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Scientific Reports Dec 2017There is an unmet need for treatments to reduce abdominal aortic aneurysm (AAA) progression. Vascular smooth muscle cell (VSMC) apoptosis precipitates AAA formation,...
There is an unmet need for treatments to reduce abdominal aortic aneurysm (AAA) progression. Vascular smooth muscle cell (VSMC) apoptosis precipitates AAA formation, whereas VSMC proliferation repairs the vessel wall. We previously demonstrated that over-expression of EC4-Fc (truncated N-cadherin), or deletion of matrix-metalloproteinase-7 (Mmp-7) reduced VSMC apoptosis in mouse atherosclerotic plaques. Additionally, MMP-7 promotes VSMC apoptosis by cleavage of N-cadherin. We investigated their combined effect on AAA formation. Increased apoptosis and proliferation were observed in human AAA (HAAA) sections compared to normal aortae (HA). This coincided with increased MMP-7 activity and reduced N-cadherin protein levels in HAAA sections compared to HA. Using a mouse model of aneurysm formation, we showed that the combination of Mmp-7 deletion and EC4-Fc overexpression significantly increased AAA severity. Medial apoptosis and proliferation were both significantly reduced in these mice compared to control mice. In vitro, MMP-7 inhibition and EC4-Fc administration significantly supressed human aortic VSMC apoptosis (via activation of PI-3 kinase/Akt signalling) and proliferation. In conclusion, combined Mmp-7 deletion and systemic over-expression of EC4-Fc reduced both proliferation and apoptosis. Reduced proliferation-mediated repair over-rides any benefit of reduced apoptosis, increasing aneurysm severity. Future studies should therefore focus on retarding VSMC apoptosis whilst promoting VSMC proliferation.
Topics: Angiotensin II; Animals; Aorta; Aortic Aneurysm, Abdominal; Apolipoproteins E; Apoptosis; Cadherins; Cell Proliferation; Disease Models, Animal; Humans; Male; Matrix Metalloproteinase 7; Mice; Mice, Inbred C57BL; Mice, Knockout; Severity of Illness Index; Signal Transduction
PubMed: 29229950
DOI: 10.1038/s41598-017-17700-8 -
Journal of the American Heart... Sep 2017Wall shear stress (WSS) is a stimulus for vessel wall remodeling. Differences in ascending aorta (AAo) hemodynamics have been reported between bicuspid aortic valve...
BACKGROUND
Wall shear stress (WSS) is a stimulus for vessel wall remodeling. Differences in ascending aorta (AAo) hemodynamics have been reported between bicuspid aortic valve (BAV) and tricuspid aortic valve patients with aortic dilatation, but the confounding impact of aortic valve stenosis (AS) is unknown.
METHODS AND RESULTS
Five hundred seventy-one subjects underwent 4-dimensional flow magnetic resonance imaging in the thoracic aorta (210 right-left BAV cusp fusions, 60 right-noncoronary BAV cusp fusions, 245 tricuspid aortic valve patients with aortic dilatation, and 56 healthy controls). There were 166 of 515 (32%) patients with AS. WSS atlases were created to quantify group-specific WSS patterns in the AAo as a function of AS severity. In BAV patients without AS, the different cusp fusion phenotypes resulted in distinct differences in eccentric WSS elevation: right-left BAV patients exhibited increased WSS by 9% to 34% (<0.001) at the aortic root and along the entire outer curvature of the AAo whereas right-noncoronary BAV patients showed 30% WSS increase (<0.001) at the distal portion of the AAo. WSS in tricuspid aortic valve patients with aortic dilatation patients with no AS was significantly reduced by 21% to 33% (<0.01) in 4 of 6 AAo regions. In all patient groups, mild, moderate, and severe AS resulted in a marked increase in regional WSS (<0.001). Moderate-to-severe AS further increased WSS magnitude and variability in the AAo. Differences between valve phenotypes were no longer apparent.
CONCLUSIONS
AS significantly alters aortic hemodynamics and WSS independent of aortic valve phenotype and over-rides previously described flow patterns associated with BAV and tricuspid aortic valve with aortic dilatation. Severity of AS must be considered when investigating valve-mediated aortopathy.
