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At least 829 records · Page 46Linked to original sources
PubMed2006

Understanding dioxin developmental toxicity using the zebrafish model.

Zebrafish (Danio rerio) have advantages over mammals as an animal model for investigating developmental toxicity. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin, TCDD), a persistent global contaminant, is the most comprehensively studied developmental toxicant in zebrafish. The hallmark responses of TCDD developmental toxicity manifested in zebrafish larvae include edema, anemia, hemorrhage, and ischemia associated with arrested growth and development. Heart and vasculature development and function are severely impaired, and jaw malformations occur secondary to inhibited chondrogenesis. The swim bladder fails to inflate, and the switch from embryonic to adult erythropoiesis is blocked. This profile of developmental toxicity responses, commonly referred to as "blue sac syndrome" because the edematous yolk sac appears blue, is observed in the larval form of all freshwater fish species exposed to TCDD at the embryonic stage of development. Components of the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator (AHR/ARNT) signaling pathway in zebrafish have been identified and functionally characterized. Their role in mediating TCDD toxicity has been determined using morpholinos to specifically knockdown the translation of zfAHR1, zfAHR2, zfARNT1, and zfARNT2 mRNAs, respectively, and a line of zfARNT2 null mutant zebrafish has provided further insight. These studies have shown that zfAHR2 and zfARNT1 mediate TCDD developmental toxicity. In addition, the growing use of molecular and genomic tools for research on zebrafish have led to advances in our understanding of the mechanism of TCDD developmental toxicity at the molecular level, including the recent finding that toxicity is not mediated by increased cytochrome P4501A (zfCYP1A) expression.

Animals↗
PubMed2005

Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex.

Inhibition of canonical Wnt/beta-catenin signaling by Dickkopf-1 (Dkk-1) or Crescent initiates cardiogenesis in vertebrate embryos. However, nearly nothing is known about the downstream effectors of these secreted Wnt antagonists or the mechanism by which they activate heart formation. Here we show that Wnt antagonists in Xenopus stimulate cardiogenesis non-cell-autonomously, up to several cells away from those in which canonical Wnt/beta-catenin signaling is blocked, indicative of an indirect role in heart induction. A screen for downstream mediators revealed that Dkk-1 and other inhibitors of the canonical Wnt pathway induce the homeodomain transcription factor Hex, which is normally expressed in endoderm underlying the presumptive cardiac mesoderm in amphibian, bird, and mammalian embryos. Loss of Hex function blocks both endogenous heart development and ectopic heart induction by Dkk-1. As with the canonical Wnt pathway antagonists, ectopic Hex induces expression of cardiac markers non-cell-autonomously. Thus, to initiate cardiogenesis, Wnt antagonists act on endoderm to up-regulate Hex, which, in turn, controls production of a diffusible heart-inducing factor. This novel function for Hex suggests an etiology for the cardiac malformations in Hex mutant mice and will make possible the isolation of factors that induce heart directly in the mesoderm.

Animals↗
PubMed2000

Heart failure in women.

Heart failure affects more than 5 million Americans. Each year, about 400,000 individuals develop heart failure, making it the nation's most rapidly growing cardiac problem. Almost one third of these individuals have New York Heart Association Functional Class III or IV heart failure and are faced with progressive clinical deterioration and frequent hospital admissions. These figures will continue to escalate as the population ages. The success of interventional procedures and pharmacologic therapies in the management of coronary artery disease has enabled this population to survive acute events, at the same time creating a population with chronic disease. Common etiologies of heart failure in women include coronary artery disease, myocardial infarction, and valvular disease. However, women are at especially high risk for developing heart failure due to diastolic dysfunction associated with hypertension and diabetes. Heart failure in women is best managed across the care continuum, incorporating pharmacologic agents, interventional procedures when appropriate, dietary restrictions, self-monitoring, and psychosocial support. Much of the recent literature has focused on women and heart disease. This emphasis is partly due to public misconception about women's health problems and the growing body of research distinguishing gender differences. Significant advances in therapy have been made to improve the quality and span of life for people with heart disease. Despite therapeutic advances, however, women have high mortality rates from heart disease, including heart failure due to ischemic causes. In fact, women with heart failure present differently than men and have different etiologies and treatment options. As we learn more about women and heart disease, the distinguishing differences unfold and become helpful in establishing a plan of care.

Adrenergic beta-Antagonists↗
PubMed1995

Characterization of fibroblast growth factor receptor 1 RNA expression in the embryonic mouse heart.

