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PubMed2006

Xapelin and Xmsr are required for cardiovascular development in Xenopus laevis.

The cardiovascular development is the elaborate process, and despite the extensive studies, the mechanisms underlying endothelial, hematopoietic, and cardiac developments, as well as the interrelation between these processes, are not fully understood. In this study, we demonstrated that Xenopus apelin and Xmsr play pivotal roles in cardiovascular development. Apelin is a recently identified ligand for an orphan G-protein-coupled receptor APJ and is involved in fluid homeostasis in mammals. Xenopus preproapelin (Xpreproapelin) was isolated and its mRNA localized to the region around the presumptive blood vessels, which are overlapping or adjacent to those expressing Xmsr, the Xenopus homologue of APJ. Overexpression of Xpreproapelin disorganized the expression of the endothelial precursor cell marker XlFli and the hematopoietic precursor cell marker SCL at the neurula, whereas embryos injected with morpholino antisense oligonucleotides for Xapelin and Xmsr displayed attenuated expression of Tie2, alpha-globin, XPOX2, and cTnI, markers of endothelium, erythrocytes, myeloid cells, and cardiomyocytes, respectively. XlFli morpholino had similar effects to Xapelin and Xmsr morpholinos on cardiac differentiation, suggesting an unexpected potential relationship between the endothelium and cardiac differentiation. Forced expression of constitutive active G alpha i rescued the phenotypes of Xmsr morpholino-injected embryos, indicating that the i/o type of G protein alpha subunit acts downstream of Xmsr.

Animals↗
PubMed1975

Biochemical aspects of cardiac muscle differentiation. Deoxyribonucleic acid synthesis and nuclear and cytoplasmic deoxyribonucleic acid polymerase activity.

DNA synthesis and DNA polymerase activity have been measured in terminally differentiating cardiac muscle of the rat. Incorporation of [3H]thymidine into DNA essentially ceases by the 17th day of postnatal development. Cardiac muscle of neonatal rats contains at least two molecular species of DNA polymerase: a 3.5 S DNA polymerase that can be extracted from nuclei with 0.2 m potassium phosphate and a 6 to 8 S soluble cytoplasmic DNA polymerase. The nuclear DNA polymerase in crude extracts has a pH optimum of 9.0 and is more active with native DNA than with denatured DNA as the primer-template. The cytoplasmic DNA polymerase in crude extracts has a pH optimum of 7.5 and is more active with denatured DNA. The activity of the 6 to 8 S cytoplasmic DNA polymerase decreases 80-fold from day 1 to day 17 after birth, which correlates temporally with the reduced rate of DNA synthesis. The activity of the 3.5 S nuclear DNA polymerase remains relatively constant throughout postnatal development. Mixing experiments (assay of neonatal enzyme extracts with adult enzyme extracts) gave additive results, suggesting that the decline in 6 to 8 S DNA polymerase activity apparently is not due to the presence of absence of soluble activators or inhibitors at different times during development. These studies may provide a system which can be used to investigate the control of DNA synthesis and cellular proliferation during the terminal stages of cardiac muscle differentiation.

Aging↗
PubMed1994

Modulation of contractile protein troponin-T in chick myocardial cells by catecholamines during development.

In the present study we quantified the contractile protein troponin-T at the cellular and subcellular level in chick embryo cardiomyocytes to investigate the modulation of cardiac development by catecholamines. We analyzed the effects of these drugs on cultures of chick cardiomyocytes obtained from Hamburger and Hamilton's (HH) stage 21, HH stage 29 and HH stage 40 embryos; cardiomyocytes are considered to be mature at HH stage 40. We analyzed the modifications these drugs induced in the transcription of the gene for chick cardiac troponin-T. Sodium dodecyl sulfate-gel electrophoresis and immunobloting showed that cytoplasmic and cytoskeletal concentrations of troponin-T are dependent on the stage of embryonic development analyzed, and on the type of catecholamine added to the culture. The most significant finding was the increase in troponin-T mRNA in the chick heart at HH stage 40, accompanied by an increase in the increase in the expression of this protein in the cytoskeletal compartment after treatment with norepinephrine. At HH stage 21, norepinephrine induced less marked changes in the accumulation of troponin-T in comparison with untreated cardiomyocytes.

Animals↗
PubMed1994

Opioid antagonist modulation of rat heart development.

