Age and mean platelet volume-based nomogram for predicting the therapeutic efficacy of metoprolol in Chinese pediatric patients with vasovagal syncope.

BACKGROUND: Vasovagal syncope (VVS) is the most common type of orthostatic intolerance in children. We investigated whether platelet-related factors related to treatment efficacy in children suffering from VVS treated with metoprolol. METHODS: Metoprolol-treated VVS patients were recruited. The median duration of therapy was three months. Patients were followed and divided into two groups, treament-effective group and treatment-ineffective group. Logistic and least absolute shrinkage selection operator regressions were used to examine treatment outcome variables. Receiver-operating characteristic (ROC) curves, precision-recall (PR) curves, calibration plots, and decision curve analyses were used to evaluate the nomogram model. RESULTS: Among the 72 patients who complete the follow-up, treatment-effective group and treatment-ineffective group included 42 (58.3%) and 30 (41.7%) cases, respectively. The patients in the treatment-effective group exhibited higher mean platelet volume (MPV) [(11.0 ± 1.0) fl vs. (9.8 ± 1.0) fl, P < 0.01] and platelet distribution width [12.7% (12.3%, 14.3%) vs. 11.3% (10.2%, 12.2%), P < 0.01] than those in the treatment-ineffective group. The sex ratio was significantly different (P = 0.046). A fit model comprising age [odds ratio (OR) = 0.766, 95% confidence interval (CI) = 0.594-0.987] and MPV (OR = 5.613, 95% CI = 2.297-13.711) might predict therapeutic efficacy. The area under the curve of the ROC and PR curves was computed to be 0.85 and 0.9, respectively. The P value of the Hosmer-Lemeshow test was 0.27. The decision curve analysis confirmed that managing children with VVS based on the predictive model led to a net advantage ranging from 0.01 to 0.58. The nomogram is convenient for clinical applications. CONCLUSION: A novel nomogram based on age and MPV can predict the therapeutic benefits of metoprolol in children with VVS.

A predictive model of response to metoprolol in children and adolescents with postural tachycardia syndrome.

BACKGROUND: The present work was designed to explore whether electrocardiogram (ECG) index-based models could predict the effectiveness of metoprolol therapy in pediatric patients with postural tachycardia syndrome (POTS). METHODS: This study consisted of a training set and an external validation set. Children and adolescents with POTS who were given metoprolol treatment were enrolled, and after follow-up, they were grouped into non-responders and responders depending on the efficacy of metoprolol. The difference in pre-treatment baseline ECG indicators was analyzed between the two groups in the training set. Binary logistic regression analysis was further conducted on the association between significantly different baseline variables and therapeutic efficacy. Nomogram models were established to predict therapeutic response to metoprolol. The receiver-operating characteristic curve (ROC), calibration, and internal validation were used to evaluate the prediction model. The predictive ability of the model was validated in the external validation set. RESULTS: Of the 95 enrolled patients, 65 responded to metoprolol treatment, and 30 failed to respond. In the responders, the maximum value of the P wave after correction (Pcmax), P wave dispersion (Pd), Pd after correction (Pcd), QT interval dispersion (QTd), QTd after correction (QTcd), maximum T-peak-to-T-end interval (Tpemax), and T-peak-to-T-end interval dispersion (Tped) were prolonged (all P < 0.01), and the P wave amplitude was increased (P < 0.05) compared with those of the non-responders. In contrast, the minimum value of the P wave duration after correction (Pcmin), the minimum value of the QT interval after correction (QTcmin), and the minimum T-peak-to-T-end interval (Tpemin) in the responders were shorter (P < 0.01, < 0.01 and < 0.01, respectively) than those in the non-responders. The above indicators were screened based on the clinical significance and multicollinearity analysis to construct a binary logistic regression. As a result, pre-treatment Pcmax, QTcmin, and Tped were identified as significantly associated factors that could be combined to provide an accurate prediction of the therapeutic response to metoprolol among the study subjects, yielding good discrimination [area under curve (AUC) = 0.970, 95% confidence interval (CI) 0.942-0.998] with a predictive sensitivity of 93.8%, specificity of 90.0%, good calibration, and corrected C-index of 0.961. In addition, the calibration curve and standard curve had a good fit. The accuracy of internal validation with bootstrap repeated sampling was 0.902. In contrast, the kappa value was 0.769, indicating satisfactory agreement between the predictive model and the results from the actual observations. In the external validation set, the AUC for the prediction model was 0.895, and the sensitivity and specificity were 90.9% and 95.0%, respectively. CONCLUSIONS: A high-precision predictive model was successfully developed and externally validated. It had an excellent predictive value of the therapeutic effect of metoprolol on POTS among children and adolescents.