Topics: Adult; Aged; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Valve; Aortic Valve Stenosis; Bicuspid Aortic Valve Disease; Blood Flow Velocity; Cross-Sectional Studies; Databases, Factual; Female; Heart Valve Diseases; Hemodynamics; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Phenotype; Predictive Value of Tests; Regional Blood Flow; Retrospective Studies; Severity of Illness Index; Stress, Mechanical
PubMed: 28903936
DOI: 10.1161/JAHA.117.005959 -
Medicine Sep 2017Absent pulmonary valve syndrome (APVS) is a rare congenital heart disease that is often associated with tetralogy of Fallot (TOF). Here, we report 2 cases of APVS...
RATIONALE
Absent pulmonary valve syndrome (APVS) is a rare congenital heart disease that is often associated with tetralogy of Fallot (TOF). Here, we report 2 cases of APVS associated with TOF diagnosed via fetal echocardiography and discuss their specific ultrasonographic characteristics.
PATIENT CONCERNS
Two pregnant women with suspicion of fetal heart anomaly were referred from their local hospitals to our hospital for fetal malformation screening and detailed fetal echocardiography. Color and spectral Doppler flow imaging were utilized to evaluate the axis, size, situs, cardiac chambers, and both inflow and outflow tracts of the heart as well as the great arteries. Both cases had a severe dilatation of the pulmonary trunk and its branches and an absence or dysplasia of the pulmonary valve, which was associated with subaortic ventricular septal defect (VSD) with an overriding aorta. In addition, the fetus in case 1 showed a patent ductus arteriosus, and the fetus in case 2 showed arterial duct agenesis. Furthermore, color Doppler flow imaging showed a bi-directional multicolored flow signal in the pulmonary valve ring.
DIAGNOSES
Both fetuses were diagnosed with APVS associated with TOF.
INTERVENTIONS
No therapeutic intervention was performed.
OUTCOMES
On the request of the pregnant women and their families, both fetuses were aborted.
LESSONS
Although APVS is a rare congenital heart disease and often associated with TOF, it has an overall poor prognosis. Nowadays, it can be easily diagnosed via ultrasonography because of its typical ultrasonographic features, such as aneurysmal dilatation of pulmonary artery, massive regurgitation of the pulmonary valve, VSD, and an overriding aorta. Therefore, early fetal echocardiography screening should be performed for every fetus.
Topics: Abnormalities, Multiple; Adult; Echocardiography, Doppler; Female; Heart Defects, Congenital; Humans; Pregnancy; Pulmonary Valve; Syndrome; Tetralogy of Fallot; Ultrasonography, Prenatal
PubMed: 28858090
DOI: 10.1097/MD.0000000000007747 -
BMC Medical Genetics Jul 2017Perturbations on the Left-Right axis establishment lead to laterality defects, with frequently associated Congenital Heart Diseases (CHDs). Indeed, in the last decade,...
BACKGROUND
Perturbations on the Left-Right axis establishment lead to laterality defects, with frequently associated Congenital Heart Diseases (CHDs). Indeed, in the last decade, it has been reported that the etiology of isolated cases of CHDs or cases of laterality defects with associated CHDs is linked with variants of genes involved in the Nodal signaling pathway.
METHODS
With this in mind, we analyzed a cohort of 38 unrelated patients with Congenital Heart Defects that can arise from initial perturbations in the formation of the Left-Right axis and 40 unrelated ethnically matched healthy individuals as a control population. Genomic DNA was extracted from buccal epithelial cells, and variants screening was performed by PCR and direct sequencing. A Nodal-dependent luciferase assay was conducted in order to determine the functional effect of the variant found.
RESULTS
In this work, we report two patients with a DAND5 heterozygous non-synonymous variant (c.455G > A) in the functional domain of the DAND5 protein (p.R152H), a master regulator of Nodal signaling. Patient 1 presents left isomerism, ventricular septal defect with overriding aorta and pulmonary atresia, while patient 2 presents ventricular septal defect with overriding aorta, right ventricular hypertrophy and pulmonary atresia (a case of extreme tetralogy of Fallot phenotype). The functional analysis assay showed a significant decrease in the activity of this variant protein when compared to its wild-type counterpart.
