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GeroScience Aug 2023Sinoatrial node (SAN) beating interval variability (BIV) and the average beating interval (BI) are regulated by a coupled-clock system, driven by Ca-calmodulin activated...
Sinoatrial node (SAN) beating interval variability (BIV) and the average beating interval (BI) are regulated by a coupled-clock system, driven by Ca-calmodulin activated adenylyl cyclase, cAMP, and downstream PKA signaling. Reduced responsiveness of the BI and BIV to submaximal, [X], β-adrenergic receptor (β-AR) stimulation, and phosphodiesterase inhibition (PDEI) have been documented in aged SAN tissue, whereas the maximal responses, [X], do not differ by age. To determine whether age-associated dysfunction in cAMP signaling leads to altered responsiveness of BI and BIV, we measured cAMP levels and BI in adult (2-4 months n = 27) and aged (22-26 months n = 25) C57/BL6 mouse SAN tissue in control and in response to β-AR or PDEI at X and [X]. Both cAMP and average BI in adult SAN were reduced at X, whereas cAMP and BI at X did not differ by age. cAMP levels and average BI were correlated both within and between adult and aged SAN. BIV parameters in long- and short-range terms were correlated with cAMP levels for adult SAN. However, due to reduced cAMP within aged tissues at [X], these correlations were diminished in advanced age. Thus, cAMP level generated by the coupled clock mechanisms is tightly linked to average BI. Reduced cAMP level at X in aged SAN explains the reduced responsiveness of the BI and BIV to β-AR stimulation and PDEI.
Topics: Animals; Mice; Signal Transduction; Sinoatrial Node; Pacemaker, Artificial
PubMed: 37084120
DOI: 10.1007/s11357-023-00787-5 -
PloS One 2020Localization of the components of the cardiac conduction system (CCS) is essential for many therapeutic procedures in cardiac surgery and interventional cardiology....
Localization of the components of the cardiac conduction system (CCS) is essential for many therapeutic procedures in cardiac surgery and interventional cardiology. While histological studies provided fundamental insights into CCS localization, this information is incomplete and difficult to translate to aid in intraprocedural localization. To advance our understanding of CCS localization, we set out to establish a framework for quantifying nodal region morphology. Using this framework, we quantitatively analyzed the sinoatrial node (SAN) and atrioventricular node (AVN) in ovine with postmenstrual age ranging from 4.4 to 58.3 months. In particular, we studied the SAN and AVN in relation to the epicardial and endocardial surfaces, respectively. Using anatomical landmarks, we excised the nodes and adjacent tissues, sectioned those at a thickness of 4 μm at 100 μm intervals, and applied Masson's trichrome stain to the sections. These sections were then imaged, segmented to identify nodal tissue, and analyzed to quantify nodal depth and superficial tissue composition. The minimal SAN depth ranged between 20 and 926 μm. AVN minimal depth ranged between 59 and 1192 μm in the AVN extension region, 49 and 980 μm for the compact node, and 148 and 888 μm for the transition to His Bundle region. Using a logarithmic regression model, we found that minimal depth increased logarithmically with age for the AVN (R2 = 0.818, P = 0.002). Also, the myocardial overlay of the AVN was heterogeneous within different regions and decreased with increasing age. Age associated alterations of SAN minimal depth were insignificant. Our study presents examples of characteristic tissue patterns superficial to the AVN and within the SAN. We suggest that the presented framework provides quantitative information for CCS localization. Our studies indicate that procedural methods and localization approaches in regions near the AVN should account for the age of patients in cardiac surgery and interventional cardiology.
Topics: Animals; Atrioventricular Node; Sheep; Sinoatrial Node
PubMed: 32379798
DOI: 10.1371/journal.pone.0232618 -
Clinics (Sao Paulo, Brazil) Dec 2006To analyze the anatomical variations of sinuatrial nodal branch(es) of the coronary artery mainly regarding their number; a recent report from Japan claims the presence...
OBJECTIVE
To analyze the anatomical variations of sinuatrial nodal branch(es) of the coronary artery mainly regarding their number; a recent report from Japan claims the presence of 2 branches in up to 50% of cases, an occurrence that would permit adequate flow compensation in case of occlusion or section of 1 of these branches.