Baseline left ventricular ejection fraction associated with symptom improvements in both children and adolescents with postural tachycardia syndrome under metoprolol therapy.

BACKGROUND: Postural tachycardia syndrome (POTS) is a common childhood disease that seriously affects the patient's physical and mental health. This study aimed to investigate whether pre-treatment baseline left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) values were associated with symptom improvement after metoprolol therapy for children and adolescents with POTS. METHODS: This retrospective study evaluated 51 children and adolescents with POTS who received metoprolol therapy at the Peking University First Hospital between November 2010 and July 2019. All patients had completed a standing test or basic head-up tilt test and cardiac echocardiography before treatment. Treatment response was evaluated 3 months after starting metoprolol therapy. The pre-treatment baseline LVEF and LVFS values were evaluated for correlations with decreases in the symptom score after treatment (ΔSS). Multivariable analysis was performed using factors with a P value of <0.100 in the univariate analyses and the demographic characteristics. RESULTS: A comparison of responders and non-responders revealed no significant differences in demographic, hemodynamic characteristics, and urine specific gravity (all P > 0.050). However, responders had significantly higher baseline LVEF (71.09% ±â€Š4.44% vs. 67.17% ±â€Š4.88%, t = -2.789, P = 0.008) and LVFS values (40.00 [38.00, 42.00]% vs. 36.79% ±â€Š4.11%, Z = -2.542, P = 0.010) than the non-responders. The baseline LVEF and LVFS were positively correlated with ΔSS (r = 0.378, P = 0.006; r = 0.363, P = 0.009), respectively. Logistic regression analysis revealed that LVEF was independently associated with the response to metoprolol therapy in children and adolescents with POTS (odds ratio: 1.201, 95% confidence interval: 1.039-1.387, P = 0.013). CONCLUSIONS: Pre-treatment baseline LVEF was associated with symptom improvement after metoprolol treatment for children and adolescents with POTS.

Interaction among Hydrogen Sulfide and Other Gasotransmitters in Mammalian Physiology and Pathophysiology.

Hydrogen sulfide (H2S), nitric oxide (NO), carbon monoxide (CO), and sulfur dioxide (SO2) were previously considered as toxic gases, but now they are found to be members of mammalian gasotransmitters family. Both H2S and SO2 are endogenously produced in sulfur-containing amino acid metabolic pathway in vivo. The enzymes catalyzing the formation of H2S are mainly CBS, CSE, and 3-MST, and the key enzymes for SO2 production are AAT1 and AAT2. Endogenous NO is produced from L-arginine under catalysis of three isoforms of NOS (eNOS, iNOS, and nNOS). HO-mediated heme catabolism is the main source of endogenous CO. These four gasotransmitters play important physiological and pathophysiological roles in mammalian cardiovascular, nervous, gastrointestinal, respiratory, and immune systems. The similarity among these four gasotransmitters can be seen from the same and/or shared signals. With many studies on the biological effects of gasotransmitters on multiple systems, the interaction among H2S and other gasotransmitters has been gradually explored. H2S not only interacts with NO to form nitroxyl (HNO), but also regulates the HO/CO and AAT/SO2 pathways. Here, we review the biosynthesis and metabolism of the gasotransmitters in mammals, as well as the known complicated interactions among H2S and other gasotransmitters (NO, CO, and SO2) and their effects on various aspects of cardiovascular physiology and pathophysiology, such as vascular tension, angiogenesis, heart contractility, and cardiac protection.

