Secondary Pacemaker Research Articles

3rd-Degree Atrioventricular Block.

3rd-Degree Atrioventricular Block.

Genomic and physiological analyses of the zebrafish atrioventricular canal reveal molecular building blocks of the secondary pacemaker region

The atrioventricular canal (AVC) is the site where key structures responsible for functional division between heart regions are established, most importantly, the atrioventricular (AV) conduction system and cardiac valves. To elucidate the mechanism underlying AVC development and function, we utilized transgenic zebrafish line sqet31Et expressing EGFP in the AVC to isolate this cell population and profile its transcriptome at 48 and 72 hpf. The zebrafish AVC transcriptome exhibits hallmarks of mammalian AV node, including the expression of genes implicated in its development and those encoding connexins forming low conductance gap junctions. Transcriptome analysis uncovered protein-coding and noncoding transcripts enriched in AVC, which have not been previously associated with this structure, as well as dynamic expression of epithelial-to-mesenchymal transition markers and components of TGF-β, Notch, and Wnt signaling pathways likely reflecting ongoing AVC and valve development. Using transgenic line Tg(myl7:mermaid) encoding voltage-sensitive fluorescent protein, we show that abolishing the pacemaker-containing sinoatrial ring (SAR) through Isl1 loss of function resulted in spontaneous activation in the AVC region, suggesting that it possesses inherent automaticity although insufficient to replace the SAR. The SAR and AVC transcriptomes express partially overlapping species of ion channels and gap junction proteins, reflecting their distinct roles. Besides identifying conserved aspects between zebrafish and mammalian conduction systems, our results established molecular hallmarks of the developing AVC which underlies its role in structural and electrophysiological separation between heart chambers. This data constitutes a valuable resource for studying AVC development and function, and identification of novel candidate genes implicated in these processes.

Regulation of HCN2 Current by PI3K/Akt Signaling.

It has long been known that heart rate is regulated by the autonomic nervous system. Recently, we demonstrated that the pacemaker current, If, is regulated by phosphoinositide 3-kinase (PI3K) signaling independently of the autonomic nervous system. Inhibition of PI3K in sinus node (SN) myocytes shifts the activation of If by almost 16 mV in the negative direction. If in the SN is predominantly mediated by two members of the HCN gene family, HCN4 and HCN1. Purkinje fibers also possess If and are an important secondary pacemaker in the heart. In contrast to the SN, they express HCN2 and HCN4, while ventricular myocytes, which do not normally pace, express HCN2 alone. In the current work, we investigated PI3K regulation of HCN2 expressed in HEK293 cells. Treatment with the PI3K inhibitor PI-103 caused a negative shift in the activation voltage and a dramatic reduction in the magnitude of the HCN2 current. Similar changes were also seen in cells treated with an inhibitor of the protein kinase Akt, a downstream effector of PI3K. The effects of PI-103 were reversed by perfusion of cells with phosphatidylinositol 3,4,5-trisphosphate (the second messenger produced by PI3K) or active Akt protein. We identified serine 861 in mouse HCN2 as a putative Akt phosphorylation site. Mutation of S861 to alanine mimicked the effects of Akt inhibition on voltage dependence and current magnitude. In addition, the Akt inhibitor had no effect on the mutant channel. These results suggest that Akt phosphorylation of mHCN2 S861 accounts for virtually all of the observed actions of PI3K signaling on the HCN2 current. Unexpectedly, Akt inhibition had no effect on If in SN myocytes. This result raises the possibility that diverse PI3K signaling pathways differentially regulate HCN-induced currents in different tissues, depending on the isoforms expressed.

