MYH7 in cardiomyopathy and skeletal muscle myopathy.

Myosin heavy chain gene 7 (MYH7), a sarcomeric gene encoding the myosin heavy chain (myosin-7), has attracted considerable interest as a result of its fundamental functions in cardiac and skeletal muscle contraction and numerous nucleotide variations of MYH7 are closely related to cardiomyopathy and skeletal muscle myopathy. These disorders display significantly inter- and intra-familial variability, sometimes developing complex phenotypes, including both cardiomyopathy and skeletal myopathy. Here, we review the current understanding on MYH7 with the aim to better clarify how mutations in MYH7 affect the structure and physiologic function of sarcomere, thus resulting in cardiomyopathy and skeletal muscle myopathy. Importantly, the latest advances on diagnosis, research models in vivo and in vitro and therapy for precise clinical application have made great progress and have epoch-making significance. All the great advance is discussed here.

Sildenafil Improves Pulmonary Vascular Remodeling in a Rat Model of Persistent Pulmonary Hypertension of the Newborn.

ABSTRACT: Persistent pulmonary hypertension of the newborn (PPHN) is characterized by pulmonary arterial remodeling mainly because of apoptosis resistance and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Sildenafil is a phosphodiesterase-5 inhibitor. Some reports have shown that sildenafil exerts protective effects against PPHN. However, the function of sildenafil in PPHN and the underlying molecular mechanisms is not clear. Here, we revealed that sildenafil effectively suppressed hypoxia-induced PASMC proliferation and apoptosis inhibition ( P < 0.05). Also, sildenafil obviously reduced ventricular hypertrophy, and inhibited pulmonary vascular remodeling in the PPHN model ( P < 0.05). Moreover, sildenafil treatment significantly attenuated the induction of Notch3 and Hes1 induced by hypoxia treatment ( P < 0.05). Furthermore, overexpression of Notch3 abolished the reduction of PASMC proliferation and promotion of PASMC apoptosis induced by sildenafil under hypoxia ( P < 0.05), whereas knockdown of Notch3 had an opposite effect ( P < 0.05). Together, our study demonstrates that sildenafil shows a potential benefit against the development of PPHN by inhibiting Notch3 signaling, providing a strategy for treating PPHN in the future.

Predictive value of monocyte to HDL-C ratio for coronary artery lesions and intravenous immunoglobulin resistance in Kawasaki disease.

We aimed to investigate the predictive validity of monocyte to high-density lipoprotein cholesterol ratio (MHR) for coronary artery lesions (CALs) and intravenous immunoglobulin (IVIG) resistance in complete Kawasaki disease (KD). MHR values of a total of 207 complete KD patients were calculated and analyzed with regard to their clinical characteristics and outcomes. We compared the differences in clinical data and laboratory parameters between CAL+ group and CAL- group as well as between IVIG-resistant group and IVIG-responsive group. Spearman's correlation analysis was applied to evaluate the correlation between C-reactive protein (CRP) and MHR. Multivariate logistic regression was used to identify risk factors of CALs and IVIG resistance. Receiver operating characteristic (ROC) curve analysis was chosen to determine the optimal cut-off value of MHR and its validity in predicting CALs and IVIG resistance. The MHR level was significantly higher in the CAL+ group, with cut-off value of 1.30 g/L, yielding a sensitivity of 0.753 and specificity of 0.805, as well as in IVIG-resistant group, with cut-off value of 1.03 g/L, yielding a sensitivity of 0.97 and specificity of 0.485. Multivariate logistic regression showed that MHR was an independent risk factor for CALs but not for IVIG resistance. According to the Spearman's correlation analysis, CRP was positively correlated with the MHR. CONCLUSIONS: As a practical, cost-effective inflammatory biomarker, MHR has a significantly predictive value in complete KD children complicated with CALs and IVIG-resistance. Paying more attention to the changes of MHR in KD children may contribute to better understanding of KD development and prognosis in clinical practice. WHAT IS KNOWN: • CALs are the most prevalent serious sequela of KD, and approximately 10%~20% of patients do not respond to IVIG therapy. • MHR could be a convenient biomarker to predict the development and progression of CVDs. It has been reported that the MHR is a new prognostic biomarker in several CVDs. WHAT IS NEW: • MHR has a significantly predictive value in KD children complicated with CALs and IVIG-resistance. • Compared with the molecular and immunological biomarkers that have been reported, MHR has the characteristics of practical, cost-effective, higher sensitivity and specificity, which can be used as a predictive indicator in complete KD patients.

