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At least 109 records · Page 6Linked to original sources
PubMed1996

Identification of an essential nonneuronal function of neurotrophin 3 in mammalian cardiac development.

Neurotrophin 3 (Nt3) is one of five neurotrophin growth factors which shape the development of the nervous system by regulating neuronal survival and differentiation. Peripheral neuronal subpopulations expressing the TrkC receptor tyrosine kinase respond to Nt3 with enhanced survival, mitogenesis or cell migration and these neurons are lost in homozygous Nt3 null (-/-) mutant mice. The unexplained perinatal lethality in the Nt3-/- mice, however, suggests a wider function for this neurotrophin. Here we report that Nt3 is essential for the normal development of atria, ventricles, and cardiac outflow tracts. Histological and echocardiographic image analysis of Nt3-/- animals reveal severe cardiovascular abnormalities including atrial and ventricular septal defects, and tetralogy of Fallot, resembling some of the most common congenital malformations in humans. The observed defects are consistent with abnormalities in the survival and/or migration of cardiac neural crest early in embryogenesis and establish an essential role for neurotrophin 3 in regulating the development of the mammalian heart.

Amino Acid Sequence↗
PubMed1993

[Anesthetic management of a patient with polyarteritis nodosa who suddenly developed cardiac rupture after valve replacement].

We recently encountered a patient with mitral insufficiency, accompanied by PN (polyarteritis nodosa), who developed a cardiac rupture immediately after a mitral valve replacement. The patient was a 60-year-old woman. After she was diagnosed as having mitral stenosis and insufficiency in 1968, the patient developed congestive heart failure and underwent repeated hospital admissions and discharges. In 1989, she was diagnosed as having PN and began to receive a high-dose steroid therapy (prednisolone; total dose 5245 mg). Because of transient brain ischemia and exacerbation of the symptoms of heart failure, the patient underwent mitral valve replacement on December 19, 1991. For anesthesia, oxygen, fentanyl, midazolam and vecuronium were administered. During surgery, catecholamine, nitroglycerin and prostaglandin E1 were continuously infused intravenously. The patient was weaned smoothly from the cardiopulmonary bypass. The operation was completed in about 6 hours. Her postoperative course was satisfactory until she suddenly developed left ventricular rupture and died 6 hours after surgery. The rupture seemed to be attributable to a weakening of the myocardial wall following long-term, high-dose steroid therapy, and to myocardial degeneration caused by PN-associated necrotizing vasculitis of myocardial arterioles.

Female↗
PubMed1993

Correlation between the embryonic head flexures and cardiac development. An experimental study in chick embryos.

The aim of the present study is to examine whether the formation of the cranial and cervical flexures is involved in the process of cardiac looping, and whether looping anomalies are causally involved in the development of cardiac malformations. For this purpose, the formation of the cranial and cervical flexures was experimentally suppressed in chick embryos by introducing a straight human hair into the neural tube. In the experimental embryos, the absence of the cervical flexure, alone or in combination with a reduced cranial flexure, was always associated with anomalies in the looping of the tubular heart. The convergence of the primary distant venous and arterial ends of the heart, as well as the normal movement of the ventricular region from its original position, cranial and ventral from the cardiac inflow, to its final position caudal to the presumptive atria, was suppressed to an extent related to the degree to which the formation of the flexures was prevented. Positional immaturity of the heart loop (increased distance between its inflow and outflow, and cranio-ventral position of the ventricular region) was associated with incomplete deformations (reduced angulations) of the cardiac wall at the atrioventricular or conoventricular junctional areas. Reduced angulations were associated with the hypoplasia of the anlagen of the cardiac septa at the level of the angulation (av-cushions, conal ridges). Hypoplasia of these anlagen was followed by incomplete or absent fusion of their opposite free edges, which finally resulted in atrioventricular or ventricular septal defects. These results show that the convergence of the venous and arterial ends of the tubular heart and the caudo-dorsal movement of its ventricular region are related to the formation of the cervical flexure, and that the mesenchymal septa of the heart seem to develop in response to deformations of the embryonic heart, which are generated by the process of cardiac looping. Therefore, the positional and morphological changes of the looping heart are regarded as playing a key role in the process of normal and abnormal morphogenesis of the heart.

Abnormalities, Multiple↗
PubMed1976

Developing cardiac rupture as initial sign of acute myocardial infarction.

