circulation ◽

10.1161/circulationaha.108.804369 ◽

2009 ◽

Vol 119 (12) ◽

pp. 1562-1575 ◽

Cited By ~ 230

Author(s):

Natalie J. Chandler ◽

Ian D. Greener ◽

James O. Tellez ◽

Shin Inada ◽

Hanny Musa ◽

...

Keyword(s):

Sinus Node ◽

Molecular Architecture

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Factors influencing development of atrial fibrillation after implantation of cardiac pacemaker for sinus node dysfunction

Medicina ◽

10.3390/medicina45030022 ◽

2009 ◽

Vol 45 (3) ◽

pp. 169

Author(s):

Audrius Aidietis ◽

Jūratė Barysienė ◽

Germanas Marinskis ◽

Sigita Aidietienė ◽

Diana Kairevičiūtė ◽

...

Keyword(s):

Atrial Fibrillation ◽

Mitral Regurgitation ◽

Sick Sinus Syndrome ◽

Sinus Node ◽

Interventricular Septum ◽

Pacemaker Implantation ◽

Cardiac Pacemaker ◽

Factors Influencing ◽

Grade Ii ◽

The Right

Objective. The aim of this study was to evaluate factors influencing the success of atrial fibrillation treatment associated with the sick sinus syndrome after pacemaker implantation. Methods and results. In 163 patients with sick sinus syndrome followed up after pacemaker implantation, statistical analysis showed that the recurrence of atrial fibrillation increased 2.8 times and 2.5 times when the left atrium or the right atrium, respectively, were increased by 1 cm (P=0.001). In addition, the recurrence of atrial fibrillation increased 2.5 times when the interventricular septum was thickened (P=0.007). Probability of atrial fibrillation recurrence was 2.73 times higher in the presence of grade II mitral regurgitation as compared to absent or grade I mitral regurgitation (P=0.029). The results of atrial fibrillation treatment did not significantly depend on age, gender, duration of atrial fibrillation symptoms, other cardiac structural changes, and concomitant noncardiac diseases. Conclusions. In patients with sick sinus syndrome, the effectiveness of atrial fibrillation treatment after pacemaker implantation is influenced by enlargement of the left and the right atria, increased interventricular septum thickness, and grade II mitral regurgitation. Evaluation of echocardiographic data before pacemaker implantation has prognostic value for determining the probability of maintenance of sinus rhythm.

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Transcriptional and Epigenetic Landscape of Cardiac Pacemaker Cells: Insights Into Cellular Specialization in the Sinoatrial Node

Frontiers in Physiology ◽

10.3389/fphys.2021.712666 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ravi Mandla ◽

Catherine Jung ◽

Vasanth Vedantham

Keyword(s):

Regulatory Networks ◽

Sinus Node ◽

Cardiac Pacemaker ◽

Heart Rhythm ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Transcriptional Networks ◽

Pacemaker Cell ◽

Pacemaker Cells ◽

Dna Regulatory Elements

Cardiac pacemaker cells differentiate and functionally specialize early in embryonic development through activation of critical gene regulatory networks. In general, cellular specification and differentiation require that combinations of cell type-specific transcriptional regulators activate expression of key effector genes by binding to DNA regulatory elements including enhancers and promoters. However, because genomic DNA is tightly packaged by histones that must be covalently modified in order to render DNA regulatory elements and promoters accessible for transcription, the process of development and differentiation is intimately connected to the epigenetic regulation of chromatin accessibility. Although the difficulty of obtaining sufficient quantities of pure populations of pacemaker cells has limited progress in this field, the advent of low-input genomic technologies has the potential to catalyze a rapid growth of knowledge in this important area. The goal of this review is to outline the key transcriptional networks that control pacemaker cell development, with particular attention to our emerging understanding of how chromatin accessibility is modified and regulated during pacemaker cell differentiation. In addition, we will discuss the relevance of these findings to adult sinus node function, sinus node diseases, and origins of genetic variation in heart rhythm. Lastly, we will outline the current challenges facing this field and promising directions for future investigation.

