Sinoatrial Node Activity Research Articles

α1-Adrenergic Receptors Control the Activity of Sinoatrial Node by Modulating Transmembrane Transport of Chloride Anions

Norepinephrine (NE), which is released by sympathetic nerve endings, causes an increase in the frequency of spontaneous action potentials in the pacemaker cardiomyocytes of the sinoatrial node (SAN), also known as the “pacemaker” of the heart. This results in an increase in heart rate (HR). It is known that two types of postsynaptic adrenoreceptors (ARs), α1-AR and β-AR, can mediate the effects of NE. The role of α1-AR in the sympathetic control of heart rate and SAN automaticity, as well as the membrane mechanisms mediation the effects of α1-AR on the pacemaker, have not yet been elucidated. In this study, we utilized immunofluorescence confocal microscopy to examine the distribution of α1A-AR in the SAN of rats. Additionally, we assessed the expression of α1A-AR mRNA in the SAN tissue using RT-PCR. Furthermore, we investigated the impact of α1-AR stimulation on key functional parameters of the pacemaker, including the corrected sinus node recovery time (SNRT/cSNRT) and the SAN accommodation, using the Langendorff perfused heart technique. We also used optical mapping of the electrical activity of perfused, isolated tissue preparations to study the effect of α1-AR stimulation on the spatiotemporal characteristics of SAN excitation. We tested the effects of chloride transmembrane conductance blockade on alteration of functional parameters and pattern of SAN excitation caused by α1-AR. Fluorescent signals corresponding to α1A-AR have been identified in SAN cardiomyocytes, indicating the presence of α1A-AR at protein level. The expression of α1A-AR in SAN has been also confirmed at the mRNA level. The stimulation of α1-AR affects SAN functioning Phenylephrine (PHE) utilized as α1A-AR agonist causes a decrease in SNRT/cSNRT, as well as an acceleration of SAN accommodation. These effects were rate dependent and were observed at a high frequency of pacemaker tissue stimulation. PHE induces changes in the excitation pattern of the SAN. The effects of PHE on functional parameters and SAN excitation pattern are attenuated by Ca2+-dependent chloride channel blocker NPPB but remains unaffected by the protein kinase C inhibitor BIM. Our results suggest that cardiac α1-ARs are important for maintaining function of SAN pacemaker at high heart rates and that α1-AR signalling cascades in the SAN target Ca2+-dependent chloride channels are involved in the α1-adrenergic modulation of the electrophysiological properties of the heart pacemaker.

α1-Adrenergic Receptors Control the Activity of Sinoatrial Node by Modulating Transmembrane Transport of Chloride Anions

α1-Adrenergic Receptors Control the Activity of Sinoatrial Node by Modulating Transmembrane Transport of Chloride Anions

Mama and papa of the early spontaneous electrical activity of the embryo sinoatrial node

