Disruption of Planar Cell Polarity Pathway Attributable to Valproic Acid-Induced Congenital Heart Disease through Hdac3 Participation in Mice / 中华医学杂志(英文版)

Background@#Valproic acid (VPA) exposure during pregnancy has been proven to contribute to congenital heart disease (CHD). Our previous findings implied that disruption of planar cell polarity (PCP) signaling pathway in cardiomyocytes might be a factor for the cardiac teratogenesis of VPA. In addition, the teratogenic ability of VPA is positively correlated to its histone deacetylase (HDAC) inhibition activity. This study aimed to investigate the effect of the VPA on cardiac morphogenesis, HDAC1/2/3, and PCP key genes (Vangl2/Scrib/Rac1), subsequently screening out the specific HDACs regulating PCP pathway.@*Methods@#VPA was administered to pregnant C57BL mice at 700 mg/kg intraperitoneally on embryonic day 10.5. Dams were sacrificed on E15.5, and death/absorption rates of embryos were evaluated. Embryonic hearts were observed by hematoxylin-eosin staining to identify cardiac abnormalities. H9C2 cells (undifferentiated rat cardiomyoblasts) were transfected with Hdac1/2/3 specific small interfering RNA (siRNA). Based on the results of siRNA transfection, cells were transfected with Hdac3 expression plasmid and subsequently mock-treated or treated with 8.0 mmol/L VPA. Hdac1/2/3 as well as Vangl2/Scrib/Rac1 mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and Western blotting, respectively. Total HDAC activity was detected by colorimetric assay.@*Results@#VPA could induce CHD (P 0.05); VPA exposure dramatically decreased the expression of Vanlg2/Scrib together with Hdac activity (P 0.05).@*Conclusion@#VPA could inhibit Hdac1/2/3, Vangl2/Scrib, or total Hdac activity both in vitro and in vivo and Hdac3 might participate in the process of VPA-induced cardiac developmental anomalies.

Autoimmune-associated Congenital Heart Block: A New Insight in Fetal Life / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>Congenital heart block (CHB) is a rare but life-threatening disorder. More than half of CHB cases are associated with maternal autoimmune, which are termed as autoimmune-associated CHB. This review summarized the recent research findings in understanding autoimmune-associated CHB, discussed the current diagnostic approaches and management strategies, and summarized the problems and future directions for this disorder.</p><p><b>DATA SOURCES</b>We retrieved the articles published in English from the PubMed database up to January 2017, using the keywords including "Autoimmune-associated", "Autoimmune-mediated", and "Congenital heart block".</p><p><b>STUDY SELECTION</b>Articles about autoimmune-associated CHB were obtained and reviewed.</p><p><b>RESULTS</b>Observational studies consistently reported that transplacental maternal antibodies might recognize fetal or neonatal antigens in various tissues and result in immunological damages, but the molecular mechanisms underlying CHB pathogenesis still need illuminated. Multiple factors were involved in the process of atrioventricular block development and progression. While several susceptibility genes had been successfully defined, how these genes and their protein interact and impact each other remains to be explored. With currently available diagnostic tools, fetal ultrasound cardiography, and fetal magnetocardiography, most of CHB could be successfully diagnosed and comprehensively evaluated prenatally. The efficacy of current approaches for preventing the progression and recurrence of CHB and other autoimmune-mediated damages was still controversial.</p><p><b>CONCLUSIONS</b>This review highlighted the relationships between autoimmune injuries and CHB and strengthened the importance of perinatal management and therapy for autoimmune-associated CHB.</p>