CONCLUSION
Altogether, our results provide new insight into the molecular mechanism of the laterality defects and related CHDs, priming for the first time DAND5 as one of multiple candidate determinants for CHDs in humans.
Topics: Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Heart Defects, Congenital; Heart Septal Defects, Ventricular; Humans; Intercellular Signaling Peptides and Proteins; Male; Mutation; Nodal Protein; Phenotype; Polymorphism, Single Nucleotide; Signal Transduction
PubMed: 28738792
DOI: 10.1186/s12881-017-0444-1 -
Journal of the American Heart... Apr 2016Congenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar...
BACKGROUND
Congenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in NOTCH1 were a cause of bicuspid aortic valve in nonsyndromic autosomal-dominant human pedigrees. Subsequently, we described a highly penetrant mouse model of aortic valve disease, consisting of a bicuspid aortic valve with thickened cusps and associated stenosis and regurgitation, in Notch1-haploinsufficient adult mice backcrossed into a Nos3-null background.
METHODS AND RESULTS
Here, we described the congenital cardiac abnormalities in Notch1(+/-);Nos3(-/-) embryos that led to ≈65% lethality by postnatal day 10. Although expected Mendelian ratios of Notch1(+/-);Nos3(-/-) embryos were found at embryonic day 18.5, histological examination revealed thickened, malformed semilunar valve leaflets accompanied by additional anomalies of the cardiac outflow tract including ventricular septal defects and overriding aorta. The aortic valve leaflets of Notch1(+/-);Nos3(-/-) embryos at embryonic day 15.5 were significantly thicker than controls, consistent with a defect in remodeling of the semilunar valve cushions. In addition, we generated mice haploinsufficient for Notch1 specifically in endothelial and endothelial-derived cells in a Nos3-null background and found that Notch1(fl/+);Tie2-Cre(+/-);Nos3(-/-) mice recapitulate the congenital cardiac phenotype of Notch1(+/-);Nos3(-/-) embryos.
CONCLUSIONS
Our data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract.
Topics: Animals; Aortic Valve; Bicuspid Aortic Valve Disease; DNA; DNA Mutational Analysis; Disease Models, Animal; Endothelial Cells; Female; Heart Valve Diseases; Heart Valves; Male; Mice; Mice, Mutant Strains; Mutation; Receptor, Notch1
PubMed: 27107132
DOI: 10.1161/JAHA.115.003075 -
Development (Cambridge, England) Mar 2016Congenital heart defects are the most common birth defects in humans, and those that affect the proper alignment of the outflow tracts and septation of the ventricles...
Congenital heart defects are the most common birth defects in humans, and those that affect the proper alignment of the outflow tracts and septation of the ventricles are a highly significant cause of morbidity and mortality in infants. A late differentiating population of cardiac progenitors, referred to as the anterior second heart field (AHF), gives rise to the outflow tract and the majority of the right ventricle and provides an embryological context for understanding cardiac outflow tract alignment and membranous ventricular septal defects. However, the transcriptional pathways controlling AHF development and their roles in congenital heart defects remain incompletely elucidated. Here, we inactivated the gene encoding the transcription factor MEF2C in the AHF in mice. Loss of Mef2c function in the AHF results in a spectrum of outflow tract alignment defects ranging from overriding aorta to double-outlet right ventricle and dextro-transposition of the great arteries. We identify Tdgf1, which encodes a Nodal co-receptor (also known as Cripto), as a direct transcriptional target of MEF2C in the outflow tract via an AHF-restricted Tdgf1 enhancer. Importantly, both the MEF2C and TDGF1 genes are associated with congenital heart defects in humans. Thus, these studies establish a direct transcriptional pathway between the core cardiac transcription factor MEF2C and the human congenital heart disease gene TDGF1. Moreover, we found a range of outflow tract alignment defects resulting from a single genetic lesion, supporting the idea that AHF-derived outflow tract alignment defects may constitute an embryological spectrum rather than distinct anomalies.
