The Complementary Relationship Between Echocardiography and Multi-Slice Spiral CT Coronary Angiography in the Diagnosis of Coronary Artery Thrombosis in Children With Kawasaki Disease.

Aim: To compare the diagnostic values by using transthoracic echocardiography (ECHO) and multi-slice spiral CT coronary angiography (CTCA) for identifying coronary artery thrombosis in children with Kawasaki disease (KD). Methods: Total 97 KD children with coronary artery dilation complications in our hospital from June 2012 to December 2020 were included in the study. CTCA and ECHO were performed after over 1 month of illness. Results: Coronary artery thrombosis was found in 14 out of 97 patients. Among them, 10 were identified as positive by CTCA, 9 were identified as positive by ECHO, and 5 were identified as positive by both CTCA and ECHO. Conclusion: Both CTCA and ECHO can be used to diagnose coronary artery thrombosis. ECHO has advantage in identifying low-density thrombus, and CTCA is better for the clot in distal coronary artery. They can complement each other.

Correlation Between Arrhythmia and the Prognosis in Children With EFE/LVNC/DCM.

Aim: To explore the correlation between different phenotypes of arrhythmia and the prognosis in children with EFE/LVNC/DCM. Methods: A total of 167 children with cardiomyopathy diagnosed and treated in Shengjing Hospital between January 2010 and May 2019 were evaluated. After patient screening, 31 patients with endomyocardial fibroelastosis (EFE), left ventricular non-compaction, or dilated cardiomyopathy with significant arrhythmias were selected. In addition, 42 children with primary EFE were selected to evaluate the prognosis with or without arrhythmia. Follow-up was undertaken 0, 1, 3, 6, 9, and 12 months after treatment. Results: We revealed the outcomes for five types of cardiomyopathy: EFE patients with Wolff-Parkinson-White syndrome B and supraventricular tachycardia, intraventricular block and complete left bundle branch block recovered slower than EFE patients with atrial flutter and atrial fibrillation, even slower than EFE with ventricular tachycardia. The average recovering time for LVEF and LVED in EFE patients without arrythmia was 10 months after diagnosis, while 76.9% (3/13 cases) of those with significant arrythmia hadn't recovered until 24 months after diagnosis. Three of patients died at 6, 7, and 6 and half years after diagnosis. Conclusion: The long-term prognosis in children with cardiomyopathy is associated with the type of arrhythmia and time of intervention. The prognosis of EFE patients with arrhythmia is worse than EFE patients without arrhythmia. Patients with Wolff-Parkinson-White syndrome B, especially a significantly widen QRS complex, carry a poor prognosis if radiofrequency ablation is not undertaken. CLBBB patients have similar poor prognosis if proper pacemaker is not implanted timely.

A Wide and Specific Spectrum of Genetic Variants and Genotype-Phenotype Correlations Revealed by Next-Generation Sequencing in Patients with Left Ventricular Noncompaction.

BACKGROUND: Left ventricular noncompaction (LVNC) has since been classified as a primary genetic cardiomyopathy, but the genetic basis is not fully evaluated. The aim of the present study was to identify the genetic spectrum using next-generation sequencing and to evaluate genotype-phenotype correlations in LVNC patients. METHODS AND RESULTS: Using next-generation sequencing, we targeted and sequenced 73 genes related to cardiomyopathy in 102 unrelated LVNC patients. We identified 43 pathogenic variants in 16 genes in 39 patients (38%); 28 were novel variants. Sarcomere gene variants accounted for 63%, and variants in genes associated with channelopathies accounted for 12%. MYH7 and TAZ pathogenic variants were the most common, and rare variant collapsing analysis showed variants in these genes contributed to the risk of LVNC, although patients carrying MYH7 and TAZ pathogenic variants displayed different phenotypes. Patients with pathogenic variants had early age of onset and more severely decreased left ventricular ejection fractions. Survival analysis showed poorer prognosis in patients with pathogenic variants, especially those with multiple variants: All died before their first birthdays. Adverse events were noted in 17 patients, including 13 deaths, 3 heart transplants, and 1 implantable cardioverter-defibrillator insertion. Congestive heart failure at diagnosis and pathogenic variants were independent risk factors for these adverse events. CONCLUSIONS: Next-generation sequencing revealed a wide spectrum of genetic variations and a high incidence of pathogenic variants in LVNC patients. These pathogenic variants were independent risk factors for adverse events. Patients harboring pathogenic variants showed poor prognosis and should be followed closely.