Changes in electrocardiographic parameters in children with complete left bundle branch block early after transcatheter closure of ventricular septal defect / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To observe the changes in electrocardiographic parameters in children with complete left bundle branch block (CLBBB) after the transcatheter closure of simple ventricular septal defect (VSD).</p><p><b>METHODS</b>A total of 21 children with CLBBB early after transcatheter closure of perimembranous VSD were recruited. Another 21 children without any type of arrhythmia after transcatheter closure of perimembranous VSD were enrolled as the control group. The sex, age, and the size of occluder were matched between the two groups. The changes in the following indices were compared between the two groups: left ventricular voltage, QT interval, corrected QT interval (QTc), QT dispersion (QTd), corrected QT dispersion (QTcd), JT dispersion (JTd), and corrected JT dispersion (JTcd) on the electrocardiogram before transcatheter closure and at 1, 3, 5, 30 days after transcatheter closure.</p><p><b>RESULTS</b>Left ventricular voltage and JTcd changed with operation time in the CLBBB and control groups (P<0.05). There were interaction effects between time and grouping in the changes in left ventricular voltage and QTd (P<0.05). There was a significant difference in JTcd between the CLBBB and control groups (P<0.05). There was also a significant difference in left ventricular voltage between the CLBBB and control groups at 3 and 5 days after the transcatheter closure (P<0.05).</p><p><b>CONCLUSIONS</b>There are significant differences in electrocardiographic left ventricular voltage and JTcd between VSD children with and without CLBBB early after transcatheter closure. JTcd might be useful in predicting the development of CLBBB early after transcatheter closure of VSD.</p>

Effect of Histone Deacetylase Inhibition on the Expression of Multidrug Resistance-associated Protein 2 in a Human Placental Trophoblast Cell Line / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Placental multidrug resistance-associated protein 2 (MRP2), encoded by ABCC2 gene in human, plays a significant role in regulating drugs' transplacental transfer rates. Studies on placental MRP2 regulation could provide more therapeutic targets for individualized and safe pharmacotherapy during pregnancy. Currently, the roles of epigenetic mechanisms in regulating placental drug transporters are still unclear. This study aimed to investigate the effect of histone deacetylases (HDACs) inhibition on MRP2 expression in the placental trophoblast cell line and to explore whether HDAC1/2/3 are preliminarily involved in this process.</p><p><b>METHODS</b>The human choriocarcinoma-derived trophoblast cell line (Bewo cells) was treated with the HDAC inhibitors-trichostatin A (TSA) at different concentration gradients of 0.5, 1.0, 3.0, and 5.0 μmol/L. Cells were harvested after 24 and 48 h treatment. Small interfering RNA (siRNA) specific for HDAC1/HDAC2/HDAC3 or control siRNA was transfected into cells. Total HDAC activity was detected by colorimetric assay kits. HDAC1/2/3/ABCC2 messenger RNA (mRNA) and protein expressions were determined by real-time quantitative polymerase chain reaction and Western-blot analysis, respectively. Immunofluorescence for MRP2 protein expression was visualized and assessed using an immunofluorescence microscopy and ImageJ software, respectively.</p><p><b>RESULTS</b>TSA could inhibit total HDAC activity and HDAC1/2/3 expression in company with increase of MRP2 expression in Bewo cells. Reduction of HDAC1 protein level was noted after 24 h of TSA incubation at 1.0, 3.0, and 5.0 μmol/L (vs. vehicle group, all P < 0.001), accompanied with dose-dependent induction of MRP2 expression (P = 0.045 for 1.0 μmol/L, P = 0.001 for 3.0 μmol/L, and P < 0.001 for 5.0 μmol/L), whereas no significant differences in MRP2 expression were noted after HDAC2/3 silencing. Fluorescent micrograph images of MRP2 protein were expressed on the cell membrane. The fluorescent intensities of MRP2 in the control, HDAC2, and HDAC3 siRNA-transfected cells were week, and no significant differences were noticed among these three groups (all P > 0.05). However, MRP2 expression was remarkably elevated in HDAC1 siRNA-transfected cells, which displayed an almost 3.19-fold changes in comparison with the control siRNA-transfected cells (P < 0.001).</p><p><b>CONCLUSIONS</b>HDACs inhibition could up-regulate placental MRP2 expression in vitro, and HDAC1 was probably to be involved in this process.</p>

