Region-specific delamination strength of ascending thoracic aortic aneurysm of elderly hypertensive patients with bicuspid and tricuspid aortic valves.

Both ageing and hypertension are clinical factors that may lead to a higher propensity for dissection or rupture of ascending thoracic aortic aneurysms (ATAAs). This study sought to investigate effect of valve morphology on regional delamination strength of ATAAs in the elderly hypertensive patients. Whole fresh ATAA samples were harvested from 23 hypertensive patients (age, 71 ± 8 years) who underwent elective aortic surgery. Peeling tests were performed to measure region-specific delamination strengths of the ATAAs, which were compared between patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV). The regional delamination strengths of the ATAAs were further correlated with patient ages and aortic diameters for BAV and TAV groups. In the anterior and right lateral regions, the longitudinal delamination strengths of the ATAAs were statistically significantly higher for BAV patients than TAV patients (33 ± 7 vs. 23 ± 8 mN/mm, p = 0.01; 30 ± 7 vs. 19 ± 9 mN/mm, p = 0.02). For both BAV and TAV patients, the left lateral region exhibited significantly higher delamination strengths in both directions than the right lateral region. Histology revealed that disruption of elastic fibers in the right lateral region of the ATAAs was more severe for the TAV patients than the BAV patients. A strong inverse correlation between longitudinal delamination strength and age was identified in the right lateral region of the ATAAs of the TAV patients. Results suggest that TAV-ATAAs are more vulnerable to aortic dissection than BAV-ATAAs for the elderly hypertensive patients. Regardless of valve morphotypes, the right lateral region may be a special quadrant which is more likely to initiate dissection when compared with other regions.

Effect of hypertension on the delamination and tensile strength of ascending thoracic aortic aneurysm with a focus on right lateral region.

Hypertension is a major predisposing factor to initiate thoracic aortopathy. The objective of this study is to investigate effect of hypertension on delamination and tensile strength of ascending thoracic aortic aneurysms (ATAAs). A total of 35 fresh ATAA samples were harvested from 19 hypertensive and 16 non-hypertensive patients during elective aortic surgery. Peeling tests with two extension rates were performed to determine delamination strength, while uniaxial tensile (UT) tests were employed to measure failure stresses. The delamination strength and failure stresses of the ATAAs were further correlated with patient ages for hypertensive and non-hypertensive groups. The delamination strength to peel apart the ATAA tissue along the longitudinal direction was statistically significantly lower for the hypertensive patients than that of the non-hypertensive patients (35 ± 11 vs. 49 ± 9 mN/mm, p = 0.02). A higher delamination strength was measured if peeling was performed with a higher extension rate. The circumferential failure stresses were significantly lower for the hypertensive ATAAs than those of the non-hypertensive ATAAs (1.03 ± 0.27 vs. 1.43 ± 0.38 MPa, p = 0.02). Histology showed that laminar structures of elastic fibers were mainly disrupted in the hypertensive ATAAs. The longitudinal delamination strength of the ATAAs was significantly decreased and strongly correlated with ages for the hypertensive patients. Strong inverse correlations were also identified between the circumferential and longitudinal failure stresses of the ATAAs and ages for the hypertensive patients. Results suggest that the ATAAs of the elderly hypertensive patients may have a higher propensity for dissection or rupture. The dissection properties of the ATAA tissue are rate dependent.

Hybrid aortic arch procedure in acute type A aortic dissection with right carotid artery occlusion.

Acute type A aortic dissection complicated by carotid artery is associated with a high risk of perioperative stroke. We reported a case of application of hybrid aortic arch debranching procedure in acute type A aortic dissection complicated by right carotid artery occlusion, which resulted in no neurological complications after operation and patent carotid artery after discharging.

Identification of key genes involved in calcific aortic valve disease based on integrated bioinformatics analysis.