Endogenous opioids are known to regulate morphogenesis in both neural and non-neural systems. This study examined whether endogenous opioids influence cardiac development. Naltrexone, a potent opioid antagonist that blocks the interaction of opioid peptides and opioid receptors, was administered acutely (50 mg/kg) to 1-day old rats. The numbers of myocardial and epicardial cells in the ventricles and atria that synthesized DNA, as determined by [3H]-thymidine incorporation and autoradiography, were markedly increased from control levels. Labeling indices were significantly elevated for at least 12 hr following a single injection of naltrexone. Examination of 10-day old rats exposed to naltrexone from birth revealed higher labeling indices, as well as increases in body and heart weights and in areal measurements of the entire heart and the ventricles. The effects of naltrexone were not mediated through the sympathetic nervous system or thyroid hormone. These results lead one to suggest that an opioid peptide is tonically acting as a negative regulatory factor in the formation of the heart. Alterations in the endogenous opioid system in early life may contribute to cardiac dysmorphogenesis. Moreover, these data indicate that opioid antagonists could act as an important therapeutic influence with regard to cardiac malformations.

Aging↗
PubMed2002

Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3.

Receptors for bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta (TGFbeta) superfamily, are persistently expressed during cardiac development, yet mice lacking type II or type IA BMP receptors die at gastrulation and cannot be used to assess potential later roles in creation of the heart. Here, we used a Cre/lox system for cardiac myocyte-specific deletion of the type IA BMP receptor, ALK3. ALK3 was specifically required at mid-gestation for normal development of the trabeculae, compact myocardium, interventricular septum, and endocardial cushion. Cardiac muscle lacking ALK3 was specifically deficient in expressing TGFbeta2, an established paracrine mediator of cushion morphogenesis. Hence, ALK3 is essential, beyond just the egg cylinder stage, for myocyte-dependent functions and signals in cardiac organogenesis.

Animals↗
PubMed1990

Polarized release of enveloped viruses in the embryonic chick heart: demonstration of epithelial polarity in the presumptive myocardium.

The presumptive myocardium of the embryonic vertebrate heart is composed of cells which exhibit the morphology of a cuboidal epithelium. To examine the functional polarity of these developing myocytes, embryonic chick hearts (Hamburger-Hamilton stages 10-13) were infected with either influenza virus (FLU) or vesicular stomatitis virus (VSV). These viruses have been shown to sort vectorially to either apical (FLU) or basolateral (VSV) membrane surfaces in monolayers of polarized kidney (MDCK) cells. Our results demonstrate that these viruses bud with comparable polarity from differentiating myocytes. However, there appear to be stage-dependent differences in the polarized budding of the two viruses: restricted basolateral release of VSV is present before or shortly after the formation of the heart tube, whereas polarized budding of FLU is established later in development. These results are discussed in terms of plasma membrane organization during the early stages of cardiac development.

Animals↗
PubMed1998

Growth hormone: a new therapy for heart failure?

There is now little doubt that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) play a role in cardiac development and in cardiovascular physiology in adult life. Congenital lack of GH is associated with defective cardiac growth, ventricular wall thinning, and impaired systolic function. These abnormalities limit exercise capacity and contribute to the poor quality of life in patients with GH deficiency. In addition, studies with in vitro muscle preparations have shown that IGF-1 affects myocardial contractility by a direct mechanism. These findings suggested that GH would benefit patients affected by heart failure. Indeed, GH and/or IGF-1 have proven beneficial in various models of experimental heart failure. Tested in patients with classes II-IV heart failure, they improved cardiac performance and clinical status. These effects were associated with improved myocardial energetics and de-activation of the neurohormonal system. Because of the uncontrolled nature of the studies and the small number of cases examined, conclusions as to the effectiveness of GH and IGF-1 must await the results from larger trials.

Cardiac Output, Low↗
PubMed2002

New frontiers in molecular pediatric cardiology.

Numerous advances in understanding the molecular basis of congenital heart disease have been published in the past year. Highlights are reviewed, focusing on two major topics: genetic syndromes and cardiac organogenesis. Genetic syndromes are discussed in the context of complementary data from targeted mutations in animals and genetic mapping studies in humans. These include the DiGeorge, Holt-Oram, Alagille, familial primary pulmonary hypertension, and Noonan syndromes. Novel concepts in cardiac organogenesis are discussed, including the existence and contribution of an anterior heart field to the developing cardiac outflow tract, novel cell-cell signaling involving migrating neural crest, the origins of the conduction system and initial embryonic heartbeat, and the possibility of a population of cardiac stem cells in the adult heart. The studies reviewed have potential clinical relevance in the near future and will be of interest to the clinician interested in congenital heart disease.