Генетика и эпигенетика сна и сновидений

Multifunctional dream is an epigenetic gift to a person with great intelligence, new quantum ideas (each material object has quantum states and parallel worlds) and future inventions (discoveries). The circadian system of Homo sapiens and the structural-functional clock of the human body, are synchronized genetically and epigenetically. Life activity of H. sapiens is wave-shaped cyclic oscillations of various intensive processes of circadian stress. The multi-oscillator system, includes evolutionary structural-functional central and peripheral rhythm drivers, primary and secondary pacemakers. Three of the most powerful modern rhythm drivers for humans, the first is light. The second most powerful rhythm driver is power. The third, epigenetic, including social factors, first of all, social status and self-actualization of personality. The main medical and social significance of the visceral brain is the formation of emotions. Visceral brain is involved in the regulation of internal organ functions, smell, automatic regulation, emotions, memory, sleep, waking, etc. Visceral brain determines selection and implementation of adaptation forms of behavior, dynamics of innate forms of behavior, maintenance of homeostasis, generative processes. It provides hormonal stimulation of the body, creation of emotional background, formation and implementation of processes of higher nervous activity. Cognitive memory is one of the largest and most powerful concepts that represents the basic function of memory in general. The knowledge that a person receives in learning is first perceived as something external, but then gradually they turn into experience and beliefs. Cognitive memory retains all acquired knowledge, representing a kind of “library”, with the process of assimilation and preservation becoming more complicated as the information obtained becomes more complex. The brain memory mechanism is a network of cyclic neural circuits (CPNs). When the secretion of γ-aminobutyric acid in the brain is deficient, many CNCs are turned off from the memory mechanism, which causes cognitive dysfunction. This is one of the causes of memory impairment in Alzheimer’s disease and senile dementia of Alzheimer’s type. Sleep is the main tool and mechanism in the formation of cognitive memory, its quantitative and qualitative volume, integration of transition to a qualitatively new level of self-development and self-improvement, allowing to create a new intellectual “qualification mind”. H. sapiens of the 21st century will have the ability to understand the physiological and neurophysiological patterns of sleep, manage and change their sleep habits. Digitization of sleep is the future for industry, healthcare, science, and personalized health.

The Zebrafish Heart: an Archetype for Neurocardiology

The intracardiac nervous system (ICNS) is the final common pathway for reflex control of cardiac output by the autonomic nervous system (ANS). The normal operation of this system is key to supporting cardiovascular homeostasis, and ANS dysfunction or remodelling can contribute to the development of multiple cardiopathies. Thus the role of the ICNS in cardiac control is essential, however our current understanding of this role is incomplete. The majority of work on the ICNS to date has been in mammalian models, but because the neural elements comprising this network are embedded in cardiac tissues, visualization and experimental access to the entire network for integrative studies of neuronal function has been limiting. To address these issues, we have developed the zebrafish, a cyprinid teleost, as an alternate model for cardiac anatomical and neurophysiological studies. In this ancestral vertebrate the two‐chambered heart, although anatomically distinct from the mammalian four chamber arrangement, is dually innervated by sympathetic and parasympathetic limbs of the ANS and has a well‐developed ICNS which is functional in spontaneously beating isolated preparations. Activation of extrinsic cardiac nerves evokes tachycardia (via B2‐adrenoceptors) and bradycardia (M2 muscarinic receptors). Thus the essential features of ANS control of the heart are conserved across the vertebrates. We have mapped the general innervation patterns of the sinoatrial valve region (SAR), atrium and ventricle. A ganglionated plexus in the SAR surrounds the valve and contains most of the intracardiac neuronal somata; the majority is cholinergic with the remainder adrenergic, nitrergic and serotonergic. Furthermore, peptidergic axon terminals contact plexal somata. Optical mapping of the isolated heart confirms the site of origin of normal primary pacemaker activity within the SAR, where cells in the base of the valve leaflets express Islet‐1 (Isl‐1) and hyperpolarization‐activated, cyclic nucleotide‐gated channel 4 (HCN4), known markers for mammalian pacemaker cells. In addition, intracellular recordings from these cells display spontaneous diastolic membrane depolarization patterns typical of pacemaker cells. Extrinsic cardiac nerve stimulation, in addition to evoking bradycardia, can displace the pacemaker site to a secondary pacemaker in the atrioventricular region (AVR), where a population of cells also expresses Isl‐1 and HCN4. A small ganglion containing cholinergic somata is present in the AVR, suggesting local neural control of atrioventricular pacemaker activity. We have thus established the zebrafish heart as a viable model for studies of integrative neural control of pacemaker function. In particular, this model provides a platform to use optogenetic techniques to target intracardiac neurons and pacemaker cells, in combination with traditional electrophysiological methods, to perform detailed analyses of the intracardiac neuronal circuitry involved in cardiac control. This work will provide a solid foundation for further studies of ANS‐related cardiac pathophysiologies in zebrafish analogs of human cardiac disease states.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada (FMS, TAQ, RPC)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Computational assessment of the functional role of sinoatrial node exit pathways in the human heart.

