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PubMed1994

Late effects of intensive treatment for acute myeloid leukemia and myelodysplasia in childhood.

PURPOSE: To perform a comprehensive assessment of the late effects of short-term intensive chemotherapy for childhood acute myeloid leukemia (AML) and myelodysplasia, and compare the sequelae of intensive chemotherapy alone with those of total-body irradiation (TBI). PATIENTS AND METHODS: Of 33 survivors studied, 26 (group A) received intensive chemotherapy including anthracyclines, one also received busulfan, cyclophosphamide (Bu/Cy), and bone marrow transplantation (BMT). Seven patients (group B) received chemotherapy, TBI, and BMT. Hearing, sight, growth, and endocrine, renal, and cardiac function were assessed. RESULTS: The mean height standard deviation score of 25 nontransplanted group A patients was +0.67 at diagnosis, -0.11 following treatment (P = .016), and +0.34 7 years later (P > .05), indicating no long-term growth impairment. The patients had normal gonadal function and the girls had normal uterine size and ovarian volume. The Bu/Cy patient had primary ovarian failure. Four group B children required growth hormone and four sex steroids for growth or gonadal failure. The girls had reduced uterine size and ovarian volume. Three had thyroid dysfunction and six had cataracts. Abnormalities of renal function were found in both groups and hearing loss in group A only. The mean cardiac shortening fraction was significantly reduced at 29.2% in group A and 28.6% in group B compared with 36% in normal subjects. Two group A patients have developed cardiac failure. CONCLUSION: Chemotherapy and TBI before BMT for AML has resulted in growth failure, gonadal and thyroid damage, and cataracts in most children, whereas chemotherapy alone caused cardiac, renal, and hearing abnormalities only.

Acute Disease↗
PubMed1998

Vinculin knockout results in heart and brain defects during embryonic development.

The vinculin gene codes for a cytoskeletal protein, found in focal adhesion plaques and in cell-cell adherens junctions. Vinculin was inactivated by homologous recombination using a targeting vector in embryonic stem (ES) cells. The heterozygous ES cells were introduced into mice by established procedures to produce heterozygous animals that were normal and fertile. No homozygous vinculin-/- embryos were born and analyses during the gestational period showed that the vinculin null embryos were small and abnormal from day E8 but some survived until E10. The most prominent defect was lack of midline fusion of the rostral neural tube, producing a cranial bilobular appearance and attenuation of cranial and spinal nerve development. Heart development was curtailed at E9.5, with severely reduced and akinetic myocardial and endocardial structures. Mutant embryos were 30-40% smaller, somites and limbs were retarded and ectodermal tissues were sparse and fragile. Fibroblasts (MEF) isolated from mutant embryos were shown to have reduced adhesion to fibronectin, vitronectin, laminin and collagen compared to wild-type levels. In addition, migration rates over these substrata were two-fold higher and the level of focal adhesion kinase (FAK) activity was three-fold higher. We conclude that vinculin is necessary for normal embryonic development, probably because of its role in the regulation of cell adhesion and locomotion, cell behaviors essential for normal embryonic morphogenesis, although specific roles in neural and cardiac development cannot be ruled out.

Animals↗
PubMedDate not supplied

[Ventricular activation time of the fetal heart].

The prenatal risk determined by smoking pregnant woman was studied by a fetal electrocardiogram at different gestational ages. There were 28 low risk pregnancy women selected and qualified by means of an 80% completion of the Perechtl optimal criterion, 13 which smoked more than 5 cigarettes daily and 15 (53%) non-smokers. A new computerized technique was defined and applied for recording a continuous fetal electrocardiogram for long periods of time. Measurements of the QRS complex, inscription time of the intrinsecoid deflection (TIDI) and intrinsecoid deflection (DI) lengths were taken and compared with the gestational age. It was observed that there is a relationship of statistical significance (p less than 0.005) between the gestational age and the QRS length in the nonsmoking women. This relationship was smaller in the smoking group and furthermore it was negative when comparing the gestational age with the TIDI. There was no statistical difference in the weight of the child at birth in both groups, nevertheless the fetal electrocardiogram is useful in determining the development of the ventricular mass. In the smoking group the lack of relationship between the QRS length and the gestational age is probably owing to the retarded cardiac development and expressed ahead of all other features in fetal growth including low weight at birth.

Adult↗
PubMed1982

[Morphological characteristics of the cardiac myocytes of the frog (Rana ridibunda) in the cardiogenesis process].