Effect of histone acetylation/deacetylation imbalances on key gene of planar cell polarity pathway / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the effect of histone acetylation/deacetylation imbalances on embryonic hearts of mice and its effect on key genes of planar cell polarity (PCP) pathway-Vangl2, Scrib and Rac1 in H9C2 cells.</p><p><b>METHODS</b>Forty pregnant C57/B6 mice were randomly assigned into three groups: blank group (n=10), vehicle group (n=10), and valproic acid (VPA)-treated group (n=20). In the VPA-treated group, VPA, a histone deacetylase (HDAC) inhibitor, was administered to each individual dam intraperitoneally at a single dose of 700 mg/kg on embryonic day 10.5 (E10.5). The vehicle and blank groups received equivalent saline or no interventions, respectively. Dams were sacrificed on E15.5, and death rates of embryos were evaluated. Subsequently, embryonic hearts of survival fetus were removed to observe cardiac abnormalities by hematoxylin-eosin (HE) staining. H9C2 cells were cultured and allotted to the blank, vehicle, and VPA-treated groups: the VPA treated group received VPA exposure at concentrations of 2.0, 4.0 and 8.0 mmol/L; the vehicle and blank groups received equivalent saline or no interventions, respectively. HDAC1-3 as well as Vangl2, Scrib and Rac1 mRNA and protein expression levels were determined by quantitative real-time PCR and Western blot, respectively. The total HDAC activity was analyzed by colorimetric assay.</p><p><b>RESULTS</b>The fetus mortality rate after VPA treatment was 31.7%, with a significantly higher rate of cardiac abnormalities in comparison with the controls (P<0.05). In comparison with the blank and vehicle groups, HDAC1 mRNA was significantly increased at various concentrations of VPA treatment at all time points of exposure (P<0.05), together with a reduction of protein level after 48 and 72 hours of exposure (P<0.05). The inhibition of HDAC2 mRNA after various concentrations of VPA incubation was pronounced at 24 hours of exposure (P<0.05), while the protein levels were reduced at all time points (P<0.05). HDAC3 mRNA was prominently induced by VPA (4.0 and 8.0 mmol/L) at all time points of treatment (P<0.05). In contrast, the protein level was inhibited after VPA treatment (P<0.05). In comparison with the blank and vehicle groups, Vangl2 mRNA as well as Scrib mRNA/protein expression levels were markedly reduced after 48 and 72 hours of VPA treatment (P<0.05), together with a reduction of protein level in Vangl2 at 72 hours (P<0.05). Compared with the blank and vehicle groups, a significant repression in the total HDAC activity was observed in the VPA-treated group at concentrations of 4.0 and 8.0 mmol/L after 24 hours of treatment (P<0.05), and the effect persisted up to 48 and 72 hours, exhibiting pronounced inhibition at all concentrations (P<0.05).</p><p><b>CONCLUSIONS</b>VPA might result in acetylation/deacetylation imbalances by inhibiting HDAC1-3 protein expression and total HDAC activity, leading to the down-regulation of mRNA and protein expression of Vangl2 and Scrib. This could be one of the mechanisms contributing to congenital heart disease.</p>

Research advances on role of microRNAs in congenital heart diseases / 中国当代儿科杂志

MicroRNAs (miRNAs) are a class of small non-coding RNAs, which mainly regulate gene expression through post-transcriptional process. They are highly conserved, tissue-specific and highly specific in miRNA-binding on 3'-untranslated regions. MicroRNAs have been identified as crucial regulators in myocardial cell proliferation, differentiation and apoptosis, migration of cardiac neural crest cells, cardiac morphogenesis and cardiac patterning processes, which may provide a new insight into the research on developmental mechanism of congenital heart diseases. The research on miRNAs in congenital heart diseases includes clinical research and animal experiments. This article reviews two types of research advances, the mechanism of congenital heart diseases, and the current status and limitation of the domestic reports.

Risk factors for accelerated junctional escape rhythm in children early after percutaneous ventricular septal defect closure / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To identify the risk factors for accelerated junctional escape rhythm (AJER) in children early after percutaneous ventricular septal defect (VSD) closure.</p><p><b>METHODS</b>A retrospective controlled study was conducted on 42 children who had AJER within one week after percutaneous VSD closure between January 2008 and October 2012. These subjects were compared with controls without AJER after VSD closure in terms of age, sex, diameter of VSD, occluder size, difference between occluder size and diameter of VSD, and distance between VSD and aortic valve ring. Risk factors for AJER were identified by logistic regression analysis.</p><p><b>RESULTS</b>Compared with the control group, the AJER group had a longer distance betweenVSD and aortic valve ring, a larger diameter of VSD (basal diameter), a larger occluder size (waist diameter) , and a bigger difference between the waist diameter of occluder and diameter of VSD (P<0.05). Logistic regression analysis showed that distance between VSD and aortic valve ring (OR=1.813, P<0.05) and occluder size (OR=1.671, P<0.05) are primary risk factors for AJER.</p><p><b>CONCLUSIONS</b>AJER early after percutaneous VSD closure is related to diameter of VSD, occluder size, difference between the waist diameter of occluder and diameter of VSD, and distance between VSD and aortic valve ring. The distance between VSD and aortic valve ring and occluder size are primary risk factors for AJER.</p>