Topics: Animals; Animals, Newborn; Disease Models, Animal; Epidermal Growth Factor; Female; Gene Deletion; Gene Expression Regulation, Developmental; Heart; Heart Defects, Congenital; Heart Septal Defects, Ventricular; Heart Ventricles; Humans; In Situ Hybridization; MEF2 Transcription Factors; Male; Membrane Glycoproteins; Mice; Morphogenesis; Neoplasm Proteins; Organogenesis; Sequence Analysis, RNA; Tissue Distribution; Transcription, Genetic; Transposition of Great Vessels
PubMed: 26811383
DOI: 10.1242/dev.126383 -
PloS One 2016To compare multi-detector computed tomography (MDCT) with cardiac catheterization and transthoracic echocardiography (TTE) in comprehensive evaluation of the global...
OBJECTIVE
To compare multi-detector computed tomography (MDCT) with cardiac catheterization and transthoracic echocardiography (TTE) in comprehensive evaluation of the global cardiovascular anatomy in patients with pulmonary atresia with ventricular septal defect (PA-VSD).
METHODS
The clinical and imaging data of 116 patients with PA-VSD confirmed by surgery were reviewed. Using findings at surgery as the reference standard, data from MDCT, TTE and catheterization were reviewed for assessment of native pulmonary vasculature and intracardiac defects.
RESULTS
MDCT was more accurate than catheterization and TTE in identification of native pulmonary arteries. MDCT is also the most accurate test for delineation of the major aortopulmonary collateral arteries. The inter-modality agreement for evaluation of overriding aorta and VSD were both excellent. In the subgroup with surgical correlation, excellent agreement was found between TTE and surgery, and substantial agreement was also found at MDCT.
CONCLUSION
MDCT can correctly delineate the native pulmonary vasculatures and intracardiac defects and may be a reliable method for noninvasive assessment of global cardiovascular abnormalities in patients with PA-VSD.
Topics: Adolescent; Cardiac Catheterization; Child; Child, Preschool; Collateral Circulation; Echocardiography; Female; Heart Septal Defects; Heart Ventricles; Humans; Infant; Male; Multidetector Computed Tomography; Preoperative Care; Pulmonary Artery; Pulmonary Atresia; Retrospective Studies; Ventricular Septum
PubMed: 26741649
DOI: 10.1371/journal.pone.0146380 -
The Journal of Biological Chemistry Nov 2015About two-thirds of human congenital heart disease involves second heart field-derived structures. Histone-modifying enzymes, histone deacetylases (HDACs), regulate the...
About two-thirds of human congenital heart disease involves second heart field-derived structures. Histone-modifying enzymes, histone deacetylases (HDACs), regulate the epigenome; however, their functions within the second heart field remain elusive. Here we demonstrate that histone deacetylase 3 (HDAC3) orchestrates epigenetic silencing of Tgf-β1, a causative factor in congenital heart disease pathogenesis, in a deacetylase-independent manner to regulate development of second heart field-derived structures. In murine embryos lacking HDAC3 in the second heart field, increased TGF-β1 bioavailability is associated with ascending aortic dilatation, outflow tract malrotation, overriding aorta, double outlet right ventricle, aberrant semilunar valve development, bicuspid aortic valve, ventricular septal defects, and embryonic lethality. Activation of TGF-β signaling causes aberrant endothelial-to-mesenchymal transition and altered extracellular matrix homeostasis in HDAC3-null outflow tracts and semilunar valves, and pharmacological inhibition of TGF-β rescues these defects. HDAC3 recruits components of the PRC2 complex, methyltransferase EZH2, EED, and SUZ12, to the NCOR complex to enrich trimethylation of Lys-27 on histone H3 at the Tgf-β1 regulatory region and thereby maintains epigenetic silencing of Tgf-β1 specifically within the second heart field-derived mesenchyme. Wild-type HDAC3 or catalytically inactive HDAC3 expression rescues aberrant endothelial-to-mesenchymal transition and epigenetic silencing of Tgf-β1 in HDAC3-null outflow tracts and semilunar valves. These findings reveal that epigenetic dysregulation within the second heart field is a predisposing factor for congenital heart disease.