The calcific aortic valve disease (CAVD) develops as an aortic valve sclerosis and progresses to an advanced form of stenosis. In many biological fields, bioinformatics becomes a fundamental component. The key mechanisms involved in CAVD are discovered with the use of bioinformatics to investigate gene function and pathways. We downloaded the original data (GSE51472) from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/). After standardization, 2978 differentially expressed genes (DEGs) were identified from the data sets GSE51472 containing samples from normal, calcified, and sclerotic aortic valves. Analysis of DEGs based on the series test of clusters (STCs) revealed the two most significant patterns. Based on the result of the STC, the functional enrichment analysis of gene ontology (GO) was conducted to investigate the molecular function (MF), biological process (BP), and cell compound (CC) of the DEGs. With a p value of 0.01, DEGs associated with "chronic inflammation," "T-cell receptor complexes," and "antigen binding" had the highest significance within BP, CC, and MF. DEG enrichment in signaling pathways was analyzed using KEGG pathway enrichment. Using a p < 0.05 level of significance, the most enriched biological pathways related to CAVD were "Chemokine signaling pathway," "Cytokine-cytokine receptor interaction," "Tuberculosis," "PI3K-Akt signaling pathway," and "Transcriptional misregulation in cancer." Finally, the construction of gene co-expression networks and pathway networks illustrated the pathogensis of CAVD. TLR2, CD86, and TYROBP were identified as hub genes for the development of CAVD. Moreover, "MAPK signaling pathway," "Apoptosis," and "Pathways in cancer" were regarded as the core pathways among the samples of normal, sclerotic and calcified aortic valve samples.

Effect of diabetes mellitus on the dissection properties of the rabbit descending thoracic aortas.

Effect of diabetes mellitus (DM) on the dissection properties of thoracic aortas remains largely unclear and relevant biomechanical analysis is lacking. In the present study forty adult rabbits (1.6-2.2 kg) were collected and type 1 diabetic rabbit model was induced by injection of alloxan. A total of 10 control and 30 diabetic (with different time exposure to diabetic condition) rabbit descending thoracic aortas were harvested. Peeling tests were performed to quantitatively determine force/width values and dissection energy in the control and diabetic aortas. Histological and mass fraction analyses were performed to characterize the dissected morphology and to quantify dry weight percentages of elastin and collagen. The resisting force/width values were significantly higher for the diabetic thoracic aortas (in 8 weeks) than those of the control thoracic aortas (axial: 26.1 ± 4.0 vs. 20.5 ± 3.1 mN/mm, p = 0.04; circ: 19.7 ± 2.8 vs. 15.3 ± 1.9 mN/mm, p = 0.03). There was a higher resistance to the dissection in both axial and circumferential directions for the diabetic aortas. The dissection energy generated by axial and circumferential peeling of the diabetic aortas (in 6 and 8 weeks) was statistically significantly higher than that of the control aortas (axial: 5.6 ± 0.7 vs. 4.3 ± 0.5 mJ/cm2, p = 0.02; circ: 3.9 ± 0.3 vs. 3.2 ± 0.3 mJ/cm2, p = 0.02). Histology showed that dissection mainly occurred in the aortic media and the dissected surfaces were close to external elastic lamina for some specimens. The mass fractions of collagen within the diabetic aortas increased significantly as compared to the control aortas, whereas no significant change was found for that of elastin. Our data suggest that the experimentally induced DM may lead to a lower propensity of dissection for the rabbit thoracic aortas. The dissection properties of the rabbit thoracic aortas vary with time exposed to diabetic condition.

Prevalence and spectrum of PITX2c mutations associated with congenital heart disease.

Congenital heart disease (CHD) is the most common form of birth defect and is the leading noninfectious cause of infant death. A growing body of evidence demonstrates that genetic risk factors are involved in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic defects underlying CHD in an overwhelming majority of patients remain unclear. In this study, the whole coding region and splice junction sites of the PITX2c gene, which encodes variant 3 of paired-like homeodomain transcription factor 2 crucial for normal cardiovascular morphogenesis, were sequenced in 382 unrelated patients with CHD, and 2 novel heterozygous mutations, p.W147X and p.N153D, were identified in 2 unrelated patients with CHD, respectively, including a 1-year-old male patient with double outlet right ventricle in combination with ventricular septal defect and a 4-year-old female patient with ventricular septal defect. The mutations were absent in 400 control chromosomes and were both predicted to be disease-causing by MutationTaster. Multiple alignments of PITX2c proteins across species displayed that the altered amino acids were completely conserved evolutionarily. Functional analysis revealed that the mutated PITX2c proteins were associated with a significantly reduced transactivational activity compared with their wild-type counterpart. These findings provide a novel insight into the molecular mechanisms implicated in CHD, suggesting potential implications for the antenatal prophylaxis and allele-specific treatment of CHD.

GATA4 loss-of-function mutations underlie familial tetralogy of fallot.