METHODS
The sinuatrial nodal branch(es) of 50 human hearts fixed in formol solution were dissected with the aid of a Normo Health 3.0 degree visor magnifying lens, measured, and classified as to the origin, route, and number of branches.
RESULTS
In 94% (n = 47) of cases, a single sinuatrial nodal branch was found. classified: (A) two right side types, R1 (in 46% of cases, n = 23), situated medial to the right auricle and R2 (in 4% of cases, n = 2), situated on the posterior surface of the right atrium; (B) three left side types, L1 (in 24% of cases, n = 12), situated medial to the left auricle, L2 (in 16% of cases, n = 8), situated posterior to the left auricle, and L3 (in 4% of cases, n = 2), situated on the posterior surface of the left atrium. Except for R2, each type was subdivided into 'a' or 'b' types, according to whether the sinuatrial nodal branch(es) occurred in a clockwise or counterclockwise orientation around the base of the superior cava vena. In 4% of cases (n = 2), 2 sinuatrial nodal branch(es) were observed with 1 branch originating from each of the coronary arteries. In 1 case (2%), 3 sinuatrial nodal branch(es) were found, 2 from the right coronary artery and the third probably from the bronchial branch of the thoracic aorta. In 30% of the cases, the sinuatrial nodal branch(es) formed a ring around the base of the superior cava vena. In all cases, the sinuatrial nodal branch(es) supplied collateral branches to the atrium and/or the auricle of the same side as its origin and/or to the opposite side.
CONCLUSION
The low frequency of 2 sinuatrial nodal branch(es) in Brazilian individuals, compared to the higher frequency found among the Japanese, is probably due to a variation associated with ethnic group origin.
Topics: Adult; Asian People; Coronary Circulation; Coronary Vessels; Heart Ventricles; Humans; Sinoatrial Node; White People
PubMed: 17187092
DOI: 10.1590/s1807-59322006000600011 -
Journal of the American Heart... Jun 2016Radiofrequency ablation (RFA) for atrioventricular nodal reentrant tachycardia appears to reduce atrial tachycardia, which might relate to parasympathetic denervation at...
BACKGROUND
Radiofrequency ablation (RFA) for atrioventricular nodal reentrant tachycardia appears to reduce atrial tachycardia, which might relate to parasympathetic denervation at cardiac ganglionated plexuses.
METHODS AND RESULTS
Compared to 7 control canines without RFA, in 14 canines, RFA at the bottom of Koch's triangle attenuated vagal stimulation-induced effective refractory periods prolongation in atrioventricular nodal and discontinuous atrioventricular conduction curves but had no effect on the sinoatrial node. RFA attenuated vagal stimulation-induced atrial effective refractory periods shortening and vulnerability window of atrial fibrillation widening in the inferior right atrium and proximal coronary sinus but not in the high right atrium and distal coronary sinus. Moreover, RFA anatomically impaired the epicardial ganglionated plexuses at the inferior vena cava‒inferior left atrial junction. This method was also investigated in 42 patients who had undergone ablation of atrioventricular nodal reentrant tachycardia, or 12 with an accessory pathway (AP) at the posterior septum (AP-PS), and 34 patients who had an AP at the free wall as control. In patients with atrioventricular nodal reentrant tachycardia and AP-PS, RFA at the bottom of Koch's triangle prolonged atrial effective refractory periods and reduced vulnerability windows of atrial fibrillation widening at the inferior right atrium, distal coronary sinus and proximal coronary sinus but not the high right atrium. In patients with AP-free wall, RFA had no significant atrial effects.
CONCLUSIONS
RFA at the bottom of Koch's triangle attenuated local autonomic innervation in the atrioventricular node and atria, decreased vagal stimulation-induced discontinuous atrioventricular nodal conduction, and reduced atrial fibrillation inducibility due to impaired ganglionated plexuses. In patients with atrioventricular nodal reentrant tachycardia or AP-PS, RFA prolonged atrial effective refractory periods, and narrowed vulnerability windows of atrial fibrillation.