Similarities and differences between multiple inflammatory syndrome in children associated with COVID-19 and Kawasaki disease: clinical presentations, diagnosis, and treatment.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been spreading rapidly around the world, while "multisystem inflammatory syndrome in children" (MIS-C) is a new type of syndrome that has now been reported in many countries. Similar and different characteristics between KD and MIS-C have been reported in a variety of literature. We aimed to focus on reviewing clinical presentations, diagnosis, and treatment of KD and MIS-C. METHODS: We searched articles in the electronic databases, including the Cochrane Library database, EMBASE, and MEDLINE with the keywords "multiple inflammatory syndrome" and/or "COVID-19" and/or "Kawasaki disease" and "children". RESULTS: Main presentations of MIS-C and KD include fever, rashes, mucous membrane involvement, conjunctivitis, hands and feet erythema/edema, and cervical lymphadenopathy. However, compared with the highest incidence of KD among some Asian countries, MIS-C is common among Black and Hispanic children. MIS-C is common in older children and teenagers, whereas classic KD is common in children under five years of age. Gastrointestinal symptoms, shock, and coagulopathy are common in MIS-C patients but are not common in classic KD. Cardiac manifestations are more common than KD, including myocarditis with cardiac dysfunction and coronary artery dilation or aneurysms. Severe cases in MIS-C present with vasodilated or cardiogenic shock that requires fluid resuscitation, muscular support, and even mechanical ventilation and extracorporeal membrane oxygenation (ECMO), whereas KD rarely presents with these manifestations and requires these treatments. Increased serum ferritin, leukopenia, lymphopenia and thrombocytopenia are common in MIS-C. However, thrombocytosis is a characteristic feature of KD. Intravenous immunoglobulin (IVIG) and moderate-high dose aspirin are still a standard recommended treatment for KD. In addition to the above-mentioned medications, steroids and biological drugs are frequently used in patients with MIS-C. Most of the children with KD have a good prognosis; however, the long-term clinical outcomes of MIS-C are not clear. CONCLUSIONS: The overall presentation and treatment of MIS-C appear to overlap with KD. However, there are still great differences between the syndromes, and it is controversial to say whether MIS-C is a new entity or is a "severe type" of KD.

Prediction of intravenous immunoglobulin resistance in Kawasaki disease in children.

BACKGROUND: We aimed to explore predictive measures for intravenous immunoglobulin (IVIG) resistance in children with Kawasaki disease (KD). METHODS: Patients diagnosed with KD were enrolled in this study. Univariate analysis and multiple logistic regression were utilized to analyze the clinical features and laboratory results prior to IVIG-treatment of the two groups. Independent predictors of IVIG resistance were analyzed, and a predictive model for KD children with IVIG resistance was constructed. RESULTS: A total of 277 children with KD, 180 boys and 97 girls, aged 2-128 (median 23) months, were enrolled in the study. Compared with the IVIG-responsive group, the IVIG-resistant group had higher levels of the peripheral neutrophil count, mean platelet volume, mean platelet volume-to-lymphocyte ratio and C-reactive protein, and total serum bilirubin, but lower levels of peripheral lymphocyte count, serum albumin and serum prealbumin. Age (in months), peripheral neutrophil count, lymphocyte count and mean platelet volume and serum albumin were independent indicators for IVIG resistance by multivariate logistic regression analysis. A logistic regression model and a scoring system were set up, where cut-off values of - 0.46 and 6.5 points yielded sensitivities of 83.9% and 77.4%, and specificities of 74.8% and 61.0%, respectively. The areas under the curve (AUC) were 0.808 in the logistic regression model, and 0.750 in the scoring system. CONCLUSION: Our model for predicting IVIG-resistant children with KD, involving age (months), peripheral neutrophil count, lymphocyte count and mean platelet volume and serum albumin prior to IVIG-treatment, is helpful for clinical prediction of children with IVIG-resistant KD.

Body mass index is a promising predictor of response to oral rehydration saline in children with vasovagal syncope.

BACKGROUND: Vasovagal syncope (VVS) greatly impairs quality of life. The therapeutic efficacy of oral rehydration saline (ORS) for unselected VVS patients is not satisfactory due to the diverse mechanisms of the disease. Body mass index (BMI) was demonstrated to reflect blood volume to a certain extent. Therefore, the present study explored the capability of BMI to predict the therapeutic response of children with VVS to ORS treatment. METHODS: Seventy-four children with VVS who visited the Syncope Unit of Pediatrics at Peking University First Hospital from November 2010 to June 2019 receiving ORS treatment were enrolled for this retrospective case-control study. A comparison of demographic, clinical, and hemodynamic characteristics was performed between responders and non-responders. The correlation between baseline BMI and response time was analyzed. To determine the value of baseline BMI in predicting the therapeutic efficacy of ORS in children with VVS, a receiver operating characteristic curve analysis was performed. RESULTS: Fifty-two children were identified as responders, and the remaining 22 children were identified as non-responders. The baseline BMI of the responders was much lower than that of the non-responders (16.4 [15.5, 17.8] kg/m2vs. 20.7 ±e6 kg/m2, P < 0.001), and baseline BMI was positively correlated with response time in the head-up tilt test after adjusting for sex (r = 0.256, 95% confidence interval [CI]: 0.067-0.439, P = 0.029). The area under the receiver operating characteristic curve of baseline BMI was 0.818 (95% CI: 0.704-0.932, P < 0.001), and an optimal cut-off value of 18.9 kg/m2 yielded a sensitivity of 83% and a specificity of 73% to predict the efficacy of ORS in VVS. CONCLUSION: Prior to treatment, baseline BMI is a promising predictor of response to ORS in children with VVS.