Novel pathogenic variant of MYBPC3 responsible for hypertrophic cardiomyopathy.

OBJECTIVES: This study aims to investigate the pathogenic gene variant in a family with hypertrophic cardiomyopathy by using whole-exome sequencing and to explore the relationship between the gene variant and clinical phenotype. METHODS: Peripheral blood was collected from a family with hypertrophic cardiomyopathy, and deoxyribonucleic acid was extracted. The possible pathogenic genes were detected by whole-exome sequencing, and the variant was verified by Sanger sequencing. Functional change in the variant was predicted by bioinformatics software. Clinical data of the family members are analysed simultaneously. RESULTS: The proband carries a novel heterozygous nonsense variant of MYBPC3:c.2731G > T (p.E911X). The analysis of amino acid conservation suggests that the variation is highly conserved. The three-dimensional protein structure shows that the variant in MYBPC3 results in the incompleteness of the fibronectintype-III2 (p872-967) domain and deletion of Ig-like C2-type 6 (p971-1065) and fibronectin type-III 3 and Ig-like C2-type 7 (p1181-1274) domains, in which p1253-1268 is predicted to have a transmembrane helix structure. Clinical data indicate that the phenotypes of variant carriers with hypertrophic cardiomyopathy are diverse, suggesting the functional damages to the protein of MYBPC3. CONCLUSION: The phenotypes of variant carriers with hypertrophic cardiomyopathy caused by the novel variant in MYBPC3: c.2731G > T (p.E911X) exhibit variable severity and clinical manifestations. Whole-exome sequencing can be used to comprehensive screen hypertrophic cardiomyopathy genes and provide a strong basis for early screening and accurate diagnosis and treatment of hypertrophic cardiomyopathy in children.

The Influence of Bosentan on MicroRNA-27a/PPARγ/ET-1 Signaling Pathway in Pulmonary Artery Hypertension.

Pulmonary artery hypertension (PAH) is a common and serious disease which is characterized by pulmonary vascular remodeling. Bosentan (BST) is the first approved oral targeted drug of endothelin-1 (ET-1) receptor antagonists for the treatment of PAH. MicroRNA-27a (miR-27a) and peroxisome proliferator-activated receptor γ (PPARγ) were found to be related to the pathogenesis of PAH. To further explore the signal transduction mechanism of BST in the treatment of PAH, we examined the effects of BST on endothelin receptors, miR-27a, and PPARγ. Meanwhile, the influence of miR-27a in the formation and development of PAH was discussed. Our results demonstrated that during the pathophysiology of PAH, miR-27a, PPARγ, and ET-1 were cross-inhibited, which indicated that the miR-27a/PPARγ/ET-1 signaling pathway was dysregulated; in addition, BST could competitively bind to ET-1 receptors and inhibit the miR-27a/PPARγ/ET-1 signaling pathway, thereby delaying the proliferation of PASMCs and affecting the development of PAH. Our results give a new understanding of the pathogenesis and treatment of PAH and provide more reliable evidence for the application of BST in the treatment of PAH in the clinic.

New pathogenic variant of BMPR2 in pulmonary arterial hypertension.