Pathological data are given of 4 patients in whom the development of cardiac rupture was the initial sign of myocardial infarction. The term 'concealed cardiac rupture' is proposed for this condition. In each instance the clinical diagnosis was 'onset of infarction', whereas the necropsy suggested that the acute onset of symptoms was caused by the start of rupture. The arguments for classifying the cases as 'concealed rupture' are (1) the lack of correlation between histological and clinical dating of the infarct, (2) the observation that the tear may take considerable time before actual epicardial breakthrough occurs, and (3) the fact that a high percentage of infarcts may pass clinically unnoticed.

Aged↗
PubMed2005

Mammalian E4 is required for cardiac development and maintenance of the nervous system.

Ubiquitin conjugation typically requires three classes of enzyme: E1, E2, and E3. A fourth type of enzyme (E4), however, was recently shown to be required for the degradation of certain types of substrate in yeast. We previously identified UFD2a (also known as E4B) as an E4 in mammals. UFD2a is exclusively expressed in cardiac muscle during mouse embryonic development, but it is abundant in neurons of adult mice and is implicated in the pathogenesis of neurodegenerative disease. The precise physiological function of this enzyme has remained largely unknown, however. Here, we show that mice lacking UFD2a die in utero, manifesting marked apoptosis in the developing heart. Polyubiquitylation activity for an E4 substrate was greatly reduced in Ufd2a(-/-) mouse embryonic fibroblasts. Furthermore, Ufd2a(+/-) mice displayed axonal dystrophy in the nucleus gracilis, as well as degeneration of Purkinje cells accompanied by endoplasmic reticulum stress. These animals also developed a neurological disorder. UFD2a thus appears to be essential for the development of cardiac muscle, as well as for the protection of spinocerebellar neurons from degeneration induced by endoplasmic reticulum stress.

Animals↗
PubMed1992

Gene expression during cardiac development.

The vertebrate heart forms as two concentric epithelial cylinders of myocardium and endocardium separated by an extended basement membrane matrix commonly referred to as cardiac jelly. Subsequent maturation involves a complex series of events including asymmetric changes in cell shape and division which contribute to bending and the formation of the bulboventricular loop, the formation of specialised tissues including endocardial cushion tissue of the atrioventricular (AV) and outflow tract regions, the development of conductive tissue and myocyte maturation leading to the overall pattern of expression characteristic of mature heart muscle. These processes depend on a precise spatial and temporal control of gene expression both of genes encoding regulatory molecules and those encoding structural components of the heart. In this chapter we address three aspects of cardiac development, namely, the determination of cell fate during formation of endocardial cushion tissue in the embryonic heart, transitions in troponin gene expression during fetal myocyte maturation, and the use of cloning techniques based on the polymerase chain reaction for identifying transcription factors present in the heart.

Animals↗
PubMed2006

Reduced cardiac L-type Ca2+ current in Ca(V)beta2-/- embryos impairs cardiac development and contraction with secondary defects in vascular maturation.

Cardiac myocyte contraction depends on transmembrane L-type Ca2+ currents and the ensuing release of Ca2+ from the sarcoplasmic reticulum. Here we show that these L-type Ca2+ currents are essential for cardiac pump function in the mouse at developmental stages where the functional significance of the heart becomes imperative to blood flow and to the continuing growth and survival of the embryo. Disruption of the Ca(V)beta2 gene, which encodes for the predominant ancillary beta subunit of cardiac Ca2+ channels, resulted in diminished L-type Ca2+ currents in cardiomyocytes of embryonic day 9.5 (E9.5). This led to a functionally compromised heart, causing defective remodeling of intra- and extraembryonic blood vessels and embryonic death following E10.5. The defects in vascular remodeling were also observed when the Ca(V)beta2 gene was selectively targeted in cardiomyocytes, demonstrating that they are secondary to cardiac failure rather than a result of the lack of Ca(V)beta2 proteins in the vasculature. Partial rescue of the Ca2+ channel currents by a Ca2+ channel agonist significantly postponed embryonic death in Ca(V)beta2-/- mice. Taken together, these data strongly support the essential role of L-type Ca2+ channel activity in cardiomyocytes for normal heart development and function and that this is a prerequisite for proper maturation of the vasculature.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2001

Magnetic resonance microscopy in cardiac development.