Significance of Tp-Te interval for risk stratification of ventricular premature contractions in children / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the significance of Tp-Te interval for risk stratification of ventricular premature contractions (VPC) in children.</p><p><b>METHODS</b>A total of 120 children with VPC were divided into benign VPC (n=40), organic disease (n=40) and ventricular parasystole groups (n=40) according to the etiology of VPC; another 40 children who underwent physical examination were selected as the normal control group. The four groups were compared in terms of Tp-Te intervals and Tp-Te/QT ratios in leads V3, V4 and V5.</p><p><b>RESULTS</b>The Tp-Te interval in lead V3 was significantly longer in the organic disease group than in the other groups (P<0.05), the benign VPC group had a significantly shorter Tp-Te interval in lead V4 than the normal control and organic disease groups (P<0.05), and the organic disease group had a significantly longer Tp-Te interval in lead V5 than the benign VPC group (P<0.05). The Tp-Te/QT ratios in leads V3-V5 were significantly higher in the organic disease group than in the other groups (P<0.05). The Tp-Te/QT ratios in leads V4 and V5 showed significant differences between the ventricular parasystole and benign VPC groups (P<0.05).</p><p><b>CONCLUSIONS</b>Tp-Te interval is susceptible to changes in heart rate, and it is of little value for the risk stratification of VPC in children. Tp-Te/QT ratio, however, may be used as an important non-invasive index for clinical risk stratification of VPC in children and is worthy of further study.</p>

Perinatal integrative intervention for critical pulmonary artery valve stenosis / 中华儿科杂志

<p><b>OBJECTIVE</b>To investigate the effect of different operation time to percutaneous balloon pulmonic valvuloplasty (PBPV) to critical pulmonary valve stenosis (CPS).</p><p><b>METHOD</b>Twenty-one infants (age ≤ 60 days at operating day) suffered from CPS, diagnosed by fetal echocardiogram and confirmed by echocardiography after birth, were enrolled in this case-control-study with written informed consent during April 2007 to December 2011. Of the 21 cases, 7 had prenatal diagnosis in our prenatal diagnosis center (prenatal group, Pre) and 14 were referred from other hospitals, who were divided into postpartum group A (Post A, referred within 28 days after birth) and postpartum group B (Post B, referred 29 to 60 days after birth). To Pre-group, the integrative interventional protocol was cautiously made by the consultative specialists, including intrauterine diagnosis, perinatal care and urgent PBPV soon after birth. To Post-group, emergency PBPV was preformed after the referral. Tei index of right ventricular and pressure-gradient (PG) between right ventricular and pulmonary artery were measured before and at different time points one year after PBPV.</p><p><b>RESULT</b>The values of SpO2 in Pre-group ranged from 82%-92% (86.57% ± 5.34%) under the state of continuous intravenous infusion of alprostadil. PBPV was successfully preformed within 3-6 days after birth. The values of SpO2 increased to 97.33% ± 1.15% post procedure. The values of PG pre- and post- procedure were (86.34 ± 11.77) mm Hg and (31.43 ± 8.46) mm Hg respectively. Preoperative RV Tei-index was 0.68 ± 0.05, it decreased rapidly after procedure, and recovered to normal one month after procedure. Only one case showed restenosis seven months after procedure and repeated PBPV. Fourteen referral cases (6 cases in Post A group and 8 cases in Post B group, accompanied in 1 and 3 cases with heart failure), the values of SpO2 ranged from 83%-91% under state of continuous intravenous infusion of alprostadil. And the operating time was 10-57 days after birth. The values of SpO2 recovered to normal post procedure, and heart failure alleviated. Increased preoperative RV pressure obviously decreased significantly post-procedure. And increased Tei-index declined gradually, at one-year follow-up, the value of Tei-index in Post A group recovered to normal, whereas that of Post B was (0.51 ± 0.06), compared to Pre and Post A groups, the difference was significant (P < 0.05) . One case showed restenosis nine months after procedure and repeated PBPV was performed. The hypoxic exposure durations were (4.43 ± 0.68) , (16.33 ± 4.46) , (41.25 ± 9.19) , respectively, and the difference among the three groups was significant (P < 0.05).</p><p><b>CONCLUSION</b>To the fetuses with definite prenatal diagnosis of critical pulmonary valve stenosis, preoperative general condition can be adjusted to more suitable for emergency operation. Early PBPV can achieve shorter hypoxic exposure and better recovery of right ventricular function post procedure. Perinatal integrated intervention for CPS can significantly improve the prognosis and quality of life in this patient population.</p>

