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Development (Cambridge, England) Dec 2012The Notch signaling pathway is an important contributor to the development and homeostasis of the cardiovascular system. Not surprisingly, mutations in Notch receptors...
The Notch signaling pathway is an important contributor to the development and homeostasis of the cardiovascular system. Not surprisingly, mutations in Notch receptors and ligands have been linked to a variety of hereditary diseases that impact both the heart and the vasculature. In particular, mutations in the gene encoding the human Notch ligand jagged 1 result in a multisystem autosomal dominant disorder called Alagille syndrome, which includes tetralogy of Fallot among its more severe cardiac pathologies. Jagged 1 is expressed throughout the developing embryo, particularly in endothelial cells. Here, we demonstrate that endothelial-specific deletion of Jag1 leads to cardiovascular defects in both embryonic and adult mice that are reminiscent of those in Alagille syndrome. Mutant mice display right ventricular hypertrophy, overriding aorta, ventricular septal defects, coronary vessel abnormalities and valve defects. Examination of mid-gestational embryos revealed that the loss of Jag1, similar to the loss of Notch1, disrupts endothelial-to-mesenchymal transition during endocardial cushion formation. Furthermore, adult mutant mice exhibit cardiac valve calcifications associated with abnormal matrix remodeling and induction of bone morphogenesis. This work shows that the endothelium is responsible for the wide spectrum of cardiac phenotypes displayed in Alagille Syndrome and it demonstrates a crucial role for Jag1 in valve morphogenesis.
Topics: Alagille Syndrome; Animals; Calcinosis; Calcium-Binding Proteins; Cardiomyopathies; Coronary Vessel Anomalies; Endothelial Cells; Endothelium; Heart Defects, Congenital; Heart Septal Defects, Ventricular; Heart Valve Diseases; Hypertrophy, Right Ventricular; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphogenesis; Organ Culture Techniques; Receptors, Notch; Serrate-Jagged Proteins
PubMed: 23095891
DOI: 10.1242/dev.084871 -
Cardiology in the Young Oct 2012We present the case studies of two adult patients with tetralogy of Fallot who were scheduled for surgery. After addressing the right ventricular outflow tract...
We present the case studies of two adult patients with tetralogy of Fallot who were scheduled for surgery. After addressing the right ventricular outflow tract obstruction, the aorta was opened and the ventricular septal defect was approached in a straightforward manner as it was located just under the overriding aortic valve. The second patient presented with was a situs inversus, dextroapex Fallot. In this setting, the aortic approach simplified the repair expeditiously. After 2 years, both patients are in New York Heart Association class I, with no residual ventricular septal defect, no aortic regurgitation, and complete relief of right ventricular outflow tract obstruction.
Topics: Aortic Valve; Cardiac Catheterization; Cardiac Surgical Procedures; Follow-Up Studies; Humans; Male; Middle Aged; Situs Inversus; Tetralogy of Fallot
PubMed: 22391340
DOI: 10.1017/S1047951112000030 -
Cardiology Journal 2011The aim of this study was to investigate the incidence, origins and courses of coronary artery anomalies using a combination of angiographic and surgical methods in...
BACKGROUND
The aim of this study was to investigate the incidence, origins and courses of coronary artery anomalies using a combination of angiographic and surgical methods in Turkish children with tetralogy of Fallot (ToF).
METHODS
Seventy-seven patients in whom coronary artery anomalies had been identified by angiography and/or at operation out of 549 ToF and 58 Fallot-type double outlet right ventricle (total 607) patients, were enrolled in the study.
RESULTS
Coronary artery anomalies were identified in 12.7% of the patients. The incidence was 12.2% (67/549) in patients with aortic overriding 50%, and 17.2% (10/58) with aortic overriding 〉 50% (p 〉 0.05). The incidence of anomalous coronary arteries crossing the right ventricular outflow tract (RVOT) was 7.91%. The commonest anomaly was the left anterior descending artery (LAD) or accessory LAD arising from the right coronary artery (RCA; n = 25). Other frequent anomalies were single coronary ostium (n = 21) and enlarged conal branch of RCA (n = 18). In 62.3% (48/77) of the patients with a coronary anomaly, the anomalous vessels were crossing the RVOT. The ratio of crossing the RVOT was 92.0% for LAD arising from the RCA, 66.7% for conal branch, and 42.9% for single coronary ostium.
CONCLUSIONS
Two thirds of the anomalous coronary arteries were crossing the RVOT, and had surgical importance. The most frequent coronary artery anomaly that crossed the RVOT was the LAD or the accessory LAD arising from the RCA. Also, an enlarged conus artery should be considered as an anomaly because of its surgical importance, given its high rate of crossing the RVOT.