OBJECTIVES: The aim of this study was to evaluate the variant frequency of pulmonary arterial hypertension-related genes and provide theoretical basis for genetic screening of patients with pulmonary arterial hypertension further. METHODS: Ten genes associated with pulmonary arterial hypertension were sequenced in 7 cases of idiopathic pulmonary arterial hypertension and 34 cases of congenital heart disease (CHD) associated with pulmonary arterial hypertension by next-generation high-throughput sequencing. Function prediction and gene variant amino acid conservation were carried out by bioinformatics software. Family study was performed on the patients with the variant. RESULTS: A new bone morphogenetic protein receptor type 2(BMPR2) variant (c.344T>C, p. F115S) was discovered in a girl who was diagnosed with idiopathic pulmonary arterial hypertension. Her second aunt and third aunt carried the same variant and were confirmed as patients with pulmonary arterial hypertension as well. No variants or single nucleotide polymorphisms were found in other pulmonary arterial hypertension-associated genes. CONCLUSIONS: BMPR2 variant is the most common variant of pulmonary arterial hypertension. Genetic screening of BMPR2 variant and family survey in patients with pulmonary arterial hypertension is suggested for the sake of definite cause and better treatment.

Association between the promoter methylation of the TBX20 gene and tetralogy of fallot.

OBJECTIVES: To investigate the association between promoter methylation of the TBX20 gene and tetralogy of Fallot (TOF)． Methods. The methylation level of TBX20 promoter regions in 23 patients with TOF and five controls were analyzed through bisulfite sequencing polymerase chain reaction. Meanwhile, the expression of TBX20 mRNA was measured using real time fluorescence quantitative polymerase chain reaction. RESULTS: The region -400 to -48 in the TBX20 promoter consisting of 42 CpG sites was predicted to contain multiple transcription factor binding sites. In this study, the overall methylation level in this region was lower in patients with TOF than in the controls (P = .035). Among the 42 CpG sites, the methylation percentages of the CpG 26 site in the TOF cases were lower than those in the controls (P = .016). The mRNA expression of TBX20 in the right ventricular outflow tract myocardium was increased in TOF cases in contrast to those in the controls (P < .001). The methylation levels in TOF cases were correlated with mRNA expression values (r = -0.81, P < .001). CONCLUSION: The downregulated methylation level at TBX20 promoter may be responsible for the elevated mRNA expression levels in patients with TOF. The abnormal methylation status of the TBX20 promoter may contribute to the pathogenesis of TOF.

Unique mechanistic insights into the beneficial effects of soluble epoxide hydrolase inhibitors in the prevention of cardiac fibrosis.

Tissue fibrosis represents one of the largest groups of diseases for which there are very few effective therapies. In the heart, myocardial infarction (MI) resulting in the loss of cardiac myocytes can culminate in adverse cardiac remodeling leading to eventual heart failure. Adverse cardiac remodeling includes myocyte hypertrophy, fibrosis, and electrical remodeling. We have previously demonstrated the beneficial effects of several potent soluble epoxide hydrolase inhibitors (sEHIs) in different models of cardiac hypertrophy and failure. Here, we directly determine the molecular mechanisms underlying the beneficial effects of sEHIs in cardiac remodeling post-MI. Treatment with a potent sEHI, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU), which was started 1 wk post-MI in a murine model, results in a significant improvement in cardiac function. Importantly, treatment with TPPU results in a decrease in cardiac fibrosis as quantified using histological and immunostaining techniques. Moreover, single-cell-based assays demonstrate that treatment with TPPU results in a significant decrease not only in the percentages but also the proliferative capacity of different populations of cardiac fibroblasts as well as a reduction in the migration of fibroblasts into the heart from the bone marrow. Our study provides evidence for a possible unique therapeutic strategy to reduce cardiac fibrosis and improve cardiac function post-MI.

Urotensin II contributes to collagen synthesis and up-regulates Egr-1 expression in cultured pulmonary arterial smooth muscle cells through the ERK1/2 pathway.