Potential therapeutic effect of SO2 on fibrosis.

Fibrosis is a pathological feature of most chronic diseases and leads to the dysfunction of various organs. However, there is currently no effective method for treating fibrosis. In recent years, a small gas, sulfur dioxide (SO2), which can be generated endogenously in mammals, has been found to have vasorelaxation activity, improve cardiac function and decrease myocardial injury. Endogenous SO2 also mediates the process of fibrosis. Inhibition of endogenous SO2 can aggravate small pulmonary artery remodeling and abnormal collagen accumulation. SO2 treatment significantly improves pulmonary fibrosis and pulmonary arterial remodeling. Overexpression of the key enzymes associated with endogenous SO2 generation, aspartate aminotransferase (AAT) 1 and AAT2, mimics the effect of SO2 on the down-regulation of collagen synthesis, while AAT1 or AAT2 knockdown aggravates abnormal collagen accumulation in vascular smooth muscle cells (VSMCs). SO2 also improves myocardial fibrosis induced by myocardial infarction or diabetes in rats, and inhibits myocardial fibroblast proliferation and migration by the extracellular signal-regulated protein kinase pathway. The mechanisms underlying the inhibition of fibrosis by SO2 are related to its antioxidant effect, anti-inflammation effect, improvement in cardiac function, and cell proliferation inhibition. Therefore, SO2 has a potential therapeutic effect on fibrosis.

Gut microbiota analysis and its significance in vasovagal syncope in children.

BACKGROUND: Vasovagal syncope (VVS) is common in children and greatly affect both physical and mental health. But the mechanisms have not been completely explained. This study was designed to analyze the gut microbiota in children with VVS and explore its clinical significance. METHODS: Fecal samples from 20 VVS children and 20 matched controls were collected, and the microbiota were analyzed by 16S rRNA gene sequencing. The diversity and microbiota compositions of the VVS cases and controls were compared with the independent sample t test or Mann-Whitney U test. The correlation between the predominant bacteria and clinical symptoms was analyzed using Pearson or Spearman correlation test. RESULTS: No significant differences in diversity were evident between VVS and controls (P > 0.05). At the family level, the relative abundance of Ruminococcaceae was significantly higher in VVS children than in controls (median [Q1, Q3]: 22.10% [16.89%, 27.36%] vs. 13.92% [10.31%, 20.18%], Z = -2.40, P < 0.05), and LEfSe analysis revealed Ruminococcaceae as a discriminative feature (linear discriminant analysis [LDA] score > 4, P < 0.05). The relative abundance of Ruminococcaceae in VVS patients was positively correlated with the frequency of syncope (r = 0.616, P < 0.01). In terms of its correlation with hemodynamics, we showed that relative abundance of Ruminococcaceae was negatively correlated with the systolic and diastolic pressure reduction at the positive response in head-up tilt test (HUTT; r = -0.489 and -0.448, all P < 0.05), but was positively correlated with the mean pressure drop and decline rate (r = 0.489 and 0.467, all P < 0.05) as well as diastolic pressure drop and decline rate at the HUTT positive response (r = 0.579 and 0.589, all P < 0.01) in VVS patients. CONCLUSION: Ruminococcaceae was the predominant gut bacteria and was associated with the clinical symptoms and hemodynamics of VVS, suggesting that gut microbiota might be involved in the development of VVS.

Role of endoplasmic reticulum stress-associated gene TRIB3 in rats following kainic acid-induced seizures.