Topics: Animals; Body Patterning; Epigenesis, Genetic; Female; Fetal Heart; Heart Defects, Congenital; Heart Valves; Histone Deacetylases; Humans; Male; Mice; Mice, Knockout; Mice, Transgenic; Pregnancy; Signal Transduction; Transforming Growth Factor beta1
PubMed: 26420484
DOI: 10.1074/jbc.M115.684753 -
BMC Developmental Biology Jul 2015Nearly half of all individuals with Down Syndrome (DS) have some type of congenital heart defect (CHD), suggesting that DS sensitizes to CHD but does not cause it. We...
BACKGROUND
Nearly half of all individuals with Down Syndrome (DS) have some type of congenital heart defect (CHD), suggesting that DS sensitizes to CHD but does not cause it. We used a common mouse model of DS, the Ts65Dn mouse, to study the contribution of Tbx5, a known modifier of CHD, to heart defects on a trisomic backgroun. Mice that were heterozygous for a Tbx5 null allele were crossed with Ts65Dn mice. Thoraxes of progeny were fixed in 10% formalin, embedded in paraffin, and sectioned for analysis of CHD. Gene expression in embryonic hearts was examined by quantitative PCR and in situ hybridization. A TBX5 DNA binding site was verified by luciferase assays.
METHODS
Mice that were heterozygous for a Tbx5 null allele were crossed with Ts65Dn mice. Thoraxes of progeny were fixed in 10% formalin, embedded in paraffin, and sectioned for analysis of CHD. Gene expression in embryonic hearts was examined by quantitative PCR and in situ hybridization. A TBX5 DNA binding site was verified by luciferase assays.
RESULTS
We crossed mice that were heterozygous for a Tbx5 null allele with Ts65Dn mice. Mice that were trisomic and carried the Tbx5 mutation (Ts65Dn;Tbx5 (+/-) ) had a significantly increased incidence of overriding aorta compared to their euploid littermates. Ts65Dn;Tbx5 (+/-) mice also showed reduced expression of Pitx2, a molecular marker for the left atrium. Transcript levels of the trisomic Adamts1 gene were decreased in Tbx5 (+/-) mice compared to their euploid littermates. Evidence of a valid binding site for TBX5 upstream of the trisomic Adamts1 locus was also shown.
CONCLUSION
Haploinsufficiency of Tbx5 and trisomy affects alignment of the aorta and this effect may stem from deviations from normal left-right patterning in the heart. We have unveiled a previously unknown interaction between the Tbx5 gene and trisomy, suggesting a connection between Tbx5 and trisomic genes important during heart development.
Topics: Animals; Disease Models, Animal; Down Syndrome; Female; Gene Dosage; Heart Defects, Congenital; Male; Mice; Mice, 129 Strain; Mice, Inbred C3H; Mice, Inbred C57BL; T-Box Domain Proteins; Trisomy
PubMed: 26208718
DOI: 10.1186/s12861-015-0080-y -
Multimedia Manual of Cardiothoracic... 2015Sternotomy is considered to be the gold standard incision in cardiac surgery, resulting in low failure rates and excellent proven long-term outcomes. It can also be used...
Sternotomy is considered to be the gold standard incision in cardiac surgery, resulting in low failure rates and excellent proven long-term outcomes. It can also be used in thoracic surgery for mediastinal, bilateral pulmonary or lower trachea and main stem bronchus surgery. Sternotomy has to be performed properly to avoid short- and long-term morbidity and mortality. The surgical technique is well established and certain principles are recognized to be crucial to minimize complications. The identification of the correct landmarks, midline tissue preparation, osteotomy with the avoidance of injury to underlying structures like pleura, pericardium, innominate vein, brachiocephalic artery and ectatic ascending aorta, and targeted bleeding control are important steps of the procedure. As important as the performance of a proper sternotomy is a correct sternal closure. An override or shift of the sternal edges has to be avoided by placing the wires at a proper distance from each other without injuring the thoracic pedicle. The two sternal halves have to be tightly re-approximated to facilitate healing of the bone and to avoid instability, which is a risk factor for wound infection. With a proper performance of sternotomy and sternal closure, instability and wound infections are rare and depend on patient-related risk factors.
Topics: Bone Wires; Cardiac Surgical Procedures; Humans; Osteotomy; Sternotomy; Wound Closure Techniques
PubMed: 26188337
DOI: 10.1093/mmcts/mmv017