Magnetic resonance microscopy (MRM) is a fast and non-destructive imaging technique that can analyze the three-dimensional structure of the embryonic heart both qualitatively and quantitatively. Intravascular contrast agents have been developed to accentuate the anatomy of cardiac chambers, the cardiac outflow tract, and major arteries and veins throughout the embryonic body. MRM generates non-distorted three-dimensional data of vascular anatomy in a fraction of the time required by conventional optical image reconstruction techniques. The three-dimensional nature of these data allows the creation of visual models that can be manipulated for fast and easy interpretation of the complex relationships between heart chambers and aortic arches. This is particularly helpful because these relationships change in complex ways during development. The non-destructive nature of MRM makes it well suited for investigating rare or valuable specimens and live subjects. MRM techniques have been developed for imaging the embryo in utero and in vitro, although MRM studies of fixed embryo specimens are easier to perform and produce data with better contrast and higher resolution.

Animals↗
PubMed1990

[Human cardiac development: total volumetric increase of the heart, ventricular myocardium and endocardial cushions during the embryonic period].

PURPOSE: To compare the volumetric growth of the whole heart (WH), ventricular myocardium (VM), and endocardial cushions (EC) among each other and in relation to the growth of the embryo. PATIENTS AND METHODS: Collection of human embryos serially sectioned and stained (27 embryos) in post-somitic period. The volumes of WH, VM and EC were morphometrically determined and statistically correlated to the embryo's crown-rump length (C-R) by using the allometric equation Y = a chi b. RESULTS: The cardiac growth, and the growth of the VM and EC, presented significant (p less than 0.01) but allometically negative correlations in relation to C-R length. It indicates that cardiac changes in shape are more pronounced than in size. However, relative to the heart itself VM is the component that presents greater volumetric increase during the second month of gestation. EC decreases and end the embryonic period proper with less of 3% of the cardiac volume. CONCLUSION: Our quantitative results agree with more recent morphological studies which consider EC with small significance in valves and septa development, probably functioning more as a plastic component than in genesis of cardiac structures. On the contrary some lack in growth of the VM should disturb deeply cardiac development.

Embryonic and Fetal Development↗
PubMed1991

Expression of collagen binding integrins during cardiac development and hypertrophy.

The interaction between components of the extracellular matrix and the cell surface of cardiac myocytes appears to be regulated in part by receptors belonging to the integrin superfamily. The expression of the integrins was investigated at different stages of development of the heart as well as during cardiac hypertrophy. The characterization of the membrane proteins showed that a beta 1-integrin and associated alpha-chains were responsible for the interaction with collagen, laminin, and fibronectin. Immunoprecipitation data indicated that the presence of specific alpha-chains varied with development. These data were correlated with the ability of the isolated myocytes to attach to specific components of the extracellular matrix. The expression of the alpha 1-chain was prominently associated with the recognition of interstitial collagens. The presence of the alpha 1-chain was also associated with stages when collagen synthesis was increased, especially during fetal and neonatal growth and cardiac hypertrophy. Immunohistochemical localization with the antiserum against beta 1-integrin demonstrated its specific localization near the Z lines of cardiac myocytes. The localization both in vitro and in vivo indicated that the beta 1-integrin may play a role in myofibrillogenesis during development. The present immunohistochemical, cell adhesion, and biochemical data clearly indicate that integrins play a major role in the regulation of the interaction between cardiac myocytes and the extracellular matrix during development and disease.

Animals↗
PubMed1991

Immunolocalization of basic fibroblast growth factor during chicken cardiac development.

Basic fibroblast growth factor (bFGF) has been identified in cultured cardiac myocytes as well as in myocardial tissue of both embryonic and adult organisms; bFGF has also been demonstrated to regulate proliferation and differentiation of these cells in culture. Such studies suggest a possible role for bFGF in cardiac myogenesis. In vitro studies using cultured endothelial and neuronal cells also suggest that myocyte-derived bFGF may be involved in the regulation of vascularization and/or innervation of the developing heart. We have generated a spatial and temporal map for bFGF in the developing chick heart using immunohistochemical techniques and our monospecific polyclonal rabbit antihuman bFGF IgG. A progressive decrease in bFGF expression was seen in the highly trabeculated region of the ventricular myocardium, relative to the myocardium directly underlying the epicardial tissue, with increasing developmental age. bFGF expression was limited to the cytoplasm of cardiac myocytes; neither vascular endothelium nor smooth muscle contained anti-bFGF immunoreactive material. A correlation between the temporal and spatial pattern of bFGF expression seen here, with the pattern of myocyte proliferation and differentiation reported by others, suggests a role for bFGF in the autocrine regulation of myocyte proliferation and differentiation.