AimThe human right atrium and sinoatrial node (SAN) anatomy is complex. Optical mapping experiments suggest that the SAN is functionally insulated from atrial tissue except at discrete SAN-atrial electrical junctions called SAN exit pathways, SEPs. Additionally, histological imaging suggests the presence of a secondary pacemaker close to the SAN. We hypothesise that a) an insulating border-SEP anatomical configuration is related to SAN arrhythmia; and b) a secondary pacemaker, the paranodal area, is an alternate pacemaker but accentuates tachycardia. A 3D electro-anatomical computational model was used to test these hypotheses.MethodsA detailed 3D human SAN electro-anatomical mathematical model was developed based on our previous anatomical reconstruction. Electrical activity was simulated using tissue specific variants of the Fenton-Karma action potential equations. Simulation experiments were designed to deploy this complex electro-anatomical system to assess the roles of border-SEPs and paranodal area by mimicking experimentally observed SAN arrhythmia. Robust and accurate numerical algorithms were implemented for solving the mono domain reaction-diffusion equation implicitly, calculating 3D filament traces, and computing dominant frequency among other quantitative measurements.ResultsA centre to periphery gradient of increasing diffusion was sufficient to permit initiation of pacemaking at the centre of the 3D SAN. Re-entry within the SAN, micro re-entry, was possible by imposing significant SAN fibrosis in the presence of the insulating border. SEPs promoted the micro re-entry to generate more complex SAN-atrial tachycardia. Simulation of macro re-entry, i.e. re-entry around the SAN, was possible by inclusion of atrial fibrosis in the presence of the insulating border. The border shielded the SAN from atrial tachycardia. However, SAN micro-structure intercellular gap junctional coupling and the paranodal area contributed to prolonged atrial fibrillation. Finally, the micro-structure was found to be sufficient to explain shifts of leading pacemaker site location.ConclusionsThe simulations establish a relationship between anatomy and SAN electrical function. Microstructure, in the form of intercellular gap junction coupling, was found to regulate SAN function and arrhythmia.

Zebrafish heart as a model to study the integrative autonomic control of pacemaker function

The cardiac pacemaker sets the heart's primary rate, with pacemaker discharge controlled by the autonomic nervous system through intracardiac ganglia. A fundamental issue in understanding the relationship between neural activity and cardiac chronotropy is the identification of neuronal populations that control pacemaker cells. To date, most studies of neurocardiac control have been done in mammalian species, where neurons are embedded in and distributed throughout the heart, so they are largely inaccessible for whole-organ, integrative studies. Here, we establish the isolated, innervated zebrafish heart as a novel alternative model for studies of autonomic control of heart rate. Stimulation of individual cardiac vagosympathetic nerve trunks evoked bradycardia (parasympathetic activation) and tachycardia (sympathetic activation). Simultaneous stimulation of both vagosympathetic nerve trunks evoked a summative effect. Effects of nerve stimulation were mimicked by direct application of cholinergic and adrenergic agents. Optical mapping of electrical activity confirmed the sinoatrial region as the site of origin of normal pacemaker activity and identified a secondary pacemaker in the atrioventricular region. Strong vagosympathetic nerve stimulation resulted in a shift in the origin of initial excitation from the sinoatrial pacemaker to the atrioventricular pacemaker. Putative pacemaker cells in the sinoatrial and atrioventricular regions expressed adrenergic β2 and cholinergic muscarinic type 2 receptors. Collectively, we have demonstrated that the zebrafish heart contains the accepted hallmarks of vertebrate cardiac control, establishing this preparation as a viable model for studies of integrative physiological control of cardiac function by intracardiac neurons.