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Cholinergic regulation of cardiac pacemaker activity by L-type Cav1.3 channels

EP Europace ◽

10.1093/europace/euab116.580 ◽

2021 ◽

Vol 23 (Supplement_3) ◽

Author(s):

L Talssi ◽

I Bidaud ◽

ME Mangoni ◽

P Mesirca

Keyword(s):

Heart Rate ◽

Action Potentials ◽

Receptor Agonist ◽

Sinus Node ◽

Cardiac Pacemaker ◽

Intracellular Concentration ◽

Pacemaker Activity ◽

Cholinergic Regulation ◽

Frequency Of Action Potentials

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Fondation Recherche Médicale Introduction The cholinergic regulation of heart rate (HR) is mediated by acetylcholine (ACh)-dependent activation of M2-receptors (M2R). Activated M2R promote release of the βγ-subunit of G-proteins to directly gate GIRK1/4 channels (underlying the cardiac IKACh current), while αi-subunits inhibit adenylate cyclase (AC) activity. AC inhibition reduces the intracellular concentration of cAMP, decreasing the activity of ion channels involved in pacemaking, including "funny" f-(HCN4) and L-type Cav1.3 calcium channels. Purpose To determine the role of L-type Cav1.3 channels in cholinergic regulation of heart rate. Methods We recorded the frequency of activation and position of pacemaker leading site in ex vivo sinus nodes and the HR of isolated Langendorff perfused hearts of mice at baseline or during ACh perfusion. We used control wild type (WT) mice, and five genetically modified mouse models: Cav1.3 knockout (KO, ablated Cav1.3-mediated L-type current), GIRK4KO (ablated IKACh current), HCN4-CNBD (selective deletion of cAMP-dependent regulation of HCN4), GIRK4KO/HCN4-CNBD and GIRK4KO/Cav1.3KO. We performed in vivo telemetric recordings of heart rate (HR) in WT and GIRK4KO/Cav1.3KO animals. Results Data from optical mapping experiments showed that, under basal conditions, perfusion of 3 μM ACh significantly reduced the frequency of action potentials in WT (44%), HCN4-CNBD (38%), Cav1.3KO (65%) and GIRK4KO (8%) isolated mouse sinus node tissues. ACh application did not significantly affect the frequency of action potentials recorded in tissue from GIRK4KO/HCN4-CNBD and GIRK4KO/Cav1.3KO animals. Furthermore, in all sinus nodes tested, regardless of genotype, ACh shifted the pacemaker leading site from its normal position by at least 0.7 mm. Upon stimulation of the β-adrenergic pathway by Isoproterenol, to reproduce conditions of accentuated antagonism, 3µM ACh reduced HR in isolated hearts from WT (43.8%), HCN4-CNBD (38.7%), Cav1.3KO (25,4%), GIRK4KO (16.9%) and GIRK4KO/HCN4-CNBD (16.4%) mice. No significant HR reduction was recorded in hearts from GIRK4KO/Cav1.3KO animals. In vivo data indicate that HR reduction induced by combined injection of Hexamethonium ( a Nicotinic acetylcholine receptor blocker) with Carbamoylcholine (CCH, M2 receptor agonist) or with 2-Chloro-N6-Cyclopentyladenosine (CCPA, A1 receptor agonist) is higher in WT than in GIRK4KO/Cav1.3KO animals (68% vs 48% CCH, and 79% vs 62% CCPA, respectively). Conclusion Our data indicate that L-type Cav1.3 channels are involved in cholinergic regulation of heart rate in mice. In addition, when the intracellular concentration of cAMP is elevated (i.e. under conditions of accentuated antagonism), cholinergic regulation of sinus node pacemaking is reliant on Cav1.3 and KACh channels.