AIM: The objective of this study was to investigate the effects of urotensin II (UII) treatment on the proliferation and collagen synthesis of cultured rat pulmonary arterial smooth muscle cells (PASMCs) and to explore whether these effects are mediated by mitogen-activated protein kinase (MAPK) signaling pathways and early growth response 1 (Egr-1). METHODS: The proliferation of cultured PASMCs stimulated with different doses of UII was detected by BrdU incorporation. The mRNA expression levels of procollagen I (procol I), procollagen III (procol III), extracellular regulated protein kinase 1/2 (ERK1/2), stress-stimulated protein kinase (Sapk), p38 MAPK (p38), and Egr-1 mRNA in cultured PASMCs after treatment with UII, the UII-specific antagonist urantide, and the ERK1/2 inhibitor PD98059 were detected by real-time polymerase chain reaction (PCR), and the protein expression levels of procol I, procol III, phosphorylated (p)-ERK1/2, p-Sapk, p-p38, and Egr-1 were detected by Western blotting. RESULTS: Treatment with UII increased the proliferation of cultured PASMCs in a dose-dependent manner (P<0.05). However, treatment with urantide and PD98059 inhibited the promoting effect of UII on PASMC proliferation (P<0.05). Real-time PCR analysis showed that UII up-regulated the expression of procol I, procol III, ERK1/2, Sapk, and Egr-1 mRNA (P<0.05), but not p38 mRNA. However, the up-regulating effect of UII was inhibited by PD98059 and urantide. Western blotting analysis showed that UII increased the synthesis of collagen I, collagen III, p-ERK1/2, p-Sapk, and Egr-1, and these effects also were inhibited by PD98059 and urantide (P<0.05). CONCLUSIONS: Egr-1 participates in the UII-mediated proliferation and collagen synthesis of cultured rat PASMCs via activation of the ERK1/2 signaling pathway.

Global, Regional, and National Burden of Myocarditis in 204 Countries and Territories From 1990 to 2019: Updated Systematic Analysis.

BACKGROUND: Myocarditis is characterized by high disability and mortality, and imposes a severe burden on population health globally. However, the latest global magnitude and secular trend of myocarditis burden have not been reported. OBJECTIVE: This study aimed to delineate the epidemiological characteristics of myocarditis burden globally for optimizing targeted prevention and research. METHODS: Based on the Global Burden of Disease Study 2019, the myocarditis burden from 1990 to 2019 was modeled using the Cause of Death Ensemble tool, DisMod-MR, and spatiotemporal Gaussian regression. We depicted the epidemiology and trends of myocarditis by sex, age, year, region, and sociodemographic index (SDI). R program version 4.2.1 (R Project for Statistical Computing) was applied for all statistical analyses, and a 2-sided P-value of <.05 was considered statistically significant. RESULTS: The number of incident cases (1,268,000) and deaths (32,450) associated with myocarditis in 2019 increased by over 1.6 times compared with the values in 1990 globally. On the other hand, the age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) decreased slightly from 1990 to 2019. The disability-adjusted life years (DALYs) decreased slightly in the past 3 decades, while the age-standardized DALY rate (ASDR) decreased greatly from 18.29 per 100,000 person-years in 1990 to 12.81 per 100,000 person-years in 2019. High SDI regions always showed a more significant ASIR. The ASIR slightly decreased in all SDI regions between 1990 and 2019. Middle SDI regions had the highest ASMR and ASDR in 2019. Low SDI regions had the lowest ASMR and ASDR in 2019. The age-standardized rates (ASRs) of myocarditis were higher among males than among females from 1990 to 2019 globally. All ASRs among both sexes had a downward trend, except for the ASMR among males, which showed a stable trend, and females had a more significant decrease in the ASDR than males. Senior citizens had high incident cases and deaths among both sexes in 2019. The peak numbers of DALYs for both sexes were noted in the under 1 age group in 2019. At the national level, the estimated annual percentage changes in the ASRs had significant negative correlations with the baseline ASRs in 1990. CONCLUSIONS: Globally, the number of incident cases and deaths associated with myocarditis have increased significantly. On the other hand, the ASRs of myocarditis showed decreasing trends from 1990 to 2019. Males consistently showed higher ASRs of myocarditis than females from 1990 to 2019 globally. Senior citizens gradually predominated in terms of myocarditis burden. Policymakers should establish targeted control strategies based on gender, region, age, and SDI; strengthen aging-related health research; and take notice of the changes in the epidemic characteristics of myocarditis.

Analysis of the disease burden of cardiomyopathy in children aged 0-14 years in China from 1990 to 2019.