An investigation has been performed on formation of the cardiac muscle tissue and ultrastructuraluralural organization of the cardiac myocytes in the frog (Rana ridibunda) at the age of an embryo and larva, as well as in young and mature species. A principle similarity in processes of ultrastruct differentiation of the cardiac myocytes has been revealed in lower and higher Vertebrata. Observations on dynamics of the proliferative activity in poorly differentiated cardiomyocytes demonstrate that certain asynchronity in the development of various parts of the frog heart appears rather early. Owing to the quantitative ultrastructural analysis performed, it is possible to conclude that the material of yolk plates is used for organelle synthesis that ensures the specialized function of the developing cardiac myocytes.

Animals↗
PubMed2003

Fibroblast growth factor receptor-1 is essential for in vitro cardiomyocyte development.

Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling plays a crucial role in mesoderm formation and patterning. Heartless mutant studies in Drosophila suggest that FGFR1, among the different FGFRs, may play a role in cardiogenesis. However, fgfr1-/- mice die during gastrulation before heart formation. To establish the contribution of FGFR1 in cardiac development, we investigated the capacity of murine fgfr1+/- and fgfr1-/- embryonic stem (ES) cells to differentiate to cardiomyocytes in vitro. Clusters of pulsating cardiomyocytes were observed in >90% of 3-dimensional embryoid bodies (EBs) originated from fgfr1+/- ES cells at day 9 to 10 of differentiation. In contrast, 10% or less of fgfr1-/- EBs showed beating foci at day 16. Accordingly, fgfr1-/- EBs were characterized by impaired expression of early cardiac transcription factors Nkx2.5 and d-Hand and of late structural cardiac genes myosin heavy chain (MHC)-alpha, MHC-beta, and ventricular myosin light chain. Homozygous fgfr1 mutation resulted also in alterations of the expression of mesoderm-related early genes, including nodal, BMP2, BMP4, T(bra), and sonic hedgehog. Nevertheless, fgfr1+/- and fgfr1-/- EBs similarly express cardiogenic precursor, endothelial, hematopoietic, and skeletal muscle markers, indicating that fgfr1-null mutation exerts a selective effect on cardiomyocyte development in differentiating ES cells. Accordingly, inhibitors of FGFR signaling, including the FGFR1 tyrosine kinase inhibitor SU 5402, the MEK1/2 inhibitor U0126, and the protein kinase C inhibitor GF109 all prevented cardiomyocyte differentiation in fgfr1+/- EBs without affecting the expression of the hematopoietic/endothelial marker flk-1. In conclusion, the data point to a nonredundant role for FGFR1-mediated signaling in cardiomyocyte development.

Animals↗
PubMed2006

Adrenoceptor polymorphisms and the risk of cardiac injury and dysfunction after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Cardiac abnormalities occur commonly after subarachnoid hemorrhage (SAH) and may be caused by excessive release of catecholamines from the myocardial sympathetic nerves. We hypothesized that adrenoceptor polymorphisms resulting in greater catecholamine sensitivity would be associated with an increased risk of cardiac injury. METHODS: This was a prospective cohort study. The primary outcome variables were the serum level of cardiac troponin I (cTi, abnormal if >1.0 microg/L) and the left ventricular ejection fraction (LVEF, abnormal if <50%). Six adrenoceptor polymorphisms were genotyped: beta1AR Arg389Gly, beta1AR Ser49Gly, beta2AR Gly16Arg, beta2AR Gln27Glu, beta2AR Thr164Ile, and alpha2AR del322-325. The effect of each polymorphism on the risk of developing cardiac abnormalities was quantified using multivariable logistic regression. RESULTS: The study included 182 patients. The CC genotype (Arg/Arg) of beta1AR Arg389Gly (odds ratio [OR] 3.4, P=0.030) and the CC genotype (Gln/Gln) of beta2AR Gln27Glu (OR 3.1, P=0.032) were predictive of cTi release. The presence of the alpha2AR deletion was predictive of reduced LVEF (OR 4.2, P=0.023). The combination of the beta1AR 389 CC and the beta2AR 27 CC genotypes resulted in a marked increase in the odds of cTi release (OR 15.5, P=0.012). The combination of the beta1AR 389 CC and the alpha2AR deletion genotypes resulted in a marked increase in the odds of developing a reduced LVEF (OR 10.3, P=0.033). CONCLUSIONS: Genetic polymorphisms of the adrenoceptors are associated with an increased risk of cardiac abnormalities after SAH. These data support the hypothesis that cardiac dysfunction after SAH is a form of neurocardiogenic injury.

