Multiple Pacemakers Research Articles

TMEM16A in smooth muscle cells acts as a pacemaker channel in the internal anal sphincter

Maintenance of fecal continence requires a continuous or basal tone of the internal anal sphincter (IAS). Paradoxically, the basal tone results largely from high-frequency rhythmic contractions of the IAS smooth muscle. However, the cellular and molecular mechanisms that initiate these contractions remain elusive. Here we show that the IAS contains multiple pacemakers. These pacemakers spontaneously generate propagating calcium waves that drive rhythmic contractions and establish the basal tone. These waves are myogenic and act independently of nerve, paracrine or autocrine signals. Using cell-specific gene knockout mice, we further found that TMEM16A Cl− channels in smooth muscle cells (but not in the interstitial cells of Cajal) are indispensable for pacemaking, rhythmic contractions, and basal tone. Our results identify TMEM16A in smooth muscle cells as a critical pacemaker channel that enables the IAS to contract rhythmically and continuously. This study provides cellular and molecular insights into fecal continence. R01HL139686 and R21HD097458. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

TMEM16A in smooth muscle cells acts as a pacemaker channel in the internal anal sphincter.

Maintenance of fecal continence requires a continuous or basal tone of the internal anal sphincter (IAS). Paradoxically, the basal tone results largely from high-frequency rhythmic contractions of the IAS smooth muscle. However, the cellular and molecular mechanisms that initiate these contractions remain elusive. Here we show that the IAS contains multiple pacemakers. These pacemakers spontaneously generate propagating calcium waves that drive rhythmic contractions and establish the basal tone. These waves are myogenic and act independently of nerve, paracrine or autocrine signals. Using cell-specific gene knockout mice, we further found that TMEM16A Cl- channels in smooth muscle cells (but not in the interstitial cells of Cajal) are indispensable for pacemaking, rhythmic contractions, and basal tone. Our results identify TMEM16A in smooth muscle cells as a critical pacemaker channel that enables the IAS to contract rhythmically and continuously. This study provides cellular and molecular insights into fecal continence.

PO-05-014 SUCCESSFUL IMPLANTATION OF A MICRA LEADLESS PACEMAKER THROUGH THE LEFT SUBCLAVIAN VEIN IN A PATIENT WITH SITUS AMBIGUOUS

Primary ciliary dyskinesia patients often have situs ambiguous, a congenital condition with abnormal arrangement of visceral organs in the abdomen and chest. It is associated with an increased risk of congenital heart defects and anomalous venous connections. As a result, placement of the leadless pacemaker through the femoral approach may not be viable in these patients. Herein we describe a successful placement of a leadless pacemaker through the left subclavian approach in a patient with primary ciliary dyskinesia with associated interrupted IVC, right internal jugular (RIJ) thrombus, failed epicardial pacers, and extraction of infected transvenous pacer. N/A A 36-year-old female with primary ciliary dyskinesia, situs ambiguous, RIJ thrombus, and azygous venous connection presents with paroxysmal atrial fibrillation, sinus node dysfunction and syncope (A); History of multiple pacemakers, including failed epicardial pacer, substance abuse and recurrent bacteremia with multiple transvenous pacer infections requiring extractions. Ultrasound access was gained in the left subclavian vein via the modified Seldinger technique. Access was serially dilated until a 23Fr dilator. A manual curve was applied to the tip of the Micra-introducer sheath and the long 27Fr hydrophilic micra-introducer sheath was advanced over a Lunderquist wire, using a stiff rail, into middle of the right atrium (B). The 105 cm Micra delivery catheter was inserted into the sheath, and advanced with fluoroscopic guidance into the right atrium. The introducer sheath was pulled back into the SVC and the delivery catheter was counter-clocked, flexed downward and advanced across the tricuspid valve. The pacemaker was directed to the midseptal position. Contrast was injected to verify positioning against the myocardium (C). The device was deployed with satisfactory parameters noting R waves of 12mV and threshold less than 1V at 0.24 msec pulse with. The pacer was then released with tugging testing confirming adequate deployment. (D). The patient was discharged safely home 2 days later. The left subclavian vein is a viable and safe approach for placing the Micra leadless pacemaker.