We used reverse transcriptase-polymerase chain reaction (RT-PCR) to clone fibroblast growth factor receptor (FGFR) 1 isoforms from embryonic mouse heart and as a more sensitive method to characterize FGFR1 RNA expression in embryonic and adult mouse hearts. We describe the cloning of both full-length short (2259 base pairs) and long (2526 base pairs) FGFR1 isoform cDNAs which generated 86 and 102 kilodalton proteins, respectively, following in vitro translation. An assessment of FGFR1 RNA indicates that FGFR1-IIIc is the major form in both the embryonic and adult heart but there is an approximately 8.5-fold decrease in RNA levels in the adult. Differential RNA blotting as well as RT-PCR analyses are consistent with a switch in the relative expression of the short versus long FGFR1 isoforms during heart development. The long isoforms are more abundant in the embryo and the short isoforms predominate in the adult. This may be important in the regulation of growth and development of the heart.

Amino Acid Sequence↗
PubMed2005

Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-alpha.

Mice that overexpress the inflammatory cytokine tumor necrosis factor-alpha in the heart (TNF mice) develop heart failure characterized by atrial and ventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias, and increased mortality (males > females). Abnormalities in Ca2+ handling, prolonged action potential duration (APD), calcium alternans, and reentrant atrial and ventricular arrhythmias were previously observed with the use of optical mapping of perfused hearts from TNF mice. We therefore tested whether altered voltage-gated outward K+ and/or inward Ca2+ currents contribute to the altered action potential characteristics and the increased vulnerability to arrhythmias. Whole cell voltage-clamp recordings of K+ currents from left ventricular myocytes of TNF mice revealed an approximately 50% decrease in the rapidly activating, rapidly inactivating transient outward K+ current Ito and in the rapidly activating, slowly inactivating delayed rectifier current IK,slow1, an approximately 25% decrease in the rapidly activating, slowly inactivating delayed rectifier current IK,slow2, and no significant change in the steady-state current Iss compared with controls. Peak amplitudes and inactivation kinetics of the L-type Ca2+ current ICa,L were not altered. Western blot analyses revealed a reduction in the proteins underlying Kv4.2, Kv4.3, and Kv1.5. Thus decreased K+ channel expression is largely responsible for the prolonged APD in the TNF mice and may, along with abnormalities in Ca2+ handling, contribute to arrhythmias.

Action Potentials↗
PubMed2002

Calcium-dependent arrhythmias in transgenic mice with heart failure.

Transgenic mice overexpressing the inflammatory cytokine tumor necrosis factor (TNF)-alpha (TNF-alpha mice) in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias on ambulatory telemetry monitoring, and decreased survival compared with nontransgenic littermates. Programmed stimulation in vitro with single extra beats elicits reentrant ventricular arrhythmias in TNF-alpha (n = 12 of 13 hearts) but not in control hearts. We performed optical mapping of voltage and Ca(2+) in isolated perfused ventricles of TNF-alpha mice to study the mechanisms that lead to the initiation and maintenance of the arrhythmias. When compared with controls, hearts from TNF-alpha mice have prolonged of action potential durations (action potential duration at 90% repolarization: 23 +/- 2 ms, n = 7, vs. 18 +/- 1 ms, n = 5; P < 0.05), no increased dispersion of refractoriness between apex and base, elevated diastolic and depressed systolic [Ca(2+)], and prolonged Ca(2+) transients (72 +/- 6 ms, n = 10, vs. 54 +/- 5 ms, n = 8; P < 0.01). Premature beats have diminished action potential amplitudes and conduct in a slow, heterogeneous manner. Lowering extracellular [Ca(2+)] normalizes conduction and prevents inducible arrhythmias. Thus both action potential prolongation and abnormal Ca(2+) handling may contribute to the initiation of reentrant arrhythmias in this heart failure model by mechanisms distinct from enhanced dispersion of refractoriness or triggered activity.

Action Potentials↗
PubMed1982

The late prognostic value of acute scintigraphic measurement of myocardial infarction size.

Infarct, perfusion and blood pool scintigraphy were performed in 62 patients during hospitalization for acute myocardial infarction. The largest measured infarct or perfusion image defect and left ventricular ejection fraction were related to the late prognosis determined a mean of 16 months after the event. Breakpoint values for all scintigraphic variables could separate those who were asymptomatic on follow-up from those who died. The best indicators for selection of survivors and nonsurvivors were a scintigraphic infarct size greater than or equal to 25 cm2 and a perfusion abnormality greater than or equal to 35% of the projected left ventricular area. Among patients with perfusion abnormalities above this limit, 61% died; 93% of those with small perfusion abnormalities survived. Scintigraphic measurements of relative myocardial perfusion and function best separated patients asymptomatic on follow-up from those who developed heart failure and also best identified those with an unfavorable evolution, who developed heart failure or died. Early scintigraphic parameters appeared more accurate than other clinical laboratory indicators for determining late prognosis and could be important in planning treatment after acute infarction.