Catecholamines↗
PubMed2002

Developmentally modulated cardiac conduction failure in transgenic mice with fetal or postnatal overexpression of DNA nonbinding mutant Nkx2.5.

INTRODUCTION: Nkx2.5 is a conserved homeodomain (HD) containing transcription factor essential for early cardiac development. We generated a DNA nonbinding missense mutation, I183P in the HD, similar to the missense HD mutation found in patients. Transgenic mice expressing this mutation under beta-MHC promoter [beta-MHC(I183P)] showed a postnatal lethal phenotype with heart failure. In contrast, mice expressing the mutation under alpha-MHC promoter [alpha-MHC(I183P)] survive, with later onset heart failure. The aim of this study was to investigate the interrelationship between lethal cardiac failure and the electrophysiologic (EP) phenotypes using cardiac-specific promoters with mutant gene expression at different stages of development and maturation. METHODS AND RESULTS: In beta-MHC(I183P) and wild-type littermates, six-lead ECG and in vivo endocardial EP studies were performed at 2.5, 3, 4, and 5 weeks of age. In alpha-MHC(I183P) and their wild-type controls, ECGs were acquired at 3, 19, 31, and 64 weeks and in vivo EP studies assessed at 19 +/- 4 weeks of age. Beta-MHC(I183P) mice display AV nodal, atrial, and ventricular EP dysfunction by 3 weeks of age. Bradycardia and PR prolongation were evident on telemetered ambulatory ECG of beta-MHC(I183P) mice. In contrast, alpha-MHC(I183P) mice had no abnormalities on serial ECG through 31 weeks or EP findings at 19 weeks, except increased myocardial tissue refractoriness. However, by 64 weeks, PR intervals lengthened in alpha-MHC(I183P) mice. CONCLUSION: Both prenatal and postnatal overexpression of DNA nonbinding mutant Nkx2.5 are associated with AV conduction malfunction and heart failure; however, more profound progressive EP defects are seen when this mutation expresses during fetal and neonatal periods. These conduction abnormalities may contribute to the lethal heart failure and early mortality evident in DNA nonbinding mutant Nkx2.5 mice.

Animals↗
PubMed1985

Cardiac tamponade following percutaneous transluminal coronary angioplasty: four case reports.

Percutaneous transluminal coronary angioplasty (PTCA) has had complications related to dilating catheters and guide wires such as coronary artery dissection, spasm, rupture, and perforation. This report describes four patients who developed cardiac tamponade following PTCA, presumably from right ventricular (RV) perforation. All four received large doses of heparin during PTCA and three received antiplatelet therapy. In three cases, cardiac tamponade occurred several hours after PTCA. All patients did well following operative intervention and no patient required repair of a cardiac perforation. We postulate that impaired hemostasis in the presence of an otherwise inconsequential RV perforation causes tamponade. Three alternatives to provide standby pacing are proposed.

Adult↗
PubMed2006

Muscularizing tissues in the endocardial cushions of the avian heart are characterized by the expression of h1-calponin.

Muscularization of mesenchymal tissues in the developing heart is an important event in the morphogenesis of the valvuloseptal complex in four-chambered hearts. Perturbation of muscularization has been implicated in the pathogenesis of cardiac malformations in several animal models for congenital heart disease, including the Trisomy 16 mouse and the TGFbeta2 knockout mouse. Studies to unravel the mechanism of muscularization, as well as studies to determine the extent of the process in frequently used animal-model systems for cardiac development, have, thus far, been hampered by the lack of useful differentiation markers for muscularizing tissues, albeit that it had been demonstrated that, in the mouse, muscularizing cells are characterized by an elevated level of smooth muscle actin expression. In this study, we investigated whether muscularization of endocardial cushions in the avian heart is also accompanied by the expression of smooth muscle cell markers. The results presented in this study demonstrate that, in quail and chick, a specific population of muscularizing cells is recognized by the expression of smooth muscle h1-calponin. Interestingly, other genes typically found in smooth muscle cells (e.g., smooth muscle actin and caldesmon) are not expressed in muscularizing tissues. We conclude that muscularization of cushion-derived mesenchymal tissues is associated with a discrete genetic program reflected by the expression of h1-calponin and predict that h1-calponin will prove an invaluable tool in elucidating the regulation of muscularization and other aspects related to this event.

Amino Acid Sequence↗
PubMed1991

Late toxicities and complications in three-year survivors of small cell lung cancer.