Objectives: To assess the disease burden and changing trend of cardiomyopathy in children aged 0-14 years in China from 1990 to 2019. Methods: This study was based on the Global Burden of Disease Study 2019; the age-specific prevalence rate, mortality rate and disability-adjusted life year (DALY) rate were used for analysis. Estimated annual percentage change (EAPC) in burden rate and its 95% confidence interval were calculated. The data of China were compared with the global average level. Results: In 2019, the numbers of prevalence, deaths, and DALYs of cardiomyopathy in children aged 0-14 years in China were 4,493 [95% uncertainty interval (UI): 2687 ~ 6,838], 434 (95%UI: 337 ~ 565) and 37,522 (95%UI: 29,321 ~ 48,891), with declining amplitudes of 16.32, 70.56, and 70.74%, compared with 1990, respectively. In 2019, the prevalence rate of cardiomyopathy in Chinese children aged 0-14 years was 2.00/100,000 (95%UI: 1.2/100,000 ~ 3.04/100,000), higher than 1990 [1.66/100,000 (95%UI:1.00/100,000 ~ 2.53/100,000)]; mortality rate was 0.19/100,000 (95%UI: 0.15/100,000 ~ 0.25/100,000), significantly lower than 1990 [0.46/100,000 (95%UI: 0.25/100,000 ~ 0.95/100,000)]; DALY rate was 16.69/100,000 (95%UI: 13.04/100,000 ~ 21.75/100,000), also significantly lower than 1990 [39.71/100,000 (95%UI: 22.06/100,000 ~ 82.8/100,000)]. All burden rates of cardiomyopathy in Chinese children aged 0-14 years old were all lower than the global averages of 2019; the burden rates of male children were higher than female children. In all calendar years from 1990 to 2019, the mortality and DALY rates of children younger than 1-year-old were significantly higher than in the other age groups of 0-14 years old. From 1990 to 2019, the prevalence rate of cardiomyopathy aged 0-14 years old gradually increased, with EAPC of 0.82 (95%CI: 0.71-0.93); mortality rate and DALY rate decreased [EAPC = -2.32 (95%CI: -2.59 to -2.05)]. Conclusion: From 1990 to 2019, the disease burden of cardiomyopathy in children of China aged 0-14 years was heterogeneous; the burden of male children was higher than females; and the burden of cardiomyopathy in children younger than 1 year old needs more attention.

Predictive analysis of catecholamines and electrolytes for recurrence of orthostatic intolerance in children.

Background: Orthostatic intolerance (OI) is usually mediated by the autonomic nerve and most often happens in the upright position. However, it can also occur in other positions and can be relieved by lying down while likely to have another attack after relief. In the current study, we aim to evaluate the predictive effect of catecholamines and electrolytes on the recurrence of OI in children. Materials and methods: Children who were diagnosed with vasovagal syncope (VVS), postural tachycardia syndrome (POTS), and VVS combined with POTS were enrolled in this retrospective study and were followed up after 1-year physical treatment. Catecholamines in urine collected within 24 h, renin, angiotensin II, aldosterone in plasma, and electrolytes in both blood and urine collected in the morning were tested. A multivariate analysis and a receiver operating characteristic curve were used to validate the prediction effect. Results: In the VVS cohort, the 24 h urine adrenaline (AD) and norepinephrine (NE) levels of the non-recurrence group were lower than the 24 h urine AD and NE levels of the recurrence group, with a significant difference of P < 0.05. A different content can also be witnessed in the POTS cohort that the urine of the non-recurrence group contained lower sodium and chlorine. As for the VVS + POTS cohort, the non-recurrence group has lower AD and NE levels and higher potassium and phosphorus levels in urine, the difference of which proved prominent as well. Conclusion: The study provides further evidence that AD, NE, and electrolytes in urine are promising factors that are closely related to the recurrence of OI in children. The integrated evaluation system merging AD and NE may have better predictive ability.

Predictive value of EGSYS score in the differential diagnosis of cardiac syncope and neurally mediated syncope in children.