Characterization and influence of cardiac background sodium current in the atrioventricular node

Background inward sodium current (IB,Na) that influences cardiac pacemaking has been comparatively under-investigated. The aim of this study was to determine for the first time the properties and role of IB,Na in cells from the heart's secondary pacemaker, the atrioventricular node (AVN). Myocytes were isolated from the AVN of adult male rabbits and mice using mechanical and enzymatic dispersion. Background current was measured using whole-cell patch clamp and monovalent ion substitution with major voltage- and time-dependent conductances inhibited. In the absence of a selective pharmacological inhibitor of IB,Na, computer modelling was used to assess the physiological contribution of IB,Na. Net background current during voltage ramps was linear, reversing close to 0mV. Switching between Tris- and Na+-containing extracellular solution in rabbit and mouse AVN cells revealed an inward IB,Na, with an increase in slope conductance in rabbit cells at −50mV from 0.54±0.03 to 0.91±0.05nS (mean±SEM; n=61 cells). IB,Na magnitude varied in proportion to [Na+]o. Other monovalent cations could substitute for Na+ (Rb+>K+>Cs+>Na+>Li+). The single-channel conductance with Na+ as charge carrier estimated from noise-analysis was 3.2±1.2pS (n=6). Ni2+ (10mM), Gd3+ (100μM), ruthenium red (100μM), or amiloride (1mM) produced modest reductions in IB,Na. Flufenamic acid was without significant effect, whilst La3+ (100μM) or extracellular acidosis (pH6.3) inhibited the current by >60%. Under the conditions of our AVN cell simulations, removal of IB,Na arrested spontaneous activity and, in a simulated 1D-strand, reduced conduction velocity by ~20%. IB,Na is carried by distinct low conductance monovalent non-selective cation channels and can influence AVN spontaneous activity and conduction.

Irregular excitation patterns in reaction-diffusion systems due to perturbation by secondary pacemakers

Spatiotemporal excitation patterns in the FitzHugh-Nagumo model are studied, which result from the disturbance of a primary pacemaker by a secondary pacemaker. The primary and secondary pacemakers generate regular waves with frequencies f(pace) and f(pert), respectively. The pacemakers are spatially separated, but waves emanating from them encounter each other via a small bridge. This leads to three different types I-III of irregular excitation patterns in disjunct domains of the f(pace)-f(pert) plane. Types I and II are caused by detachments of waves coming from the two pacemakers at corners of the bridge. Type III irregularities are confined to a boundary region of the system and originate from a partial penetration of the primary waves into a space, where circular wave fronts from the secondary pacemaker prevail. For this type, local frequencies can significantly exceed f(pace) and f(pert). The degree of irregularity found for the three different types is quantified by the entropy of the local frequency distribution and an order parameter for phase coherence.

Acute desensitization of acetylcholine and endothelin-1 activated inward rectifier K+ current in myocytes from the cardiac atrioventricular node

The atrioventricular node (AVN) is a vital component of the pacemaker-conduction system of the heart, co-ordinating conduction of electrical excitation from cardiac atria to ventricles and acting as a secondary pacemaker. The electrical behaviour of the AVN is modulated by vagal activity via activation of muscarinic potassium current, IKACh. However, it is not yet known if this response exhibits ‘fade’ or desensitization in the AVN, as established for the heart’s primary pacemaker – the sinoatrial node. In this study, acute activation of IKACh in rabbit single AVN cells was investigated using whole-cell patch clamp at 37°C. 0.1–1μM acetylcholine (ACh) rapidly activated a robust IKACh in AVN myocytes during a descending voltage-ramp protocol. This response was inhibited by tertiapin-Q (TQ; 300nM) and by the M2 muscarinic ACh receptor antagonist AFDX-116 (1μM). During sustained ACh exposure the elicited IKACh exhibited bi-exponential fade (τf of 2.0s and τs 76.9s at −120mV; 1μM ACh). 10nM ET-1 elicited a current similar to IKACh, which faded with a mono-exponential time-course (τ of 52.6s at −120mV). When ET-1 was applied following ACh, the ET-1 activated response was greatly attenuated, demonstrating that ACh could desensitize the response to ET-1. For neither ACh nor ET-1 was the rate of current fade dependent upon the initial response magnitude, which is inconsistent with K+ flux mediated changes in electrochemical driving force as the underlying mechanism. Collectively, these findings demonstrate that TQ sensitive inwardly rectifying K+ current in cardiac AVN cells, elicited by M2 muscarinic receptor or ET-1 receptor activation, exhibits fade due to rapid desensitization.