Tetralogy of Fallot (TOF) represents the most common form of cyanotic congenital heart disease and accounts for significant morbidity and mortality in humans. Emerging evidence has implicated genetic defects in the pathogenesis of TOF. However, TOF is genetically heterogeneous and the genetic basis for TOF in most patients remains unclear. In this study, the GATA4 gene were sequenced in 52 probands with familial TOF, and three novel heterozygous mutations, including A9P and L51V both located in the putative first transactivational domain and N285S in the C-terminal zinc finger, were identified in three probands, respectively. Genetic analysis of the pedigrees demonstrated that in each family the mutation cosegregated with TOF with complete penetrance. The missense mutations were absent in 800 control chromosomes and the altered amino acids were highly conserved evolutionarily. Functional analysis showed that the GATA4 mutants were consistently associated with diminished DNA-binding affinity and decreased transcriptional activity. Furthermore, the N285S mutation completely disrupted the physical interaction between GATA4 and TBX5. To our knowledge, this report associates GATA4 loss-of-function mutations with familial TOF for the first time, providing novel insight into the molecular mechanism involved in TOF and suggesting potential implications for the early prophylaxis and allele-specific therapy of TOF.

Novel GATA6 mutations associated with congenital ventricular septal defect or tetralogy of fallot.

Congenital heart disease (CHD) is the most common form of developmental malformation and is the leading noninfectious cause of infant mortality. Emerging evidence indicates that genetic defects are involved in the pathogenesis of CHD. Nevertheless, CHD is genetically heterogeneous, and the molecular basis for CHD in a majority of patients remains unknown. In this study, the whole coding region of GATA6, a gene encoding a zinc-finger transcription factor crucial for normal cardiogenesis, was sequenced in 380 unrelated patients with CHD. The relatives of the index patients harboring the identified mutations and 200 unrelated control individuals were subsequently genotyped. The functional effect of the mutations was characterized using a luciferase reporter assay system. As a result, two novel heterozygous GATA6 mutations, p.D404Y and p.E460X, were identified in two families with ventricular septal defect and tetralogy of Fallot, respectively. The mutations co-segregated with CHD in the families with complete penetrance, and were absent in 400 control chromosomes. Functional analysis demonstrated that the mutated GATA6 proteins were associated with significantly decreased transactivational activity in comparison with their wild-type counterpart. These findings provide novel insight into the molecular mechanism implicated in CHD, suggesting potential implications for the early prophylaxis and personalized treatment of CHD.

A novel GATA4 mutation responsible for congenital ventricular septal defects.

Ventricular septal defect (VSD) is the most common type of cardiovascular developmental anomaly and is an important risk factor for the substantially increased morbidity and mortality in newborns. Aggregating evidence implicates genetic defects in the pathogenesis of congenital VSD. However, VSD is genetically heterogeneous and the genetic determinants for VSD in most patients remain to be identified. In this study, the whole coding region of the GATA4 gene, which encodes a zinc-finger transcription factor pivotal to cardiogenesis, was initially sequenced in 210 unrelated patients with VSD. The relatives of the index patient carrying the identified mutation and 200 unrelated ethnically-matched healthy individuals used as controls were subsequently genotyped. The functional effect of the mutant GATA4 was characterized in contrast to its wild-type counterpart using a luciferase reporter assay system. A novel heterozygous GATA4 mutation, p.G296R, was identified in a family with VSD inherited as an autosomal dominant trait. Absent in 200 control individuals, the mutation co-segregated with VSD in the family with 100% penetrance and was completely conserved evolutionarily across species. Functional analysis displayed that the p.G296R mutation of GATA4 was associated with a decreased transcriptional activity. The findings expand the spectrum of mutations in GATA4 linked to VSD and provide more insight into the molecular mechanism involved in VSD. The results of the present study imply the potential implications in the genetic diagnosis and gene-specific therapy of this common malformation in infancy.

A novel NKX2-5 mutation in familial ventricular septal defect.

Ventricular septal defect (VSD) is the most common cardiovascular malformation and an important contributor to the substantial morbidity and mortality in infancy. Growing evidence suggests that genetic defects play important roles in the pathogenesis of congenital VSD. However, VSD is of great genetic heterogeneity and the genetic basis for VSD in the majority of the patients remains largely unhnown. In this study, the entire coding region of the NKX2-5 gene, which encodes a homeodomain-containing transcription factor crucial to cardiogenesis, was initially sequenced in 136 unrelated patients with VSD. The relatives of a proband harboring the identified mutation and 200 unrelated control individuals were genotyped. The functional characteristic of the mutant transcription factor was analyzed in contrast to its wild-type counterpart using a luciferase reporter assay system. A novel heterozygous NKX2-5 mutation, p.P59A, was identified in a family with autosomal dominant inherited VSD. Absent in the 200 control individuals, the mutation was highly conserved evolutionarily and co-segregated with VSD in the family with complete penetrance. Functional analysis revealed that the p.P59A mutation of NKX2-5 was associated with a decreased transcriptional activity. These findings expand the spectrum of the mutations in NKX2-5 linked to VSD and provide new insight into the molecular mechanisms involved in VSD. The resuls of the present study may have potential implications in the genetic diagnosis and gene-specific therapy of this common childhood disease.