Background and objective: Syncope is a common emergency with diverse etiologies in children. Among these, cardiac syncope (CS) is associated with high mortality and is usually difficult to diagnose. However, there is still no validated clinical prediction model to distinguish CS from other forms of pediatric syncope. The Evaluation of Guidelines in Syncope Study (EGSYS) score was designed to identify CS in adults and has been validated in several studies. In this study, we aimed to assess the ability of the EGSYS score in predicting CS in children. Methods: In this retrospective study, we calculated and analyzed the EGSYS scores of 332 children hospitalized for syncope between January 2009 and December 2021. Among them, 281 were diagnosed with neurally mediated syncope (NMS) through the head-up tilt test, and 51 were diagnosed with CS using electrocardiography (ECG), echocardiography (ECHO), coronary computed tomography angiography (CTA), myocardial enzymes and genetic screening. The receiver operating characteristic (ROC) curve and Hosmer-Lemeshow test were used to evaluate the predictive value of the EGSYS score system. Results: The median scores of 51 children with CS and 281 children with NMS were 4 [interquartile range (IQR): 3-5] and -1 (IQR: -2-1), respectively. The area under the ROC curve (AUC) was 0.922 [95% confidence interval (CI): 0.892-0.952; P < 0.001], indicating that the EGSYS score system has good discrimination. The best cutoff point was ≥3, with a sensitivity and specificity of 84.3% and 87.9%, respectively. The Hosmer-Lemeshow test demonstrated satisfactory calibration (χ²=1.468, P > 0.05) of the score, indicating a good fit of the model. Conclusion: The EGSYS score appeared to be sensitive for differentiating CS from NMS in children. It might be used as an additional diagnostic tool to aid pediatricians in accurately identifying children with CS in the clinical practice.

Combination of Intracardiac Echocardiography and Contact Force Sensing for Left Ventricular Papillary Muscle Arrhythmias.

OBJECTIVES: The catheter ablation of ventricular arrhythmias (VAs) arising from the left ventricular (LV) papillary muscles (PMs) is challenging. This study sought to address whether the combination of intracardiac echocardiography (ICE) and contact force sensing (CFS) can improve the acute and long-term ablation outcomes of left ventricular papillary muscle arrhythmias. METHODS AND RESULTS: From May 2015 to August 2022, a total of thirty-three patients underwent catheter ablation for LV PM arrhythmias: VAs were located in anterolateral PMs in 11 and posteromedial PMs in 22. A combination of intracardiac echocardiography (ICE) and contact force sensing (CFS) was used in 21 of the 33 procedures. A mean of 6.93 ± 4.91 for lesions was used per patient, comparable between the CFS/ICE and no ICE/CFS (4.90 ± 2.23 vs. 10.17 ± 5.89; p = 0.011). The mean CF achieved in the ICE/CFS group was 7.52 ± 3.31 g. Less X-ray time was used in the combination group (CFS/ICE: 165.67 ± 47.80 S vs. no ICE/CFS: 365.00 ± 183.73 S; p < 0.001). An acute success rate of 100% was achieved for the ICE/CFS group (n = 22) and 66.67% for the no ICE/CFS group (n = 8). VA recurrence at the 11.21 ± 7.21-month follow-up was 14.2% for the ICE/CFS group and 50% for the no ICE/CFS group (p = 0.04). No severe complications occurred in all patients. CONCLUSIONS: The combination of intracardiac echocardiography (ICE) and contact force sensing (CFS) could provide precise geometries of cardiac endocavitary structures and accurate contact information for the catheter during ablation, which improved acute and long-term ablation outcomes. The routine adoption of this strategy should be considered to improve the outcomes of LV PM VA ablation.

Inhibitor of DNA-binding-1/inhibitor of differentiation-1 (ID-1) is implicated in various aspects of gastric cancer cell biology.