Topics: Analysis of Variance; Animals; Atrioventricular Node; Cardiac Pacing, Artificial; Catheter Ablation; Dogs; Female; Heart Rate; Humans; Male; Middle Aged; Neural Conduction; Parasympathectomy; Sinoatrial Node; Tachycardia, Atrioventricular Nodal Reentry; Vagus Nerve Stimulation
PubMed: 27287698
DOI: 10.1161/JAHA.115.003083 -
American Journal of Physiology. Heart... May 2012Since Keith and Flack's anatomical discovery of the sinoatrial node (SAN), the primary pacemaker of the heart, the question of how such a small SAN structure can pace... (Review)
Review
Since Keith and Flack's anatomical discovery of the sinoatrial node (SAN), the primary pacemaker of the heart, the question of how such a small SAN structure can pace the entire heart has remained for a large part unanswered. Recent advances in optical mapping technology have made it possible to unambiguously resolve the origin of excitation and conduction within the animal and human SAN. The combination of high-resolution optical mapping and histological structural analysis reveals that the canine and human SANs are functionally insulated from the surrounding atrial myocardium, except for several critical conduction pathways. Indeed, the SAN as a leading pacemaker requires anatomical (fibrosis, fat, and blood vessels) and/or functional barriers (paucity of connexins) to protect it from the hyperpolarizing influence of the surrounding atrium. The presence of conduction barriers and pathways may help explain how a small cluster of pacemaker cells in the SAN pacemaker complex manages to depolarize different, widely distributed areas of the right atria as evidenced functionally by exit points and breakthroughs. The autonomic nervous system and humoral factors can further regulate conduction through these pathways, affecting pacemaker automaticity and ultimately heart rate. Moreover, the conduction barriers and multiple pathways can form substrates for reentrant activity and thus lead to atrial flutter and fibrillation. This review aims to provide new insight into the function of the SAN pacemaker complex and the interaction between the atrial pacemakers and the surrounding atrial myocardium not only in animal models but also human hearts.
Topics: Animals; Arrhythmias, Cardiac; Atrial Function; Autonomic Nervous System; Dogs; Heart Conduction System; Heart Rate; Humans; Models, Animal; Sinoatrial Node
PubMed: 22268110
DOI: 10.1152/ajpheart.00892.2011 -
Biophysical Journal Aug 2017Sinoatrial node myocytes act as cardiac pacemaker cells by generating spontaneous action potentials (APs). Much information is encoded in sinoatrial AP waveforms, but...
Sinoatrial node myocytes act as cardiac pacemaker cells by generating spontaneous action potentials (APs). Much information is encoded in sinoatrial AP waveforms, but both the analysis and the comparison of AP parameters between studies is hindered by the lack of standardized parameter definitions and the absence of automated analysis tools. Here we introduce ParamAP, a standalone cross-platform computational tool that uses a template-free detection algorithm to automatically identify and parameterize APs from text input files. ParamAP employs a graphic user interface with automatic and user-customizable input modes, and it outputs data files in text and PDF formats. ParamAP returns a total of 16 AP waveform parameters including time intervals such as the AP duration, membrane potentials such as the maximum diastolic potential, and rates of change of the membrane potential such as the diastolic depolarization rate. ParamAP provides a robust AP detection algorithm in combination with a standardized AP parameter analysis over a wide range of AP waveforms and firing rates, owing in part to the use of an iterative algorithm for the determination of the threshold potential and the diastolic depolarization rate that is independent of the maximum upstroke velocity, a parameter that can vary significantly among sinoatrial APs. Because ParamAP is implemented in Python 3, it is also highly customizable and extensible. In conclusion, ParamAP is a powerful computational tool that facilitates quantitative analysis and enables comparison of sinoatrial APs by standardizing parameter definitions and providing an automated work flow.
Topics: Action Potentials; Computational Biology; Muscle Cells; Reference Standards; Reproducibility of Results; Sinoatrial Node; Statistics as Topic
PubMed: 28834713
DOI: 10.1016/j.bpj.2017.07.001 -
Circulation Jul 2021Up to 50% of the adult human sinoatrial node (SAN) is composed of dense connective tissue. Cardiac diseases including heart failure (HF) may increase fibrosis within the...
