Molecular Architecture of the Human Sinus Node

Chandler, Natalie; Greener, Ian; Tellez, James O.; Inada, Shin; Musa, Hanny; Molenaar, Peter; DiFrancesco, Dario; Baruscotti, Mirko; Longhi, Renato; Anderson, Robert H.; Billeter, R.; Sharma, Vinod; Sigg, Daniel C.; Boyett, Mark R.; Dobrzynski, Halina

doi:10.1161/circulationaha.108.804369

Cited by 366 publications

(283 citation statements)

References 35 publications

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“…3B. As we have shown previously (Chandler et al, 2009), Cx43 was highly expressed in the atrial muscle, but was not detectable in the sinus node and was expressed at an intermediate level in the paranodal area. Although histology alone was sufficient to identify and distinguish the sinus node, paranodal and atrial muscle, the use of, and lack of Cx43 labeling was important in identifying the head and tail of the sinus node tissue.…”

Section: Methodssupporting

confidence: 63%

“…The preparations were frozen in liquid N 2 and cryosectioned; sections at different levels were stained with Masson's trichrome and various marker proteins were labeled using immunofluorescence. The 3D anatomical model was combined with mathematical models of feasible human sinus node, paranodal and atrial action potentials (Chandler et al, 2009) -numerical simulation was used to calculate the initiation and spread of the action potential through the tissue. Full details of the methods used are available in Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

“…In a previous study of ion channel expression in the human sinus node (Chandler et al, 2009), we reported that running alongside the sinus node is a discrete tissue with characteristics transitional between those of the sinus node and atrial muscle. Since this tissue had not been previously reported, we named it the 'paranodal area'.…”

Section: Anatomical Model Of Human Sinus Nodementioning

confidence: 96%

“…In our earlier study on ion channel expression in the human sinus node, we observed that the expression pattern of some ion channels in the paranodal area is intermediate between that of the sinus node and atrial muscle. For example, expression of K ir 2.1, Na v 1.5 and Na v b1 is high in the atrial muscle and low in the sinus node (Chandler et al, 2009). This explains why the atrial muscle has a stable resting potential, whereas the sinus node does not, and the atrial muscle has an action potential with a fast upstroke, whereas the sinus node has an action potential with a slow upstroke.…”

Section: Properties and Possible Function Of The Paranodal Areamentioning

confidence: 99%

“…Because the model is a mathematical array with accurate anatomy, segmentation of different tissue types and myocyte orientation, it can be used in mathematical simulations. Based on ion channel expression, we have formulated a mathematical model of the action potential in the human sinus node (Chandler et al, 2009). We have used this model of the human sinus node action potential together with a model of the human atrial potential (Courtemanche et al, 1988).…”

Section: Myocyte Orientationmentioning

confidence: 99%

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Computer Three‐Dimensional Anatomical Reconstruction of the Human Sinus Node and a Novel Paranodal Area

Chandler

Aslanidi

Buckley

et al. 2011

The Anatomical Record

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We have previously shown in rabbit that the pacemaker of the heart (the sinus node) is widespread and matches the wide distribution of the leading pacemaker site within the right atrium. There is, however, uncertainty about the precise location of the pacemaker in human heart, and its spatial relationships with the surrounding right atrial muscle. Therefore, the aim of the current study was to investigate the distribution of the sinus node tissue in a series of healthy human hearts and, for one of the hearts to construct a computer three-dimensional anatomical model of the sinus node, including the likely orientation of myocytes. A combination of experimental techniques-diffusion tensor magnetic resonance imaging (DT-MRI), histology, immunohistochemistry, image processing and computer modelling-was used. Our data show that the sinus node was larger than in previous studies and, most importantly, we identified a previously unknown area running alongside the sinus node (the ''paranodal area"), which is even more extensive than the sinus node. This area possesses properties of both nodal and atrial tissues and may have a role in pacemaking. For example, it could explain the wide spread distribution of the leading pacemaker site in human right atrium, a phenomenon known as the wandering pacemaker observed in clinics. In summary, a Additional Supporting Information may be found in the online version of this article.Abbreviations used: AM ¼ Atrial muscle; ANP ¼ Atrial natriuretic peptide; Ao ¼ Aorta; Cx40, Cx43 ¼ Connexin 40 and 43; 3D ¼ Three-dimensional; DT-MRI ¼ Diffusion tensor magnetic resonance imaging; HCN4 ¼ Ion channel responsible for hyperpolarization-activated or 'funny' current, I f ; IVC ¼ Inferior vena cava; Kir2.1 ¼ Ion channel responsible for background inward rectifier K þ current, I K1 ; Kir6.2 ¼ Ion channel responsible for ATP-sensitive K þ current, I KATP ; Kv1.4 ¼ Ion channel responsible for transient outward K þ current, I to ; LAA ¼ Left atrial appendage; MiRP2 ¼ Accessory protein for K þ channels; N av1.5, Nav 1 ¼ Na þ channel responsible for inward Na þ current, I Na ; PA ¼ Pulmonary artery; PV ¼ Pulmonary vein; RA ¼ Right atrium; RAA ¼ Right atrial appendage; RV ¼ Right ventricle; SCV ¼ Superior caval vein; SK2 ¼ Ion channel responsible for Ca 2þ -activated K þ current, I KCa ; TASK1 Twin-pore domain K þ channel; Tbx3 ¼ Transcription factor; TC ¼ Terminal crest.

