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PubMed2006

Activation of Notch1 signaling in cardiogenic mesoderm induces abnormal heart morphogenesis in mouse.

Notch signaling is implicated in many developmental processes. In our current study, we have employed a transgenic strategy to investigate the role of Notch signaling during cardiac development in the mouse. Cre recombinase-mediated Notch1 (NICD1) activation in the mesodermal cell lineage leads to abnormal heart morphogenesis, which is characterized by deformities of the ventricles and atrioventricular (AV) canal. The major defects observed include impaired ventricular myocardial differentiation, the ectopic appearance of cell masses in the AV cushion, the right-shifted interventricular septum (IVS) and impaired myocardium of the AV canal. However, the fates of the endocardium and myocardium were not disrupted in NICD1-activated hearts. One of the Notch target genes, Hesr1, was found to be strongly induced in both the ventricle and the AV canal of NICD1-activated hearts. However, a knockout of the Hesr1 gene from NICD-activated hearts rescues only the abnormality of the AV myocardium. We searched for additional possible targets of NICD1 activation by GeneChip analysis and found that Wnt2, Bmp6, jagged 1 and Tnni2 are strongly upregulated in NICD1-activated hearts, and that the activation of these genes was also observed in the absence of Hesr1. Our present study thus indicates that the Notch1 signaling pathway plays a suppressive role both in AV myocardial differentiation and the maturation of the ventricular myocardium.

Animals↗
PubMed1999

Altered hemodynamics in chick embryos after extraembryonic venous obstruction.

OBJECTIVE: To obtain insight into hemodynamics during abnormal cardiac development, a chick model was developed recently in which a spectrum of conotruncal anomalies, in combination with abnormal semilunar valves and/or pharyngeal arch artery malformations, was induced through extraembryonic venous obstruction (venous clip) at stage 17 (70-h incubation). METHODS: In chick embryos of stage 24 and stage 34 control (n = 8; n = 21) and with venous clip (n = 11; n = 18), we simultaneously measured dorsal flow velocities with a 20-MHz pulsed Doppler velocity meter and dorsal aortic (stage 24) and vitelline artery (stage 34) blood pressures with a servo-null system. After the hemodynamic recordings were collected, all 58 embryos were subjected to morphological examination. The hemodynamic data were correlated with the morphology. Statistical comparison was performed between control and experimental values. RESULTS: At stage 24, venous clip embryos showed impaired looping. Physiologically, only a decrease in peak acceleration was found in these embryos (p < 0.05). At stage 34, a spectrum of conotruncal malformations was seen, that consisted of a ventricular septal defect in combination with abnormal semilunar valves and/or pharyngeal arch malformations. A dextroposed aorta in combination with a ventricular septal defect was diagnosed as double-outlet right ventricle. Hemodynamically, peak systolic and mean velocities, peak systolic and mean blood flows and stroke volume were increased while the heart rate was reduced after placement of the venous clip (p < 0.05). In both stages, pressure readings showed no statistically significant differences between control and experimental embryos. CONCLUSION: Our findings suggest that the hemodynamic changes seen in venous clip embryos reflect the presence of a compensatory mechanism.

Animals↗
PubMed1988

The development of alcohol-induced cardiac dysfunction in the rat.

Hemodynamic, contractile and energetic functions of isolated working hearts from ethanol-fed and control rats were studied to determine the time course of cardiac dysfunction development during long-term consumption of alcohol. Hearts from fasted, 24 hr withdrawn rats were studied after 2, 4, 7 and 11 months consuming ethanol as 38% of daily calories in a nutritionally-adequate liquid diet. After 2 months, the right ventricle of the alcoholic rat hearts was significantly enlarged; left ventricular weight was not significantly different from control and there was little evidence that left ventricular function was compromised. After 4 months and 7 months, there was biventricular cardiomegaly and evidence of reduced left ventricular function in the alcoholics, although altered sensitivity to the positive inotropic agent, dobutamine, was not evident in those hearts. After 11 months, cardiac output, stroke work, and peak power of the alcoholic rat hearts were significantly depressed, the responsiveness of the left ventricle to dobutamine was diminished, and both ventricles were enlarged compared to controls. Cardiac function during early withdrawal was studied in rats that had consumed alcohol for 14-16 months. Hearts from non-fasted rats at 0 hr of withdrawal exhibited diminished responsiveness to dobutamine compared to controls; at 24 hr and 72 hr of withdrawal no differences between alcoholic and control rat heart dobutamine responsiveness were observed. The data indicated that: (a) cardiomegaly, beginning with right ventricular enlargement, was an early indicator of alcohol's cardiac effects in rats; (b) left ventricular enlargement of the alcoholic rat hearts was associated with basal left ventricular dysfunction; and (c) evidence of cardiac subsensitivity to dobutamine, which is characteristic of this alcoholic rat model, depended on the nutritional status and withdrawal state of the rat at the time that the heart was excised for study.