BACKGROUND
Up to 50% of the adult human sinoatrial node (SAN) is composed of dense connective tissue. Cardiac diseases including heart failure (HF) may increase fibrosis within the SAN pacemaker complex, leading to impaired automaticity and conduction of electric activity to the atria. Unlike the role of cardiac fibroblasts in pathologic fibrotic remodeling and tissue repair, nothing is known about fibroblasts that maintain the inherently fibrotic SAN environment.
METHODS
Intact SAN pacemaker complex was dissected from cardioplegically arrested explanted nonfailing hearts (non-HF; n=22; 48.7±3.1 years of age) and human failing hearts (n=16; 54.9±2.6 years of age). Connective tissue content was quantified from Masson trichrome-stained head-center and center-tail SAN sections. Expression of extracellular matrix proteins, including collagens 1 and 3A1, CILP1 (cartilage intermediate layer protein 1), and POSTN (periostin), and fibroblast and myofibroblast numbers were quantified by in situ and in vitro immunolabeling. Fibroblasts from the central intramural SAN pacemaker compartment (≈10×5×2 mm) and right atria were isolated, cultured, passaged once, and treated ± transforming growth factor β1 and subjected to comprehensive high-throughput next-generation sequencing of whole transcriptome, microRNA, and proteomic analyses.
RESULTS
Intranodal fibrotic content was significantly higher in SAN pacemaker complex from HF versus non-HF hearts (57.7±2.6% versus 44.0±1.2%; <0.0001). Proliferating phosphorylated histone 3/vimentin/CD31 (cluster of differentiation 31) fibroblasts were higher in HF SAN. Vimentin/α-smooth muscle actin/CD31 myofibroblasts along with increased interstitial POSTN expression were found only in HF SAN. RNA sequencing and proteomic analyses identified unique differences in mRNA, long noncoding RNA, microRNA, and proteomic profiles between non-HF and HF SAN and right atria fibroblasts and transforming growth factor β1-induced myofibroblasts. Specifically, proteins and signaling pathways associated with extracellular matrix flexibility, stiffness, focal adhesion, and metabolism were altered in HF SAN fibroblasts compared with non-HF SAN.
CONCLUSIONS
This study revealed increased SAN-specific fibrosis with presence of myofibroblasts, CILP1, and POSTN-positive interstitial fibrosis only in HF versus non-HF human hearts. Comprehensive proteotranscriptomic profiles of SAN fibroblasts identified upregulation of genes and proteins promoting stiffer SAN extracellular matrix in HF hearts. Fibroblast-specific profiles generated by our proteotranscriptomic analyses of the human SAN provide a comprehensive framework for future studies to investigate the role of SAN-specific fibrosis in cardiac rhythm regulation and arrhythmias.
Topics: Female; Fibroblasts; Heart Failure; Humans; Male; Middle Aged; Sinoatrial Node
PubMed: 33874740
DOI: 10.1161/CIRCULATIONAHA.120.051583 -
Cell Calcium May 2020Pacemaker action potentials emerge from the sinoatrial node (SAN) and rapidly propagate through the atria to the AV node via preferential conduction pathways, including...
Pacemaker action potentials emerge from the sinoatrial node (SAN) and rapidly propagate through the atria to the AV node via preferential conduction pathways, including one associated with the coronary sinus. However, few distinguishing features of these tracts are known. Identifying specific molecular markers to distinguish among these conduction pathways will have important implications for understanding atrial conduction and atrial arrhythmogenesis. Using a Stim1 reporter mouse, we discovered stromal interaction molecule 1 (STIM1)-expressing coronary sinus cardiomyocytes (CSC)s in a tract from the SAN to the coronary sinus. Our studies here establish that STIM1 is a molecular marker of CSCs and we propose a role for STIM1-CSCs in interatrial conduction. Deletion of Stim1 from the CSCs slowed interatrial conduction and increased susceptibility to atrial arrhythmias. Store-operated Ca currents (I) in response to Ca store depletion were markedly reduced in CSCs and their action potentials showed electrical remodeling. Our studies identify STIM1 as a molecular marker for a coronary sinus interatrial conduction pathway. We propose a role for SOCE in Ca signaling of CSCs and implicate STIM1 in atrial arrhythmogenesis.
Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium Signaling; Coronary Sinus; Gene Deletion; Heart Atria; Heart Conduction System; Ion Channel Gating; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Sinoatrial Node; Stromal Interaction Molecule 1
PubMed: 32014794
DOI: 10.1016/j.ceca.2020.102163 -
BMB Reports Dec 2015Cardiovascular function is regulated by the rhythmicity of circadian, infradian and ultradian clocks. Specific time scales of different cell types drive their functions:... (Review)
Review
Cardiovascular function is regulated by the rhythmicity of circadian, infradian and ultradian clocks. Specific time scales of different cell types drive their functions: circadian gene regulation at hours scale, activation-inactivation cycles of ion channels at millisecond scales, the heart's beating rate at hundreds of millisecond scales, and low frequency autonomic signaling at cycles of tens of seconds. Heart rate and rhythm are modulated by a hierarchical clock system: autonomic signaling from the brain releases neurotransmitters from the vagus and sympathetic nerves to the heart's pacemaker cells activate receptors on the cell. These receptors activating ultradian clock functions embedded within pacemaker cells include sarcoplasmic reticulum rhythmic spontaneous Ca2+ cycling, rhythmic ion channel current activation and inactivation, and rhythmic oscillatory mitochondria ATP production. Here we summarize the evidence that intrinsic pacemaker cell mechanisms are the end effector of the hierarchical brain-heart circadian clock system.
Topics: Animals; Circadian Rhythm; Heart Rate; Humans; Myocardial Contraction; Sinoatrial Node
PubMed: 25999176
DOI: 10.5483/bmbrep.2015.48.12.061 -
Progress in Biophysics and Molecular... 2008To characterize the effects of inhibition of Ryanodine receptor (RyR), TTX-sensitive neuronal Na+ current (iNa), "rapidly activating" delayed rectifier K+ current (iKr)... (Review)
Review
AIMS
To characterize the effects of inhibition of Ryanodine receptor (RyR), TTX-sensitive neuronal Na+ current (iNa), "rapidly activating" delayed rectifier K+ current (iKr) and ultrarapid delayed rectifier potassium current (IKur) on the pacemaker activity of the sinoatrial node (SAN) and the atrioventricular node (AVN) in the mouse.
METHODS
The structure of mouse AVN was studied by histology and immunolabelling of Cx43 and hyperpolarization-activated, cyclic nucleotide-binding channels (HCN). The effects of Ryanodine, TTX, E-4031 and 4-AP on pacemaker activities recorded from mouse intact SAN and AVN preparations have been investigated.
RESULTS
Immuno-histological characterization delineated the structure of the AVN showing the similar molecular phenotype of the SAN. The effects of these inhibitors on the cycle length (CL) of the spontaneous pacemaker activity of the SAN and the AVN were characterized. Inhibition of RyR by 0.2 and 2 microM Ryanodine prolonged CL by 42+/-12.3% and 64+/-18.1% in SAN preparations by 163+/-72.3% and 241+/-91.2% in AVN preparations. Inhibition of TTX-sensitive iNa by 100 nM TTX prolonged CL by 22+/-6.0% in SAN preparations and 53+/-13.6% in the AVN preparations. Block of iKr by E-4031 prolonged CL by 68+/-12.5% in SAN preparations and 28+/-3.4% in AVN preparations. Inhibition of iKur by 50 microM 4-AP prolonged CL by 20+/-3.4% in SAN preparations and 18+/-3.0% in AVN preparations.
CONCLUSION
Mouse SAN and AVN showed distinct different response to the inhibition of RyR, TTX-sensitive INa, IKr and iKur, which reflects the variation in contribution of these currents to the pacemaker function of the cardiac nodes in the mouse. Our data provide valuable information for developing virtual tissue models of mouse SAN and AVN.
Topics: 4-Aminopyridine; Animals; Anti-Arrhythmia Agents; Atrioventricular Node; Mice; Piperidines; Potassium Channel Blockers; Pyridines; Ryanodine; Sinoatrial Node; Tetrodotoxin
PubMed: 17850852
DOI: 10.1016/j.pbiomolbio.2007.07.003