Long-Term Prognosis of Patients With Left Ventricular Noncompaction　- Comparison Between Infantile and Juvenile Types.

BACKGROUND: The natural history of left ventricular noncompaction (LVNC) is largely unsolved, so the aim of the present study was to clarify the clinical features and long-term prognosis of children with LVNC until adulthood.Methods and Results:We conducted a nationwide survey over 20 years and compared the clinical features, anatomical characteristics and long-term prognosis of 205 patients divided into 2 classifications: infantile type (diagnosed at <1 year of age: 108 cases) and juvenile type (diagnosed 1-15 years of age: 97 cases). Most patients diagnosed during infancy had heart failure (HF) at initial presentation (60.19%), while the majority of juvenile cases were asymptomatic (53.61%) but their event-free survival rate decreased gradually, because of later HF, thromboembolism and fatal arrhythmias. The initial LVEF was significantly lower in the infantile type and correlated with the thickness of the compacted layer in the LV posterior wall (LVPWC) and LV end-diastolic dimension (LVDD) Z-score, but not to the noncompacted to compacted layer (N/C) ratio. Survival analysis showed prognosis was similarly poor for both types after 2 decades. The significant risk factors for death, heart transplantation or implantable cardioverter-defibrillator insertion were congestive HF at diagnosis and lower LVPWC Z-score but not age of onset. CONCLUSIONS: LVNC of both types showed poor long-term prognosis, therefore ongoing follow-up is recommended into adulthood. HF at diagnosis and LVPWC hypoplasia are major determinants of poor prognosis.

Exploring the genes associated with the response to intravenous immunoglobulin in patients with Kawasaki disease using DNA microarray analysis.

In this study we aimed to screen genes associated with intravenous immunoglobulin (IVIG) responding in patients with Kawasaki disease (KD) and thus explore the underlying molecular mechanism of IVIG resistance. The differentially expressed genes (DEGs) were identified by samr package in R. Then, protein-protein interaction (PPI) networks were constructed by STRING software. We further collected the regulatory data from TRANSFAC database, followed by regulatory interaction network construction. A total 194 of DEGs, including 185 up- and 9 down-regulated DEGs, were identified between IVIG-responding and non-responding patients with KD at acute stage. In contrast, no DEGs were found at convalescent stage. PPI networks and regulatory networks were constructed based on the 185 up-regulated genes at acute stage. The degrees of TFRC (transferrin receptor protein 1) and GADD45A (growth arrest and DNA-damage-inducible alpha) were higher than other genes, and meanwhile MYC (V-Myc Myelocytomatosis Viral Oncogene Homolog) and E2F1 (E2F Transcription Factor 1) were found to be two TFs (transcription factors) with the highest degrees. In conclusions, the response to IVIG in Kawasaki disease patients may be involved in the expression of TFRC, GADD45A, MYC and E2F1.

Meta-analysis of the relationship between single nucleotide polymorphism rs72689236 of caspase-3 and Kawasaki disease.

Kawasaki disease is a pediatric systemic vasculitis of unknown etiology, for which a genetic influence is suspected. But whether single nucleotide polymorphism (SNP) of caspase-3 rs72689236 is associated with Kawasaki disease is controversial. The aim of our study is to assess the association between the SNP of caspase-3 and risk for Kawasaki disease. We searched PubMed, MEDLINE, EMBASE, Springer, Elsevier Science Direct, Cochrane Library Google scholar, CNKI (China National Knowledge Infrastructure, in Chinese) and Wanfang database (in Chinese) to identify studies investigating the association between rs72689236 polymorphism and Kawasaki disease occurrence. There were five eligible studies, which included 4,241 (case group 1,560; control group 2,681) participants in this meta-analysis. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were calculated in a fixed-effects model (the Mantel-Haenszel method) or a random-effects model (the DerSimonian and Laird method) when appropriate. Significant associations were found under the overall ORs for A-allele comparison (A vs. G, pooled OR 1.33, 95 % CI 1.21-1.46), AA versus GG comparison (pooled OR 1.64, 95 % CI 1.35-2.00), GA versus GG comparison (pooled OR 1.42, 95 % CI 1.24-1.63), recessive model (AA vs. GG + GA, pooled OR 1.37, 95 % CI 1.15-1.64) and dominant model (AA + GA vs. GG, pooled OR 1.47, 95 % CI 1.29-1.67). This meta-analysis suggested that SNP rs72689236 of caspase-3 might be associated with susceptibility of Kawasaki disease and the allele A might increase the risk of Kawasaki disease in Asian samples such as Japanese and Chinese. In addition, individual studies with large sample size are needed to further evaluate the associations in various ethnic populations.