Animals↗
PubMed2003

Identification, characterization, and expression of a novel alpha-tropomyosin isoform in cardiac tissues in developing chicken.

Tropomyosins are present in various muscle (skeletal, cardiac, and smooth) and non-muscle cells with different isoforms characteristic of specific cell types. We describe here a novel smooth/striated chimeric isoform that was expressed in developing chick heart in addition to the classically described TM-4 type. This novel alpha-Tm tropomyosin isoform, designated as alpha-Tm-2, contains exon 2a (in place of exon 2b). The known striated muscle isoform (alpha-Tm-1) was also expressed in embryonic hearts along with the striated muscle isoform of TM-4. In adult heart, TM-4 was expressed, however, expression of both alpha-Tm-1 and alpha-Tm-2 isoforms was drastically reduced or downregulated. Interestingly, we were unable to detect the expression of alpha-Tm-2 in embryonic and adult skeletal muscle, however, the alpha-Tm-1 isoform is expressed in embryonic and adult skeletal muscle. Examination of other possible isoforms of the alpha-TM gene, i.e., alpha-smooth muscle tropomyosin (alpha-Sm), alpha-Fibroblast-1 (alpha-F1), and alpha-Fibroblast-2 (alpha-F2) revealed expression in embryonic hearts and a significant reduction of each of these isoforms in adult heart. In order to elucidate the role of the newly discovered tropomyosin isoform in chicken, we ectopically expressed the GFP fusion protein of alpha-Tm-1 and alpha-Tm-2 separately into cardiomyocytes isolated from neonatal rats. Each isoform was incorporated into organized myofibrils. Our results suggest that the alpha-TM gene may undergo both positive and negative transcriptional control in chicken hearts during development.

Amino Acid Sequence↗
PubMed1999

WNT11 promotes cardiac tissue formation of early mesoderm.

Cardiac tissue in the bird is derived from paired regions of lateral mesoderm within the anterior half of the embryo (Rawles [1943] Physiol. Zool. 16:22-42; Stalsberg and DeHaan [1969] Dev. Biol. 19:128-159). Previously, we reported that WNT11 is expressed in early avian mesoderm in a pattern that overlaps with the precardiac regions. To examine whether this molecule may play a role in promoting cardiogenesis, we cultured tissue explants from microdissected HH stage 4, 5, and 6 quail embryos. The isolated tissue consisted of both the mesoderm and endoderm layers from either anterior precardiac or posterior noncardiogenic regions of the embryo. As a necessary control for examining the ability of WNT11 to convert noncardiogenic mesoderm to cardiac tissue, we compared the cardiogenic potential of anterior and posterior regions. For stages 5 and 6, our results were consistent with what has been previously reported (Rawles [1943] Physiol. Zool. 16:22-42; Sugi and Lough [1994] Dev. Dyn. 200:155-162); as anterior mesoderm becomes contractile, while posterior mesoderm does not produce cardiac tissue. Surprisingly, when we examined stage 4 embryos both anterior and posterior regions gave rise to cardiac tissue in culture. To determine whether WNT11 could promote cardiac differentiation in tissue that was noncardiogenic, this molecule was ectopically expressed or added to mesoderm/endoderm explants obtained from stage 5 or 6 posterior tissue. Transfection of stage 5 posterior tissue with a WNT11 expression plasmid provoked the appearance of cardiomyocytes in 33% of the explants; half of which were contractile. Similarly transfected stage 6 posterior explants did not demonstrate cardiac differentiation. More dramatic results were obtained when noncardiogenic tissue was exposed to conditioned media containing soluble WNT11; as 63% and 33% of posterior stage 5- or stage 6-derived explants underwent cardiac differentiation. Together, these results indicate that WNT11 can promote cardiac development within noncardiac tissue. The expression of WNT11 in anterior mesoderm of early gastrula stage embryos suggests it may play a role in the formation of the vertebrate heart. Dev Dyn 1999;216:45-58.

