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      Noninvasive assessment of autonomic modulation of heart rate variability in the Ts65Dn mouse model of Down syndrome: A proof of principle study

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          Abstract

          Introduction

          The Ts65Dn mouse is the most widely used animal model of Down syndrome (DS). Differences in autonomic regulation of heart rate variability (HRV) in individuals with DS have been hypothesized. Pharmacological studies in animal models may help us understand mechanisms underlying observed changes in HRV in people with DS.

          Objective

          To investigate the use a new, noninvasive technique to assess cardiac autonomic modulation in Ts65Dn mice under the effect of adrenergic and cholinergic agonists.

          Method

          We recorded electrocardiograms (ECGs) from 12 Ts65Dn and 12 euploid control mice. A 30‐min baseline recording was followed by the injection of an adrenergic (isoproterenol [Iso]) or cholinergic (carbachol [CCh]) agonist. Heart rate and HRV were analyzed using a series of methods customized for mice.

          Results and Discussion

          The ECG apparatus described here allowed us to detect noninvasively long series of heartbeats in freely‐moving animals. During baseline conditions, the yield of detectable heartbeats was 3%–27% of the estimated total number of events, which increased to 35%–70% during the 15‐min period after either Iso or CCh injections. Ts65Dn mice displayed a robust enhanced Iso‐induced negative chronotropic rebound response compared with euploid control mice. We observed a significantly smaller CCh response in Ts65Dn versus control euploid mice in the 6‐ to 10‐min‐interval postcarbachol injection.

          Conclusion

          This work showed that the techniques described here are sufficient for this type of study. However, future studies involving the use of more selective pharmacological agents and/or genetic manipulations will be key to advance a mechanistic understanding of cardiac autonomic regulation in DS.

          Abstract

          We used a new, noninvasive technique to assess cardiac autonomic modulation in the Ts65Dn mouse model of Down syndrome under the effect of adrenergic and cholinergic agonists. This new ECG recording apparatus has the potential to be very useful to investigators studying heart rate and heart rate variability in rodent models of human disorders. However, future studies involving the use of more selective pharmacological agents and/or genetic manipulations of the mouse models of DS will be necessary to complement this work.

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          Most cited references36

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          Down's syndrome

          The sequencing of chromosome 21 and the use of models of Down's syndrome in mice have allowed us to relate genes and sets of genes to the neuropathogenesis of this syndrome, and to better understand its phenotype. Research in prenatal screening and diagnosis aims to find methods to identify fetuses with Down's syndrome, and reduce or eliminate the need for amniocentesis. Other areas of active research and clinical interest include the association of Down's syndrome with coeliac disease and Alzheimer's disease, and improved median age of death. Medical management of the syndrome requires an organised approach of assessment, monitoring, prevention, and vigilance. Improvements in quality of life of individuals with Down's syndrome have resulted from improvements in medical care, identification and treatment of psychiatric disorders (such as depression, disruptive behaviour disorders, and autism), and early educational interventions with support in typical educational settings. Approaches and outcomes differ throughout the world.
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            Basic notions of heart rate variability and its clinical applicability.

            Autonomic nervous system (ANS) plays an important role in the regulation of the physiological processes of the human organism during normal and pathological conditions. Among the techniques used in its evaluation, the heart rate variability (HRV) has arising as a simple and non-invasive measure of the autonomic impulses, representing one of the most promising quantitative markers of the autonomic balance. The HRV describes the oscillations in the interval between consecutive heart beats (RR interval), as well as the oscillations between consecutive instantaneous heart rates. It is a measure that can be used to assess the ANS modulation under physiological conditions, such as wakefulness and sleep conditions, different body positions, physical training and also pathological conditions. Changes in the HRV patterns provide a sensible and advanced indicator of health involvements. Higher HRV is a signal of good adaptation and characterizes a health person with efficient autonomic mechanisms, while lower HRV is frequently an indicator of abnormal and insufficient adaptation of the autonomic nervous system, provoking poor patient's physiological function. Because of its importance as a marker that reflects the ANS activity on the sinus node and as a clinical instrument to assess and identify health involvements, this study reviews conceptual aspects of the HRV, measurement devices, filtering methods, indexes used in the HRV analyses, limitations in the use and clinical applications of the HRV.
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              Clinical practice

              Down syndrome (DS) is one of the most common chromosomal abnormalities. Because of medical advances and improvements in overall medical care, the median survival of individuals with DS has increased considerably. This longer life expectancy requires giving the necessary care to the individual with DS over their total longer lifespan. DS medical guidelines are designed for the optimal care of the child in whom a diagnosis of DS has been confirmed. We present an overview of the most important issues related to children with DS based on the most relevant literature currently available.
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                Author and article information

                Contributors
                alberto.costa@case.edu
                Journal
                Physiol Rep
                Physiol Rep
                10.1002/(ISSN)2051-817X
                PHY2
                physreports
                Physiological Reports
                John Wiley and Sons Inc. (Hoboken )
                2051-817X
                19 June 2020
                June 2020
                : 8
                : 12 ( doiID: 10.1002/phy2.v8.12 )
                : e14486
                Affiliations
                [ 1 ] Division of Pediatric Neurology Department of Pediatrics Case Western Reserve University Cleveland OH USA
                [ 2 ] Postgraduate Program in Medicine, Cardiology Federal University of Sao Paulo Sao Paulo SP Brazil
                [ 3 ] Design of Studies and Scientific Writing Laboratory in the ABC School of Medicine Sao Paulo Brazil
                [ 4 ] Department of Psychiatry Case Western Reserve University Cleveland OH USA
                Author notes
                [*] [* ] Correspondence

                Alberto C. S. Costa, Division of Pediatric Neurology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA.

                Email: alberto.costa@ 123456case.edu

                Author information
                https://orcid.org/0000-0002-7855-1190
                Article
                PHY214486
                10.14814/phy2.14486
                7305244
                32562388
                ad688e52-2ace-4d60-a891-e52f574f43be
                © 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 November 2019
                : 25 April 2020
                : 15 May 2020
                Page count
                Figures: 5, Tables: 1, Pages: 12, Words: 8083
                Funding
                Funded by: Alana USA Foundation
                Award ID: 124124 (ACSC)
                Funded by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior: 99999.007452/2014‐04 (ALR) , open-funder-registry 10.13039/501100002322;
                Funded by: Awakening Angels Foundation
                Categories
                Heart
                Cardiovascular Conditions, Disorders and Treatments
                Autonomic Nervous System
                Neurological Conditions, Disorders and Treatments
                Genetic Conditions Disorders and Treatments
                Original Research
                Original Research
                Custom metadata
                2.0
                June 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:19.06.2020

                animal models,autonomic nervous system,cardiovascular system,down syndrome,heart rate,ts65dn

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