[Prognostic significance of serum level of vascular endothelial growth factor receptor-2 in hepatocellular carcinoma patients after transcatheter arterial chemoembolization].

OBJECTIVE: To explore the prognostic significance of serum vascular endothelial growth factor receptor-2 (VEGFR-2) in patients with hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). METHODS: A total of 69 HCC patients undergoing TACE from October 2008 to April 2012 were recruited and examined. Their serum level of VEGFR-2 level was measured by enzyme-linked immunosorbent assay (ELISA). The relationship between VEGFR-2 and their clinicopathologic features were observed. Prognostic significance of VEGFR-2 was assessed for their survival. RESULTS: Significant differences existed when the serum level of VEGFR-2 was categorized by tumor number and liver cirrhosis (P = 0.021, P = 0.049). The post-treatment serum level of VEGFR-2 was significant higher than that at pre-treatment (P = 0.045). When the mean pre-treatment serum level of VEGFR-2 (8709 ng/L) was used as a cut-off point, the patients with a low serum level of VEGFR-2 had better overall and progression-free survival than those with a high serum level of VEGF (17 vs. 28 months, P = 0.001 and 10 vs. 15 months P = 0.031 respectively). As revealed by multivariate Cox analysis, the pre-treatment serum level of VEGFR-2 was an independent and significant prognostic factor of survival for HCC patients at post-TACE. CONCLUSION: The pre-treatment serum level of VEGFR-2 may predict the post-TACE prognosis in HCC patients.

Effects of cold stress on mRNA expression of immunoglobulin and cytokine in the small intestine of broilers.

To investigate the effects of cold stress on mRNA expression of immunoglobulin and cytokine in small intestine of broilers, eighty-four 15-day-old male chickens were randomly divided into 12 groups. There were 1 control (25°C) and 5 acute stress groups (under the temperature of 12 ± 1°C) for 1, 3, 6, 12 and 24h, 3 control (25°C) and 3 chronic cold stress groups (under the temperature of 12 ± 1°C) for 5, 10, and 20d. The mRNA expression levels of IL-2, IL-4, IL-7, IL-10, IL-17, IFN-γ, IgA, IgM, IgG, plgR, and TGF-ß4 in duodenum, jejunum and ileum were detected by real-time PCR. The results showed that expression levels of IgM, IgA, IgG, plgR and IL-7 had an increased tendency in acute and chronic cold stress, especially plgR that was markedly increased in the duodenum than jejunum and ileum in the acute cold stress. In addition, the mRNA expression levels of IL-2, IFN-γ, IL-4, IL-17 and TGF-ß4 had a first increased then decreased tendency in acute and chronic cold stress groups, however, expression levels of IL-4 were higher in the stress groups than control groups. The histopathological detect showed that issues in cold stress group was seriously injured. These results demonstrated that cold stress could cause the change of immune function in chicken intestinal.

14-3-3ε gene variants in a Japanese patient with left ventricular noncompaction and hypoplasia of the corpus callosum.