Animals↗
PubMed1999

Effects of electrical fields on cardiomyocyte differentiation of embryonic stem cells.

The effects of electromagnetic fields (EMFs) on the differentiation of cardiomyocytes in embryoid bodies derived from pluripotent embryonic stem (ES) cells were investigated. A single direct current (DC) field pulse was applied to 4-day-old embryoid bodies. The electrical field induced a hyperpolarization of the anode-facing side of embryoid bodies and a depolarization at the cathode-facing side. Significant effects of a single electrical field pulse applied for 90 s on cardiomyocyte differentiation were achieved with field strengths of 250 and 500 V/m, which increased both the number of embryoid bodies differentiating beating foci of cardiomyocytes and the size of the beating foci. The 500-V/m electrical field increased intracellular reactive oxygen species (ROS), but not [Ca(2+)](i) and activated nuclear factor kappa B (NF-kappaB). A comparable increase in the number of beating embryoid bodies was achieved by an incubation for 1 h with H(2)O(2) (1-10 nM), indicating that the electrical field effect was transduced via the intracellular generation of ROS. Because the radical scavengers dehydroascorbate and pyrrolidinedithiocarbamate (APDC) and the NF-kappaB antagonist N-tosyl-L-phenylalanine chloromethyl ketone (TPCK) inhibited cardiac differentiation, we assume that ROS and NF-kappaB may play a role in early cardiac development.

Animals↗
PubMed1998

Influence of calcium on proliferation and phenotype alteration of cardiomyocyte in vitro.

An accelerated weight gain is noted in the heart of Ca-deficient, hypertensive chick embryos maintained in a shell-less culture in vitro. We previously observed that the Ca handling property of cardiomyocytes isolated from the shell-less embryo is altered, i.e., faster Ca uptake, suggesting a requirement for adequate Ca supply and/or proper Ca handling in embryonic cardiac development. In this study, we have examined the function of Ca on cardiomyocytes by analyzing the effects of 1) various Ca concentration in the culture medium (NCa, 1.8 mmol/ L; HCa, 2.8 mmol/L; LCa, 0.9 mmol/L), and 2) various modulators of Ca handling on cell proliferation and phenotype regulation in chick embryonic cardiomyocytes. The analytical parameters included cell number, DNA content, expression of cell cycle-specific and cardiomyocyte-specific proteins, and creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) enzyme activities. Cell number and total DNA were significantly larger (P < 0.01) in LCa cultures compared with those in NCa. The level of LDH was elevated (P < 0.01), but that of CPK was lowered in LCa. Expression of the G1-S-specific protein PCNA was raised, but that of the contractile proteins myosin and tropomyosin was substantially suppressed in LCa; in HCa, the cells did not proliferate as well, whereas the level of contractile proteins was higher. Thapsigargin, a sarcoplasmic reticulum (SR)-specific, Ca-ATPase inhibitor, simulated the effects of LCa by enhancing cell proliferation and lowering the expression of tropomyosin. These results suggest that culturing in low Ca concentration and inhibition of SR Ca pumping enhance myocardial cell proliferation and suppress sarcomeric protein expression, perhaps by inducing cellular de-differentiation. The in vitro effects of medium Ca concentration and Ca handling modulators on cardiomyocytes also suggest that the in vivo cardiomegaly of the SL embryos is a direct result of Ca-deficiency, and that Ca is important in the phenotype regulation of cardiomyocytes.

Animals↗
PubMed1999

Myostatin, a transforming growth factor-beta superfamily member, is expressed in heart muscle and is upregulated in cardiomyocytes after infarct.