Physiology, Injury, and Recovery of Interstitial Cells of Cajal: Basic and Clinical Science

In the last 15 years, our understanding of the cellular basis of gastrointestinal function has been altered irreversibly by the discovery that normal gastrointestinal (GI) motility requires interstitial cells of Cajal (ICC). Research in this relatively short time period has modified our original concept that the core unit that controls motility is made up of nerves and smooth muscle, to one that now includes ICC. This concept has now expanded to beyond the GI tract, suggesting that it may be a fundamental property of the regulation of smooth muscle function that requires rhythmic contraction. ICC are distributed throughout the GI tract, have important functions in the control of GI motility, and are often abnormal in diseased states. Recently, significant steps forward have been made in our understanding of the physiology of ICC as well as mechanisms of injury and recovery. These advances are the focus of this review. The Physiology of ICC Unique motor patterns are intrinsic to every organ of the GI tract, which suit their functions related to mixing, absorption, and anally directed movement. The ICC are an integral part of the control of these motor activities. The distribution of ICC throughout the musculature is associated with nerve structures. Myenteric pacemaker ICC surround the myenteric or Auerbach’s plexus and intramuscular ICC are associated with nerve varicosities throughout the muscle layers (Figures 1 and 2). Other subpopulations of ICC are associated with nonganglionated plexuses of nerve varicosities at the inner borders of the circular muscle layers in the intestine and colon (Figures 1 and 2). The best understood function is that of pacemaker activity in the stomach and small intestine where the ICC generate a periodic depolarization at a characteristic frequency in each of these organs that is called the slow wave or pacemaker activity.

Beating to time: calcium clocks, voltage clocks, and cardiac pacemaker activity

the heartbeat arises in the sinoatrial node (SAN) and then spreads throughout the heart. SAN function is therefore essential for normal cardiac physiology. The function of the SAN decreases with age, and this has been correlated with changes of ion channel expression ([12][1]). It is therefore of

Biological Pacemaker Engineered by Nonviral Gene Transfer in a Mouse Model of Complete Atrioventricular Block

We hypothesized that a nonviral gene delivery of the hyperpolarization-activated HCN2 channel combined with the beta(2)-adrenergic receptor (ADRB2) would generate a functional pacemaker in a mouse model of complete atrioventricular block (CAVB) induced by radiofrequency ablation of the His bundle. Plasmids encoding HCN2 and ADRB2 mixed with tetronic 304, a poloxamine block copolymer, were injected in the left ventricular free wall (HCN2-ADRB2 mice). Sham mice received a noncoding plasmid. CAVB was induced 5 days later. Ventricular escape rhythms in HCN2-ADRB2 mice were significantly faster than in sham mice at day 15 after ablation and later. In HCN2-ADRB2 mice, QRS complexes were larger than in sham mice and characterized by abnormal axes. Immunostaining of GFP-HCN2 fusion protein showed an expression of HCN2 channel in left ventricular myocardium for at least 45 days after injection. In the mouse, CAVB induces progressive hypertrophy and heart failure leading to 50% mortality after 110 days. HCN2-ADRB2 mice survived 3 weeks longer than sham mice. Finally, beta-adrenergic input increased ventricular escape rhythms significantly more in HCN2-ADRB2 mice than in sham mice. In conclusion, nonviral gene transfer can produce a functional cardiac biological pacemaker regulated by sympathetic input, which improves life expectancy in a mouse model of CAVB.

