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      Sinoatrial Node Structure, Mechanics, Electrophysiology and the Chronotropic Response to Stretch in Rabbit and Mouse

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          The rhythmic electrical activity of the heart’s natural pacemaker, the sinoatrial node (SAN), determines cardiac beating rate (BR). SAN electrical activity is tightly controlled by multiple factors, including tissue stretch, which may contribute to adaptation of BR to changes in venous return. In most animals, including human, there is a robust increase in BR when the SAN is stretched. However, the chronotropic response to sustained stretch differs in mouse SAN, where it causes variable responses, including decreased BR. The reasons for this species difference are unclear. They are thought to relate to dissimilarities in SAN electrophysiology (particularly action potential morphology) between mouse and other species and to how these interact with subcellular stretch-activated mechanisms. Furthermore, species-related differences in structural and mechanical properties of the SAN may influence the chronotropic response to SAN stretch. Here we assess (i) how the BR response to sustained stretch of rabbit and mouse isolated SAN relates to tissue stiffness, (ii) whether structural differences could account for observed differences in BR responsiveness to stretch, and (iii) whether pharmacological modification of mouse SAN electrophysiology alters stretch-induced chronotropy. We found disparities in the relationship between SAN stiffness and the magnitude of the chronotropic response to stretch between rabbit and mouse along with differences in SAN collagen structure, alignment, and changes with stretch. We further observed that pharmacological modification to prolong mouse SAN action potential plateau duration rectified the direction of BR changes during sustained stretch, resulting in a positive chronotropic response akin to that of other species. Overall, our results suggest that structural, mechanical, and background electrophysiological properties of the SAN influence the chronotropic response to stretch. Improved insight into the biophysical determinants of stretch effects on SAN pacemaking is essential for a comprehensive understanding of SAN regulation with important implications for studies of SAN physiology and its dysfunction, such as in the aging and fibrotic heart.

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          Most cited references 51

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          Fibroblast network in rabbit sinoatrial node: structural and functional identification of homogeneous and heterogeneous cell coupling.

          Cardiomyocytes form a conducting network that is assumed to be electrically isolated from nonmyocytes in vivo. In cell culture, however, cardiac fibroblasts can contribute to the spread of excitation via functional gap junctions with cardiomyocytes. To assess the ability of fibroblasts to form gap junctions in vivo, we combine in situ detection of connexins in rabbit sinoatrial node (a tissue that is particularly rich in fibroblasts) with identification of myocytes and fibroblasts using immunohistochemical labeling and confocal microscopy. We distinguish two spatially distinct fibroblast populations expressing different connexins: fibroblasts surrounded by other fibroblasts preferentially express connexin40, whereas fibroblasts that are intermingled with myocytes largely express connexin45. Functionality of homogeneous and heterogeneous cell coupling was investigated by dye transfer in sinoatrial node tissue explants. These studies reveal spread of Lucifer yellow, predominantly along extended threads of interconnected fibroblasts (probably via connexin40), and occasionally between neighboring fibroblasts and myocytes (probably via connexin45). Our findings show that cardiac fibroblasts form a coupled network of cells, which may be functionally linked to myocytes in rabbit SAN.
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            Stretch-activated single ion channel currents in tissue-cultured embryonic chick skeletal muscle.

            The membrane of tissue-cultured chick pectoral muscle contains an ionic channel which is activated by membrane stretch. Nicotinic channels and Ca2+-activated K+ channels are not affected by stretch. In 150 mM-external K+ and 150 mM-internal Na+ the channel has a conductance of 70 pS, linear current-voltage relationship between -50 and -140 mV and a reversal potential of +30 mV. Kinetic analysis of single-channel records indicates that there are one open (O) and three closed (C) states. The data can be fitted by the reaction scheme: C1-C2-C3-O. Only the rate constant that governs the C1-C2 transition (k1,2) is stretch-sensitive. None of the rates are voltage-sensitive. The rate constant k1,2 varies with the square of the tension as k1, 2 = k0 X e alpha T2, where alpha is a constant describing the sensitivity to stretch and T is the tension. A typical value of alpha is 0.08 (dyn cm-1)-2. Following exposure to cytochalasin B the channel becomes more sensitive to stretch. The stretch-sensitivity constant, alpha, increases from 0.08 to 2.4 (dyn cm-1)-2. The probability of the channel being open is strongly dependent upon the extracellular K+ concentration. With a suction of 2 cmHg the probability increases from 0.004 in normal saline (5 mM-K+) to 0.26 in 150 mM-K+. The channel appears to gather force from a large area of membrane (greater than 3 X 10(5) A2), probably by a cytochalasin-resistant cytoskeletal network.
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              Electrotonic coupling of excitable and nonexcitable cells in the heart revealed by optogenetics