Age Factors↗
PubMed1996

A comparison of sevoflurance to halothane in paediatric surgical patients: results of a multicentre international study.

Induction, emergence and recovery characteristics were compared during sevoflurane or halothane anaesthetic in a large (428) multicentre, international study of children undergoing elective inpatient surgical procedures. Two hundred and fourteen children in each group underwent inhalation induction with nitrous oxide/oxygen and sevoflurane or halothane. Incremental doses of either study drug were added until loss of eyelash reflex was achieved. Steady state concentrations of anaesthesia were maintained until the end of surgery when anaesthetic agents were terminated simultaneously. Time variables were recorded for induction, emergence and the first need for analgesia in the recovery room. In addition, in 86 of the children in both groups, venous blood samples were drawn for plasma fluoride levels during and after surgery. There was a trend toward smoother induction (induction of anaesthesia without coughing, breath holding, excitement laryngospasm, bronchospasm, increased secretion, and vomiting) in the sevoflurane group with faster induction (2.1 min vs 2.9 min, P = 0.037) and rapid emergence times (10.3 min vs 13.9 min, P = 0.003). Among the children given sevoflurane, 2% developed bradycardia compared with 11% in the halothane group. Postoperatively, 46% of the children in the halothane group developed nausea and or vomiting versus 31% in the sevoflurane group (P = 0.002). Two children in the halothane group developed cardiac dysrhythmia and were dropped from the study. In addition, a child in the halothane group developed malignant hyperthermia, received dantrolene, and had an uneventful recovery. Mean maximum inorganic fluoride concentration was 18.3 microM.l-1. The fluoride concentrations peaked within one h of termination of sevoflurane anaesthetic and returned rapidly to baseline within 48 h. This study suggests that sevoflurane may be the drug of choice for the anaesthetic management of children.

Adolescent↗
PubMed1999

Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice.

To elucidate the role of cardiac myosin-binding protein-C (MyBP-C) in myocardial structure and function, we have produced mice expressing altered forms of this sarcomere protein. The engineered mutations encode truncated forms of MyBP-C in which the cardiac myosin heavy chain-binding and titin-binding domain has been replaced with novel amino acid residues. Analogous heterozygous defects in humans cause hypertrophic cardiomyopathy. Mice that are homozygous for the mutated MyBP-C alleles express less than 10% of truncated protein in M-bands of otherwise normal sarcomeres. Homozygous mice bearing mutated MyBP-C alleles are viable but exhibit neonatal onset of a progressive dilated cardiomyopathy with prominent histopathology of myocyte hypertrophy, myofibrillar disarray, fibrosis, and dystrophic calcification. Echocardiography of homozygous mutant mice showed left ventricular dilation and reduced contractile function at birth; myocardial hypertrophy increased as the animals matured. Left-ventricular pressure-volume analyses in adult homozygous mutant mice demonstrated depressed systolic contractility with diastolic dysfunction. These data revise our understanding of the role that MyBP-C plays in myofibrillogenesis during cardiac development and indicate the importance of this protein for long-term sarcomere function and normal cardiac morphology. We also propose that mice bearing homozygous familial hypertrophic cardiomyopathy-causing mutations may provide useful tools for predicting the severity of disease that these mutations will cause in humans.

Alleles↗
PubMed1975

[Contractile myocardial proteins and their enzymatic activity in hypertensive disease and coronary atherosclerosis].

An investigation into the fractional composition of myocardial proteins and ATP-ase activity of myosine in 86 persons, who during their lifetime suffered from hypertensive disease and coronary incompetence, revealed significant changes therein. An increased content of actomyosine complex proteins in hypertensive disease was superseded by their considerable diminution in the event of developing cardiac insufficiency, which was at that accompanied by declining ATP-ase activity of myosine. The development of acute myocardial infarction led to a still drastically reduced concentration of sarcoplasmatic and contractile proteins of the heart muscle, as well as to their diminished enzymatic activity.

Adenosine Triphosphatases↗
PubMed1998

Preclinical cardiac dysfunction in transfusion-dependent children and young adults detected with low-dose dobutamine stress echocardiography.