In adult mammalian hearts the spontaneous diastolic depolarization of the sinoatrial node (SAN) cells is generated by two interacting systems, a so‐called “membrane‐clock” and “calcium‐clock”. Hyperpolarization‐activated pacemaker current (If) plays a key role in the “membrane‐clock”, while the “calcium‐clock” is based on rhythmic spontaneous Ca2+ release from sarcoplasmic reticulum via ryanodine receptors (RyRs). These complementing systems provide regular pacemaking even in case of damage of one of them. The aim of this study was to evaluate a role of If current and ryanodine receptors in the electrical activity of the developing mouse SAN.MethodsWe used embryos of mice, aged of E9.5, E12.5 and newborn to perform our experiments. After release from the amniotic membrane, the embryos were transferred with a pipette to a clean Petri dish with oxygenated physiological solution containing (in mM/L) 140 NaCl, 5.4 KCl, 0.1 CaCl2, 0.33 NaH2PO4, 1 MgCl2, 10 HEPES, 10 Glucose, (pH 7.38) at room temperature. To record spontaneous action potential (AP) we used conventional microelectodes technique at 37◦C. Differences were considered significant at p < 0.05ResultsMicroelectrode mapping at E9.5 revealed that the SAN cells are located in the inflow tract of the venous pole. At E12 the SAN cells are located in the cavo‐auricular junction. In neonatal mice, SAN cells were detected at intercaval area near to the crista terminalis. At E9.5, in 6 experiments, on 25‐ 30 minute exposure of 3 mkM ivabradine (Iva) an irregularity in AP generation by SAN cells was occurred. The same effects were obtained in 4 experiments on 20‐30 minutes exposure of 3 mkM ryanodine. At E12.5 exposure of Iva 3 mkM for 30 minutes reduced the pacemaker firing rate by 34% (p < 0.05) but did not break the rhythmic generation. In contrast, the exposure of 3 mkM ryanodine for 30 minutes, in 4 experiments, still caused an irregularity in AP generation by SAN cells. In neonatal isolated SAN preparations, exposure of Iva 3 mkM and 3 mkM ryanodine for 30 minutes reduced the pacemaker firing rate equally (on 32%; p < 0.05). However, co‐application of Iva and ryanodine induced an irregularity in AP generation by SAN cells (Figure).Numerical experiments within the framework of mouse SANC model (Kharche, AJP, 11) adopted for embryonic cells (Markov, IEEE, 21) have shown the decrease in the frequency of the AP generation with decreasing of the “funny” currents permeability caused by Iva action.The supposed complete RyRs opening, caused by a relatively low ryanodine concentration, led to a decrease of the AP generation frequency, but not to the rhythm disturbances. However a decrease in RyRs permeability by an order of magnitude led to the appearance of “bursts‐like” irregularity in AP generation.ConclusionThus, the membrane‐clock and the Ca2+‐clock mechanisms is critical for spontaneous electrical activity E9.5 mouse embryos, whereas the Ca2+‐clock mechanisms is critical for increase rate AP generation in development SAN cells.

Biophysical Models of Minipig Right Atrial Ganglionic Plexus Principal Neurons Identified from Transcriptomics Data

The Right Atrial Ganglionic Plexus (RAGP) is a component of the intrinsic cardiac nervous system. Its neurons are critical to the cardiac pacemaker response to vagal stimulation, regulating sino‐atrial node activity. We developed single‐compartment computational models of RAGP principal neurons by incorporating ion channels identified from transcriptomics data from HT‐qPCR (High Throughput quantitative Polymerase Chain Reaction) and RNA‐sequencing of 405 principal neurons in female Yucatan minipig RAGP. Out of the ~200 genes in the transcriptomics map, we identified 13 genes that encode ion channel proteins, namely: Naf (Scn1a, Nav 1.1), KDR (Kcnc1, Kv 3.1; Kcnab1, Kv 1.1), P‐, N‐, L‐, T‐type Ca2+ (Cacna1a, Cav 2.1; Cacna1b, Cav 2.2; Cacna1c, Cav 1.2; Cacna1g, Cav 3.1; Cacna1i, Cav 3.3), KA (Kcnd2) and HCN1, HCN2, HCN3, HCN4. The corresponding Hodgkin‐Huxley‐based kinetic models of these ion channel isoforms were mined from databases: Ion Channel Genealogy, Channelpedia, and ModelDB. Since each ion channel gene had several kinetic models associated with it, we ran multiple simulations on the NetPyNE software to identify a single model per gene that would best represent the channel's dynamic behaviour in the assembled electrophysiological model. A binary transcriptomic map of the 13 genes showed 101 distinct ion channel combinations. Our 505 electrophysiological models (5 sets of the 101 cells) elicited two primary firing profiles. 65% elicited a single‐spike phasic response, ~32% elicited a tonic firing in response to a current clamp stimulus, and ~3% produced tonic firing that continued after the stimulus. The firing frequencies increased by ~13 Hz for every 0.1 nA increase in the current clamp stimulus and decreased by ~11 Hz for every 0.01 S/cm2 increase in KA channel conductance. Our electrophysiological models are available to the SPARC community in NetPyNE and NIH’s O2S2PARC platform. The models exhibit phasic and tonic excitability profiles with phasic being more prevalent. We next aim to incorporate neuromodulatory inputs and simulate a network of these neuronal models.