Effect of inhibition of Notch signal on pulmonary vascular remodeling induced by angiotensin Ⅱ / 中国当代儿科杂志

<p><b>OBJECTIVE</b>It is known that Notch signal is very important to vascular remodeling during the process of embryonic development, vessel repair and tumor growth, but there are few studies about pulmonary vascular remodeling in pulmonary hypertension. This study was to explore the effect of inhibiting Notch signal on pulmonary vascular remodeling induced by angiotensin II.</p><p><b>METHODS</b>Vessel strips taken from healthy Wistar rats were co-cultured with extrogenous angiotensin II and the potent smooth muscle cell proliferation stimulators for 7 days. Vascular wall thickness, proliferating cell nuclear antigen (PCNA) positive cell rate and caspase-3 positive cell rate were examined in vessel strips. Then some vessel strips were cultured with angiotensin II and γ-secretase inhibitor DAPT, a Notch signaling inhibitor for 7 days. The levels of Notch 1 to 4 receptor and HERP1/2 mRNA were ascertained by FQ-PCR.</p><p><b>RESULTS</b>Angiotensin II stimulation in the cultured normal pulmonary arteries resulted in an increase in the vascular medial thickness by nearly 50%, and a significant increase in the PCNA positive cell rate and a decrease in the caspase-3 positive cell rate. DAPT treatment did not result in the alterations of Notch 1 to 4 receptor levels, but decreased remarkably HERP1 and HERP2 mRNA expression. DAPT treatment also decreased angiotensin II-induced vascular medial thickness and PCNA positive cell rate and increased caspase-3 positive cell rate.</p><p><b>CONCLUSIONS</b>Inhibiting Notch signal by γ-secretase inhibitor may lead to the suppression of pulmonary vascular remodeling induced by angiotensin II, suggesting that the inhibition of Notch signal pathway might be a novel strategy for the treatment of pulmonary hypertension.</p>

Echocardiography diagnosis of fetal cardiac structural abnormalities / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the application of echocardiography diagnosis of fetal cardiac structural abnormalities.</p><p><b>METHODS</b>The echocardiography findings of 9 352 fetus were studied.</p><p><b>RESULTS</b>A total of 472 cases showed cardiac structural abnormalities, including 7 cases of ventricular septal defect, 53 cases of atrioventricular septal defect, 49 cases of atrial septal defect, 26 cases of tetralogy of Fallot, 21 cases of persistent truncus arteriosus, 20 cases of Ebstein's anomaly and 206 cases of other cardiac abnormalities. There were 17 cases with cardiac arrhythmia, 9 with heart failure, and 5 with hydrops.</p><p><b>CONCLUSIONS</b>Fetal echocardiography is a promising diagnostic tool for prenatal evaluation of cardiac structural abnormalities. The echocardiography diagnosis and evaluation for fetal congenital cardiovascular malformations is the foundation of the guidance and monitoring in intrauterine fetal cardiac intervention.</p>

Effect of doxycycline on the development of pulmonary hypertension induced by four methods in rats / 中华儿科杂志

