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      Hypoxia Induces Dilated Cardiomyopathy in the Chick Embryo: Mechanism, Intervention, and Long-Term Consequences

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          Abstract

          Background

          Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos.

          Methods

          Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine.

          Principal Findings

          Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF 165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype.

          Conclusions/Significance

          Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.

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          Most cited references36

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          Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure.

          Although increased external load initially induces cardiac hypertrophy with preserved contractility, sustained overload eventually leads to heart failure through poorly understood mechanisms. Here we describe a conditional transgenic system in mice characterized by the sequential development of adaptive cardiac hypertrophy with preserved contractility in the acute phase and dilated cardiomyopathy in the chronic phase following the induction of an activated Akt1 gene in the heart. Coronary angiogenesis was enhanced during the acute phase of adaptive cardiac growth but reduced as hearts underwent pathological remodeling. Enhanced angiogenesis in the acute phase was associated with mammalian target of rapamycin-dependent induction of myocardial VEGF and angiopoietin-2 expression. Inhibition of angiogenesis by a decoy VEGF receptor in the acute phase led to decreased capillary density, contractile dysfunction, and impaired cardiac growth. Thus, both heart size and cardiac function are angiogenesis dependent, and disruption of coordinated tissue growth and angiogenesis in the heart contributes to the progression from adaptive cardiac hypertrophy to heart failure.
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            New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic function.

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              Myocardial structure and function differ in systolic and diastolic heart failure.

              To support the clinical distinction between systolic heart failure (SHF) and diastolic heart failure (DHF), left ventricular (LV) myocardial structure and function were compared in LV endomyocardial biopsy samples of patients with systolic and diastolic heart failure. Patients hospitalized for worsening heart failure were classified as having SHF (n=22; LV ejection fraction (EF) 34+/-2%) or DHF (n=22; LVEF 62+/-2%). No patient had coronary artery disease or biopsy evidence of infiltrative or inflammatory myocardial disease. More DHF patients had a history of arterial hypertension and were obese. Biopsy samples were analyzed with histomorphometry and electron microscopy. Single cardiomyocytes were isolated from the samples, stretched to a sarcomere length of 2.2 microm to measure passive force (Fpassive), and activated with calcium-containing solutions to measure total force. Cardiomyocyte diameter was higher in DHF (20.3+/-0.6 versus 15.1+/-0.4 microm, P<0.001), but collagen volume fraction was equally elevated. Myofibrillar density was lower in SHF (36+/-2% versus 46+/-2%, P<0.001). Cardiomyocytes of DHF patients had higher Fpassive (7.1+/-0.6 versus 5.3+/-0.3 kN/m2; P<0.01), but their total force was comparable. After administration of protein kinase A to the cardiomyocytes, the drop in Fpassive was larger (P<0.01) in DHF than in SHF. LV myocardial structure and function differ in SHF and DHF because of distinct cardiomyocyte abnormalities. These findings support the clinical separation of heart failure patients into SHF and DHF phenotypes.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2009
                9 April 2009
                : 4
                : 4
                Affiliations
                [1 ]Laboratory for Angiogenesis and Cardiovascular Pathology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
                [2 ]Department of Surgery, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
                [3 ]Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands
                [4 ]Department of Obstetrics, Charité University Medicine, Berlin, Germany
                [5 ]Department of Reproductive & Vascular Biology, Centre for Cardiovascular Sciences, Institute for Biomedical Research, University of Birmingham, Birmingham, United Kingdom
                [6 ]Department of Maternal-Fetal Medicine, Hospital Clinic, University of Barcelona, Barcelona, Spain
                [7 ]Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
                [8 ]Center of Transgene Technology and Gene Therapy, University of Leuven, Leuven, Belgium
                [9 ]Department of Obstetrics and Gynecology, Ulleval University Hospital, Oslo, Norway
                [10 ]Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, University of Frankfurt, Frankfurt, Germany
                [11 ]Institute of Obstetrics and Gynecology, IRCCS Foundation Policlinico, Mangiagalli & Regina Elena, University of Milan, Milan, Italy
                [12 ]Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
                [13 ]Department of Embryology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
                [14 ]Research Group Molecular Muscle Physiology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
                [15 ]Department of Cardiology, Franz Volhard Clinic, Helios Clinic Berlin-Buch, Charité University, Berlin, Germany
                University of Cincinnati, United States of America
                Author notes

                Conceived and designed the experiments: AT ER SV JB MvB MJ WHL IM ES FlN. Performed the experiments: AT ER SV JB SA FC ACS IC LH IM ES. Analyzed the data: AT ER SV JB MvB PC EG EHA LH MJ WHL IM ES AA FlN. Contributed reagents/materials/analysis tools: AT ER SV JB SA FC MvB PC ACS MT IC EG EHA LH MJ WHL IM ES AA FlN. Wrote the paper: AT ER SV JB MvB MT LH MJ WHL AA FlN.

                Article
                09-PONE-RA-08370R1
                10.1371/journal.pone.0005155
                2663815
                19357774
                24194642-14f7-4dad-87a7-ff98f707daad
                Tintu 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.
                Page count
                Pages: 11
                Categories
                Research Article
                Developmental Biology/Developmental Molecular Mechanisms
                Developmental Biology/Embryology
                Cardiovascular Disorders/Heart Failure

                Uncategorized

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