[Genetic screening for novel GATA4 mutations associated with congenital atrial septal defect].

OBJECTIVE: To screen the gene GATA4 for novel mutations associated with congenital atrial septal defect (ASD). METHODS: The clinical data and peripheral venous blood specimen from 85 unrelated subjects with congenital ASD were collected and analyzed in contrast to 200 healthy individuals. The coding exons and the exon/intron boundaries of GATA4 gene were amplified by polymerase chain reaction and sequenced using the di-deoxynucleotide chain termination procedure. The obtained sequences were aligned with those publicized in GenBank with the help of programme BLAST to identify the sequence variations. The software Clustal W was applied to analysis of the conservation of altered amino acids. RESULTS: Three novel heterozygous missense GATA4 mutations were identified in 3 of 85 ASD patients, respectively. Namely, the triplet substitutions of ATG for GTG at codon 267, GCC for ACC at codon 354, and CAA for CCA at codon 407, predicting the conversions of valine into methionine at amino acid residue 267 (V267M), threonine into alanine at amino acid residue 354 (T354A), and proline into glutamine at amino acid residue 407 (P407Q), were identified. No mutation was detected in 200 healthy controls. A cross-species alignment of GATA4 encoded protein sequences showed that the valine at amino acid residue 267 and proline at amino acid residue 407 were completely conserved evolutionarily. CONCLUSION: Three novel heterozygous missense GATA4 mutations were identified in patients with congenital ASD, which reveals new molecular etiology responsible for ASD, and contributes to the early prophylaxis and therapy for ASD.

[Novel GATA4 mutations identified in patients with congenital heart disease].

OBJECTIVE: To identify the novel genetic determinants in patients with congenital heart disease (CHD). METHODS: The clinical data and peripheral venous blood samples from 120 unrelated individuals with idiopathic CHD were collected and evaluated compared to 100 unrelated healthy controls. The complete coding exons and the partial flanking introns of GATA4 gene were amplified by polymerase chain reaction and sequenced by di-deoxynucleotide chain termination. The generated sequences were aligned with those retrieved from GenBank with the aid of programme BLAST to identify the sequence variations. The software Clustal W was utilized to analyze the conservation of altered amino acids. RESULTS: Three novel heterozygous missense GATA4 mutations were identified in 3 of 120 CHD cases. Namely, the triplet substitutions of AGA for AGC at codon 90, GAG for GAC at codon 95, and AAT for AAG at codon 329, predicting the conversions of serine into arginine at amino acid residue 90 (S90R), aspartic acid into glutamic acid at amino acid residue 95 (D95E) and lysine into asparagine at amino acid residue 329 (K329N), were detected. None of these three mutations were probed in 100 controls. A cross-species alignment of GATA4 encoded protein sequences displayed that the lysine at amino acid residue 329 was completely conserved evolutionarily. Additionally, a single nucleotide polymorphism c. 99G>T was observed. However, the polymorphic frequency distribution in CHD patients was not statistically different from that in controls (for genotypes, chi(2) = 0.2640, P = 0.6074; for alleles, chi(2) = 0.2514, P = 0.6161). CONCLUSION: The idiopathic CHD has a marked heterogeneity and the mutated GATA4 gene may be responsible for CHD in a subset of patients.

Investigation on Quality of Construction and Sanitation of Double-urn-and-single-funel Latrines in Countryside of Zhengzhou / 环境与健康杂志

Objective To understand the quality of construction and sanitation of double_urn_and_single_funel(DUSF)latrines widely popularized in He'nan province and its current problems.Methods The qualities of contruction and sanitary management of 1269 DUSF latrines were investigated in countryside of Zhengzhou.Results The total qualified rate of the construction quality was 86.9% for 1269 observed DUSF latrines.The constituent ratios of latrines with good,moderate and bad sanitary management were 43.4%,33.4% and 23.2% respectively.The percentages of the latrines with auxiliary facilities such as flax brushes,tolet paper collectors and water storage tanks were 66.5%,67.3%and 39.4% respectively.Conclusion The quality of construction of DUSF latrines in countryside of Zhengzhou was qualified on the whole.But the sanitary management and maintenance of DUSF latrines should be improved further.