Entrainment of the natural pacemakers of the heart precedes atrial fibrillation

A new measure of heart rate variability is proposed to investigate the interaction of the sino-atrial (SA) and atrio-ventricular (AV) pacemakers. Using electrocardiogram (ECG) fiduciary markers corresponding to the depolarization time of the SA and AV pacemakers, the variability of SA and AV depolarization rate is jointly analyzed by spectral analysis. The result of this joint analysis provides evidence of a distinct pattern of interaction between the SA and AV nodes prior to the onset of paroxysmal atrial fibrillation (PAF): frequency entrainment between the primary and secondary pacemakers of the heart, occurring at the respiratory frequency. We propose a measure of this entrainment as a diagnostic indicator for PAF, and compare it to standard diagnostic measures. The entrainment measure is found to have greater diagnostic power than five other common ECG-derived measures.

Electrophysiological features of the mouse sinoatrial node in relation to connexin distribution.

The sinoatrial (SA) node consists of a relatively small number of poorly coupled cells. It is not well understood how these pacemaker cells drive the surrounding atrium and at the same time are protected from its hyperpolarizing influence. To explore this issue on a small tissue scale we studied the activation pattern of the mouse SA node region and correlated this pattern with the distribution of different gap junction proteins, connexin (Cx)37, Cx40, Cx43 and Cx45. The mouse SA node was electrophysiologically mapped using a conventional microelectrode technique. The primary pacemaker area was located in the corner between the lateral and medial limb of the crista terminalis. Unifocal pacemaking occurred in a group of pacemaking fibers consisting of 450 cells. In the nodal area transitions of nodal and atrial waveform were observed over small distances ( approximately 100 microm). Correlation between the activation pattern and connexin distribution revealed extensive labeling by anti-Cx45 in the primary and secondary pacemaker area. Within these nodal areas no gradient in Cx45 labeling was found. A sharp transition was found between Cx40- and Cx43-expressing myocytes of the crista terminalis and the Cx45-expressing myocytes of the node. In addition, strands of myocytes labeled for Cx43 and Cx40 protrude into the nodal area. Cx37 labeling was only present between endothelial cells. Furthermore, a band of connective tissue largely separates the nodal from the atrial tissue. Our results demonstrate strands of Cx43 and Cx40 positive atrial cells protruding into the Cx45 positive nodal area and a band of connective tissue largely separating the nodal and atrial tissue. This organization of the mouse SA node provides a structural substrate that both shields the nodal area from the hyperpolarizing influence of the atrium and allows fast action potential conduction from the nodal area into the surrounding atrium.

A prospective audit of pacemaker function, implant lifetime, and cause of death in the patient.

AIM: To audit prospectively the reasons for pacemaker implantation, the duration of the pacemaker use, the cause of death, and pacemaker function after removal from the patient. METHODS: Pacemakers were...

The pacemaker current I(f) in single human atrial myocytes and the effect of beta-adrenoceptor and A1-adenosine receptor stimulation.

1. We used single human atrial myocytes to study I(f) occurrence, properties and pharmacological modulation. Cells were obtained by chunk enzymatic digestion from samples of right atrial appendages of patients undergoing corrective cardiac surgery. 2. Patch-clamped cells in the whole-cell configuration were superfused with a modified Tyrode solution to reduce contamination by interfering currents and to amplify I(f). The average cell membrane capacitance was 85.06+/-2.41 pF (n=531). Data were consistent with the geometrical dimensions of the cells (length 94.2+/-1.89 microm, width 17.9+/-0.42 microm, n=126). 3. When hyperpolarizing to -120 mV from a holding potential of -40 mV, 252 of 306 tested cells (82%) expressed a hyperpolarization-activated inward current (I(f) density=3.77+/-0.25 pA pF(-1)); the current was considered to be present in a given cell if its density at -120 mV was larger than 0.5 pA pF(-1). 4. Current activation was sigmoidal and fitted a Boltzmann model; the average activation curve (n=25) showed a maximum current amplitude of 205.97+/-19.94 pA, corresponding to 3.87+/-0.63 pA pF(-1), voltage of half-maximal activation (V(1/2)) at -86.68+/-2.19 mV and a slope of -11.39+/-0.69 mV. The reversal potential of I(f) measured by tail-current analysis was -13.07+/-1.92 mV (n=6). The addition of CsCl (5 mM) fully and reversibly blocked the current. 5. In the presence of the beta-adrenoceptor agonist isoprenaline (Iso, 1 microM), V(1/2) was significantly shifted toward less negative potentials by 6.06+/-1.96 mV (n=16, P=0.0039). The selective A1-adenosine receptor agonist cyclopentyladenosine (CPA, 1 microM) caused a statistically significant shift of V(1/2) toward more negative potentials with respect to the control curve, both in the absence (-7.37+/-1.83 mV, P=0.0005, n=11) and in the presence of 1 microM Iso (-4.97+/-1.78, P=0.031, n=6). 6. These results demonstrate that a current with the properties of I(f) described in cardiac primary and secondary pacemakers occurs in the majority of human atrial cells. While the pathophysiological relevance of I(f) in human atrial tissue remains to be defined, our data clearly show that it is modulated through stimulation of beta-adrenoceptors and A1-adenosine receptors.