Transfusion-dependent (TD) patients develop cardiac iron overload that will eventually lead to cardiac pump failure. Low-dose dobutamine stress echocardiography may complement resting echocardiography and identify preclinical myocardial dysfunction caused by early cardiac hemosiderosis. Twenty-six iron-overloaded TD patients had stress echocardiography with 5 microg/kg per minute of dobutamine. Indexed left ventricular (LV) mass, LV dimensions, meridional wall stress, and cardiac index were significantly increased. TD patients had similar LV shortening fraction by M-mode (40.5% +/- 5.6% vs 39.4% +/- 4.5%) but had a lower mean LV ejection fraction (53.3% +/- 3.9% vs 46.8% +/- 6.9%, P < .002) and a subnormal increase in cardiac index during dobutamine stress (35% +/- 20% vs 11% +/- 16%, P < .0001). Impairment in LV relaxation was demonstrated by a prolonged isovolumetric relaxation time (0.060 +/- 0.005 vs 0.088 +/- 0.019 seconds, P < .0001), increased peak mitral E wave, and abnormal E/A ratio. Asymptomatic TD patients demonstrate decreased systolic functional reserve and abnormal left ventricular relaxation that may be caused by cardiac hemosiderosis. Low-dose dobutamine stress echocardiography may be useful for detecting and following cardiac dysfunction in patients at risk for cardiac hemosiderosis.

Adolescent↗
PubMed2002

Non-sedating antihistamine drugs and cardiac arrhythmias -- biased risk estimates from spontaneous reporting systems?

AIMS: This study used spontaneous reports of adverse events to estimate the risk for developing cardiac arrhythmias due to the systemic use of non-sedating antihistamine drugs and compared the risk estimate before and after the regulatory action to recall the over-the-counter status of some of these drugs. METHODS: All suspected adverse drug reactions (ADRs) reported until July 1999 to the Netherlands Pharmacovigilance Foundation Lareb were used to calculate the ADR reporting odds ratio, defined as the ratio of exposure odds among reported arrhythmia cases, to the exposure odds of other ADRs (non-cases), adjusted for gender, age, reporter, year of reporting and comedication, stratified for the periods before and after the governmental decision in the Netherlands. RESULTS: Seven-hundred and thirty-seven cases of arrhythmia were reported, out of which there were 43 instances where the patients were using non-sedating antihistamines. In general non-sedating antihistamines are associated with cardiac arrhythmia to a higher extent in comparison with other drugs (ADR reporting odds ratio 2.05 [95% CI: 1.45, 2.89]). The association between arrhythmias and non-sedating antihistamine drugs calculated before 1998 was not significantly higher than 1 (OR 1.37 [95% CI: 0.85, 2.23]), whereas the risk estimate calculated after the governmental decision did significantly differ from 1 (OR 4.19 [95% CI: 2.49, 7.05]). CONCLUSIONS: Our data suggest that non-sedating antihistamines might have an increased risk for inducing arrhythmias. Our findings, however, strongly suggest that the increased risk identified can at least partly be explained by reporting bias as a result of publications about and mass media attention for antihistamine induced arrhythmias.

Adolescent↗
PubMed1996

"Orthoryhthmia" or postural cardiac dysrhythmia: clinical significance.

The objective of present paper is to present results of preliminary observations and studies carried out in fifty individuals developing cardiac dysrhythmia on assuming a supine posture. Detailed history taking, clinical examination, and study of metabolic parameters were carried out. Blood pressure, ECGs and rhythm strips were recorded in supine and upright postures, after exercise and DMT, after i.v. injection of atropine and after oral administration of probanthine. Majority of the individuals studied were asymptomatic. Palpitation was the commonest symptom. Bradycardia was observed in all as well as a low blood pressure. Supraventricular ectopic rhythm was the commonest dysrhythmia observed. Arythmia appeared on assuming a supine posture and tended to disappear in upright position and after exercise. I.v. atropine had a similar effect in a majority of cases, oral probanthine was not very effective. These observations highlight the existence of a hitherto unreported effect of posture on cardiac rhythm. This phenomenon appears to be a benign condition and can be termed as "orthorhythmia".

Arrhythmias, Cardiac↗
PubMed1992

Duration of QRS disturbances after severe tricyclic antidepressant intoxication.