TRIB3 (tribblespseudokinase 3) is a pseudokinase that affects several cellular functions, and its expression is increased during endoplasmic reticulum stress (ER stress). How recurrent seizures affect the regulation of TRIB3 in the hippocampus during epilepsy remains unclear. In this study, we investigated the role of TRIB3 in the kainic acid (KA)-induced seizures and related brain injury. In a rat model of kainic acid-induced seizures, neuronal excitotoxic injury and apoptosis, and increases in the expression of TRIB3 and ER stress markers glucose-regulated protein 78 (GRP78) and C/EBP homologous binding protein (CHOP) were observed in the hippocampus by 24 h to 30 d after KA administration. Furthermore, phosphorylation of AKT, which is inhibited by TRIB3, was decreased in the hippocampus after KA-evoked seizure. These results indicate that ER stress, TRIB3 and AKT signaling are involved in the acute and prolonged hippocampal injury following KA induced seizure, suggesting that the ER stress-associated gene TRIB3 plays an important role in neuronal apoptosis after seizure.

Inhibitory Effects of Sulfur Dioxide on Rat Myocardial Fibroblast Proliferation and Migration.

BACKGROUND: Myocardial fibrosis is an important pathological change in many heart diseases, but its pathogenesis is very complex and has not yet been fully elucidated. The study was designed to examine whether endogenous sulfur dioxide (SO2) is a novel myocardial fibroblast proliferation and migration inhibitor. METHODS: Primary rat myocardial fibroblasts were isolated and transfected with aspartate aminotransferase (AAT1 and AAT2) knockdown lentivirus or empty lentivirus. SO2 content in the supernatant was determined with high-performance liquid chromatography, and the expressions of AAT1, AAT2, proliferating cell nuclear antigen (PCNA), phosphorylated extracellular signal-regulated protein kinase (p-ERK), and total ERK (T-ERK) in the cells were detected. Cell migration was detected by wound healing test. Independent sample t-test (for two groups) and one-way analysis of variance (three or more groups) were used to analyze the results. RESULTS: Both AAT1 and AAT2 knockdown significantly reduced SO2levels (F = 31.46, P < 0.01) and AAT1/2 protein expression (AAT1, t = 12.67, P < 0.01; AAT2, t = 9.61, P < 0.01), but increased PCNA expression and Cell Counting Kit-8 (CCK-8) activity as well as the migration in rat primary myocardial fibroblasts (P < 0.01). Supplementation of SO2rather than pyruvate significantly inhibited the increase in proliferation and migration caused by AAT knockdown (P < 0.01). Mechanistically, the ratio of p-ERK to T-ERK was significantly increased in the AAT1/2 knockdown groups compared with that in the empty lentivirus group (AAT1, t = -7.36, P < 0.01; AAT2, t = -10.97, P < 0.01). Whereas PD98059, an inhibitor of ERK activation, successfully blocked AAT knockdown-induced PCNA upregulation (F = 74.01, P > 0.05), CCK-8 activation (F = 50.14, P > 0.05), and migration augmentation in myocardial fibroblasts (24 h, F = 37.08, P > 0.05; 48 h, F = 58.60, P > 0.05). CONCLUSION: Endogenous SO2might be a novel myocardial fibroblast proliferation and migration inhibitor via inhibiting the ERK signaling pathway.

Sulfur dioxide ameliorates rat myocardial fibrosis by inhibiting endoplasmic reticulum stress.

Myocardial remodeling occurs after myocardial infarction (MI), the leading cause of mortality worldwide. Although myocardial fibrosis plays an important role in the process of myocardial remodeling, there is not yet an effective method of reducing it. The aim of the present study was to determine the effects of sulfur dioxide (SO2) on myocardial fibrosis and the possible mechanisms of these effects. SO2 treatment reduced the extent of myocardial fibrosis and post-MI levels of collagens I and III in the left-ventricular myocardium. SO2 also improved MI-induced thinning of the left ventricular wall while enlarging the left ventricular internal diameter. SO2 was able to reduce matrix metalloproteinase (MMP)-9 activity and increase tissue matrix metalloproteinase inhibitor (TIMP)-1 content in myocardium after MI. However, the mechanism underlying these effects of SO2 on myocardial fibrosis are unknown. Western blot analysis of endoplasmic reticulum (ER) stress-related proteins showed that glucose-regulated protein 78, C/EBP homologous protein, caspase-12, and phosphorylated eukaryotic initiation factor 2α expression levels were significantly increased in MI rats and decreased by SO2 treatment. The ER stress promoter dithiothreitol reversed these effects of SO2. In conclusion, SO2 alleviated myocardial fibrosis in MI rats through a mechanism related to inhibition of excessive ER stress.