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      Development of electrocardiogram intervals during growth of FVB/N neonate mice

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          Abstract

          Background

          Electrocardiography remains the best diagnostic tool and therapeutic biomarker for a spectrum of pediatric diseases involving cardiac or autonomic nervous system defects. As genetic links to these disorders are established and transgenic mouse models produced in efforts to understand and treat them, there is a surprising lack of information on electrocardiograms (ECGs) and ECG abnormalities in neonate mice. This is likely due to the trauma and anaesthesia required of many legacy approaches to ECG recording in mice, exacerbated by the fragility of many mutant neonates. Here, we use a non-invasive system to characterize development of the heart rate and electrocardiogram throughout the growth of conscious neonate FVB/N mice.

          Results

          We examine ECG waveforms as early as two days after birth. At this point males and females demonstrate comparable heart rates that are 50% lower than adult mice. Neonatal mice exhibit very low heart rate variability. Within 12 days of birth PR, QRS and QTc interval durations are near adult values while heart rate continues to increase until weaning. Upon weaning FVB/N females quickly develop slower heart rates than males, though PR intervals are comparable between sexes until a later age. This suggests separate developmental events may contribute to these gender differences in electrocardiography.

          Conclusions

          We provide insight with a new level of detail to the natural course of heart rate establishment in neonate mice. ECG can now be conveniently and repeatedly used in neonatal mice. This should serve to be of broad utility, facilitating further investigations into development of a diverse group of diseases and therapeutics in preclinical mouse studies.

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          Most cited references43

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          SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome.

          Long QT syndrome (LQT) is an inherited disorder that causes sudden death from cardiac arrhythmias, specifically torsade de pointes and ventricular fibrillation. We previously mapped three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, and LQT3 on 3p21-24. Here we report genetic linkage between LQT3 and polymorphisms within SCN5A, the cardiac sodium channel gene. Single strand conformation polymorphism and DNA sequence analyses reveal identical intragenic deletions of SCN5A in affected members of two unrelated LQT families. The deleted sequences reside in a region that is important for channel inactivation. These data suggest that mutations in SCN5A cause chromosome 3-linked LQT and indicate a likely cellular mechanism for this disorder.
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            A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease.

            Heterozygous Tbx5(del/+) mice were generated to study the mechanisms by which TBX5 haploinsufficiency causes cardiac and forelimb abnormalities seen in Holt-Oram syndrome. Tbx5 deficiency in homozygous mice (Tbx5(del/del)) decreased expression of multiple genes and caused severe hypoplasia of posterior domains in the developing heart. Surprisingly, Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (ANF) and connexin 40 (cx40) transcription, implicating these as Tbx5 target genes and providing a mechanism by which 50% reduction of T-box transcription factors cause disease. Direct and cooperative transactivation of the ANF and cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated. These studies provide one potential explanation for Holt-Oram syndrome conduction system defects, suggest mechanisms for intrafamilial phenotypic variability, and account for related cardiac malformations caused by other transcription factor mutations.
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              Prevalence of congenital heart disease.

              Today most patients with congenital heart disease survive childhood to be cared for by adult cardiologists. The number of physicians that should be trained to manage these lesions is unknown because we do not know the number of patients. To answer this question, the expected numbers of infants with each major type of congenital heart defect born in each 5-year period since 1940 were estimated from birth rates and incidence. The numbers expected to survive with or without treatment were estimated from data on natural history and the results of treatment. Finally, lesions were categorized as simple, moderate, or complex, based on the amount of expertise in management needed for optimal patient care. From 1940 to 2002, about 1 million patients with simple lesions, and half that number each with moderate and complex lesions, were born in the United States. If all were treated, there would be 750,000 survivors with simple lesions, 400,000 with moderate lesions, and 180,000 with complex lesions; in addition, there would be 3,000,000 subjects alive with bicuspid aortic valves. Without treatment, the survival in each group would be 400,000, 220,000, and 30,000, respectively. The actual numbers surviving will be between these 2 sets of estimates. Survival of patients with congenital heart disease, treated or untreated, is expected to produce large numbers of adults with congenital disease, and it is likely that many more adult cardiologists will need to be trained to manage moderate and complex congenital lesions.
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                Author and article information

                Journal
                BMC Physiol
                BMC Physiology
                BioMed Central
                1472-6793
                2010
                24 August 2010
                : 10
                : 16
                Affiliations
                [1 ]Human Molecular Genetics Program, Children's Memorial Research Center, 2300 Children's Plaza, PO Box 211, Chicago, IL 60614, USA
                [2 ]Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
                [3 ]Mouse Specifics, Inc., Boston, MA, 02169, USA
                [4 ]Biostatistics Research Core, Children's Memorial Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
                Article
                1472-6793-10-16
                10.1186/1472-6793-10-16
                2936334
                20735846
                ee7b64fd-2014-4ca7-bcb3-4eb659dfd323
                Copyright ©2010 Heier et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 March 2010
                : 24 August 2010
                Categories
                Research Article

                Anatomy & Physiology
                Anatomy & Physiology

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