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Section: Methodssupporting

confidence: 63%

Section: Methodsmentioning

confidence: 99%

Section: Anatomical Model Of Human Sinus Nodementioning

confidence: 96%

Section: Properties and Possible Function Of The Paranodal Areamentioning

confidence: 99%

Section: Myocyte Orientationmentioning

confidence: 99%

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Computer Three‐Dimensional Anatomical Reconstruction of the Human Sinus Node and a Novel Paranodal Area

Chandler

Aslanidi

Buckley

et al. 2011

The Anatomical Record

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101

100

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Optical Mapping of the Sinoatrial Node and Atrioventricular Node

2012

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Within the heart there burns a sort of vestal fire, so subtle that it escapes immediately through any incision made to reveal it. Hippocrates SummaryTechnological advances often precede scientific breakthroughs that have led to leaps in our understanding of human physiology. The advent of the electrical galvanometer was a landmark advancement that enabled careful study of the electrical activation of the heart. Similarly, optical imaging, or mapping, using fluorescent, voltage sensitive dyes has enabled the careful study of the sinoatrial (SA) and atrioventricular (AV) nodes, and improved our understanding of how anatomic structure is related to electrophysiological function. We review the major findings of optical mapping studies of the sinoatrial node (SAN) and atrioventricular node (AVN), with particular emphasis on clinically relevant physiology and pathophysiology. We pay particular attention to clinical implications of these seminal findings derived from animal models and from the optical mapping study of human hearts. The studies presented are intended to improve the reader's understanding of SAN and AVN physiology, as well as to offer insight into the advantages and limitations of optical mapping. Optical mapping methodologyThe sinoatrial node (SAN) and atrioventricular node (AVN) of large mammals such as canines and humans are complex, three-dimensional structures consisting of electrically specialized tissues that are largely insulated from the surrounding structures. The SAN and AVN are essentially encased in fibrofatty tissues, vasculature and connective tissue, and surrounded by atrial myocardium. This complex anatomy prevents surface electrodes from delineating activation within the SAN and AVN. Microelectrode recordings provide a reliable tool to visualize electrical responses of specialized cell types that are integral parts of these structures, but cannot reveal a broad pattern of activation due to the focal spatial nature of these recordings. Moreover, the depth of microelectrode impalement is difficult to verify, and cells located closer to the endocardial surface may be activated substantially later (SAN) or earlier (AVN) than those at depth. Optical mapping (OM) takes advantage of fluorescent, voltage sensitive dyes whose absorption and emission spectra change with changes in transmembrane voltage, to accurately image action potentials from a large area, in terms of anatomic surface and to a lesser extent, depth. Recorded optical action potentials (AP) are a composite of the APs from superficial and deeper anatomic structures, which can be deconstructed to reveal the electrical and functional properties of individual structures that make up the SAN and AVN. The ability to deconstruct these complex optical AP signals is critical to understanding the function of these complex structures. Optical mapping has enabled studies of the origin and propagation of electrical activity within and surrounding the SAN and AVN to improve our understanding of function during physiological and pathological sta...

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The functional architecture of skeletal compared to cardiac musculature: Myocyte orientation, lamellar unit morphology, and the helical ventricular myocardial band

et al. 2015

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The functional architecture of skeletal compared to cardiac musculature; myocyte orientation, lamellar unit morphology, and the helical ventricular myocardial band. AbstractHow the cardiomyocytes are aggregated within the heart walls remains contentious. We still do not fully understand how the end-to-end longitudinal myocytic chains are arranged, nor the true extent and shape of the lamellar units they aggregate to form. In this review, we show that an understanding of the complex arrangement of cardiomyocytes requires knowledge of 3-dimensional cell orientation (helical and intrusion angle), and appreciation of cell packing within the connective tissue matrix. We show how visualisation and segmentation of high resolution 3-dimensional image data can accurately identify the morphology and orientation of the myocytic chains, and the lamellar units. Some maintain that the ventricles can be unwrapped in the form of a "helical ventricular myocardial band". Implying the ventricular muscle is arranged comparable to that of skeletal muscles, in an ordered fashion, as a compartmentalised band with selective regional innervation and deformation, and a defined origin and insertion. In contrast to the simpler interpretation of the helical ventricular myocardial band, we provide insight as to how the complex myocytic chains, the heterogeneous lamellar units, and connective tissue matrix form an interconnected meshwork, which facilitates the complex internal deformations of the ventricular wall. We highlight the dangers of disregarding the intruding cardiomyocytes. Preparation of the band destroys intruding myocytic chains, and thus disregards the functional implications of the antagonistic auxotonic forces they produce. We conclude that the ventricular myocardium is not analogous to skeletal muscle, but is a complex 3-dimensional meshwork, with a heterogeneous branching lamellar architecture.

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Molecular Architecture of the Human Sinus Node

Cited by 366 publications

References 35 publications

Computer Three‐Dimensional Anatomical Reconstruction of the Human Sinus Node and a Novel Paranodal Area

Computer Three‐Dimensional Anatomical Reconstruction of the Human Sinus Node and a Novel Paranodal Area

Optical Mapping of the Sinoatrial Node and Atrioventricular Node

The functional architecture of skeletal compared to cardiac musculature: Myocyte orientation, lamellar unit morphology, and the helical ventricular myocardial band

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