<p><b>OBJECTIVE</b>Based on establishment of four rat models of experimental pulmonary hypertension (PH), the authors examined the inhibition of matrix metalloproteinases (MMPs) by doxycycline and its effect on the development of PH and associated pulmonary vascular remodeling.</p><p><b>METHOD</b>Healthy male Sprague-Dawley rats (weight 350 g to 400 g) were randomly divided into nine groups: Normal control group (N), four model groups (H, M, P, PM) and their corresponding drug intervention groups (HD, MD, PD, PMD) in which doxycycline was given by gavage at a 20 mg/kg daily dosage. On day 28 (day 35 for PM and PMD models), the animals were catheterized to record mean pulmonary arterial pressure (mPAP) and then sacrificed. Fulton Index [RV/(LV + S)] was measured immediately. Morphometric parameters, including percent vascular wall thickness and muscularization of non-muscularized peripheral pulmonary arterioles were determined microscopically. The activity of MMPs was measured by gelatin zymography in the lung tissue.</p><p><b>RESULTS</b>(1) Rats in all model groups (H, M, P, PM) developed significant pulmonary arterial hypertension and right ventricular hypertrophy in comparison with their corresponding drug intervention groups (HD, MD, PD, PMD) and normal control group (N) (P < 0.01). For example, mPAP (mm Hg)(1 mm Hg = 0.133 kPa):N: 18.10 +/- 1.45, H: 27.20 +/- 1.55, HD: 23.90 +/- 2.13; Fulton Inedx(%):N: 23.41 +/- 1.84, H: 34.44 +/- 2.70, HD: 27.55 +/- 2.45. (2) The percent vascular wall thickness (WT%) and percentage of muscularization of non-muscular pulmonary arterioles were significantly increased in all model groups compared with drug intervention groups and normal group (P < 0.01). For example, WT%:N: 10.90 +/- 3.11, H:41.41 +/- 5.21, HD: 17.73 +/- 3.12; Muscularization(%):N: 13.83 +/- 3.72, H: 44.93 +/- 2.43, HD: 29.89 +/- 4.45. (3) The activity of MMPs was inhibited by doxycycline effectively as assessed by gelatin zymography (P < 0.01). For example, the activity of MMP2 (A x 10(3)):N: 1.43 +/- 0.24, H: 3.58 +/- 0.28, HD: 2.29 +/- 0.31.</p><p><b>CONCLUSION</b>Doxycycline attenuated PH and associated pulmonary vascular remodeling in all rat PH models. The study suggests that high expression and enhanced activity of MMPs may play a brutial role in the development of PH. Such phenomenon seems to be common in a variety of PH models of different etiology.</p>

Effect of resveratrol on myocardial fibrosis in mice with chronic viral myocarditis / 中国当代儿科杂志

<p><b>OBJECTIVE</b>Some research has shown that resveratrol can ameliorate myocardial injury and improve cardiac function in mice with acute viral myocarditis (VMC), and can inhibit cardiac fibroblast proliferation and myofibroblast differentiation in vitro. This study was designed to investigate whether resveratrol has similar effects in the mouse model of chronic VMC.</p><p><b>METHODS</b>One hundred mice were inoculated with 0.3 mL of Coxsackievirus B3 1*106 TCID50. Thirty days later, the survivors (n=62) were used as a model of chronic VMC, and were randomly assigned to 4 groups: untreated VMC, and low- (10 mg/kg), middle- (100 mg/kg) and high-dose (1 000 mg/kg) resveratrol-treated VMC (once daily, for 30 days). Ten mice which received neither Coxsackievirus B3 nor resveratrol treatment served as the control group. After 30 days of resveratrol treatment, the mice were sacrificed. Serum concentrations of collagenous pre-peptides (PINP, PICP and PIIINP) were assessed using ELISA. Hematoxylin-eosin staining, picrosirius red staining and circularly polarized light were used to examine the histochemistry of myocardial collagen.</p><p><b>RESULTS</b>The myocardial collagen volume fraction in the high-dose (0.74+/-0.19) and the middle-dose (1.07+/-0.12) resveratrol-treated VMC groups was significantly lower than that in the untreated VMC (2.33+/-0.18) and the low-dose resveratrol-treated VMC (2.17+/-0.19) groups (P<0.05). Compared with the untreated VMC group, serum concentrations of PICP and PIIINP in the high-dose and the middle-dose resveratrol-treated VMC groups were significantly reduced (P<0.05), while PINP concentrations increased significantly (P<0.05).</p><p><b>CONCLUSIONS</b>Resveratrol can inhibit hyperplasia of myocardial collagen in the mouse model of chronic VMC, acting as an effective anti-fibrotic agent in the myocardium.</p>