While the clinical toxicity of tricyclic antidepressants, particularly the development of seizures and arrhythmias, has been strongly correlated with a QRS interval of greater than or equal to 100 msec on electrocardiography, the resolution pattern of QRS abnormalities remains poorly defined. We prospectively monitored 22 consecutive patients who were referred to a regional poison center after a tricyclic antidepressant ingestion associated with a QRS interval of greater than 100 msec. An ECG was obtained every 6-8 h in all patients until the QRS interval was less than 100 msec. Among enrolled patients the mean maximal QRS interval was 145 msec. Ten patients (45.5%) developed seizures while 6 (27%) developed cardiac arrhythmias. The time from ingestion to the last ECG demonstrating a widened QRS interval was a median 12.3 h (range 1-70 h); the time from ingestion to the first ECG with a QRS less than 100 msec was a median 19.3 h (range 3-78 h). No patients developed seizures or life-threatening cardiac arrhythmias after the QRS interval was less than 100 msec. Ten patients received sodium bicarbonate while 12 did not. There were no significant differences in the duration of QRS widening between the two groups. These data suggest that the typical period of QRS prolongation after severe tricyclic antidepressant ingestion is 12-18 h but may be as long 3 d. The factors which determine the duration of QRS widening are unclear. Sodium bicarbonate may not reduce the total duration of QRS disturbances.

Adolescent↗
PubMed1995

Collagen production and replication by cardiac fibroblasts is enhanced in response to diverse classes of growth factors.

The tissue distribution and cellular effects of platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), transforming growth factor beta-1 (TGF beta 1) and insulin-like growth factor 1 (IGF-1) suggest a potential role for these factors in cardiovascular matrix deposition. The objective of this study was to assess the capacity of these growth factors to promote cardiac fibroblast collagen production and replication in vitro which will lead to studies identifying their role in vivo during cardiac development and disease. Fibroblasts were isolated from fetal rat hearts by explant culture, and their response to growth factors was assessed with respect to fibroblast replication and collagen synthesis. Fibroblast replication was stimulated by PDGF and by bFGF.IGF-1 and TGF beta 1 had no effect on fibroblast replication. Collagen production was stimulated by all of the growth factors tested in order of potency TGF beta 1 > PDGF, IGF > bFGF. None of the growth factors affected the proportion of newly synthesized collagen rapidly degraded. We have shown that TGF beta 1, PDGF, bFGF and IGF-1 are all capable of increasing collagen deposition by cardiac fibroblasts by either stimulating fibroblast replication or collagen synthesis or both. The sensitivity of cardiac fibroblasts to these factors is consistent with their playing a role in the rapid changes in cardiac collagen deposition seen during development and disease.

Animals↗
PubMed1998

Characteristics of cardiac hypertrophy in the juvenile visceral steatosis mouse with systemic carnitine deficiency.

The juvenile visceral steatosis (JVS) mouse exhibits hereditary systemic carnitine deficiency and develops cardiac hypertrophy. The aim of this study was to clarify the characteristics of cardiac hypertrophy in the JVS mouse. Total carnitine content in IVS mouse heart was about 10% of that of control mouse heart at 4 and 8 weeks of age. The heart weight/body weight ratio was bigger in JVS mice than that in control mice at 2 weeks of age, and this difference in ratio increased with age. The wall areas of both ventricles and septum in JVS mice were larger than those of the control mice at 2 and 8 weeks. The myocyte diameter in both ventricular walls and septum in JVS mice was longer than that of the control mice. On electron microscopy, the percent of mitochondria in the myocyte was 66% in JVS mice, and 37% in control mice. The percent of lipid fraction in JVS mice was six-fold higher than that in control mice. Total content of adenine nucleotides in JVS mouse heart was about 60% of that in control mouse heart. Adenylate energy charge in JVS mouse heart was 63 and 45% of that in the control mouse heart at 4 and 8 weeks, respectively. Overall, the cardiac enlargement observed in this animal model could be accounted for by a proportional increase in the myocyte diameter in the ventricles and septum, accompanied by an increase in mitochondria. Furthermore, this cellular growth is associated with decreases in the levels of ATP and ADP, and adenylate energy charge.

Adenosine Diphosphate↗
PubMed2003

Molecular markers of cardiac endocardial cushion development.

Endocardial cushions are precursors of mature heart valves. They form within the looped heart tube as discrete swellings and develop into thin, pliable leaflets that prevent regurgitation of blood. The embryonic origins of cardiac valves include endothelial, myocardial, and neural crest cells. Recently, an increasing number of animal models derived from mutational screens, gene inactivation, and transgenic studies have identified specific molecules required for normal development of the cardiac valves, and critical molecular pathways are beginning to emerge. To further this process, we have sought to assemble a diverse set of molecular markers encompassing all stages of cardiac valve development. Here, we provide a detailed comparative gene expression analysis of thirteen endocardial cushion markers. We identify endocardial cushion expression of the transcription factor Fog1, and we demonstrate active Wnt/beta-catenin signaling in developing endocardial cushions suggesting pathways that have not been previously appreciated to participate in cardiac valve formation.

Animals↗