Animals↗
PubMed2007

Molecular and immunohistochemical analyses of cardiac troponin T during cardiac development in the Mexican axolotl, Ambystoma mexicanum.

The Mexican axolotl, Ambystoma mexicanum, is an excellent animal model for studying heart development because it carries a naturally occurring recessive genetic mutation, designated gene c, for cardiac nonfunction. The double recessive mutants (c/c) fail to form organized myofibrils in the cardiac myoblasts resulting in hearts that fail to beat. Tropomyosin expression patterns have been studied in detail and show dramatically decreased expression in the hearts of homozygous mutant embryos. Because of the direct interaction between tropomyosin and troponin T (TnT), and the crucial functions of TnT in the regulation of striated muscle contraction, we have expanded our studies on this animal model to characterize the expression of the TnT gene in cardiac muscle throughout normal axolotl development as well as in mutant axolotls. In addition, we have succeeded in cloning the full-length cardiac troponin T (cTnT) cDNA from axolotl hearts. Confocal microscopy has shown a substantial, but reduced, expression of TnT protein in the mutant hearts when compared to normal during embryonic development.

Ambystoma mexicanum↗
PubMed2004

A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels.

The homeobox gene Hhex has recently been shown to be essential for normal liver, thyroid and forebrain development. Hhex(-/-) mice die by mid-gestation (E14.5) and the cause of their early demise remains unclear. Because Hhex is expressed in the developing blood islands at E7.0 in the endothelium of the developing vasculature and heart at E9.0-9.5, and in the ventral foregut endoderm at E8.5-9.0, it has been postulated to play a critical role in heart and vascular development. We show here, for the first time, that a null mutation of Hhex results in striking abnormalities of cardiac and vascular development which include: (1) defective vasculogenesis, (2) hypoplasia of the right ventricle, (3) overabundant endocardial cushions accompanied by ventricular septal defects, outflow tract abnormalities and atrio-ventricular (AV) valve dysplasia and (4) aberrant development of the compact myocardium. The dramatic enlargement of the endocardial cushions in the absence of Hhex is due to decreased apoptosis and dysregulated epithelial-mesenchymal transformation (EMT). Interestingly, vascular endothelial growth factor A (Vegfa) levels in the hearts of Hhex(-/-) mice were elevated as much as three-fold between E9.5 and E11.5, and treatment of cultured Hhex(-/-) AV explants with truncated soluble Vegfa receptor 1, sFlt-1, an inhibitor of Vegf signaling, completely abolished the excessive epithelial-mesenchymal transformation seen in the absence of Hhex. Therefore, Hhex expression in the ventral foregut endoderm and/or the endothelium is necessary for normal cardiovascular development in vivo, and one function of Hhex is to repress Vegfa levels during development.

Animals↗
PubMed2005

Teratogenic effects of bis-diamine on the developing cardiac conduction system.

BACKGROUND: Congenital heart defects, including conotruncal anomalies, are often associated with arrhythmias. Bis-diamine induces conotruncal anomalies in embryos when administered to pregnant female rats. To investigate the mechanism of arrhythmia in conotruncal anomalies, we histologically examined the development of the cardiac conduction system in this animal model. METHODS: A single dose of 200 mg of bis-diamine was administered to pregnant Wistar rats on ED 10.5 of pregnancy. The embryos were removed on each day from ED 11.5 to 15.5. Immunoexpression of HNK-1, connexin40, and connexin43 were examined in serial sections. The distribution pattern of TUNEL-positive cells around the conduction system was also examined. RESULTS: HNK-1 immunoreactivity was evident in interventricular septum, in both the control and the bis-diamine-treated embryos from ED 12.5. Although a chain of connexin40-immunoreactive cells from interventricular septum to trabeculae, corresponding to the His bundle and its branches, was demonstrated at ED 13.5 in the control embryos, this chain was first detected at ED 14.5 in the bis-diamine-treated embryos. Immunoexpression of connexin43 in the working myocardium was also less in the bis-diamine-treated embryos than in the control at ED 13.5. The number of TUNEL-positive cells in the interventricular septum was highest at ED 12.5 in the control and at ED 13.5 in the bis-diamine-treated embryos. Furthermore, these TUNEL-positive cells were HNK-1 negative, vimentin-positive, and alpha smooth muscle actin-positive. CONCLUSIONS: Bis-diamine disturbed the normal development of gap junctions and apoptosis of myofibroblasts around the HNK-1-positive conduction tissue through overall poor myocardial proliferation and growth.