Effect of chronic tryptophan depletion on the circadian rhythm of wheel-running activity in rats

The effect of chronic treatment with a tryptophan (TRP)-free diet on the free-running circadian wheel-running rhythm and the central serotonergic system was investigated in blinded male rats. The long-term TRP-free diet did not change periods of activity, but disordered their patterns. This seemed to be due to masking, entrainment, enhancement of the morning activity, and obscuring of the activity onset as well as appearance of some periodic activities within the subjective night. A long-term TRP-free diet decreased the concentration of TRP, 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in all brain regions tested: frontal cortex, hippocampus, thalamus, hypothalamus, midbrain, and pons. Density of 5-HT 1A receptor binding was significantly decreased in the frontal cortex and hypothalamus, whereas no significant change was observed in the density of 5-HT 2 receptor binding in all regions. These results suggest that the period of primary circadian pacemaker is not affected, but its oscillation, as well as the coupling strength between the primary and secondary pacemakers, is weakened by the dysfunction of the serotonergic system caused by chronic TRP depletion.

Pacemaker current exists in ventricular myocytes.

I(f), the "cardiac pacemaker current," is a nonselective cation channel activated on hyperpolarization in primary and secondary pacemaker regions of the mammalian heart. The cardiac pacing rate can be modulated by shifting the activation of I(f) to more positive (faster pacing) or more negative (slower pacing) voltages. We report for the first time the presence of this pacemaker current in ventricular myocytes. The potential importance of this observation to the mechanism of differentiation of nonpacing regions in the heart is discussed.

Long-term outcome of paced and nonpaced patients with severe carotid sinus syndrome

The natural history of patients with severe carotid sinus syndrome, and the efficacy of permanent pacemaker treatment are not clearly known. A randomized treatment/nontreatment prospective study was performed in 60 patients affected by carotid sinus syndrome whose symptoms were judged to involve risk of major trauma or interfered with their daily activity. They were randomly assigned to 2 groups: 28 patients to no therapy (nonpacing group), and 32 to VVI (n = 18) or DDD (n = 14) pacemaker implant (pacing group). Syncope recurred in 16 patients (57%) of the nopacing group (mean follow-up 36 ± 10 months) and in only 3 (9%) of the pacing group (mean follow-up 34 ± 10 months) (p = 0.0002); moreover, 19 (68%) in the nonpacing group needed a secondary pacemaker implant because of the severity of symptoms. The actuarial rate of absence of syncopal recurrence after 1, 2, 3 and 4 years was 64, 54, 38 and 38%, respectively, for the nonpacing group, and 100, 97, 93 and 84%, respectively, for the pacing group (p = 0.0001). The actuarial rate of absence of minor symptoms after 1, 2, 3 and 4 years was 21, 14, 7 and 7%, respectively, for the nonpacing group and 66, 43, 27 and 27%, respectively, for the pacing group (p = 0.002). Reproducibility of carotid sinus reflex was tested after 15 ± 8 months in 54 patients; an abnormal response to carotid sinus massage persisted in all 54. In conclusion, symptoms recur in most patients with untreated carotid sinus syndrome, and pacing is a useful therapy for preventing recurrences.