Topics: Adolescent; Cardiac Surgical Procedures; Chi-Square Distribution; Child; Child, Preschool; Coronary Angiography; Coronary Vessel Anomalies; Female; Humans; Incidence; Infant; Male; Predictive Value of Tests; Sinus of Valsalva; Tetralogy of Fallot; Turkey
PubMed: 21947991
DOI: 10.5603/cj.2011.0011 -
Ultrasound in Obstetrics & Gynecology :... May 2011Placental dysfunction leading to fetal growth restriction (FGR) is an important risk factor for neurodevelopmental delay. Recent observations clarify that FGR evolves... (Review)
Review
Placental dysfunction leading to fetal growth restriction (FGR) is an important risk factor for neurodevelopmental delay. Recent observations clarify that FGR evolves prenatally from a preclinical phase of abnormal nutrient and endocrine milieu to a clinical phase that differs in characteristics in preterm and term pregnancies. Relating childhood neurodevelopment to these prenatal characteristics offers potential advantages in identifying mechanisms and timing of critical insults. Based on available studies, lagging head circumference, overall degree of FGR, gestational age, and umbilical artery (UA), aortic and cerebral Doppler parameters are the independent prenatal determinants of infant and childhood neurodevelopment. While head circumference is important independent of gestational age, overall growth delay has the greatest impact in early onset FGR. Gestational age has an overriding negative effect on neurodevelopment until 32-34 weeks' gestation. Accordingly, the importance of Doppler status is demonstrated from 27 weeks onward and is greatest when there is reversed end-diastolic velocity in the UA or aorta. While these findings predominate in early-onset FGR, cerebral vascular impedance changes become important in late onset FGR. Abnormal motor and neurological delay occur in preterm FGR, while cognitive effects and abnormalities that can be related to specific brain areas increase in frequency as gestation advances, suggesting different pathophysiology and evolving vulnerability of the fetal brain. Observational and management studies do not suggest that fetal deterioration has an independent impact on neurodevelopment in early-onset FGR. In late-onset FGR further research needs to establish benefits of perinatal intervention, as the pattern of vulnerability and effects of fetal deterioration appear to differ in the third trimester.
Topics: Blood Flow Velocity; Cerebral Arteries; Child Development; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Placenta; Pregnancy; Ultrasonography, Prenatal; Umbilical Arteries
PubMed: 21520312
DOI: 10.1002/uog.9008 -
Journal of Zoo and Wildlife Medicine :... Jun 2010A 20-mo-old, female, 9-kg European beaver (Castor fiber) presented with apathy, reduced appetite of 3-day duration and a grade 5/6 systolic heart murmur. Thoracic...
A 20-mo-old, female, 9-kg European beaver (Castor fiber) presented with apathy, reduced appetite of 3-day duration and a grade 5/6 systolic heart murmur. Thoracic radiographs revealed a diffuse broncho-interstitial pattern suspicious for bronchopneumonia. The echocardiographic findings of a hypertrophied right ventricle, ventricular septal defect with overriding aorta, and infundibular pulmonic stenosis were consistent with Fallot's tetralogy. Even though the bronchopneumonia rather than the congenital cardiac defect was considered of primary importance for the presenting clinical signs, the latter was relevant for the decision not to continue any medical treatment. Both disease processes were confirmed on necropsy. Fallot's tetralogy, European beaver, Castor fiber, heart murmur, ultrasound.
Topics: Animals; Bronchopneumonia; Echocardiography, Doppler; Female; Rodentia; Tetralogy of Fallot
PubMed: 20597235
DOI: 10.1638/2009-0235R.1 -
Journal of Clinical Medicine Research Oct 2009An infant, showing peripheral cyanosis, was born after lower abdominal peripheral caesarian section of the pregnant women having TORCH positive test with the infection...
UNLABELLED
An infant, showing peripheral cyanosis, was born after lower abdominal peripheral caesarian section of the pregnant women having TORCH positive test with the infection of Toxoplasma gondiiand Cytomegalovirus. She had three abortions prior to this pregnancy. Doppler echocardiography of the baby showed profound intracardiac defects. After birth, echocardiography was carried out for diagnosis of associated cardiac anomalies. Doppler echocardiography showed pentalogy of Fallot, and the present case represents the Pentalogy of Fallot having pulmonary atresia. The baby's heart anomalies were ASD (Atrial Septal Defect - 6 mm RT to LT Shunt), VSD (Ventricular Septal Defect - bidirectional shunt), PDA (Patent Ductus Arteriosus - filling both the pulmonary arteries), and Overriding of Aorta with pulmonary atresia. In conclusion, whenever the diagnosis pentalogy of fallot is suspected, a multidisciplinary approach is essential.