BACKGROUND: Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by a prominent trabecular meshwork and deep intertrabecular recesses, and is thought to be due to an arrest of normal endomyocardial morphogenesis. However, the genes contributing to this process remain poorly understood. 14-3-3ε, encoded by YWHAE, is an adapter protein belonging to the 14-3-3 protein family which plays important roles in neuronal development and is involved in Miller-Dieker syndrome. We recently showed that mice lacking this gene develop LVNC. Therefore, we hypothesized that variants in YWHAE may contribute to the pathophysiology of LVNC in humans. METHODS AND RESULTS: In 77 Japanese patients with LVNC, including the probands of 29 families, mutation analysis of YWHAE by direct DNA sequencing identified 7 novel variants. One of them, c.-458G>T, in the YWHAE promoter, was identified in a familial patient with LVNC and hypoplasia of the corpus callosum. The -458G>T variant is located within a regulatory CCAAT/enhancer binding protein (C/EBP) response element of the YWHAE promoter, and it reduced promoter activity by approximately 50%. Increased binding of an inhibitory C/EBPß isoform was implicated in decreasing YWHAE promoter activity. Interestingly, we had previously shown that C/EBPß is a key regulator of YWHAE. CONCLUSIONS: These data suggest that the -458G>T YWHAE variant contributes to the abnormal myocardial morphogenesis characteristic of LVNC as well as abnormal brain development, and implicate YWHAE as a novel candidate gene in pediatric cardiomyopathies.

[Relationship between sorafenib-associated hand-food skin reaction and efficacy in treatment of advanced hepatocellular carcinoma].

OBJECTIVE: To investigate the link between the antitumor efficacy of sorafenib and its cutaneous side effects in advanced hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed the incidence of hand-foot skin reactions (HFRS) of 51 patients with advanced HCC who treated by sorafenib combined with transcatheter arterial chemoembolization (TACE), comparing tumor disease control rate (DCR), median progression free survival (mPFS) and median overall survival (mOS) in the different severity HFRS groups. The Cox proportional hazard model was applied to the multivariate survival analysis for the PFS. RESULTS: Fifty-one HCC patients treated with sorafenib combined with TACE were included in this study. 13/51 without HFRS (grade 0), 38/51 developed at all grade 1-3, 27 developed at grade 1-2, 11 developed at grade 3. The DCR were 38.5%, 70.4% and 90.9% in the three groups (P < 0.05). Group grade 0 vs grade 1-3, P = 0.031, the difference had statistical significance. Group grade 1-2 vs grade 3, P = 0.352, the difference had no statistical significance. The mPFS were 2.8 months (95%CI 1.6 - 4.0), 4.5 (95%CI 1.3 - 7.7) months and 12.8 (95%CI 3.7 - 21.9) months (P < 0.05), group grade 0 vs grade 1-2, P = 0.019, HR (hazard ratio): 2.8 (95%CI 1.3 - 6.3), P = 0.010, group grade 0 vs grade 3, P < 0.01, HR 6.6 (95%CI 2.3 - 19.0), P < 0.01, group grade 1-2 vs grade 3, P = 0.054; the three groups' mOS were 8.5 months (95%CI 5.9 - 11.1), 13.0 (95%CI 10.1 - 15.9) months and 25.4 months, P < 0.05, there were statistically significant differences between the any two groups. CONCLUSIONS: HFRS should be closely monitored in HCC patients treated with sorafenib in relation to its potential role as a surrogate marker of efficacy, but it has yet to be demonstrated whether the efficacy increasing with the severity of HFRS or not.

[One case of adult Kawasaki disease].

Kawasaki disease is far more frequent in children than in adults. The pathogenesis of Kawasaki disease is unknown, but it involves changes to the coronary artery and other diverse clinical manifestations. There are currently no specific laboratory diagnostic indexes, and especially since the disease is rare in adults, so it is extremely easy to misdiagnose or to overlook entirely. Our retrospective analysis of an diagnosis of and treatment for Kawasaki disease in an adult provides a guide to clinical doctors in terms of understanding Kawasaki disease, early diagnosis of it, and improved prognosis.

[The limitation of MB isoenzyme of creatine kinase mass in assess myocardial injury with muscular disease].

