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      Hand factor ablation causes defective left ventricular chamber development and compromised adult cardiac function

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          Abstract

          Coordinated cardiomyocyte growth, differentiation, and morphogenesis are essential for heart formation. We demonstrate that the bHLH transcription factors Hand1 and Hand2 play critical regulatory roles for left ventricle (LV) cardiomyocyte proliferation and morphogenesis. Using an LV-specific Cre allele ( Hand1 LV -Cre), we ablate Hand1-lineage cardiomyocytes, revealing that DTA-mediated cardiomyocyte death results in a hypoplastic LV by E10.5. Once Hand1-linage cells are removed from the LV, and Hand1 expression is switched off, embryonic hearts recover by E16.5. In contrast, conditional LV loss-of-function of both Hand1 and Hand2 results in aberrant trabeculation and thickened compact zone myocardium resulting from enhanced proliferation and a breakdown of compact zone/trabecular/ventricular septal identity. Surviving Hand1; Hand2 mutants display diminished cardiac function that is rescued by concurrent ablation of Hand-null cardiomyocytes. Collectively, we conclude that, within a mixed cardiomyocyte population, removal of defective myocardium and replacement with healthy endogenous cardiomyocytes may provide an effective strategy for cardiac repair.

          Author summary

          The left ventricle of the heart drives blood flow throughout the body. Impaired left ventricle function, associated either with heart failure or with certain, severe cardiac birth defects, constitutes a significant cause of mortality. Understanding how heart muscle grows is vital to developing improved treatments for these diseases. Unfortunately, genetic tools necessary to study the left ventricle have been lacking. Here we engineer the first mouse line to enable specific genetic study of the left ventricle. We show that, unlike in the adult heart, the embryonic left ventricle is remarkably tolerant of cell death, as remaining cells have the capacity to proliferate and to restore heart function. Conversely, disruption of two related genes, Hand1 and Hand2, within the left ventricle causes cells to assume the wrong identity, and to consequently overgrow and impair cardiac function. Ablation of these mutant cells rescues heart function. We conclude that selective removal of defective heart muscle and replacement with healthy cells may provide an effective therapy to treat heart failure.

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          Most cited references34

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          Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms.

          We have presented recommendations for the optimum acquisition of quantitative two-dimensional data in the current echocardiographic environment. It is likely that advances in imaging may enhance or supplement these approaches. For example, three-dimensional reconstruction methods may greatly augment the accuracy of volume determination if they become more efficient. The development of three-dimensional methods will depend in turn on vastly improved transthoracic resolution similar to that now obtainable by transesophageal echocardiography. Better resolution will also make the use of more direct methods of measuring myocardial mass practical. For example, if the epicardium were well resolved in the long-axis apical views, the myocardial shell volume could be measured directly by the biplane method of discs rather than extrapolating myocardial thickness from a single short-axis view. At present, it is our opinion that current technology justifies the clinical use of the quantitative two-dimensional methods described in this article. When technically feasible, and if resources permit, we recommend the routine reporting of left ventricular ejection fraction, diastolic volume, mass, and wall motion score.
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            Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification.

            Cardiogenesis requires the generation of endothelial, cardiac, and smooth muscle cells, thought to arise from distinct embryonic precursors. We use genetic fate-mapping studies to document that isl1(+) precursors from the second heart field can generate each of these diverse cardiovascular cell types in vivo. Utilizing embryonic stem (ES) cells, we clonally amplified a cellular hierarchy of isl1(+) cardiovascular progenitors, which resemble the developmental precursors in the embryonic heart. The transcriptional signature of isl1(+)/Nkx2.5(+)/flk1(+) defines a multipotent cardiovascular progenitor, which can give rise to cells of all three lineages. These studies document a developmental paradigm for cardiogenesis, where muscle and endothelial lineage diversification arises from a single cell-level decision of a multipotent isl1(+) cardiovascular progenitor cell (MICP). The discovery of ES cell-derived MICPs suggests a strategy for cardiovascular tissue regeneration via their isolation, renewal, and directed differentiation into specific mature cardiac, pacemaker, smooth muscle, and endothelial cell types.
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              Long-term follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis.