In order to determine the biological roles of the inhibitor of DNA-binding-1/inhibitor of differentiation-1 (ID-1) protein in MGC803 and AGS cell lines, we ectopically expressed or downregulated ID-1 in the both gastric cell lines and measured various parameters of tumor cell development, including cell proliferation, cell cycle progression, apoptosis and cell migration. The ectopic expression of ID-1 significantly enhanced cell proliferation, cell cycle progression and cell migration, and protected MGC803 and AGS cell lines from cisplatin-induced apoptosis. The opposite effects were observed after downregulation of ID-1, which in combination with cisplatin treatment enhanced apoptosis in a synergistic fashion. Collectively, these findings demonstrate that ID-1 plays pivotal and diverse roles in the biology of certain gastric cancer cells, further suggesting that ID-1 is implicated in the pathogenesis and progression of gastric cancer.

NT-Pro-BNP and echocardiography for the early assessment of cardiovascular dysfunction in neonates with sepsis.

To investigate the predictive manner of N-terminal fragment of brain natriuretic peptide (NT-Pro-BNP) and echocardiography in the early assessment of cardiovascular dysfunction (CVD) in neonates with sepsis, we recruited 108 neonates with sepsis in intensive care units and divided them into a sepsis with CVD (sepsis + CVD) group (n = 48) and a sepsis only group (n = 60). Neonates with other infections (n = 65) constituted the control group. Clinical, laboratory, and bedside echocardiography findings were evaluated. Compared to both the sepsis only and control groups, the sepsis + CVD group showed an earlier onset of symptoms [52.94 (0-185.6) h], higher NT-Pro-BNP levels (P = .02), a higher Tei index (0.52 + 0.03; P = .03), and lower ejection fraction (62.61% ± 12.31%, P < .05). Compared to the control group, the sepsis + CVD group exhibited hematogenous etiology (P < .05), lower albumin (ALB) levels (P = .04), lower white blood cell counts (P = .03), a higher high-sensitivity C-reactive protein/ALB ratio, and a larger right-ventricle-inner diameter (10.74 + 2.42 mm; P = .01). CVD in the septic neonates could be predicted by either NT-Pro-BNP levels (cut-off: 12,291.5 pg/L; sensitivity, 80%; specificity, 79%; area under the curve-receiver operating characteristic, 0.81) or Tei index (cut-off: 0.45; sensitivity, 74%; specificity, 77%; area under the curve-receiver operating characteristic, 0.78). NT-Pro-BNP levels and echocardiography can be used to determine early onset of CVD in neonatal sepsis, which facilitates timely pharmacological interventions and treatment.

circ­Grm1 promotes pulmonary artery smooth muscle cell proliferation and migration via suppression of GRM1 expression by FUS.

Pulmonary arterial hypertension is a progressive and fatal disease. Recent studies suggest that circular RNA (circRNAs/circs) can regulate various biological processes, including cell proliferation. Therefore, it is possible that circRNA may have important roles in pulmonary artery smooth muscle cell proliferation in hypoxic pulmonary hypertension (HPH). The aim of the present study was to determine the role and mechanism of circRNA­glutamate metabotropic receptor 1 (circ­Grm1; mmu_circ_0001907) in pulmonary artery smooth muscle cell (PASMC) proliferation and migration in HPH. High­throughput transcriptome sequencing was used to screen circRNAs and targeted genes involved in HPH. Cell Counting Kit­8 (CCK­8), 5­ethynyl­2­deoxyuridine and wound healing assays were employed to assess cell viability and migration. Reverse transcription­quantitative PCR and western blotting were used to detect target gene expression in different groups. Bioinformatical approaches were used to predict the interaction probabilities of circ­Grm1 and Grm1 with FUS RNA binding protein (FUS). The interactions of circ­Grm1, Grm1 and FUS were evaluated using RNA silencing and RNA immunoprecipitation assays. The results demonstrated that circ­Grm1 was upregulated in hypoxic PASMCs. Further experiments revealed that the knockdown of circ­Grm1 could suppress the proliferation and migration of hypoxic PASMCs. Transcriptome sequencing revealed that Grm1 could be the target gene of circ­Grm1. It was found that circ­Grm1 could competitively bind to FUS and consequently downregulate Grm1. Moreover, Grm1 could inhibit the function of circ­Grm1 by promoting the proliferative and migratory abilities of hypoxic PASMCs. The results also demonstrated that circ­Grm1 influenced the biological functions of PASMCs via the Rap1/ERK pathway by regulating Grm1. Overall, the current results suggested that circ­Grm1 was associated with HPH and promoted the proliferation and migration of PASMCs via suppression of Grm1 expression through FUS.