CaMKII signalling is reduced in the sinus node of a heart failure experimental model

Heart failure (HF) is a complex syndrome in which sudden cardiac death is associated to pump failure, ventricular arrhythmias or severe bradycardias. Sinoatrial node (SAN) activity is regulated synergically by membrane ion currents (voltage-clock) and intracellular calcium handling (Ca2+-clock). Whereas SAN dysfunction has been associated with voltage-clock remodelling in HF patients, the Ca2+-clock remodelling in SAN remains to be elucidated. Here, we studied intracellular Ca2+ handling in SAN from a transverse aortic constriction (TAC) mouse model of HF.

Impacts of frailty on heart rate variability in aging mice: Roles of the autonomic nervous system and sinoatrial node.

Heart rate variability (HRV) is determined by intrinsic sinoatrial node (SAN) activity and the autonomic nervous system (ANS). HRV is reduced in aging; however, aging is heterogeneous. Frailty, which can be measured using a frailty index (FI), can quantify health status in aging separately from chronological age. The purpose of this study was to investigate the impacts of age and frailty on HRV in mice. Frailty was measured in aging mice between 10 and 130 weeks of age. HRV was assessed using time domain, frequency domain, and Poincaré plot analyses in anesthetized mice at baseline and after ANS blockade, as well as in isolated atrial preparations. HRV was reduced in aged mice (90-130 weeks and 50-80 weeks old) compared to younger mice (10-30 weeks old); however, there was substantial variability within age groups. In contrast, HRV was strongly correlated with FI score regardless of chronological age. ANS blockade resulted in reductions in heart rate that were largest in 90- to 130-week-old mice and were correlated with FI score. HRV after ANS blockade or in isolated atrial preparations was increased in aged mice but again showed high variability among age groups. HRV was correlated with FI score after ANS blockade and in isolated atrial preparations. HRV is reduced in aging mice in association with a shift in sympathovagal balance and increased intrinsic SAN beating variability; however, HRV is highly variable within age groups. HRV was strongly correlated with frailty, which was able to detect differences in HRV separately from chronological age.

A single cell transcriptomics map of paracrine networks in the intrinsic cardiac nervous system

SummaryWe developed a spatially-tracked single neuron transcriptomics map of an intrinsic cardiac ganglion, the right atrial ganglionic plexus (RAGP) that is a critical mediator of sinoatrial node (SAN) activity. This 3D representation of RAGP used neuronal tracing to extensively map the spatial distribution of the subset of neurons that project to the SAN. RNA-seq of laser capture microdissected neurons revealed a distinct composition of RAGP neurons compared to the central nervous system and a surprising finding that cholinergic and catecholaminergic markers are coexpressed, suggesting multipotential phenotypes that can drive neuroplasticity within RAGP. High-throughput qPCR of hundreds of laser capture microdissected single neurons confirmed these findings and revealed a high dimensionality of neuromodulatory factors that contribute to dynamic control of the heart. Neuropeptide-receptor coexpression analysis revealed a combinatorial paracrine neuromodulatory network within RAGP informing follow-on studies on the vagal control of RAGP to regulate cardiac function in health and disease.

Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia

Electrical activity in the heart exhibits 24-hour rhythmicity, and potentially fatal arrhythmias are more likely to occur at specific times of day. Here, we demonstrate that circadian clocks within the brain and heart set daily rhythms in sinoatrial (SA) and atrioventricular (AV) node activity, and impose a time-of–day dependent susceptibility to ventricular arrhythmia. Critically, the balance of circadian inputs from the autonomic nervous system and cardiomyocyte clock to the SA and AV nodes differ, and this renders the cardiac conduction system sensitive to decoupling during abrupt shifts in behavioural routine and sleep-wake timing. Our findings reveal a functional segregation of circadian control across the heart’s conduction system and inherent susceptibility to arrhythmia.