Synchronization in reaction-diffusion systems with multiple pacemakers.

Spatially extended oscillatory systems can be entrained by pacemakers, regions that oscillate with a higher frequency than the rest of the medium. Entrainment happens through waves originating at a pacemaker. Typically, biological and chemical media can contain multiple pacemaker regions, which compete with each other. In this paper, we perform a detailed numerical analysis of how wave propagation and synchronization of the medium depend on the properties of these pacemakers. We discuss the influence of the size and intrinsic frequency of pacemakers on the synchronization properties. We also study a system in which the pacemakers are embedded in a medium without any local dynamics. In this case, synchronization occurs if the coupling determined by the distance and diffusion is strong enough. The transition to synchronization is reminiscent of systems of discrete coupled oscillators.

Normalization of aberrant pretherapeutic dynamic functional connectivity of extrastriate visual system in patients who underwent thalamotomy with stereotactic radiosurgery for essential tremor: a resting-state functional MRI study.

The tremor circuitry has commonly been hypothesized to be driven by one or multiple pacemakers within the cerebello-thalamo-cortical pathway, including the cerebellum, contralateral motor thalamus, and primary motor cortex. However, previous studies, using multiple methodologies, have advocated that tremor could be influenced by changes within the right extrastriate cortex, at both the structural and functional level. The purpose of this work was to evaluate the role of the extrastriate cortex in tremor generation and further arrest after left unilateral stereotactic radiosurgery thalamotomy (SRS-T). The authors considered 12 healthy controls (HCs, group 1); 15 patients with essential tremor (ET, right-sided, drug-resistant; group 2) before left unilateral SRS-T; and the same 15 patients (group 3) 1 year after the intervention, to account for delayed effects. Blood oxygenation level-dependent functional MRI during resting state was used to characterize the dynamic interactions of the right extrastriate cortex, comparing HC subjects against patients with ET before and 1 year after SRS-T. In particular, the authors applied coactivation pattern analysis to extract recurring whole-brain spatial patterns of brain activity over time. The authors found 3 different sets of coactivating regions within the right extrastriate cortex in HCs and patients with pretherapeutic ET, reminiscent of the "cerebello-visuo-motor," "thalamo-visuo-motor" (including the targeted thalamus), and "basal ganglia and extrastriate" networks. The occurrence of the first pattern was decreased in pretherapeutic ET compared to HCs, whereas the other two patterns showed increased occurrences. This suggests a misbalance between the more prominent cerebellar circuitry and the thalamo-visuo-motor and basal ganglia networks. Multiple regression analysis showed that pretherapeutic standard tremor scores negatively correlated with the increased occurrence of the thalamo-visuo-motor network, suggesting a compensatory pathophysiological trait. Clinical improvement after SRS-T was related to changes in occurrences of the basal ganglia and extrastriate cortex circuitry, which returned to HC values after the intervention, suggesting that the dynamics of the extrastriate cortex had a role in tremor generation and further arrest after the intervention. The data in this study point to a broader implication of the visual system in tremor generation, and not only through visual feedback, given its connections to the dorsal visual stream pathway and the cerebello-thalamo-cortical circuitry, with which its dynamic balance seems to be a crucial feature for reduced tremor. Furthermore, SRS-T seems to bring abnormal pretherapeutic connectivity of the extrastriate cortex to levels comparable to those of HC subjects.

The Estimated Pacemaker for Great Apes Supports the Hominoid Slowdown Hypothesis.

The recent surge of genomic data has prompted the investigation of substitution rate variation across the genome, as well as among lineages. Evolutionary trees inferred from distinct genomic regions may display branch lengths that differ between loci by simple proportionality constants, indicating that rate variation follows a pacemaker model, which may be attributed to lineage effects. Analyses of genes from diverse biological clades produced contrasting results, supporting either this model or alternative scenarios where multiple pacemakers exist. So far, an evaluation of the pacemaker hypothesis for all great apes has never been carried out. In this work, we tested whether the evolutionary rates of hominids conform to pacemakers, which were inferred accounting for gene tree/species tree discordance. For higher precision, substitution rates in branches were estimated with a calibration-free approach, the relative rate framework. A predominant evolutionary trend in great apes was evidenced by the recovery of a large pacemaker, encompassing most hominid genomic regions. In addition, the majority of genes followed a pace of evolution that was closely related to the strict molecular clock. However, slight rate decreases were recovered in the internal branches leading to humans, corroborating the hominoid slowdown hypothesis. Our findings suggest that in great apes, life history traits were the major drivers of substitution rate variation across the genome.

