Peripheral Sinoatrial Node Cells Research Articles

Role of atrium in automaticity of the sinus node.

As the electrical source of hearts, sino-atrial node cells (SANCs) play significant roles in rhythmic firings. Due to the complex structure and function of SANCs, electrical interactions of SAN and its surrounding atrium has not yet been fully understood. The aim of the present study is to investigate effects of coupling conductance between SAN and atrial cells as well as the ectopic beats in atrium on automaticity of the SAN by computer simulation methods. On the basis of a dynamic mathematical single cell model considering the heterogeneity of central and peripheral SANCs, a two-dimensional inhomogeneous tissue slice including SAN and atrium was developed. The operator splitting method was used to integrate the tissue model. The results demonstrated that the coupling conductance between SAN and atrium had effects on the direction of spontaneous action potential conduction in SAN. Weak coupling resulted in a shift of the earliest pacemaker site from central to peripheral SANCs. Additionally, the ectopic beat-induced excitation in atrium was found to be able to enter into and overdrive suppress the automaticity of SAN. Even if the ectopic beat was delivered after the spontaneous firing had started in central SANCs, the spontaneous conduction toward the periphery could also be suppressed by the retrograde activation from the entering atrial depolarization wave. These findings suggested a direct link between sinus node dysfunction and atrial arrhythmias, and therefore were helpful in explaining the role of atrium in sinus node dysfunction.

The Cardiac Conduction System

The human heart beats 2.5 billion times during a normal lifespan, a feat accomplished by cells of the cardiac conduction system (CCS). The functional components of the CCS can be broadly divided into the impulse-generating nodes and the impulse-propagating His-Purkinje system. Human diseases of the conduction system have been identified that alter impulse generation, impulse propagation, or both. CCS dysfunction is primarily due to acquired conditions such as myocardial ischemia/infarct, age-related degeneration, procedural complications, and drug toxicity. Inherited forms of CCS disease are rare, but each new mutation provides invaluable insight into the molecular mechanisms governing CCS development and function. Applying a multidisciplinary approach, which includes human genetic screening, biophysical analysis, and transgenic mouse technology, has yielded a broad array of gene families involved in maintaining normal CCS physiology (Figure 1). In this review, we discuss gene families that have been implicated in human CCS diseases of rhythm, conduction block, accessory conduction, and development (Table). We also investigate evolving therapeutic strategies that may serve as adjuvant or replacement therapy to current implantable pacemakers. Figure 1. Cardiac conduction system cell. Genes identified in human cardiac conduction system disease are highlighted. View this table: Table. Genetic Basis of Conduction System Disease The human sinoatrial node (SAN) is a crescent-shaped, intramural structure with its head located subepicardially at the junction of the right atrium and the superior vena cava and its tail extending 10 to 20 mm along the crista terminalis.26 The SAN has complex 3-dimensional tissue architecture with central and peripheral components made up of distinct ion channel and gap junction expression profiles.27 Central and peripheral cells have different action potential characteristics and conduction properties (Figure 2).27 Experimental and computational models have demonstrated that SAN heterogeneity is necessary to maintain normal automaticity and impulse conduction.28,–,30 Figure 2. Electrophysiological heterogeneity of the …

Effects of Atrium on the Electrical Activity of Sino-Atrial Node

As the electrical source of hearts, sino-atrial node (SAN) plays a significant role in rhythmic firing. The aim of this study is to determine effects of atrium on the electrical activity of SAN. Based on a mathematical model considering central and peripheral SAN cells as well as an atrial model, one-dimensional fiber with a gradual heterogeneity of SANC was developed. The forth-order Runge-Kutta and three-point centered difference methods were used to integrate the conduction model. The results demonstrated that as a load of SAN, atrium decreased the spontaneous sinus rate casing a shift of leading pacemaker site from the periphery to the center. If the ectopic beat produced by a premature stimulation was late after the end of the atrial refractory, the pause following it was compensatory. Otherwise, the pause was non-compensatory. In this case, the peripheral SANC excited earlier than the central SANC. During multiple premature beats, at short intervals the propagation could block in SAN due to a long refractory period of the action potential close to the central SANC. Leading pacemaker site shift was observed during the following several spontaneous SANC excitation. Therefore, the existence of atrium is suggested affecting not only sinus rates, but also the mode of electrical propagation and the site of the earliest excitation.

Determinants of Heterogeneity, Excitation and Conduction in the Sinoatrial Node: A Model Study

The sinoatrial node (SAN) is a complex structure that exhibits anatomical and functional heterogeneity which may depend on: 1) The existence of distinct cell populations, 2) electrotonic influences of the surrounding atrium, 3) the presence of a high density of fibroblasts, and 4) atrial cells intermingled within the SAN. Our goal was to utilize a computer model to predict critical determinants and modulators of excitation and conduction in the SAN. We built a theoretical “non-uniform” model composed of distinct central and peripheral SAN cells and a “uniform” model containing only central cells connected to the atrium. We tested the effects of coupling strength between SAN cells in the models, as well as the effects of fibroblasts and interspersed atrial cells. Although we could simulate single cell experimental data supporting the “multiple cell type” hypothesis, 2D “non-uniform” models did not simulate expected tissue behavior, such as central pacemaking. When we considered the atrial effects alone in a simple homogeneous “uniform” model, central pacemaking initiation and impulse propagation in simulations were consistent with experiments. Introduction of fibroblasts in our simulated tissue resulted in various effects depending on the density, distribution, and fibroblast-myocyte coupling strength. Incorporation of atrial cells in our simulated SAN tissue had little effect on SAN electrophysiology. Our tissue model simulations suggest atrial electrotonic effects as plausible to account for SAN heterogeneity, sequence, and rate of propagation. Fibroblasts can act as obstacles, current sinks or shunts to conduction in the SAN depending on their orientation, density, and coupling.