Endo-Epicardial Mapping of InVivo Human Sinoatrial Node Activity.

The aim of the current study was to examine electrophysiological characteristics of sinoatrial node (SAN) activity from an endo-epicardial perspective. Electrophysiological properties of the invivo human SAN and its exit pathways remain poorly understood. Twenty patients (75% male; median age 66 years [59 to 73 years]) with structural heart disease underwent simultaneous endo-epicardial mapping (256 unipolar electrodes, interelectrode distance 2mm). Conduction times, endo-epicardial delays (EEDs), and R/S ratio were examined in the surrounding 10mm of SAN activation. Areas of conduction block were defined as conduction delays≥12ms and endo-epicardial asynchrony as EED≥15 m. Three distinct activation patterns were observed in a total of 28 SAN-focal activation patterns (SAN-FAPs) (4 patients exhibited >1 different exit site), including SAN activation patterns with: 1) solely an endocardial exit site (n=10 [36%]); 2) solely an epicardial exit site (n=13 [46%]); and 3) simultaneously activated endo-epicardial exit sites (n=5 [18%]). Median (interquartile range) EED at the origin of the SAN-FAP was 10ms (6 to 14 ms) and the prevalence of endo-epicardial asynchrony in the surroundings of the SAN-FAP was 5% (2% to 18%). Electrograms at the origin of the SAN-FAPs exhibited significantly larger R-peaks in the mid right atrium (RA) compared with the superior RA (mid R/S ratio 0.15 [0.067 to 0.34] vs. superior R/S ratio 0.045 [0.026 to 0.062]; p=0.004). Conduction velocity within a distance of 10mm from the SAN-FAP was 125cm/s (80 to 250 cm/s). All 6 SAN-FAPs at the mid RA were observed in patients with a history of atrial fibrillation. Variations in activation patterns of the SAN observed in this study highlight the complex 3-dimensional SAN geometry and indicate the presence of interindividual differences in SAN exit pathways. Solely in patients with a history of atrial fibrillation, SAN activity occurred more caudally, which indicates changes in preferential SAN exitpathways.

Similitude Methods and Three-Dimensional Simulation of the Electrical Activity of the Rabbit Sinoatrial Node and Adjacent Atrial Myocardium

This study focuses on possible applications of similitude design methods for three-dimensional simulation of the electrical activity of the sinoatrial node of the rabbit heart and the adjacent atrial myocardium. The proposed mathematical model has a hierarchical shape, where the relationship between the sinoatrial node and adjacent atrial myocardium is at the top and the dynamics of ion processes on the cardiomyocyte membranes is at the lower level of the model. Examples of using this three-dimensional model are given for the description of: (a) rhythm generation in the sinoatrial node of the heart; (b) the effect of doubling of the action potential duration in the site of the atrial myocardium with reduced electrical intercellular conductivity; and (c) the modulation effect of the electrical fibroblast–cardiomyocyte relationship on the peacemaker activity.

Pharmacologic Approach to Sinoatrial Node Dysfunction.

The spontaneous activity of the sinoatrial node initiates the heartbeat. Sino-atrial node dysfunction (SND) and sick sinoatrial (sick sinus) syndrome are caused by the heart's inability to generate a normal sinoatrial node action potential. In clinical practice, SND is generally considered an age-related pathology, secondary to degenerative fibrosis of the heart pacemaker tissue. However, other forms of SND exist, including idiopathic primary SND, which is genetic, and forms that are secondary to cardiovascular or systemic disease. The incidence of SND in the general population is expected to increase over the next half century, boosting the need to implant electronic pacemakers. During the last two decades, our knowledge of sino-atrial node physiology and of the pathophysiological mechanisms underlying SND has advanced considerably. This review summarizes the current knowledge about SND mechanisms and discusses the possibility of introducing new pharmacologic therapies for treating SND.