Abnormalities, Drug-Induced↗
PubMed1995

Cell adhesion events mediated by alpha 4 integrins are essential in placental and cardiac development.

alpha 4 integrins are cell surface receptors that mediate cell-extracellular matrix (ECM) and cell-cell adhesions by interacting with fibronectin (FN) and vascular cell adhesion molecule 1 (VCAM-1), respectively. We have generated a null mutation in the gene for the alpha 4 integrin subunit. Homozygous null embryos express no alpha 4 integrins and show two unexpected defects, both of which lead to embryonic lethality. The first defect is failure of fusion of the allantois with the chorion during placentation. The second is in the development of the epicardium and coronary vessels leading to cardiac hemorrhage. Both processes clearly involve alpha 4 integrin interactions that were previously unsuspected. alpha 4 integrin and VCAM-1 are expressed at the sites of these interactions. These results raise the possibility of abortifacients targeting alpha 4 integrins, and raise serious questions about potential side effects of drugs currently being designed to block alpha 4 integrin functions in inflammation.

Animals↗
PubMed2006

Essential role of insulin and insulin-like growth factor 1 receptor signaling in cardiac development and function.

Cardiovascular disease is the leading cause of death in people with type 2 diabetes and is linked to insulin resistance even in the absence of diabetes. Here we show that mice with combined deficiency of the insulin receptor and insulin-like growth factor 1 (IGF-1) receptor in cardiac and skeletal muscle develop early-onset dilated cardiomyopathy and die from heart failure within the first month of life despite having a normal glucose homeostasis. Mice lacking the insulin receptor show impaired cardiac performance at 6 months, and mice lacking the insulin receptor plus one Igf1r allele have slightly increased mortality. By contrast, mice lacking the IGF-1 receptor or the IGF-1 receptor plus one Ir allele appear normal. Morphological characterization and oligonucleotide array analysis of gene expression demonstrate that prior to development of these physiological defects, mice with combined deficiency of both insulin and IGF-1 receptors have a coordinated down-regulation of genes encoding components of the electron transport chain and mitochondrial fatty acid beta-oxidation pathways and altered expression of contractile proteins. Thus, while neither the insulin receptor nor IGF-1 receptor in muscle is critical for glucose homeostasis during the first month of life, signaling from these receptors, particularly the insulin receptor, is required for normal cardiac metabolism and function.

Animals↗
PubMed1997

Differential expression of PSA-NCAM and HNK-1 epitopes in the developing cardiac conduction system of the chick.

Although the critical role of the His-Purkinje system (HPS) in the propagation of cardiac action potentials from the atria to the ventricular myocardium in the mature heart is well appreciated, its functional and anatomical development are not well understood. The embryonic heart begins beating early in development devoid of a mature conduction system, and the HPS cannot be identified by conventional histochemical analysis until the seventh embryonic day of chicken development. Although many biochemical markers have been found that apparently identify HPS precursors, little is known about how these biochemical markers function in the maturation of the cardiac conduction system. Using immunohistological techniques, we demonstrated that the maturation of the HPS may be observed by the expression of two distinct populations of conduction system precursors, identified by the expression of cell surface carbohydrates PSA-NCAM (PSA) and HNK-1, both of which are known to participate in cell-cell and cell-substrate interactions in the development of the nervous system. By stage 25, PSA was detected in ventricular trabeculae and the interventricular septum (IVS) in a pattern that resembles bundle branches and Purkinje fibers. Beginning at stage 28, HNK-1 epitope expression in the IVS was observed in myocardium just superior to the PSA-positive bundles in a pattern that resembles the common His bundle. This junctional region was also positive for atrial myosin heavy chain (alpha MHC), another marker for the HPS. These data suggest that a complex, coordinated process of biochemical and morphological change governs the development of the cardiac conduction system.

Animals↗