Aged↗
PubMed1996

Expression of opioid receptors during heart ontogeny in normotensive and hypertensive rats.

BACKGROUND: The opioidergic systems are involved in modulating nociceptive stimuli. In addition, the recent results suggest that endogenous and exogenous opioids could play a role in the modulation of blood pressure and cardiac functions. However, little is known regarding the expression and role of opioid-binding sites in the heart. The decreased sensitivity to noxious stimuli in hypertensive rats raises the possibility of different developmental pattern expression of opioid-binding sites in normotensive versus hypertensive rats. METHODS AND RESULTS: Opioid receptor expression in hearts from hypertensive and normotensive rats was studied during heart development by binding assays. From P1 until P90, the development of the heart in the two rat strains was accompanied by a gradual increase in the density of kappa-opioid receptors. Hearts from hypertensive rats expressed significantly higher levels of kappa receptors compared with those of normotensive rats. At ages older than P7, mu-opioid receptors could not be detected in hearts of both strains, whereas delta-opioid-binding sites gradually increased until reaching adult levels. Seven-day-old cardiomyocyte cultures of both rat strains expressed similar densities of delta or kappa receptors to those observed in hearts from 7-day-old neonates. The mu-binding sites were not detected in cardiomyocytes cultures. Similar to the in vivo state, cultured myocytes from hypertensive rats had significantly higher levels of kappa-binding sites (1.5 fold) compared with those of normotensive rats. The kappa sites are pertussis toxin sensitive, and the state of coupling of the receptor to G protein is similar for the two rat strains. CONCLUSION: The role of opioid-binding sites in the heart is not completely clear. Hypertensive rats are known to be less sensitive to noxious stimuli compared with normotensive rats. It is controversial whether the site if application of noxious stimuli plays an important role in the sensitivity to pain in hypertensive rats. We suggest that the opioidergic system could play a role in the modulation of blood pressure in addition to its known effect on nociception.

Animals↗
PubMed2004

Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium.

Developmental changes in contractile behavior are known to occur during fetal and postnatal heart development. In this study, we examined whether adaptations take place in titin. A range of species was used to evaluate titin isoform expression and altered function during cardiac muscle development. A novel titin exon microarray that allows all 363 titin exons to be monitored simultaneously was used for transcript studies. Results reveal expression of fetal titin isoforms, characterized by additional spring elements both in the tandem Ig and PEVK region of the molecule. At the protein level, the fetal cardiac isoform predominates in fetal and neonatal myocardium and gradually disappears during postnatal development with a time course that varies in different species. Passive myocardium, contrary to previous reports, was found to be less stiff in the neonate than in the adult. This can be explained by the unique spring composition of fetal cardiac titin expressed by the neonate. Changes in titin expression are likely to impact functional transitions and diastolic filling behavior during development of the heart.

Aging↗
PubMed1997

Unilateral vitelline vein ligation alters intracardiac blood flow patterns and morphogenesis in the chick embryo.

To study the role of blood flow in normal and abnormal heart development, an embryonic chicken model was developed. The effect of altered venous inflow on normal intracardiac blood flow patterns was studied by visualization of blood flow with India ink. At stage 17, India ink was injected into a capillary or small venule within a specific yolk sac region. After determination of the normal intracardiac flow pattern, the right lateral vitelline vein was ligated, and the new intracardiac flow pattern was studied. Ligation resulted in disturbance of normal intracardiac flow patterns, which was most obvious in the conotruncus. The long-term effect of these abnormal intracardiac flow patterns on the development of the heart and pharyngeal arch arteries was investigated by permanent ligation in ovo with a microclip at stage 17 and subsequent evaluation at stages 34, 37, and 45. These experiments revealed anomalies of the vascular system in 58 of the 91 ligated embryos studied. We observed intracardiac malformations consisting of subaortic ventricular septal defects (n = 52), semilunar valve anomalies (n = 19), atrioventricular anomalies (n = 7), and pharyngeal arch artery malformations (n = 32). It is concluded that abnormal intracardiac blood flow, resulting from hampered venous inflow, may result in serious intracardiac and pharyngeal arch artery malformations comparable to defects observed in embryonic chicken models subjected to neural crest ablation, cervical flexure experiments, and excessive retinoic acid treatment.