KEYWORDS
Pentalogy of fallot; Overriding Aorta; Ventricular Septal Defect; Atrial Septal Defect; Pulmonary Atresia; Doppler Echocardiography.
PubMed: 22461877
DOI: 10.4021/jocmr2009.09.1261 -
PloS One Jul 2009Rapid growth of the embryonic heart occurs by addition of progenitor cells of the second heart field to the poles of the elongating heart tube. Failure or perturbation...
BACKGROUND
Rapid growth of the embryonic heart occurs by addition of progenitor cells of the second heart field to the poles of the elongating heart tube. Failure or perturbation of this process leads to congenital heart defects. In order to provide further insight into second heart field development we characterized the insertion site of a transgene expressed in the second heart field and outflow tract as the result of an integration site position effect.
RESULTS
Here we show that the integration site of the A17-Myf5-nlacZ-T55 transgene lies upstream of Hes1, encoding a basic helix-loop-helix containing transcriptional repressor required for the maintenance of diverse progenitor cell populations during embryonic development. Transgene expression in a subset of Hes1 expression sites, including the CNS, pharyngeal epithelia, pericardium, limb bud and lung endoderm suggests that Hes1 is the endogenous target of regulatory elements trapped by the transgene. Hes1 is expressed in pharyngeal endoderm and mesoderm including the second heart field. Analysis of Hes1 mutant hearts at embryonic day 15.5 reveals outflow tract alignment defects including ventricular septal defects and overriding aorta. At earlier developmental stages, Hes1 mutant embryos display defects in second heart field proliferation, a reduction in cardiac neural crest cells and failure to completely extend the outflow tract.
CONCLUSIONS
Hes1 is expressed in cardiac progenitor cells in the early embryo and is required for development of the arterial pole of the heart.
Topics: Animals; Base Sequence; Basic Helix-Loop-Helix Transcription Factors; Blotting, Western; Cell Proliferation; DNA Primers; Heart; Homeodomain Proteins; In Situ Hybridization; Mice; Mice, Transgenic; Morphogenesis; Myocardium; Transcription Factor HES-1; Transgenes
PubMed: 19609448
DOI: 10.1371/journal.pone.0006267 -
American Journal of Physiology. Heart... Sep 2009A multilayered model of the aortic wall is introduced to investigate the transport of low-density lipoprotein (LDL) under hypertension, taking into account the...
A multilayered model of the aortic wall is introduced to investigate the transport of low-density lipoprotein (LDL) under hypertension, taking into account the influences of increased endothelial cell turnover and deformation of the intima at higher pressure. Meanwhile, the thickness and properties of the endothelium, intima, internal elastic lamina (IEL), and media are affected by the transmural pressure. The LDL macromolecules enter the intima through leaky junctions over the endothelium, which are created by dying or dividing cells. Water molecules enter the intima via the paracellular pathway through breaks in tight junctions after passing the glycocalyx as well as through leaky junctions. The glycocalyx is modeled as a Brinkman porous medium to describe the fluid filtration associated with its structure. Combined Navier-Stokes and Brinkman equations are solved for the transmural flow, and the convective-diffusion equation is employed for LDL transport. The permeation of LDL over the surface of smooth muscle cells is modeled through a uniform reaction evenly distributed in the macroscopically homogeneous media layer. Simulations are performed in an axisymmetric plane centered at a leaky cell. The overriding issue addressed is that LDL fluxes across the leaky junction, the intima, fenestral pores in the IEL, and the media layer are highly affected by the transmural pressure, which affects the endothelial cell turnover rate and the compaction of intima. The present model, for the first time and with no adjustable parameters, is capable of making many realistic predictions including the proper magnitudes for the permeability of endothelium and intimal layers and the hydraulic conductivity of all layers as well as their trends with pressure. Results for the volume flux through the wall and the hydraulic conductivity of the entire arterial wall, the endothelium, and subendothelial layers at 70 and 180 mmHg are in good agreement with previous experimental studies.
Topics: Aorta; Atherosclerosis; Blood Pressure; Cell Division; Cholesterol, LDL; Computational Biology; Diffusion; Endothelium, Vascular; Humans; Hypertension; Models, Cardiovascular; Predictive Value of Tests
PubMed: 19592615
DOI: 10.1152/ajpheart.00324.2009 -
American Journal of Physiology.... Sep 2009The relationship between cardiac energy metabolism and the depression of myocardial performance during oxygen deprivation has remained enigmatic. Here, we combine in...