Neurohumoral Control of Sinoatrial Node Activity and Heart Rate: Insight From Experimental Models and Findings From Humans.

The sinoatrial node is perhaps one of the most important tissues in the entire body: it is the natural pacemaker of the heart, making it responsible for initiating each-and-every normal heartbeat. As such, its activity is heavily controlled, allowing heart rate to rapidly adapt to changes in physiological demand. Control of sinoatrial node activity, however, is complex, occurring through the autonomic nervous system and various circulating and locally released factors. In this review we discuss the coupled-clock pacemaker system and how its manipulation by neurohumoral signaling alters heart rate, considering the multitude of canonical and non-canonical agents that are known to modulate sinoatrial node activity. For each, we discuss the principal receptors involved and known intracellular signaling and protein targets, highlighting gaps in our knowledge and understanding from experimental models and human studies that represent areas for future research.

The Ionotropic P2X4 Receptor has Unique Properties in the Heart by Mediating the Negative Chronotropic Effect of ATP While Increasing the Ventricular Inotropy.

Background: Mounting evidence indicate that reducing the sinoatrial node (SAN) activity may be a useful therapeutic strategy to control of heart failure. Purines, like ATP and its metabolite adenosine, consistently reduce the SAN spontaneous activity leading to negative cardiac chronotropy, with variable effects on the force of myocardial contraction (inotropy). Apart from adenosine A1 receptors, the human SAN expresses high levels of ATP-sensitive ionotropic P2X4 receptors (P2X4R), yet their cardiac role is unexplored. Methods: Here, we investigated the activity of P2 purinoceptors on isolated spontaneously beating atria (chronotropy) and on 2 Hz-paced right ventricular (RV, inotropy) strips from Wistar rats. Results: ATP (pEC 50 = 4.05) and its stable analogue ATPγS (pEC 50 = 4.69) concentration-dependently reduced atrial chronotropy. Inhibition of ATP breakdown into adenosine by NTPDases with POM-1 failed to modify ATP-induced negative chronotropy. The effect of ATP on atrial rate was attenuated by a broad-spectrum P2 antagonist, PPADS, as well as by 5-BDBD, which selectively blocks the P2X4R subtype; however, no effect was observed upon blocking the A1 receptor with DPCPX. The P2X4R positive allosteric modulator, ivermectin, increased the negative chronotropic response of ATP. Likewise, CTP, a P2X agonist that does not generate adenosine, replicated the P2X4R-mediated negative chronotropism of ATP. Inhibition of the Na+/Ca2+ exchanger (NCX) with KB-R7943 and ORM-10103, but not blockage of the HCN channel with ZD7288, mimicked the effect of the P2X4R blocker, 5-BDBD. In paced RV strips, ATP caused a mild negative inotropic effect, which magnitude was 2 to 3-fold increased by 5-BDBD and KB-R7943. Immunofluorescence confocal microscopy studies confirm that cardiomyocytes of the rat SAN and RV co-express P2X4R and NCX1 proteins. Conclusions: Data suggest that activation of ATP-sensitive P2X4R slows down heart rate by reducing the SAN activity while increasing the magnitude of ventricular contractions. The mechanism underlying the dual effect of ATP in the heart may involve inhibition of intracellular Ca2+-extrusion by bolstering NCX function in the reverse mode. Thus, targeting the P2X4R activation may create novel well-tolerated heart-rate lowering drugs with potential benefits in patients with deteriorated ventricular function.

Mathematical Simulation of the Rabbit Heterogeneous Intact Sinoatrial Node Using Similitude Theory

Abstract—In this work, the electrical activity of the heterogeneous intact sinoatrial node at interaction with the atrial myocardium is simulated based on a detailed approach. The reduction of this model used the methods of the theory of similarity. The results of the calculation of the reduced model are compared with the solutions obtained in the initial model. The model also found that an increase in the number of non-excitable sites in the atrial myocardium bordering the pacemaker causes a slowdown in the overall rhythm of electrical activity.