OBJECTIVE: To examine the changes in serum MB isoenzyme of creatine kinase mass (CK-MB mass), cardiac troponin I (cTnI), and myoglobulin (Mb) in children with myocarditis and muscular disease in order to evaluate the significance of index CK-MB mass for the diagnosis of myocardium injury in these diseases. METHODS: Blood samples were collected from 40 children with myocarditis, 38 children with muscular diseases, and 10 healthy children, for the measurement of creatine kinase (CK), CK-MB activity, CK-MB mass, cTnI, and Mb. Myocarditis patients also received electrocardiogram and pulse Doppler electrocardiogram examination while muscular diseases patients were subjected to electro-myographic examination, inherit-metabolic diseases screening and related gene analysis. The data were analyzed for differences between groups, and differences between values before and after the treatment. RESULTS: In comparison with healthy controls [CK (U/L): 95.0 ± 27.0, CK-MB activity (U/L): 22.6 ± 1.3, CK-MB mass (µg/L): 2.4 ± 0.3, cTnI (µg/L): 0.012 ± 0.001], the patients with myocarditis had significantly (all P < 0.01) higher mean values in CK (1033.0 ± 408.0), CK-MB activity (101.2 ± 31.5), CK-MB mass (38.2 ± 13.2) and cTnI (5.544 ± 1.554) before the treatment. After 2 weeks of treatment these indexes returned to the level of controls, with cTnI responded the last (CK: 59.3 ± 25.1, CK-MB activity: 24.6 ± 13.2, CK-MB mass: 3.3 ± 2.9, cTnI: 0.125 ± 0.128). One week after treatment, the incidences of CK and CK-MB mass elevation were significantly lower than the values before the treatment [CK: 5.9% (1/17) vs. 56.4% (22/39); CK-MB mass: 8.3% (1/12) vs. 61.1% (22/36), both P < 0.01], with the change in CK-MB mass appeared significantly earlier than cTnI [8.3% (1/12) vs. 73.7% (14/19), P < 0.05]. The patients with muscular disease also had significantly elevated mean value in CK (10193.0 ± 1447.0), CK-MB activity (311.7 ± 44.4), and CK-MB mass (229.2 ± 47.9) in comparison with healthy controls before the treatment (all P < 0.01). But their cTnI (0.021 ± 0.002) was not significantly different from the control at this time. Two weeks after treatment, the elevated indexes were still significantly higher than the control (CK: 5735.6 ± 6187.8, CK-MB activity: 170.7 ± 143.0, CK-MB mass: 207.4 ± 136.6), while the level of cTnI (0.230 ± 0.150) remained at the level of the control group. The incidence of index elevation was not significantly different from the values before the treatment for all the indexes tested [CK: 85.7% (6/7) vs. 97.4% (37/38); CK-MB activity: 85.7% (6/7) vs. 97.4% (37/38); CK-MB mass: 100.0% (2/2) vs. 94.1% (32/34); cTnI: 0(0/1) vs. 6.4% (2/31), all P > 0.05]. CONCLUSIONS: In patients with myocarditis, CK-MB mass and cTnI both follow a consistent pattern of change: elevated in the acute stage of the disease but return to normal after recovery. In patients with muscular diseases, these 2 indexes have different pattern of change. CK-MB mass is significantly higher than control even after the treatment, while cTnI value remain unchanged. Therefore, CK-MB mass has very limited value as an index for myocardial injury in these patients.

Gonadal mosaicism of a TAZ (G4.5) mutation in a Japanese family with Barth syndrome and left ventricular noncompaction.

TAZ (G4.5) was initially identified as the gene associated with Barth syndrome and left ventricular noncompaction (LVNC). The purpose of this study was to investigate patients with LVNC for disease-causing mutations in TAZ. In 124 Japanese patients, including 50 families, mutation analysis of TAZ was performed using DNA sequencing. A splice donor mutation was identified in two brothers with Barth syndrome and LVNC, and a sister who was asymptomatic. However, the variant was not identified in either parent or the maternal grandparents, all of whom were asymptomatic. Due to the recurrent inheritance of this variant by each of the children we concluded that this was evidence of gonadal mosaicism in the obligate carrier mother, the first reported occurrence of this in Barth syndrome.

Assessment of coronary artery lesions in children with Kawasaki disease: evaluation of MSCT in comparison with 2-D echocardiography.