Lateral thoracotomy for epicardial pacemaker placement in patients with congenital heart disease.

Our institution adopted a lateral thoracotomy approach to epicaridal pacemaker implantation with the objective of avoiding epicardial scar tissue and to achieve adequate lead pacing and sensing. We sought to assess the short-term outcomes of this approach. A single-centre review was conducted in paediatric patients and adults with congenital heart disease or inherited arrhythmia syndromes who underwent a lateral thoracotomy for epicardial pacemaker placement from August 2010 to January 2016. Patient histories were recorded along with outcomes including complications, lead and generator performance. Twenty-one operations were performed in 20 patients (median age 17 years, range 3 months-49 years), including 19 pacemakers and 2 implantable-cardioverter defibrillators (ICDs). Prior epicardial pacemakers had been placed in 11 (55%) patients, including 3 with multiple pacemakers. Most patients had undergone at least 1 prior cardiac operation, with a mean of 3.2 (range 0-7) prior cardiac operations. Through our lateral thoracotomy approach, 17 of the 19 attempted atrial leads (89%) and 20 of the 20 attempted ventricular leads (100%) were successfully implanted with acceptable pacing thresholds. Complications included 1 (5%) bleeding, 2 (10%) pacemaker pocket revisions and 1 late death at 6 months unrelated to the pacemaker. There were no lead failures at a mean follow-up period of 27.5 months (range of 0.7-56.1 months). The lateral thoracotomy is a useful approach for epicardial pacemaker implantation in patients with congenital heart disease or inherited arrhythmia syndromes including those with multiple prior operations.

Mammalian genome evolution is governed by multiple pacemakers.

Genomic evolution is shaped by a dynamic combination of mutation, selection and genetic drift. These processes lead to evolutionary rate variation across loci and among lineages. In turn, interactions between these two forms of rate variation can produce residual effects, whereby the pattern of among-lineage rate heterogeneity varies across loci. The nature of rate variation is encapsulated in the pacemaker models of genome evolution, which differ in the degree of importance assigned to residual effects: none (Universal Pacemaker), some (Multiple Pacemaker) or total (Degenerate Multiple Pacemaker). Here we use a phylogenetic method to partition the rate variation across loci, allowing comparison of these pacemaker models. Our analysis of 431 genes from 29 mammalian taxa reveals that rate variation across these genes can be explained by 13 pacemakers, consistent with the Multiple Pacemaker model. We find no evidence that these pacemakers correspond to gene function. Our results have important consequences for understanding the factors driving genomic evolution and for molecular-clock analyses. ClockstaR-G is freely available for download from github (https://github.com/sebastianduchene/clockstarg).

Alterations of field potentials in isotropic cardiomyocyte cell layers induced by multiple endogenous pacemakers under normal and hypothermal conditions.

The use of autonomous contracting randomly grown cardiomyocyte monolayers cultivated on microelectrode arrays (MEAs) represents an accepted experimental setting for preclinical experimental research in the field of cardiac electrophysiology. A dominant pacemaker forces a monolayer to adhere to a regular and synchronized contraction. Randomly distributed multiple pacemakers interfere with this dominant center, resulting in more or less frequent changes of propagation direction. This study aims to characterize the impact of changing propagation directions at single electrodes of the MEA on the four intrinsic parameters of registered field potentials (FPs) FPrise, FPMIN, FPpre, and FPdur and conduction velocity (CV) under normal and hypothermal conditions. Primary cultures of chicken cardiomyocytes (n = 18) were plated directly onto MEAs and FPs were recorded in a temperature range between 37 and 29°C. The number and spatiotemporal distribution of biological and artificial pacemakers of each cell layer inside and outside of the MEA registration area were evaluated using an algorithm developed in-house. In almost every second myocardial cell layer, interfering autonomous pacemakers were detected at stable temperatures, showing random spatial distributions with similar beating rates. Additionally, a temperature-dependent change of the dominant pacemaker center was observed in n = 16 experiments. A significant spread-direction-dependent variation of CV, FPrise, FPMIN, and FPpre up to 14% could be measured between different endogenous pacemakers. In conclusion, based on our results, disregarding the spatial origin of excitation may lead to misinterpretations and erroneous conclusions of FP parameters in the verification of research hypotheses in cellular electrocardiology.