Reduced Basal Heart Rate Variability in a Calcineurin Aβ Deficient Mouse

PurposeHeart rate and heart rhythm, quantified by heart rate variability (HRV) in vivo, are both determined by intrinsic pacemaker activity of sinoatrial node (SAN) pacemaker cells (SANC), and input to SAN from the autonomic nervous system (ANS). The spontaneous action potential (AP) firing rate and rhythm of SANC are governed, at least in part, by phosphorylation of proteins that regulate their intracellular calcium cycling and ion channel functions. Calcineurin Aβ (CnAβ), the catalytic subunit of a calcium‐activated serine/threonine phosphatase, influences SANC function protein phosphorylation. Increased calcium cycling and ion channel phosphorylation leads to an increase in SANC AP firing rate and reduced AP firing interval variability. CnAβ likely impacts SANC AP firing rate and AP interval variability, making CnAβ a prime candidate of in vivo HR and HRV regulation. Thus, we hypothesized the role of CnAβ in CnAβ−/− mice, in which cardiac Cn activity is decreased by 80%, would manifest an increased in vivo HR and reduced HRV.MethodsElectrocardiograms (EKG) were measured (via telemetry) in awake, unrestrained, 3‐month‐old male CnAβ−/− mice (n = 9) and wildtype littermates (n = 9). Four 1.5‐hour basal recordings were obtained at least 24 hours apart. A segment of at least 2048 beats with minimal noise were selected for each EKG time series recording and analyzed for different types of HRV parameters (LabChart). HRV parameters in the time domain quantify variance of unordered beat‐to‐beat intervals, frequency domain parameters measure how variance of ordered beat‐to‐beat intervals embedded within an EKG time series distribute as a function of frequency, and non‐linear domain parameters detect variation in fractals buried within the heart rhythm. Statistical analyses were performed using a linear mixed effect model (R) accounting for the four repeated measures.ResultsC.F. table. Mean basal HR was substantially higher in CnAβ−/− than in WT, and time, non‐linear, and most frequency domain HRV descriptors were markedly reduced in CnAβ−/− than WT.ConclusionBecause CnAβ regulates intrinsic SANC function to enable increased calcium cycling and ion channel phosphorylation, our results suggest intrinsic SANC function is a factor that contributes to HR and HRV in vivo. Whether the altered HR and HRV in the CnAβ−/− heart are driven solely by CnAβ dependent mechanisms intrinsic to SANC or, in addition, reflect changes in ANS input to the heart require further studies.Support or Funding InformationFunded by the National Institute of Health/National Institute on Aging Intramural Research Program. Average^ Basal HRV Values in CnAβ−/− vs WT Mice Parameter WT CnAβ−/− Mean HR (bpm) 460 ± 10.8 507 ± 9.6* TIME DOMAIN SD NN (ms) 9.87 ±0.8 5.39 ± 0.4** Range NN (ms) 47.77 ± 3.7 26.68 ± 2.4** Coefficient of Variance (%) 7.22 ± 0.5 4.34 ± 0.3** FREQUENCY DOMAIN Total Power (Power Spectral Density) 284.93 ± 23.5 184.21 ± 19.0* High Frequency (PSD) 70.28 ± 6.2 66.42 ± 9.5 Low Frequency (PSD) 62.58 ± 5.2 40.09 ± 4.7* Very Low Frequency (PSD) 152.07 ± 19.8 77.70 ± 10.5* NON‐LINEAR DOMAIN Beta Slope −2.15 ± 0.1 −2.84 ± 0.1** SDl(ms) 5.72 ± 0.4 2.80 ± 0.7* SD2 (ms) 12.57 ± 0.9 7.00 ± 0.6** Multiscale Entropy 1.57 ± 0.1 0.93 ± 0.1** Values are mean ± SE p<0.05 p<0.01 Average of 4 basal recordings over separate days This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Choosing the anesthetic and sedative drugs for supraventricular tachycardia ablations: A focused review.