The relationship between cardiac energy metabolism and the depression of myocardial performance during oxygen deprivation has remained enigmatic. Here, we combine in vivo (31)P-NMR spectroscopy and MRI to provide the first temporal profile of in vivo cardiac energetics and cardiac performance of an anoxia-tolerant vertebrate, the freshwater turtle (Trachemys scripta) during long-term anoxia exposure (approximately 3 h at 21 degrees C and 11 days at 5 degrees C). During anoxia, phosphocreatine (PCr), unbound levels of inorganic phosphate (effective P(i)(2-)), intracellular pH (pH(i)), and free energy of ATP hydrolysis (dG/dxi) exhibited asymptotic patterns of change, indicating that turtle myocardial high-energy phosphate metabolism and energetic state are reset to new, reduced steady states during long-term anoxia exposure. At 21 degrees C, anoxia caused a reduction in pH(i) from 7.40 to 7.01, a 69% decrease in PCr and a doubling of effective P(i)(2-). ATP content remained unchanged, but the free energy of ATP hydrolysis (dG/dxi) decreased from -59.6 to -52.5 kJ/mol. Even so, none of these cellular changes correlated with the anoxic depression of cardiac performance, suggesting that autonomic cardiac regulation may override putative cellular feedback mechanisms. In contrast, during anoxia at 5 degrees C, when autonomic cardiac control is severely blunted, the decrease of pH(i) from 7.66 to 7.12, 1.9-fold increase of effective P(i)(2-), and 6.4 kJ/mol decrease of dG/dxi from -53.8 to -47.4 kJ/mol were significantly correlated to the anoxic depression of cardiac performance. Our results provide the first evidence for a close, long-term coordination of functional cardiac changes with cellular energy status in a vertebrate, with a potential for autonomic control to override these immediate relationships.
Topics: Adaptation, Physiological; Adenosine Triphosphate; Animals; Aorta; Autonomic Nervous System; Energy Metabolism; Heart; Heart Rate; Hydrogen-Ion Concentration; Hydrolysis; Hypoxia; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Myocardial Contraction; Myocardium; Phosphates; Phosphocreatine; Pulmonary Circulation; Regional Blood Flow; Temperature; Time Factors; Turtles
PubMed: 19587113
DOI: 10.1152/ajpregu.00102.2009 -
American Journal of Physiology.... Apr 2009We have previously shown that a maternal high-fat diet, rich in saturated fatty acids (SFA), alters the lipid metabolism of their adult offspring. The present study was...
We have previously shown that a maternal high-fat diet, rich in saturated fatty acids (SFA), alters the lipid metabolism of their adult offspring. The present study was designed to investigate 1) whether alterations in hepatic LDL-receptor (LDL-r) expression may serve as a potential mechanism of developmental programming behind the altered lipid metabolism of the offspring, 2) whether altered lipid metabolism leads to aortic vascular dysfunction in the offspring, 3) whether deleterious effects of SFA exposure preweaning are influenced by postweaning diet, and 4) whether gender-specific programming effects are observed. Female C57Bl/6 mice were fed a high-SFA diet or regular chow during gestation and lactation while their pups, both male and female, received either SFA or a chow diet after weaning. Male offspring obtained from mothers fed an SFA diet and those who continued on chow postweaning had higher plasma triglycerides and total cholesterol, whereas female offspring had higher plasma total and LDL cholesterol levels, lower hepatic LDL-r mRNA expression, and reduced aortic contractile responses compared with the offspring that were fed chow throughout the study. A comparison of the postweaning diet revealed significantly lower hepatic LDL-r expression along with significantly higher plasma LDL-cholesterol concentration in the female offspring that were obtained from mothers fed an SFA diet and who continued on an SFA diet postweaning, compared with the female offspring that were obtained from mothers fed an SFA diet but who continued on chow postweaning. In conclusion, we report a novel observation of hepatic LDL-r-mediated programming of altered lipid metabolism, along with aortic vascular dysfunction, in the female offspring of mothers fed a high-SFA diet. Male offspring only exhibited dyslipidemia, suggesting gender-mediated programming. This study further highlighted the role of postweaning diets in overriding the effects of maternal programming.
Topics: Animal Nutritional Physiological Phenomena; Animals; Aorta; Aortic Diseases; Blood Glucose; Body Weight; Dietary Fats; Dose-Response Relationship, Drug; Dyslipidemias; Eating; Enzyme Inhibitors; Fatty Acids, Nonesterified; Female; Gestational Age; Lactation; Lipids; Liver; Male; Maternal Nutritional Physiological Phenomena; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase; Pregnancy; Prenatal Exposure Delayed Effects; RNA, Messenger; Receptors, LDL; Sex Factors; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents
PubMed: 19193942
DOI: 10.1152/ajpregu.90932.2008