Expression of connective tissue growth factor and its down-regulation by simvastatin administration in pulmonary hypertensive rats / 中华儿科杂志

<p><b>OBJECTIVE</b>To explore the role of expression of connective tissue growth factor (CTGF) in pulmonary vascular remodeling of pulmonary hypertensive rats, and investigate the regulation of CTGF expression by simvastatin in this animal model.</p><p><b>METHODS</b>Eighty male Sprague-Dawley rats (350 to 400 g) were randomized to 7 groups. The rats in group PM(1 - 21) (n = 10) and PM(1 - 35) (n = 12) were treated with pneumonectomy + monocrotaline (MCT), and sacrificed at the 21st or 35th experimental day;those in groups PMS(1 - 35) (n = 12), PMS(21 - 35) (n = 12), PMV(1 - 35) (n = 12) and PMV(21 - 35) (n = 12) were given daily lavage of simvastatin (or vehicle) as intervention measure which began from the 1st and 21st experimental days, respectively; additional 10 rats were used as control without any intervention. The animals were sacrificed at the end of experiment (35 th day) as hemodynamic measurements and study on the morphological parameters relevant to pulmonary vascular remodeling were performed on each group of rats. The expression of ET-1 mRNA, CTGF mRNA and protein, and synthesis of collagen in these pneumonectomized, MCT-treated rats were compared between control and rats treated with simvastatin.</p><p><b>RESULTS</b>Rats in PM(1 - 35) Group developed severe PAH (mPAP = 39.75 +/- 3.62 mm Hg) (1 mm Hg = 0.133 kPa), right ventricular hypertrophy [RV/(LV + S) ratio = 0.627 +/- 0.040], and arterial medial hypertrophy (WT% = 61.73 +/- 5.39), these parameters of the control animals were 17.10 +/- 1.20 mm Hg, 0.262 +/- 0.018 and 14.71 +/- 1.16, respectively. CTGF mRNA and protein were mainly located in pulmonary arterial smooth muscle cells and interstitial macrophage shown by in situ hybridization and immunohistochemistry, respectively. The expression of ET-1 mRNA and CTGF mRNA detected by fluorescent quantitative RT-PCR in Group PM(1 - 35) were significantly increased in comparison with controls, and so did the CTGF protein expression determined by Western blotting in these diseased rats. The content of hydroxyproline (1.30 +/- 0.19 microg/mg wet lung) was remarkably higher than that of control animals (0.56 +/- 0.10 microg/mg wet lung). The up-regulation of ET-1 and CTGF gene expression, and elevated synthesis of hydroxyproline were reversed in rats intervened with simvastatin. The pulmonary hypertension, right ventricular hypertrophy and medial hypertrophy were attenuated in all simvastatin-treated rats no matter the intervention was initiated from the beginning or midway of the study.</p><p><b>CONCLUSION</b>The up-regulation of CTGF gene expression may play an important role in the development of pulmonary vascular remodeling in PAH. Simvastatin can prevent and, to some extent, reverse the vascular remodeling via down-regulation of CTGF gene expression.</p>

Interventional approach to the treatment of aneurysms of the perimembranous ventricular septal defects / 中华儿科杂志