Animals↗
PubMed1988

Maturation of the heart.

The transition from fetal to newborn to adult previously has been associated with a progressive increase in myocardial contractile function. The purpose of this review is to summarize new information on the biochemical and molecular processes that regulate the perinatal maturation of heart function. The developing heart experiences a perinatal increase in the cellular quantity of the sarcoplasmic reticulum and the myofibrils, the organelles that regulate and utilize cytosolic calcium to produce cardiac contraction. It also has become evident that the function of the available ion pump proteins is reduced in fetuses and newborns compared to adults of the same species. The resultant limited regulation of cytosolic calcium concentrations by the sarcoplasmic reticulum enhances the role of the sarcolemma in this process. Although it appears that the perinatal maturation of sarcoplasmic reticular function is not under direct molecular regulation, alternative splicing may regulate its gene products. A great deal of the perinatal maturation of myofibrillar protein function appears to be regulated by molecular processes. This has been best demonstrated in detail for myosin. In some species, such as the rat, much of the perinatal increase in myocardial contractile function can be explained by a parallel change in myosin isoforms. This isoform shift alters the activity of its ion pump, thereby allowing it to utilize more calcium. In contrast, the perinatal maturation of contractile function in several larger species cannot be explained fully by the extent of the molecular changes that have been identified currently in these species.

Calcium-Transporting ATPases↗
PubMed2004

Annexin II-mediated plasmin generation activates TGF-beta3 during epithelial-mesenchymal transformation in the developing avian heart.

Epithelial-mesenchymal transformation (EMT), the process by which epithelial cells are converted into motile, invasive mesenchymal cells, is critical to valvulogenesis. Transforming growth factor-beta3 (TGF-beta3), an established mediator of avian atrioventricular (AV) canal EMT, is secreted as a latent complex. In vitro, plasmin-mediated proteolysis has been shown to release active TGF-betas from the latent complex. Annexin II, a co-receptor for tissue plasminogen activator (tPA) and plasminogen, promotes cell-surface generation of the serine protease plasmin. Here, we show that annexin II-mediated plasmin activity regulates release of active TGF-beta3 during chick AV canal EMT. Primary embryonic endocardial-derived cells express annexin II which promotes plasminogen activation in vitro. Incubation of heart explant cultures with either alpha(2)antiplasmin (alpha(2)AP), a major physiological plasmin inhibitor, or anti-annexin II IgG, blocked EMT by approximately 80%, and 50%, respectively. Anti-annexin II IgG-mediated inhibition of EMT was overcome by the addition of recombinant TGF-beta3. Upon treatment with anti-annexin II IgG or alpha(2)AP, conditioned medium from heart explant cultures showed absence of the active fragment of TGF-beta3 by Western blot analysis and a approximately 50% decrease in TGF-beta specific bioactivity. Our results suggest that annexin II-mediated plasmin activity regulates the release of active TGF-beta during cardiac valve development in the avian heart.

Animals↗
PubMed1991

Control of adenylate cyclase activity in developing rat heart and liver: effects of prenatal exposure to terbutaline or dexamethasone.

Adrenergic stimulation and glucocorticoids have been hypothesized to control the development of beta-adrenergic receptors and responsiveness. In the current study, rats were exposed to a beta-agonist (terbutaline) or a glucocorticoid (dexamethasone) during late gestation, and the development of adenylate cyclase activity and beta-receptor binding was evaluated in membranes prepared from the heart and liver. In control heart, basal, isoproterenol-stimulated and forskolin-stimulated adenylate cyclase showed distinct developmental spikes of activity that were unrelated to changes in receptor binding sites, but that instead corresponded temporally to periods of sympathetic neuronal activation. Prenatal exposure to terbutaline initially enhanced all three enzymatic measures in the immediate postpartum period but delayed the appearance and exaggerated the magnitude of the subsequent peaks; again, these changes occurred without specific relation to effects on receptor binding. Dexamethasone produced a similar shift in the peaks of cardiac enzyme activity. In the liver, where beta-adrenergic receptors and responsiveness decline after birth, terbutaline and dexamethasone had much smaller effects on adenylate cyclase. These results suggest that beta-adrenergic stimulation serves as a trophic factor controlling the ontogenetic rise of adenylate cyclase activity; regulation involves the level of the enzyme itself rather than changes in receptor binding capabilities or receptor-specific linkages. Consequently, prenatal administration of beta-agonists or glucocorticoids can cause long-term alterations in enzyme activity and responsiveness.