MiR-1/133 attenuates cardiomyocyte apoptosis and electrical remodeling in mice with viral myocarditis.

BACKGROUND: The role of miR-1 and miR-133 in regulating the expression of potassium and calcium ion channels, and mediating cardiomyocyte apoptosis in mice with viral myocarditis (VMC) is investigated herein. METHODS: Male Balb/c mice were randomly divided into groups: control group, VMC group, VMC + miR-1/133 mimics group, or VMC + miR-1/133 negative control (NC) group. VMC was induced with coxsackievirus B3 (CVB3). MiR-1/133 mimics ameliorated cardiac dysfunction in VMC mice and was compared to the VMC+NC group. RESULTS: Hematoxylin and eosin staining showed a well-arranged myocardium without inflammatory cell infiltration in the myocardial matrix of the control group. However, in the VMC and VMC+NC groups, the myocardium was disorganized and swollen with necrosis, and the myocardial matrix was infiltrated with inflammatory cells. These changes were alleviated by miR-1/133 mimics. TUNEL staining revealed decreased cardiomyocyte apoptosis in the VMC + miR-1/133 mimics group compared with the VMC group. In addition, miR-1/133 mimics up-regulated the expression of miR-1 and miR-133, the potassium channel genes Kcnd2 and Kcnj2, as well as Bcl-2, and down-regulated the expression of the potassium channel suppressor gene Irx5, L-type calcium channel subunit gene a1c (Cacna1c), Bax, and caspase-9 in the myocardium of VMC mice. MiR-1/133 also up-regulated the protein levels of Kv4.2 and Kir2.1, and down-regulated the expression of CaV1.2 in the myocardium of VMC mice. CONCLUSIONS: MiR-1 and miR-133 decreased cardiomyocyte apoptosis by mediating the expression of apoptosis-related genes in the hearts of VMC mice.

The Anti-inflammatory Effect of Soluble Epoxide Hydrolase Inhibitor and 14, 15-EET in Kawasaki Disease Through PPARγ/STAT1 Signaling Pathway.

Soluble epoxide hydrolase (sEH) is responsible for rapid degradation of 14, 15-EET, which is one of the isomers of EETs and plays an important role in cardiovascular diseases. In this study, we investigated the mechanism by which sEH inhibitor AUDA played an anti-inflammatory effect in HCAECs. Our results indicated that AUDA treatment promoted PPARγ expression, while knockdown of PPARγ blocked the cell growth and STAT1 expression inhibition induced by 100 µmol/L AUDA in HCAECs. AUDA also inhibited the overexpression of TNF-α, IL-1 ß, and MMP-9 induced by KD sera in HCAECs. Moreover, 30 blood samples from children with Kawasaki disease (KD) were collected with 30 healthy children as the control group. QPCR and ELISA assays were used to detect the level of 14, 15-EET, TNF-α, IL-1ß, and MMP-9. We found that the level of 14, 15-EET was higher in peripheral blood of children with KD compared with healthy controls (P < 0.05). In comparison to KD children with non-coronary artery lesion (nCAL), the level of 14, 15-EET was higher in peripheral blood of KD children with coronary artery lesion (CAL) (P < 0.05). Compared with healthy control group, the expression levels of TNF-α, IL-1ß, and MMP-9 in patients with KD were significantly up-regulated. Compared with nCAL KD children, the expression levels of TNF-α, IL-1ß, and MMP-9 in CAL children were abnormally high (P < 0.05). Our study indicated that AUDA played an anti-inflammatory effect in HCAECs through PPARγ/STAT1 signaling pathway, and 14, 15-EET is up-regulated in children with KD, suggesting that 14, 15-EET involved in the progression of KD.