<p><b>OBJECTIVES</b>To explore applicable protocol for the positioning of ventricular septal defect (VSD) occluder and the selection of the device by retrospective analysis of transcatheter closure approach to the aneurysms of the perimembranous VSD.</p><p><b>METHODS</b>Thirty-five cases of perimembranous VSD with septal aneurysm (19 males and 16 females) from May, 2004 to May, 2005 were included, with a mean age of 5.3 y and mean weight of 17.6 kg. Their angiographic and ultrasound data, and interventional processes were analyzed. Seven segments of the aneurysms were assessed: the diameter of the defect on the left ventricle, the diameter of the defect on the right ventricle, the thickness of ventricular septum, the distance from the farthest end of the aneurysm to the defect, the diameter of the widest part of the aneurysm and the distance between the two farthest orifices on the aneurysm.</p><p><b>RESULTS</b>Sixteen cystiform aneurysms and nineteen tubiform ones were identified with left ventricular angiography. The diameters of the orifices of aneurysms and the diameters of the VSDs ranged from 1.5 mm to 4.1 mm and 2.7 mm to 11.9 mm, separately, with the mean of 2.9 mm and 4.3 mm. From the echocardiography, the distances of the rim of defect to the aortic valve ranged from 2.0 mm to 7.0 mm, with the mean of 4.3 mm. All the interventions were successfully done with symmetrical devices from 4 mm to 14 mm. The left disc of the device was positioned at the defect surface from the left ventricle in 29 cases, and was released at the left side of the orifice in 3 cases.</p><p><b>CONCLUSIONS</b>The positioning of the left disc is mostly determined by the condition for the correct formation of the right disc in the right ventricle after deploying. Generally the defect surface in the left ventricle is most ideal to release the left disc of the device. If the body of aneurysm was too long for the right disc to restore its configuration, the left disc should be released on the left side of the orifice. The selection of device size is determined by the placement of the left disc. When the left disc is to be released at the defect surface in the left ventricle, the device size should be equal to or 1 to 2 mm larger than the diameter of the defect on the left ventricle. When the left disc is to be deployed on the left side of an orifice, the device size should be equal to or 1 mm larger than the defect diameter on the left ventricle when there is a single orifice. In the case of multiple orifices, the minimal size of the device which can cover all the orifices should be selected.</p>

Clinical value of serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 for the prediction and early diagnosis of coronary artery lesion in patients with Kawasaki disease / 中华儿科杂志

<p><b>OBJECTIVE</b>Kawasaki disease (KD) complicated with coronary artery lesion (CAL) seriously threatens survival quality and life of patients, suggesting that it is very important to early predict the risk of CAL and to early diagnose the disease. Nevertheless, up to now there has been no specific clinical biochemical marker for it because of the poor understanding of the pathological process of KD with CAL. Matrix metalloproteinases (MMPs) and their specific tissue inhibitor of metalloproteinases (TIMPs) play an important role in arterial wall extracellular matrix breakdown and remodeling and are involved in CAL in other diseases. In the present study the practical value of serum MMP-9 and TIMP-1 levels in the prediction and early diagnosis of CAL in KD patients was investigated.</p><p><b>METHODS</b>All subjects were from Chinese population. Serum levels of MMP-9 and TIMP-1 were measured by rapid one-step sandwich enzyme immunoassay in 59 KD patients including 15 with CAL and 44 without CAL by 2 D-echocardiography and coronary angiography, and 20 normal healthy children as controls. Blood samples of patients were obtained before and after intravenous immunoglobulin (IVIG) treatment in acute stage, subacute stage and convalescent stage as well. Serum MMP-9 and TIMP-1 levels and the ratio of MMP-9/TIMP-1 were compared by statistical method in KD patients and controls, as well as in KD with CAL and without CAL.</p><p><b>RESULTS</b>In acute stage serum MMP-9 and TIMP-1 levels and the ratio of MMP-9/TIMP-1 were higher (P < 0.01) in patients with KD than those in healthy children. After IVIG treatment in KD patients serum MMP-9 level and the ratio of MMP-9/TIMP-1 decreased (P < 0.01). Before IVIG treatment serum MMP-9 level and the ratio of MMP-9/TIMP-1 were higher (P < 0.01) in patients with CAL than those in patients without CAL, and in acute stage after IVIG treatment serum MMP-9 level of KD patients with CAL was still higher than that of KD patients without CAL.</p><p><b>CONCLUSION</b>In acute stage of KD serum MMP-9 level and the ratio of MMP-9/TIMP-1 were higher in patients with CAL than those in patients without CAL, suggesting that during acute phase of KD the great increase in serum MMP-9 and the imbalance of the MMP-9/TIMP-1 ratio might be high risk factors of KD coronary artery lesion. Therefore, the measurement of serum MMP-9 and TIMP-1 might be of important clinical value in the prediction and the early diagnosis of KD with coronary artery lesion.</p>