              Heart pumping is triggered and coordinated by action potentials (APs) originating in and spreading among electrically excitable heart muscle cells (myocytes) via electrotonic coupling. Cardiac nonmyocytes are thought not to participate in AP conduction in situ, although heterocellular electrotonic coupling is common in cell culture. We used optogenetic tools involving cell-specific expression of a voltage-reporting fluorescent protein to monitor electrical activity in myocytes or nonmyocytes of mouse hearts. We confirm the suitability of this technique for measuring cell type-specific voltage signals and show that, when expressed in nonmyocytes, myocyte AP-like signals can be recorded in cryoinjured scar border tissue. This direct evidence of heterocellular electrotonic coupling in the whole heart necessitates a review of current concepts on cardiac electrical connectivity. Electrophysiological studies of excitable organs usually focus on action potential (AP)-generating cells, whereas nonexcitable cells are generally considered as barriers to electrical conduction. Whether nonexcitable cells may modulate excitable cell function or even contribute to AP conduction via direct electrotonic coupling to AP-generating cells is unresolved in the heart: such coupling is present in vitro, but conclusive evidence in situ is lacking. We used genetically encoded voltage-sensitive fluorescent protein 2.3 (VSFP2.3) to monitor transmembrane potential in either myocytes or nonmyocytes of murine hearts. We confirm that VSFP2.3 allows measurement of cell type-specific electrical activity. We show that VSFP2.3, expressed solely in nonmyocytes, can report cardiomyocyte AP-like signals at the border of healed cryoinjuries. Using EM-based tomographic reconstruction, we further discovered tunneling nanotube connections between myocytes and nonmyocytes in cardiac scar border tissue. Our results provide direct electrophysiological evidence of heterocellular electrotonic coupling in native myocardium and identify tunneling nanotubes as a possible substrate for electrical cell coupling that may be in addition to previously discovered connexins at sites of myocyte–nonmyocyte contact in the heart. These findings call for reevaluation of cardiac nonmyocyte roles in electrical connectivity of the heterocellular heart.

                Author and article information

                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                22 July 2020
                : 11
                1Department of Physiology and Biophysics, Dalhousie University , Halifax, NS, Canada
                2Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg - Bad Krozingen, and Faculty of Medicine, University of Freiburg , Freiburg, Germany
                3Department of Electrical and Computer Engineering, Dalhousie University , Halifax, NS, Canada
                4School of Biomedical Engineering, Dalhousie University , Halifax, NS, Canada
                5Department of Physiology, Institut de Génomique Fonctionnelle , Montpellier, France
                Author notes

                Edited by: Leonid Katsnelson, Institute of Immunology and Physiology (RAS), Russia

                Reviewed by: Victor A. Maltsev, National Institute on Aging, National Institutes of Health (NIH), United States; Ed White, University of Leeds, United Kingdom

                *Correspondence: Eva A. Rog-Zielinska, eva.rog-zielinska@ 123456uniklinik-freiburg.de
                T. Alexander Quinn, alex.quinn@ 123456dal.ca

                These authors have contributed equally to this work

                This article was submitted to Cardiac Electrophysiology, a section of the journal Frontiers in Physiology

                Copyright © 2020 MacDonald, Madl, Greiner, Ramadan, Wells, Torrente, Kohl, Rog-Zielinska and Quinn.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 65, Pages: 15, Words: 0
                Funded by: Mitacs 10.13039/501100004489
                Funded by: European Research Council 10.13039/501100000781
                Funded by: Deutsche Forschungsgemeinschaft 10.13039/501100001659
                Funded by: Natural Sciences and Engineering Research Council of Canada 10.13039/501100000038
                Funded by: Canadian Institutes of Health Research 10.13039/501100000024
                Original Research


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