123 patients with small cell lung cancer (SCLC) presented to the National Cancer Center Hospital (Tokyo) between 1978 and 1986. 22 of 71 patients with limited stage disease (LD) and none of 52 patients with extensive disease (ED) survived for 3 years. 15 of the 22 three year survivors had significant late complications. All patients received chemotherapy and either thoracic irradiation, resection or both. No prophylactic cranial irradiation was given. 4 patients developed cardiac failure, 2 with a dilated cardiomyopathy, despite the fact that no patient received over 420 mg/m2 of doxorubicin. 12 patients of the 17 who received thoracic irradiation developed radiation pneumonitis and 3 required hospitalisation for severe haemoptysis (2) or cavity formation (1). 1 patient who received nimustine developed a fatal myelodysplastic syndrome and 2 additional patients developed second primary tumours in the oesophagus (1) and stomach (1). Mild peripheral neuropathy (WHO grade 1) was persistent in 3 patients and asymptomatic azotemia (WHO grade 1) in 7. Despite advances in the treatment of SCLC there are very few asymptomatic long-term survivors.

Adult↗
PubMed1989

Regulation of cardiac beta-adrenergic receptors by captopril. Implications for congestive heart failure.

The interaction of the renin-angiotensin system and the sympathetic nervous system in patients with congestive heart failure is not well understood. We tested the hypothesis that angiotensin-converting enzyme inhibitors can resensitize the beta-adrenergic receptor system. Guinea pigs were given captopril, isoproterenol, or both for 2 weeks. At death, cardiac sarcolemmal and light vesicle fractions and intact mononuclear leukocytes were prepared. Captopril treatment led to an up-regulation of cardiac beta 1- but not mononuclear leukocyte beta 2-adrenergic receptors and an increase in isoproterenol-stimulated adenylate cyclase activity in the heart. Animals treated with isoproterenol developed cardiac hypertrophy, had increased plasma norepinephrine levels, and had a decreased number and responsiveness of both cardiac and mononuclear leukocyte beta-adrenergic receptors. Concomitant treatment with captopril attenuated alterations of heart weight, plasma norepinephrine levels, and cardiac beta-receptor density and function. In contrast to its cardiac effects, captopril treatment did not diminish the down-regulation of mononuclear leukocyte beta 2-adrenergic receptors by isoproterenol. Our data suggest that captopril may resensitize the cardiac but not the mononuclear leukocyte beta-adrenergic receptor-adenylate cyclase system after long-term catecholamine exposure.

Adenylyl Cyclases↗
PubMed2003

The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis.

Cardiac hypertrophy is a common response to pressure overload and is associated with increased mortality. Mechanical stress in the heart can result in the integrin-mediated activation of focal adhesion kinase and the subsequent recruitment of the Grb2 adapter molecule. Grb2, in turn, can activate MAPK cascades via an interaction with the Ras guanine nucleotide exchange factor SOS and with other signaling intermediates. We analyzed the role of the Grb2 adapter protein and p38 MAPK in cardiac hypertrophy. Mice with haploinsufficiency of the Grb2 gene (Grb2(+/-) mice) appear normal at birth but have defective T cell signaling. In response to pressure overload, cardiac p38 MAPK and JNK activation was inhibited and cardiac hypertrophy and fibrosis was blocked in Grb2(+/-) mice. Next, transgenic mice with cardiac-specific expression of dominant negative forms of p38alpha (DN-p38alpha) and p38beta (DN-p38beta) MAPK were examined. DN-p38alpha and DN-p38beta mice developed cardiac hypertrophy but were resistant to cardiac fibrosis in response to pressure overload. These results establish that Grb2 action is essential for cardiac hypertrophy and fibrosis in response to pressure overload, and that different signaling pathways downstream of Grb2 regulate fibrosis, fetal gene induction, and cardiomyocyte growth.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Late cardiac tamponade after open heart surgery.

Delayed cardiac tamponade after open heart surgery is relatively uncommon, but constitutes a life-threatening condition that must be diagnosed and managed promptly. We report 21 patients who developed cardiac tamponade 5 to 53 days after open heart operations. Possible etiological factors included anticoagulant therapy (19 patients), excessive mediastinal drainage in the postoperative period (10 patients), postpericardiotomy syndrome (4 patients), and coagulation disorders (1 patient). The clinical presentation was insidious and the diagnosis was often difficult to establish at the outset. A high index of clinical suspicion and echocardiography were the most reliable means to reach an early diagnosis. Twenty patients in whom delayed tamponade was suspected were operated and all of them survived. In one patient tamponade was not diagnosed antemortem and he died; on autopsy left heart compression by a large loculated clot was found. Decompression of the pericardial space can be accomplished by pericardiocentesis or by surgical means (subxiphoid pericardiotomy, median sternotomy, or thoracotomy). Although pericardiocentesis alone may be effective, mainly when the postpericardiotomy syndrome is the suspected etiology, we recommend open procedures since the presence of blood clots and adhesions has been a frequent finding.