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Cholinergic regulation of cardiac pacemaker activity by l-type cav1.3 channels

European Heart Journal ◽

10.1093/ehjci/ehaa946.3597 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

L Talssi ◽

I Bidaud ◽

P Mesirca ◽

M Mangoni

Keyword(s):

Heart Rate ◽

Action Potentials ◽

Ex Vivo ◽

Sinus Node ◽

Cardiac Pacemaker ◽

Intracellular Concentration ◽

Pacemaker Activity ◽

Funding Source ◽

Cholinergic Regulation ◽

Frequency Of Action Potentials

Abstract Introduction The cholinergic regulation of heart rate (HR) is mediated by acetylcholine (ACh)-dependent activation of M2-receptors (M2R). Activated M2R promote release of the βγ-subunit of G-proteins to directly gate GIRK1/4 channels (underlying the cardiac IKACh current), while αi-subunits inhibit adenylate cyclase (AC) activity. AC inhibition reduces the intracellular concentration of cAMP, decreasing the activity of ion channels involved in pacemaking, including “funny” f-(HCN4) and L-type Cav1.3 calcium channels. Purpose To determine the importance of L-type Cav1.3 channels in the cholinergic regulation of heart rate. Methods We recorded the frequency and the position of the pacemaker leading site in ex vivo sinus nodes and the HR of isolated Langendorff perfused hearts of mice in control or during ACh perfusion. We used control wild type (WT) mice, and five genetically modified mouse models: Cav1.3 knockout (KO, ablated Cav1.3-mediated L-type current), GIRK4KO (ablated IKACh current), HCN4-CNBD (selective deletion of cAMP-dependent regulation of HCN4), GIRK4KO/HCN4-CNBD and GIRK4KO/Cav1.3KO. Results Data from optical mapping experiments showed that, under basal conditions, perfusion of 3 μM ACh significantly reduced the frequency of action potentials in WT (44%), HCN4-CNBD (38%), Cav1.3KO (65%) and GIRK4KO (8%) isolated mouse sinus node tissues. ACh application did not significantly affect the frequency of action potentials recorded in tissue from GIRK4KO/HCN4-CNBD and GIRK4KO/Cav1.3KO animals. Furthermore, in all the sinus node tissues tested, regardless of the genotypes, ACh shifted the pacemaker leading site from its normal position by at least 0.7 mm. Upon stimulation of the β-adrenergic pathway by Isoproterenol, to reproduce conditions of accentuated antagonism, 3μM ACh reduced HR in isolated hearts from WT (43.8%), HCN4-CNBD (38.7%), Cav1.3KO (25,4%), GIRK4KO (16.9%) and GIRK4KO/HCN4-CNBD (16.4%) mice. No significant HR reduction was recorded in hearts from GIRK4KO/Cav1.3KO animals. Conclusion Our data indicate that L-type Cav1.3 channels are involved in cholinergic regulation of heart rate in mice. In addition, when the intracellular concentration of cAMP is elevated (i.e. under conditions of accentuated antagonism), the cholinergic regulation of sinus node pacemaking is predominantly ensured by Cav1.3 and KACh channels. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): “Fondation pour la recherche medicale” FRM

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Study of the Molecular Architecture of Keratin Filaments by Electron Microscopy

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100053310 ◽

1982 ◽

Vol 40 ◽

pp. 118-119

Author(s):

U. Aebi ◽

P. Rew ◽

T.-T. Sun

Keyword(s):

Electron Microscopy ◽

Structural Organization ◽

Cell Types ◽

Structural Features ◽

Molecular Architecture ◽

The Past ◽

Keratin Filaments ◽

Different Types ◽

10 Nm Filaments ◽

Different Cell Types

Various types of intermediate-sized (10-nm) filaments have been found and described in many different cell types during the past few years. Despite the differences in the chemical composition among the different types of filaments, they all yield common structural features: they are usually up to several microns long and have a diameter of 7 to 10 nm; there is evidence that they are made of several 2 to 3.5 nm wide protofilaments which are helically wound around each other; the secondary structure of the polypeptides constituting the filaments is rich in ∞-helix. However a detailed description of their structural organization is lacking to date.

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