On the number of genomic pacemakers: a geometric approach.

The universal pacemaker (UPM) model extends the classical molecular clock (MC) model, by allowing each gene, in addition to its individual intrinsic rate as in the MC, to accelerate or decelerate according to the universal pacemaker. Under UPM, the relative evolutionary rates of all genes remain nearly constant whereas the absolute rates can change arbitrarily. It was shown on several taxa groups spanning the entire tree of life that the UPM model describes the evolutionary process better than the MC model. In this work we provide a natural generalization to the UPM model that we denote multiple pacemakers (MPM). Under the MPM model every gene is still affected by a single pacemaker, however the number of pacemakers is not confined to one. Such a model induces a partition over the gene set where all the genes in one part are affected by the same pacemaker and task is to identify the pacemaker partition, or in other words, finding for each gene its associated pacemaker. We devise a novel heuristic procedure, relying on statistical and geometrical tools, to solve the problem and demonstrate by simulation that this approach can cope satisfactorily with considerable noise and realistic problem sizes. We applied this procedure to a set of over 2000 genes in 100 prokaryotes and demonstrated the significant existence of two pacemakers.

Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice

The mouse is widely used as a genetic platform to investigate the molecular mechanisms of sinoatrial node (SAN) pacemaking. Recently, it has been shown that isolated SAN cells from the ankyrin-B (AnkB)-deficient mice display severe pacemaking dysfunction similar to individuals harboring ankyrin 2 allele variants. However, these results have been limited to isolated SAN cells only and thus did not evaluate the functional anatomy of the widely distributed atrial pacemaker complex (e.g., the dynamic interaction of primary and subsidiary pacemakers). We studied pacemaker function in an intact mouse atrial preparation, which included the SAN, atrioventricular junction (AVJ), and both atria, excluding most of the septum. Optical mapping with a voltage-sensitive dye and CMOS camera ULTIMA-L was used to map spontaneous pacemaker activity with or without autonomic modulation in wild-type (WT) mice (n = 7) and in the AnkB heterozygous (AnkB(+/-); n = 9) mouse model of human SAN disease. In WT mice, isoproterenol accelerated the SAN rate (for 10 microM: from 325 + or - 19 to 510 + or - 33 beat/min, P < 0.01) and shifted the leading pacemaker site superiorly by 0.77 + or - 0.11 mm within the SAN. ACh decreased the SAN rate (from 333 + or - 26 to 96 + or - 22 beats/min, P < 0.01) and shifted the leading pacemaker either inferiorly within the SAN or abruptly toward the AVJ. After isoproterenol, AnkB(+/-) mice exhibited a larger beat-to-beat variability (SD of a cycle length: 13.4 + or - 3.6 vs. 2.5 + or - 0.8 ms, P < 0.01 vs. WT mice), disorganized shift of the leading pacemaker (2.04 + or - 0.37 mm, P < 0.05 vs. WT mice), and competing multiple pacemakers, resulting in beat-to-beat changes of the leading pacemaker location site between the SAN and AVJ regions. Notably, AnkB(+/-) mice also displayed a reduced sensitivity to ACh (rate slowing by 32 + or - 12% vs. 67 + or - 4%, P < 0.05, AnkB(+/-) vs. WT mice, respectively). In conclusion, AnkB dysfunction results in SAN abnormalities in an isolated mouse atria preparation. While AnkB dysfunction dramatically alters single SAN cell function, the mechanisms underlying cardiac automaticity are clearly complex, and phenotypes may be partially compensated by the dynamic interaction of cells within the pacemaker complex. These new findings highlight the importance of the functional anatomy of the entire atrial distributed pacemaker complex, including the SAN and AVJ, and clearly demonstrate the role of AnkB in cardiac automaticity.