BACKGROUND: Transthoracic two-dimensional echocardiography is an effective method for detecting coronary arterial injury in Kawasaki disease. However, its accuracy in the diagnosis of coronary arterial lesions is limited. OBJECTIVE: To investigate the value of multislice spiral CT for coronary angiography for observing the coronary arterial injury caused by infantile Kawasaki disease. MATERIALS AND METHODS: Coronary angiography, using a 64-slice spiral CT scanner, and 2-D echocardiography were performed in 48 children with Kawasaki disease in whom the position, internal diameter, and length of each coronary artery were measured. RESULTS: MSCT showed coronary artery injury in 15 of the 48 children. Among these 15 children, 20 coronary artery branches showed complications, including the left coronary artery branches in 15 (31.2%) and the right coronary artery branches in 5 (10.4%). Complications in the left coronary artery branches included dilation in 12 (25.0%) and stenosis, calcification and the combination of the two in one each, and the right coronary artery branches showed dilation; two branches also showed beaded changes. MSCT also showed dilation in the left anterior descending arteries in two children. These children showed no abnormality on 2-D echocardiography. CONCLUSION: MSCT is a valuable examination method for detecting coronary artery injury in Kawasaki disease.

[Effects of glutamine on matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-3 expressions in myocardium of rats with sepsis].

OBJECTIVE: The underlying mechanisms for cardiac dysfunction in sepsis include the inhibitory effect of endotoxin and inflammatory factors on myocardium and the decrease in cardiac myocardial cells in number. However, whether there is ventricular remodeling resulted from the abnormalities of extracellular collagen metabolism and whether glutamine (Gln) can protect myocardium from LPS-induced damage as in reperfusion are unknown. The aim of the present study was to examine the effects of Gln on the expressions of matrix metalloproteinase-3 (MMP-3), tissue inhibitor of metalloproteinase-3 (TIMP-3) and their mRNA in myocardium of rats with sepsis. METHODS: Classical rat model of sepsis was established by intraperitoneal injection of lipopolysaccharide (LPS) (4 mg/kg, from Escherichia coli O(55): B(5), Sigma). from 121 Wistar rats aged 18 days were divided into three groups randomly, 0 h control group (normal saline: 1 ml/kg, n = 11), LPS group (LPS: 4 mg/kg, n = 55) and Gln group (LPS: 4 mg/kg and immediately 13.64% glutamine 1 ml/kg, Fresenus, n = 55). Furthermore, LPS and Gln groups were examined at 2 h, 4 h, 6 h, 24 h and 72 h time points (n = 11). On each time point, rats of LPS and Gln groups as well as control group were anesthetized with 1% chloral hydrate injected intraperitoneally at a dosage of 1 ml/kg. Then, rats were sacrificed, and the hearts were isolated. Eight of them were frozen at minus 80 degrees C to measure the expression of TIMP-3 mRNA by using RT-PCR. The expressions of MMP-3 and TIMP-3 were observed with immunohistochemistry and the expression of MMP-3 mRNA was observed by using in situ hybridization. RESULTS: (1) Compared to 0 h, the mRNA expressions of MMP-3 and TIMP-3 in LPS group significantly increased (P < 0.01) with the peak at 6 - 24 h. While, in Gln group, they were significantly higher than those in controls but significantly lower than those in LPS group with the peak at 24 h (P < 0.01). Even at 72 h, they were still higher than those at 0 h (P < 0.05 and P < 0.01). (2) Compared to 0 h, the expressions of MMP-3 and TIMP-3 in LPS group were significantly lower at any other time point with the lowest at 6 h (P < 0.01). In Gln group, these expressions were also significantly lower than those in controls, but significantly higher than those in LPS group with the lowest being postponed to 24 h (P < 0.01). (3) The ultra structure changed obviously. Z line was unclear and the ridge of mitochondrion disappeared. While, in Gln group, the myocardial injury was slight compared to that in LPS group. CONCLUSIONS: MMP-3 mRNA expression was increased and TIMP-3 mRNA expression was depressed in LPS-induced sepsis. Myocardial extracellular matrix was damaged in sepsis. Glutamine might decrease the effects of LPS on MMP-3 and TIMP-3 expressions and postpone the time of myocardial matrix injury.