Modeling of the influence of gap-junction coupling on synchronization of central and peripheral sinoatrial node cells

Mathematical modeling of the electric activity of pairs of true (central) and latent (peripheral) sinoatrial pacemaker cells coupled through gap junctions revealed that attenuation of coupling conductance increases the beat phase shift; below a critical conductance there is no synchronization. The phase difference also depends on the type of interacting cells, being maximal for a “central”-“peripheral” cell pair.

Sinus node dysfunction following targeted disruption of the murine cardiac sodium channel gene Scn5a

We have examined sino-atrial node (SAN) function in hearts from adult mice with heterozygous targeted disruption of the Scn5a gene to clarify the role of Scn5a-encoded cardiac Na+ channels in normal SAN function and the mechanism(s) by which reduced Na+ channel function might cause sinus node dysfunction. Scn5a+/- mice showed depressed heart rates and occasional sino-atrial (SA) block. Their isolated peripheral SAN pacemaker cells showed a reduced Na+ channel expression and slowed intrinsic pacemaker rates. Wild-type (WT) and Scn5a+/- SAN preparations exhibited similar activation patterns but with significantly slower SA conduction and frequent sino-atrial conduction block in Scn5a+/- SAN preparations. Furthermore, isolated WT and Scn5a+/- SAN cells demonstrated differing correlations between cycle length, maximum upstroke velocity and action potential amplitude, and cell size. Small myocytes showed similar, but large myocytes reduced pacemaker rates, implicating the larger peripheral SAN cells in the reduced pacemaker rate that was observed in Scn5a+/- myocytes. These findings were successfully reproduced in a model that implicated i(Na) directly in action potential propagation through the SAN and from SAN to atria, and in modifying heart rate through a coupling of SAN and atrial cells. Functional alterations in the SAN following heterozygous-targeted disruption of Scn5a thus closely resemble those observed in clinical sinus node dysfunction. The findings accordingly provide a basis for understanding of the role of cardiac-type Na+ channels in normal SAN function and the pathophysiology of sinus node dysfunction and suggest new potential targets for its clinical management.

One-dimensional rabbit sinoatrial node models: benefits and limitations.

Cardiac multicellular modeling has traditionally focused on ventricular electromechanics. More recently, models of the atria have started to emerge, and there is much interest in addressing sinoatrial node structure and function. We implemented a variety of one-dimensional sinoatrial models consisting of descriptions of central, transitional, and peripheral sinoatrial node cells, as well as rabbit or human atrial cells. These one-dimensional models were implemented using CMISS on an SGI Origin 2000 supercomputer. Intercellular coupling parameters recorded in experimental studies on sinoatrial node and atrial cell-pairs under-represent the electrotonic interactions that any cardiomyocyte would have in a multidimensional setting. Unsurprisingly, cell-to-cell coupling had to be scaled-up (by a factor of 5) in order to obtain a stable leading pacemaker site in the sinoatrial node center. Further critical parameters include the gradual increase in intercellular coupling from sinoatrial node center to periphery, and the presence of electrotonic interaction with atrial cells. Interestingly, the electrotonic effect of the atrium on sinoatrial node periphery is best described as opposing depolarization, rather than necessarily hyperpolarizing, as often assumed. Multicellular one-dimensional models of sinoatrial node and atrium can provide useful insight into the origin and spread of normal cardiac excitation. They require larger than "physiologic" intercellular conductivities in order to make up for a lack of "anatomical" spatial scaling. Multicellular models for more in-depth quantitative studies will require more realistic anatomico-physiologic properties.

Analysis of the chronotropic effect of acetylcholine on sinoatrial node cells.

The ionic basis underlying the negative chronotropic effect of acetylcholine (ACh) on sinoatrial (SA) node cells is unresolved and controversial. In the present study, mathematical modeling was used to address this issue. The known concentration-dependent effects of ACh on iK,ACh, iCa,L, and i(f) were introduced into models of rabbit central and peripheral SA node cells. In the central and peripheral models, 9 x 10(-8) and 14 x 10(-8) M ACh, respectively, caused a 50% decrease in pacemaking rate, whereas in rabbit SA node to approximately 7.4 x 10(-8) M ACh caused such a decrease. In the models, iK,ACh was primarily responsible for the decrease and actions of ACh on iCa,L or i(f) alone caused a negligible effect. Although the inhibition of i(f) did not directly contribute to the chronotropic effect, it was indirectly important, because it minimized the opposition by i(f ) to the decrease of rate caused by activation of iK,ACh. The central model was more sensitive to ACh than the peripheral model. The chronotropic effect of ACh is principally the result of activation of iK,ACh, and inhibition of iCa,L plays little or no role. Inhibition of i(f) and possible inhibition of ib,Na play an important facilitative role by reducing the ability of i(f) and ib,Na to curtail the chronotropic effect caused by activation of iK,ACh.