Myostatin is a secreted growth and differentiating factor (GDF-8) that belongs to the transforming growth factor-beta (TGF-beta) superfamily. Targeted disruption of the myostatin gene in mice and a mutation in the third exon of the myostatin gene in double-muscled Belgian Blue cattle breed result in skeletal muscle hyperplasia. Hence, myostatin has been shown to be involved in the regulation of skeletal muscle mass in both mice and cattle. Previous published reports utilizing Northern hybridization had shown that myostatin expression was seen exclusively in skeletal muscle. A significantly lower level of myostatin mRNA was also reported in adipose tissue. Using a sensitive reverse transcription-polymerase chain reaction (RT-PCR) technique and Western blotting with anti-myostatin antibodies, we show that myostatin mRNA and protein are not restricted to skeletal muscle. We also show that myostatin expression is detected in the muscle of both fetal and adult hearts. Sequence analysis reveals that the Belgian Blue heart myostatin cDNA sequence contains an 11 nucleotide deletion in the third exon that causes a frameshift that eliminates virtually all of the mature, active region of the protein. Anti-myostatin immunostaining on heart sections also demonstrates that myostatin protein is localized in Purkinje fibers and cardiomyocytes in heart tissue. Furthermore, following myocardial infarction, myostatin expression is upregulated in the cardiomyocytes surrounding the infarct area. Given that myostatin is expressed in fetal and adult hearts and that myostatin expression is upregulated in cardiomyocytes after the infarction, myostatin could play an important role in cardiac development and physiology.

Animals↗
PubMed1999

Percutaneous transluminal myocardial revascularization with a holmium laser system: procedural results and early clinical outcome.

Surgical transmyocardial laser revascularization has been reported to improve clinical outcome in patients with refractory angina who are not candidates for angioplasty or bypass surgery. We investigated the feasibility and safety of a nonsurgical, percutaneous technique for laser channel creation using energy from a holmium:yttrium-aluminium-garnet (YAG) laser. The laser energy was directed through a fiber enclosed in a catheter to the ventricular myocardium creating channels between the blood pool and the myocardium. Thirty-five patients with angina and coronary anatomy not amenable to revascularization with coronary angioplasty or bypass surgery underwent percutaneous transluminal myocardial revascularization. A total of 15 +/- 5 channels were formed per patient. There was no procedure-related mortality. One patient developed cardiac tamponade requiring thoracotomy and another a minor self-limiting pericardial effusion. There was no worsening of regional wall motion function in any patient. All patients were discharged alive after a postprocedure hospital stay of 2.1 +/- 1.4 days. Mean Canadian Cardiovascular Society (CCS) functional class declined from 3.68 +/- 0.4 before procedure to 0.82 +/- 0.7 at 30 days (P < 0.01). At 3 months, mean angina class was 0.94 +/- 0.65 (n = 35; P < 0.01) and at 6 months, mean angina class was 1.08 +/- 0.58 (n = 26; P < 0.01). One patient required repeat revascularization after 5 months for progression of disease in a degenerated saphenous venous graft supplying different region of myocardium. We conclude that transmyocardial revascularization using holmium:YAG laser by percutaneous technique can be carried out safely with encouraging early results and a very low complication rate. The symptomatic relief seen up to 6 months has been excellent. The long-term effects of this technique on mortality and relief of angina, however, remain to be defined. Cathet. Cardiovasc. Intervent. 47:287-291, 1999.

Angina Pectoris↗
PubMed2003

The role of neural crest and epicardium-derived cells in conduction system formation.

During cardiac development the heart tube loops and is septated into a four-chambered structure. The initial peristaltic contraction of the primitive myocardium is replaced by a system of working myocardium and a myocardial-derived central and peripheral conduction system. The genes guiding this differentiation process are still under investigation and it has yet to be decided whether we are dealing with a recruitment or a specification model. We have shown that the complicated looping process of the heart tube brings together the essential parts of the sinoatrial and primary ring myocardium, that are the embryonic precursors of the definitive conduction system. From our studies it is evident that during development there are sinoatrial tracts that run between the sinoatrial and the atrioventricular node as well as tracts surrounding the pulmonary veins and the coronary sinus. Furthermore, we show that both in the chicken and mouse embryo neural crest cells reach the confinement of the central conduction system through the inflow and outflow tract. For the Purkinje system there is a close approximation with the epicardium-derived cells. We postulate that both extracardiac-derived cell types have an influence on the differentiation of the definitive conduction system.