              We sought to describe characteristics and outcome in adults with isolated ventricular noncompaction (IVNC). Isolated ventricular noncompaction is an unclassified cardiomyopathy due to intrauterine arrest of compaction of the loose interwoven meshwork. Knowledge regarding diagnosis, morbidity and prognosis is limited. Echocardiographic criteria for IVNC include-in the absence of significant heart lesions-segmental thickening of the left ventricular myocardial wall consisting of two layers: a thin, compacted epicardial and an extremely thickened endocardial layer with prominent trabeculations and deep recesses. Thirty-four adults (age >16 years, 25 men) fulfilled the diagnostic criteria and were followed prospectively. At diagnosis, mean age was 42 + 17 years, and 12 patients (35%) were in New York Heart Association class III/IV. Left ventricular end-diastolic diameter was 65 + 12 mm and ejection fraction 33 + 13%. Apex and/or midventricular segments of both the inferior and lateral wall were involved in >80% of patients. Follow-up was 44 + 40 months. Major complications were heart failure in 18 patients (53%), thromboembolic events in 8 patients (24%) and ventricular tachycardias in 14 patients (41%). There were 12 deaths: sudden in six, end-stage heart failure in four and other causes in two patients. Four patients underwent heart transplantation. Automated cardioverter/defibrillators were implanted in four patients. Diagnosis of IVNC by echocardiography using strict criteria is feasible. Its mortality and morbidity are high, including heart failure, thrombo-embolic events and ventricular arrhythmias. Risk stratification includes heart failure therapy, oral anticoagulation, heart transplantation and implantation of an automated defibrillator/cardioverter. As IVNC is a distinct entity, its classification as a specific cardiomyopathy seems to be more appropriate.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: Validation
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Validation
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                21 July 2017
                July 2017
                : 13
                : 7
                : e1006922
                Affiliations
                [1 ] Department of Pediatrics, Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
                [2 ] Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
                [3 ] Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
                [4 ] Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
                Weis Center for Research, Geisinger Clinic, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-0209-1220
                Article
                PGENETICS-D-17-00142
                10.1371/journal.pgen.1006922
                5544250
                28732025
                4f760cd0-a26d-4816-b1a8-b3bc3aa0a5f3
                © 2017 Vincentz et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 20 January 2017
                : 13 July 2017
                Page count
                Figures: 7, Tables: 3, Pages: 20
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;
                Award ID: HL122123-03
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;
                Award ID: HL120920-03
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000069, National Institute of Arthritis and Musculoskeletal and Skin Diseases;
                Award ID: AR061392-05
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000968, American Heart Association;
                Award ID: 16SDG27260072
                Award Recipient :
                This work is also supported by NIH Grants 1R01 HL122123-03, 1R01 HL120920-03, 1R0 AR061392-05 (to ABF); the Carleton Buehl McCulloch chair (to ABF); by an award from the American Heart Association and The Children’s Heart Foundation (16SDG27260072 to JWV), and by the Indiana University Health–Indiana University School of Medicine Strategic Research Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Heart
                Medicine and Health Sciences
                Anatomy
                Cardiovascular Anatomy
                Heart
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Heart
                Myocardium
                Medicine and Health Sciences
                Anatomy
                Cardiovascular Anatomy
                Heart
                Myocardium
                Biology and Life Sciences
                Developmental Biology
                Embryology
                Embryos
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
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                Cardiac Ventricles
                Medicine and Health Sciences
                Anatomy
                Cardiovascular Anatomy
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                Biology and Life Sciences
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                Medicine and Health Sciences
                Physiology
                Cardiovascular Physiology
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and Life Sciences
                Molecular Biology
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                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Probe Techniques
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                Biology and Life Sciences
                Cell Biology
                Cell Processes
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                Custom metadata
                vor-update-to-uncorrected-proof
                2017-08-04
                All relevant data are within the paper and its Supporting Information files.

                Genetics
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