Medullary pacemaker neurons are essential for both eupnea and gasping in mammals vs. medullary pacemaker neurons are essential for gasping, but not eupnea, in mammals

The following letters are in response to the Point:Counterpoint “Medullary pacemaker neurons are essential for both eupnea and gasping in mammals vs. medullary pacemaker neurons are essential for gasping, but not eupnea, in mammals” that appears in this issue. To the Editor : Eupnea is

The lateral spread of epileptiform discharges in rat neocortical slices: effect of focal phencyclidine application.

In vitro and in vivo brain slice techniques were used to examine phencyclidine (PCP) effects on the lateral propagation of epileptiform field potentials (EFP) across adjacent areas of rat frontal neocortex. Epileptiform activity was induced by perfusing slices with Mg 2+-free artificial cerebrospinal fluid. Simultaneous field potential recordings of EFP were obtained from four microelectrodes placed 2-3 mm apart across coronal slices in the third layer. PCP, applied focally between recording sites, blocked rapid propagation across treated areas and resulted in the emergence of spatially separate, independent pacemakers. The characteristics of paroxysmal depolarization shifts did not change significantly by the blockade of lateral propagation of EFP. The same asynchronized pattern of EFP conduction was observed after local application of the N-methyl-D-aspartate (NMDA)-receptor antagonist DL-2-amino-5-phosphono-valeric acid. Local administration of haloperidol as well as NMDA before PCP application reversibly prevented appearance of multiple pacemakers. Focal application of dopamine produced an abnormal pattern of lateral conduction of EFP in 50 % of tested slices. Pacemaker failure as an indicator of functional impairment of cortical integration is the proposed mechanism for developing of schizophrenia-like psychosis associated with epilepsy. Abbreviations. APV: DL-2-amino-5-phosphono-valeric acid EEG:electroencephalogram EFP:epileptiform field potentials NMDA:N-methyl-D-aspartate PCP:phencyclidine SLPE:Schizophrenialike psychosis associated with epilepsy

Why do cubomedusae have only four swim pacemakers?

The classic view of swimming control in scyphozoan and cubozoan jellyfish involves a diffuse motor nerve net activated by multiple pacemaker sites that interact in a simple resetting hierarchy. Earlier modeling studies of jellyfish swimming, utilizing resetting linkages of multiple pacemakers, indicated that increases in pacemaker number were correlated with increases in the rate and regularity of network activity. We conducted a similar study using the cubozoan jellyfish Carybdea marsupialis, concentrating not only on the adaptive features of multiple pacemaker networks but also on the mechanism of pacemaker interaction. The best fit for our experimental data is a model in which pacemakers express a degree of independence. Thus, our results challenge the idea that pacemaker interactions in scyphozoan and cubozoan medusae are based on a strict resetting hierarchy. Furthermore, our data suggest that the combination of semi-independent linkage of pacemakers with the small pacemaker number characteristic of cubomedusae is important in (i) maintaining a biphasic modulatory capability in the swimming system, and (ii) allowing behaviorally appropriate directional responses to asymmetrical sensory inputs in the radially arranged jellyfish nervous system.

Neuroendocrine modulation of the "menopause": insights into the aging brain.

The menopause marks the permanent end of fertility in women. It was once thought that this dramatic physiological change could be explained simply by the exhaustion of the reservoir of ovarian follicles. New data from studies performed in women and animal models make us reassess this assumption. An increasing body of evidence suggests that there are multiple pacemakers that contribute to the transition to irregular cycles, decreasing fertility, and the timing of the menopause. We will present evidence that lends credence to the possibility that a dampening and desynchronization of the precisely orchestrated neural signals lead to miscommunication between the brain and the pituitary-ovarian axis, and that this constellation of hypothalamic-pituitary-ovarian events leads to the deterioration of regular cyclicity and heralds menopausal transition.