Acenocoumarol↗
PubMed2005

Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaptation.

The genetic hierarchies guiding lineage specification and morphogenesis of the mammalian embryonic heart are poorly understood. We now show by gene targeting that murine T-box transcription factor Tbx20 plays a central role in these pathways, and has important activities in both cardiac development and adult function. Loss of Tbx20 results in death of embryos at mid-gestation with grossly abnormal heart morphogenesis. Underlying these disturbances was a severely compromised cardiac transcriptional program, defects in the molecular pre-pattern, reduced expansion of cardiac progenitors and a block to chamber differentiation. Notably, Tbx20-null embryos showed ectopic activation of Tbx2 across the whole heart myogenic field. Tbx2 encodes a transcriptional repressor normally expressed in non-chamber myocardium, and in the atrioventricular canal it has been proposed to inhibit chamber-specific gene expression through competition with positive factor Tbx5. Our data demonstrate a repressive activity for Tbx20 and place it upstream of Tbx2 in the cardiac genetic program. Thus, hierarchical, repressive interactions between Tbx20 and other T-box genes and factors underlie the primary lineage split into chamber and non-chamber myocardium in the forming heart, an early event upon which all subsequent morphogenesis depends. Additional roles for Tbx20 in adult heart integrity and contractile function were revealed by in-vivo cardiac functional analysis of Tbx20 heterozygous mutant mice. These data suggest that mutations in human cardiac transcription factor genes, possibly including TBX20, underlie both congenital heart disease and adult cardiomyopathies.

Animals↗
PubMed1995

Differential expression of alpha- and beta-enolase genes during rat heart development and hypertrophy.

We have analyzed the transition between isoforms of the glycolytic enzyme enolase (2-phospho-D-glycerate hydrolyase; EC 4.2.1.11) in rat heart during normal and pathological growth. A striking fall in embryonic alpha-enolase gene expression occurs during cardiac development, mostly controlled at pretranslational steps. In fetal and neonatal hearts, muscle-specific beta-enolase gene expression is a minor contributor to total enolase. Control mechanisms of beta-enolase gene expression must include posttranscriptional steps. Aortic stenosis induces a rapid and drastic decrease in beta-enolase transcript level in cardiomyocytes, followed by the fall in beta-subunit level. In contrast, alpha-enolase transcript level is not significantly altered, although the corresponding subunit level increases in nonmuscle cells. We conclude that, like fetal heart, hypertrophic heart is characterized by a high ratio of alpha- to beta-enolase subunit concentrations. This study indicates that the decrease in beta-enolase gene expression may be linked to beneficial energetic changes in contractile properties occurring during cardiac hypertrophy.

Aging↗
PubMed2006

Malalignment of the septum primum with abnormally positioned left atrial appendage: unusual combination in a Shone's heart.

This case discusses a Shone's variant with small left ventricle and mitral valve, bicuspid aortic valve, coarctation of the aorta, an unusual arrangement of atrial appendages, and partially anomalous pulmonary venous drainage due to a deviated atrial septum. The left atrial appendage could be directly entered from the right atrium at catheterization, but it was positioned behind the great arteries. The right atrial appendage was normal in origin and orientation. The implications of this anatomy in fetal cardiac development are reviewed.

Abnormalities, Multiple↗
PubMed2003

Successful emergency aortic valve replacement following percutaneous cardiopulmonary support for the patient with aortic stenosis and cardiac arrest.

We present a 57-year-old woman with severe aortic stenosis. She was diagnosed with acute myocardial infarction by electrocardiography and the detection of elevated creatine phosphokinase in another hospital. Soon after transfer to our hospital, this patient developed cardiac arrest. Percutaneous cardiopulmonary support (PCPS) was established, and subsequently performed coronary angiography revealed normal coronary arteries. However echocardiography revealed severe aortic stenosis. Emergency aortic valve replacement (AVR) was performed, and the patient was discharged from hospital 30 days after surgery in good health. Prompt establishment of PCPS maintained her systemic circulation, and allowed us to conduct investigations for diagnosis. In patients with critical aortic stenosis, emergency AVR should be performed as early as possible following diagnosis.

Aortic Valve Stenosis↗