Adenylyl Cyclases↗
PubMed1990

[Mechanical aspects of the development of artificial heart valves].

The development of an antithrombogenic coating permits a hybrid design for artificial heart valves. A substrate material optimized for its application is coated to meet the electrochemical requirements of improved hemocompatibility. But future progress in artificial heart valves requires an improvement in design as well as of the material. The basis of both aspects is the determination of such fundamental mechanical properties as the elasticity and plasticity of the valve ring and the deformation and fraction behaviour of the occluder. Analytical and numerical calculations of various different models result in different requirements for the substrate of ring and occluder. A combination of high elastic temper and low resistance to flow requires a ring material with a Young's modulus of 40 GPa or more, and a 0.2% proof stress to (Young's modulus)2/3 ratio of 0.3 MPa1/3. The best occluder materials should have a Young's modulus of more than 50 GPa and a flexural strength of at least 800 MPa. On the basis of these criteria, a heart valve consisting of a TiA15Fe2,5 ring and occluders made partially stabilized zirconia is introduced.

Biomechanical Phenomena↗
PubMed2003

Increased fibronectin deposition in embryonic hearts of retinol-binding protein-null mice.

Precise regulation of retinoid levels is critical for normal heart development. Retinol-binding protein (RBP), an extracellular retinol transporter, is strongly secreted by cardiogenic endoderm. This study addresses whether RBP gene ablation affects heart development. Despite exhibiting an >85% decrease in serum retinol, adult RBP-null mice are viable, breed, and have normal vision when maintained on a vitamin A-sufficient diet. Comparison of RBP-null with wild-type (WT) hearts from embryos at day 9.0 (E9.0) through E12.5 revealed an RBP-null phenotype similar to that of other retinoid-deficient models. At an early stage, RBP-null hearts display retarded trabecular development, which recovers by E9.5. This is accompanied at E9.5 and E10.5 by precocious differentiation of subepicardial cardiac myocytes. Most remarkably, RBP-null hearts display augmented deposition of fibronectin protein in the cardiac jelly at E9.0 through E10.5 and in the outflow tract at E12.5. This phenomenon, which was detected by immunohistochemistry and Western blotting without increased fibronectin transcript levels, is accompanied by increased numbers of mesenchymal cells in the outflow tract but not in the atrioventricular canal. RBP-null cardiac myocytes, especially in the subepicardial layer, display increased cell proliferation. This phenotype may present a model of subclinical retinoid insufficiency characterized by alteration of an extracellular matrix component and altered cellular differentiation and proliferation, changes that may have functional consequences for adult cardiac function. This murine model may have relevance to fetal development in human populations with inadequate retinoid intake.

Animals↗
PubMedDate not supplied

[Future development of heart valve surgery. New prostheses and access routes].

Valvular surgery has evolved in the last year with the development of new valvular prostheses and new minimally invasive implanting techniques. We discuss the advantages of the new mechanical aortic prostheses of superior hemodynamic characteristics, which avoid the need to widen the valvular ring in many cases. At the same-time, we emphasize on the use of new biological aortic prostheses, with minimal transvalvular gradient and less incidence of calcification. The advantages and disadvantages of the different minimally invasive techniques are analyzed without reaching yet a definite conclusion on their application.

Forecasting↗
PubMed1998

Visualization of sulfated glycoconjugates in the chicken embryonic heart by whole-mount alcian blue staining.

In the atrioventricular canal (AVC) and outflow tract (OT) of the developing heart, endothelial cells transform specifically to mesenchymal cells. The mesenchymal cells migrate into the underlying acellular matrix termed cardiac jelly and form endocardial cushion tissue. It is believed the that the highly hydrated nature of cardiac jelly is ascribed to sulfated glycoconjugates in the components of jelly matrix. In the present study, we have visualized the distribution and its temporal changes of sulfated glycoconjugates in the embryonic heart from stage 12 to 26 using whole mount alcian blue (AB) histochemistry. Atrial matrix was AB-negative in all the stages examined. Cardiac jelly in the AVC and OT were positive and the staining intensity increased as heart development proceeded, while AB-positive staining in the matrix of the ventricle became negative by stage 19. At stages later than 19, AB-positive matrix was localized in only the AVC and OT where endothelially-derived mesenchymal cells populated.

Alcian Blue↗