Animals↗
PubMed1982

Vincristine, doxorubicin, and cyclophosphamide versus low-dose intravenous cyclophosphamide, methotrexate, and 5-fluorouracil in advanced breast cancer: a randomized trial of the Piedmont Oncology Association.

Eighty-one evaluable patients with recurrent or metastatic breast cancer were randomized to receive either vincristine 1 mg/m2, doxorubicin 40 mg/m2 on day one and cyclophosphamide 200 mg/m2 orally days 3-6 (VAC); or cyclophosphamide 350 mg/m2, methotrexate 20 mg/m2, and 5-fluorouracil 350 mg/m2 (CMF) intravenously, all on day 1. Courses of each of the above regimens were repeated every three weeks. Twenty-one of 45 patients (47%) on VAC and seven of 44 patients (16%) on CMF had complete or partial response (P less than 0.05). The duration of response was six months for CMF and nine months for VAC. Hematologic toxicity was minimal for both groups but three patients receiving VAC developed cardiac toxicity. Overall survival projections at this time indicate no differences between the VAC or CMF treated patients.

Antineoplastic Agents↗
PubMed2000

Characterization of CMF1 in avian skeletal muscle.

This study reports the identification of the CMF1 protein in somites and embryonic limb muscle. We have previously described CMF1 in developing cardiac muscle. CMF1 is a member of the LEK family of proteins, which are involved in regulating mitosis. Our current data suggest that CMF1 expressed in skeletal and cardiac myocytes is the product of a single gene and that the two proteins are homologous or very highly conserved. Immunohistochemistry shows a dynamic subcellular localization of CMF1 in differentiating skeletal myoblasts: Early myoblasts stain positively for CMF1 antigen in the nucleus, while differentiating myoblasts stain positively in the cytoplasm. CMF1 expression precedes myosin. Later, CMF1 and myosin are detected in the cytoplasm of the same cells. Transfection analysis identifies a functional nuclear localization signal (NLS) in CMF1, whose nuclear transport capability is modified by external sequences. To characterize the function of CMF1 in skeletal muscle, we used antisense oligonucleotides to disrupt CMF1 in myoblast cultures. Expression of CMF1 in early myotubes is reduced by an average of 40% on a cell by cell basis, with a 56% reduction in anti-myosin staining. These data suggest that CMF1 is involved in induction and/or accumulation of myosin in differentiating myocytes.

Amino Acid Sequence↗
PubMed2004

Blood expression profiles for tuberous sclerosis complex 2, neurofibromatosis type 1, and Down's syndrome.

Blood gene expression profiling has been applied to a variety of hematological malignancies, autoimmune disorders, and infectious diseases. This study applies this approach to genetic diseases without obvious blood phenotypes. Three genetic diseases including tuberous sclerosis complex 2, neurofibromatosis type 1, and Down's syndrome were compared with a group of healthy controls. RNA from whole blood was surveyed using Affymetrix U133A arrays. Each disease was associated with a unique gene expression pattern in blood that can be accurately distinguished by a classifier. Genes on chromosome 21 were overexpressed in Down's syndrome, and genes controlling cell cycle and proliferation were associated with tuberous sclerosis complex type 2 or neurofibromatosis type 1. A subset of genes involved in cardiac development or remodeling were overexpressed in patients with Down's syndrome and congenital heart defects. These findings suggest that blood gene expression profiling on a broader basis might be useful for genetic disease screening/diagnosis and might help elucidate mechanisms and pathways that lead to genotype-phenotype differences.

Cluster Analysis↗
PubMed1990

Isomyosin expression pattern during formation of the tubular chicken heart: a three-dimensional immunohistochemical analysis.

Three-dimensional (3-D) distribution of atrial and ventricular isomyosins is analysed immunohistochemically during the formation of the tubular chicken heart (stage 7 to 12 [H/H]) using antibodies specific for adult chicken atrial and ventricular myosin heavy chains, respectively. This analysis revealed that both types of isomyosins can be first detected at stage 8 (H/H, possessing four pairs of somites), i.e., when the heart primordium still exists as two separate cardiogenic plates. The ventricular type of isomyosin is initially expressed in those areas of cardiogenic plates in the vicinity of the anterior intestinal portal. The atrial type of isomyosin is initially expressed in zones caudal and lateral to the areas of ventricular isomyosin expression. Medial to the atrial isomyosin-expressing areas, cardiogenic plate areas exist that initially lack myosin expression. Those parts of the cardiogenic plates that fuse in front of the anterior intestinal portal, thereby forming the heart tube, are characterized by the expression of both isomyosins; however, the caudolateral parts of the heart primordium maintain their single atrial isomyosin expression during further development. Cardiac contractions are therefore first observed at stage 10 (H/H, possessing ten pairs of somites) in myocardium that coexpresses both isomyosins.