The Advent of Menopause

Letters from: [ Ernst Knobil and Samuel S. C. Yen ][1] [ Phyllis M. Wise, et al. ][1] The article “Menopause: The aging of multiple pacemakers” by Phyllis M. Wise et al . (“Patterns of Aging,” [5 July, p. 67][2]) addresses a cardinal component of the ageing process, menopause, a normal

Menopause: the aging of multiple pacemakers.

Menopause signals the permanent end of menstrual cyclicity in a woman's life. Its impact reaches far beyond just the reproductive system. An understanding of the factors that interact and govern the process of aging in the reproductive system will help us to develop strategies for alleviating the negative aspects of menopause and may help us to better comprehend the process of biological aging.

Origin of the sinus impulse.

It was generally accepted that the site of normal impulse origin within the atria was a single static focus within the sinus node. This review will examine how this model of impulse origin came about and has evolved. Early on, conflicting data suggested that the sinus node focus was not static and changed with interventions that changed heart rate, such as vagal stimulation. Furthermore, even with removal of the sinus node, a normal atrial rhythm was generated. High-resolution mapping in humans and dogs showed that the initiation of the impulse was dynamic and could be multicentric, with more than one focus initiating a single beat. Shifts in the site of origin correlated with changes in rate and were consistent with P wave changes routinely observed in the standard ECG. These studies suggested multiple pacemakers were responsible for impulse initiation. However, it was not clear how these widespread pacemakers were coordinated to function synchronously. Recent canine data suggest that the node may be partially insulated from the surrounding atrium, resulting in multicentric origin starting from a single site within the node. What has evolved is a model of impulse origin with a sinus node having discrete exit sites and a dominant pacemaker within the node that can shift to other nodal sites. Complex and changing conduction out of the node, coupled with extranodal pacemakers, which can assume dominance over the node, combine with the autonomic nervous system to control heart rate and the pattern of impulse origin within the atria.

Distention of the uterus activates its multiple pacemakers and induces their coordination.

In the pregnant human uterus, pacemaker activities and their coordination processes were studied in labor induced by uterine distention. Electrical and mechanical activities of the uterus were simultaneously recorded in 6 midtrimester (normal, n = 4; fetal death, n = 2) and 8 term (normal, n = 7; fetal death, n = 1) patients. Initially, frequent and sporadical spike discharges which did not synchronize with low magnitude and irregular mechanical activities were noted. With time, synchronization of both activities developed. These findings were noted regardless of the gestational stage of the patient and fetal viability. The patterns of development and decreases in mechanical and electrical activities, together with their synchronization patterns, were positively and negatively controlled by uterine distention and its suspension, respectively. These results suggest that the uterus has multiple pacemakers in various locations, and uterine distention works as a trigger for the elevation of excitability and for coordinated and orthodromic activities.

The lateral spread of ictal discharges in neocortical brain slices

The in vitro brain slice technique was used to examine the lateral propagation of spontaneous electrographic ictal episodes across adjacent areas of guinea pig neocortex. Epileptiform activity was induced by perfusing slices with Mg-free artificial CSF. Simultaneous field potential recordings of ictal episodes were obtained from 4 micropipettes placed 1–3 mm apart across coronal slices in middle-cortical layers. Two types of lateral spread were characterized. Ictal episodes often developed focally and then spread as a slowly moving wavefront traveling at <0.3 mm/sec into adjacent, uninvolved cortex. By contrast, other episodes began nearly synchronously at all cortical sites. The individual afterdischarges that composed each ictal episode propagated rapidly across the cortex at >30 mm/sec and were triggered by multiple pacemakers. Ictal episodes always terminated abruptly across the entire slice. The NMDA-receptor antagonist, 2-amino-phosphono-valerate, applied focally between recording sites, blocked rapid propagation across treated areas and resulted in the emergence of spatially separate, independent pacemakers. Pacemaker failure is the proposed mechanism for simultaneous and generalized termination of ictal episodes in this in vitro model of epileptogenesis.