This study provides a review of the contemporary literature for the effects of most commonly used anesthetic drugs for sedation and anesthesia during adult electrophysiologic (EP) studies where supraventricular tachycardias (SVT) need to be induced for diagnostic purposes and/or catheter ablation. Some medications may affect cardiac electrophysiology and conduction, altering the ability to induce the arrhythmia, and may have negative impact on mapping and ablation treatment. The objective of the study is to determine the best sedative choice during SVT ablations. The authors searched MEDLINE, PubMed, and Google Scholar databases for published articles within the past 20 years (1998-2018) that have evaluated the effects of common anesthetic drugs during SVT ablations. Further articles were identified through crossreferencing, discussion with electrophysiologists, and hand-searching key electrophysiology and anesthesia journals. Eight review articles, two randomized control trials, six prospective observational studies, one retrospective observational study, and two case reports were included in this review. Seven of the studies focused on the pediatric population. The findings about the effects of the commonly used anesthetics are discussed further in detail. Sevoflurane had no clinically important effects on sinoatrial (SA) node activity, or the normal atrioventricular (AV), or accessory pathway. Midazolam and fentanyl, alone or in combination, neither alter the inducibility of reentrant tachycardia nor have they shown to affect the SA node, refractory periods of AV conduction, or accessory pathways. Similar findings were reported by investigators with propofol, except for ectopic atrial tachycardia in children, which remained un-inducible in one of the studies. Remifentanil and dexmedetomidine lengthened both sinus cycle and AV conduction. Dexmedetomidine increased the atrial refractory period and diminished atrial excitability. Ketamine shortened atrial conduction and successfully returned prolongation of sinus node conduction due to dexmedetomidine. In conclusion, the current literature regarding sedation for SVT studies in the adult population is sparse. Midazolam, propofol, fentanyl, and remifentanil can be used safely in patients undergoing EP studies without significant interference with electrophysiological variables or the inducibility of reentrant tachycardias in usual clinical doses. Low-dose ketamine has potential use as an adjunctive medication in the EP lab and additional studies would be beneficial. The effects of dexmedetomidine on conduction and arrhythmia inducibility during SVT ablation is not as clear as studies have yielded conflicting results, and may not be the best choice for sedation in this patient population.

Effects of fibroblast-myocyte coupling on the sinoatrial node activity: A computational study.

While the sinoatrial node (SAN) is structurally heterogeneous, most computer simulations of electrical activity take into account SAN pacemaker cells only. Our aim was to investigate how fibroblasts affect the SAN activity. We simulated the rabbit sinoatrial node accounting for differences between central and peripheral pacemaker cells, and for fibroblast-myocyte electrical coupling. We have observed that only if fibroblast-myocyte coupling is taken into account, (1) action potential is initiated in the central part of the SAN (within 1.2mm of the center of simulated tissue); otherwise, leading centers are located on the periphery; (2) few (1 to 6) leading centers initiate action potential in the SAN; otherwise, we observed more than 8 leading centers; (3) acetylcholine superfusion results in a shift of leading centers toward the SAN periphery; and (4) sinus pauses up to 1.9second follow acetylcholine superfusion. We observed negligible effect of fibroblast-myocyte coupling on the period of SAN activation. We conclude that fibroblast-myocyte coupling may explain action potential initiation and propagation from the center of the SAN observed in experimental studies, while atrial load on the peripheral SAN fails to explain this fact.

Diadenosine Polyphosphates Suppress the Effects of Sympathetic Nerve Stimulation in Rabbit Heart Pacemaker.

The modulatory influence of diadenosine tetraphosphate (Ap4A) and diadenosine pentaphosphate (Ap5A) on the effect of intramural autonomic nerve stimulation in isolated rabbit sinoatrial node were examined. Electrical activity of the sinoatrial node was recorded intracellularly. Against the background of blockade of adrenergic effects with propranolol (3×10-6 M) or in preparations isolated 2 h after injection of reserpine (2 mg/kg), nerve stimulation induced short-term membrane hyperpolarization and diminished the sinus node firing rate. These phenomena were not affected by Ap4A or Ap5A (10-5 M). Under the action of atropine (3×10-6 M) that completely eliminated the cholinergic influences, nerve stimulation enhanced the sinus node firing rate by 17.30±3.45% from the initial rate. Both Ap4A and Ap5A moderated the stimulation-induced elevation of firing rate to 9.9±2.8 and 10.5±2.9%, respectively. The data suggest that diadenosine polyphosphates significantly modulate the sympathetic influences on the heart rhythm, but have no effect on the parasympathetic control over activity of sinoatrial node.

CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current

The spontaneous activity of sinoatrial node (SAN) pacemaker cells is generated by a functional interplay between the activity of ionic currents of the plasma membrane and intracellular Ca2+ dynamics. The molecular correlate of a dihydropyridine (DHP)-sensitive sustained inward Na+ current (Ist), a key player in SAN automaticity, is still unknown. Here we show that Ist and the L-type Ca2+ current (ICa,L) share CaV1.3 as a common molecular determinant. Patch-clamp recordings of mouse SAN cells showed that Ist is activated in the diastolic depolarization range, and displays Na+ permeability and minimal inactivation and sensitivity to ICa,L activators and blockers. Both CaV1.3-mediated ICa,L and Ist were abolished in CaV1.3-deficient (CaV1.3−/−) SAN cells but the CaV1.2-mediated ICa,L current component was preserved. In SAN cells isolated from mice expressing DHP-insensitive CaV1.2 channels (CaV1.2DHP−/−), Ist and CaV1.3-mediated ICa,L displayed overlapping sensitivity and concentration–response relationships to the DHP blocker nifedipine. Consistent with the hypothesis that CaV1.3 rather than CaV1.2 underlies Ist, a considerable fraction of ICa,L was resistant to nifedipine inhibition in CaV1.2DHP−/− SAN cells. These findings identify CaV1.3 channels as essential molecular components of the voltage-dependent, DHP-sensitive Ist Na+ current in the SAN.

Computational analysis of the human sinus node action potential: model development and effects of mutations.

We constructed a comprehensive mathematical model of the spontaneous electrical activity of a human sinoatrial node (SAN) pacemaker cell, starting from the recent Severi-DiFrancesco model of rabbit SAN cells. Our model is based on electrophysiological data from isolated human SAN pacemaker cells and closely matches the action potentials and calcium transient that were recorded experimentally. Simulated ion channelopathies explain the clinically observed changes in heart rate in corresponding mutation carriers, providing an independent qualitative validation of the model. The model shows that the modulatory role of the 'funny current' (If ) in the pacing rate of human SAN pacemaker cells is highly similar to that of rabbit SAN cells, despite its considerably lower amplitude. The model may prove useful in the design of experiments and the development of heart-rate modulating drugs. The sinoatrial node (SAN) is the normal pacemaker of the mammalian heart. Over several decades, a large amount of data on the ionic mechanisms underlying the spontaneous electrical activity of SAN pacemaker cells has been obtained, mostly in experiments on single cells isolated from rabbit SAN. This wealth of data has allowed the development of mathematical models of the electrical activity of rabbit SAN pacemaker cells. The present study aimed to construct a comprehensive model of the electrical activity of a human SAN pacemaker cell using recently obtained electrophysiological data from human SAN pacemaker cells. We based our model on the recent Severi-DiFrancesco model of a rabbit SAN pacemaker cell. The action potential and calcium transient of the resulting model are close to the experimentally recorded values. The model has a much smaller 'funny current' (If ) than do rabbit cells, although its modulatory role is highly similar. Changes in pacing rate upon the implementation of mutations associated with sinus node dysfunction agree with the clinical observations. This agreement holds for both loss-of-function and gain-of-function mutations in the HCN4, SCN5A and KCNQ1 genes, underlying ion channelopathies in If , fast sodium current and slow delayed rectifier potassium current, respectively. We conclude that our human SAN cell model can be a useful tool in the design of experiments and the development of drugs that aim to modulate heart rate.