Animals↗
PubMed1990

Increased density of glutamic acid decarboxylase-containing terminals in the medial preoptic nucleus and the area surrounding the paraventricular hypothalamic nucleus is associated with deoxycorticosterone acetate (DOCA)-salt hypertension.

gamma-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter and has been shown to exert considerable influence on the neural control of the cardiovascular function. It is not clear, however, which GABAergic systems are involved in salt-induced hypertension. This study was designed to investigate the GABAergic neurons in specific regions of the brain possibly linked to salt-induced hypertension. After 4 weeks of deoxycorticosterone acetate (DOCA) and salt treatments, the rats developed cardiac hypertrophy. All of the animals were sacrificed for immunocytochemical localization of GABAergic terminals using specific antibodies to glutamic acid decarboxylase (GAD). GAD-positive GABAergic terminal densities in discrete regions of the brain were determined by using morphometric quantitation. Results showed that GABAergic terminal densities in the medial preoptic nucleus and the area lateral to the paraventricular hypothalamic nucleus were significantly increased in DOCA-salt-treated rats 4 weeks after the experiment as compared with 4 week controls. This study provides new evidence to support further the idea that central GABAergic neurons are closely associated with pathogenesis of salt-induced hypertension. Different hypertensive mechanisms between salt-induced hypertension and genetic hypertension are also discussed.

Animals↗
PubMed2003

Neonatal transcatheter occlusion of a large coronary artery fistula with Amplatzer duct occluder.

A large fistula from the right coronary artery to the right atrium was diagnosed in a fetus at 22 weeks of gestation. Following delivery, the baby developed cardiac failure. The fistula was occluded at 3 weeks of age by transcatheter implantation of an Amplatzer duct occluder. Large coronary fistulas can be closed safely with a device even at this early age. Vigilance for ischemic events is required following implantation because of the rare possibility of thrombus extension proximally into the native coronary artery or spasm of the coronary artery.

Adult↗
PubMed1989

Pericardial effusion early in acute myocardial infarction.

The incidence and significance of pericardial effusions early in acute myocardial infarction remain unclear. Using two-dimensional echocardiography, 172 patients with an acute myocardial infarction were evaluated within 72 h of presentation. Thirty patients (17%) had a pericardial effusion (29 small, 1 moderate) while 142 (83%) did not. No patient developed cardiac tamponade or required pericardiocentesis. Patients with pericardial effusions had higher peak creatine kinase as compared to patients without effusions (2036 +/- 1466 vs. 1483 +/- 1241, p less than 0.05) and a greater number of aneurysms (20% vs. 6%, p less than 0.05). In-hospital mortality was higher in the patients with pericardial effusions (10% vs. 2%, p less than 0.05). In conclusion, pericardial effusions are common in the early AMI period but are generally small and hemodynamically insignificant. They are associated with larger infarcts and greater mortality.

Aged↗
PubMed1979

Metoprolol with and without chlorthalidone in hypertension.

After a control period on a placebo, 45 patients with mild to moderate hypertension were treated with metoprolol, 100 mg twice daily alone and in free combination with chlorthalidone 50 mg daily using a double-blind crossover technique. The beta-blocker alone induced a significant fall in blood pressure; the diastolic pressure was reduced to 100 mg Hg or less in 37 of the 45 patients and to 95 mm Hg or less in 19 patients. The addition of chlorthalidone enhanced the antihypertensive effect so that in 33 patients diastolic pressure fell to 95 mm Hg or less. The drugs were well tolerated even by a small number of patients with chronic bronchitis and diabetes mellitus. None of the patients developed cardiac failure. Adding a diuretic caused a small reduction in serum potassium concentrations, and the relevance of this observation is discussed.

Adult↗