Erythrocytic hydrogen sulfide production is increased in children with vasovagal syncope.

OBJECTIVES: To explore the differences in erythrocyte hydrogen sulfide (H2S) production in children with vasovagal syncope (VVS). STUDY DESIGN: A total of 54 children including 27 with VVS, aged 6-16 years (mean age 11.3 ± 3.3 years), and 27 healthy children, aged 3-17 years (mean age 10.4 ± 1.8 years) were included in the study. Children with VVS had symptoms of dizziness, pallor, blurred vision, nausea, and some had syncope. Erythrocyte H2S production was measured by a sulphur-sensitive electrode. Flow-mediated dilation (FMD) of brachial artery was measured for each patient by vascular ultrasound. RESULTS: H2S production from erythrocytes was significantly increased in the children with VVS compared with controls (P < .01). The erythrocytic H2S production in the VVS-vasoinhibitory subgroup was obviously higher than that in VVS-cardioinhibitory (P < .05) and VVS-mixed inhibitory subgroups (P < .05). FMD in the VVS-vasoinhibitory subgroup was greater than that in the VVS-cardioinhibitory (P < .05) and the VVS-mixed subgroups (P < .05). The erythrocytic H2S production had a positive linear correlation with FMD in children with VVS (P < .05). CONCLUSIONS: Increased erythrocyte H2S production may be involved in the pathogenesis of VVS in children.

Tilt angles and positive response of head-up tilt test in children with orthostatic intolerance.

This study aimed at examining three tilt angle-based positive responses and the time to positive response in a head-up tilt test for children with orthostatic intolerance, and the psychological fear experienced at the three angles during head-up tilt test. A total of 174 children, including 76 boys and 98 girls, aged from 4 to 18 years old (mean 11.3±2.8 years old), with unexplained syncope, were randomly divided into three groups, to undergo head-up tilt test at the angles of 60°, 70° and 80°, respectively. The diagnostic rates and times were analysed, and Wong-Baker face pain rating scale was used to access the children's psychological fear. There were no significant differences in diagnostic rates of postural orthostatic tachycardia syndrome and vasovagal syncope at different tilt angles during the head-up tilt test (p>0.05). There was a significant difference, however, in the psychological fear at different tilt angles utilising the Kruskal-Wallis test (χ2=36.398, p<0.01). It was mildest at tilt angle 60° utilising the Kolmogorov-Smirnov test (p<0.01). A positive rank correlation was found between the psychological fear and the degree of tilt angle (r(s)=0.445, p<0.01). Positive response appearance time was 15.1±14.0 minutes at 60° for vasovagal syncope children. There was no significant difference in the time to positive response, at different tilt angles during the head-up tilt test for vasovagal syncope or for postural orthostatic tachycardia syndrome. Hence, it is suggested that a tilt angle of 60° and head-up tilt test time of 45 minutes should be suitable for children with vasovagal syncope.

Difference between supine and upright blood pressure associates to the efficacy of midodrine on postural orthostatic tachycardia syndrome (POTS) in children.

Postural orthostatic tachycardia syndrome (POTS) is common, and has a serious impact on children's quality of life. Midodrine hydrochloride, an α1-adrenoreceptor agonist, is an effective treatment. The study was designed to examine the therapeutic efficacy of midodrine hydrochloride by quantifying changes in blood pressure during the head-up test (HUT), in children with POTS. Overall, 104 out of 110 children with POTS were treated with midodrine hydrochloride and successfully followed-up. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) changes were analyzed during the HUT. In a retrospective analysis, a receiver operating characteristic (ROC) curve was used to analyze the therapeutic predictive value of pre-treatment changes in SBP, DBP, and a combination of both, from the supine position to standing, in the subjects. The increase of SBP and DBP from the supine position to standing in responders were significantly lower than that of the non-responders. The ROC curve showed that midodrine hydrochloride for children with POTS would be predicted to be effective when the pre-treatment increase of SBP was ≤ 0 mmHg, or when the pre-treatment increase of DBP was ≤ 6.5 mmHg (from the supine position to standing), yielding a sensitivity of 72% and specificity of 88%. The area under the curve was 0.744 and 0.809, respectively. Hence, the results suggested that looking at the changes in blood pressure during the HUT was useful in predicting the response to midodrine hydrochloride in children with POTS.

Sulfur dioxide inhibits excessively activated endoplasmic reticulum stress in rats with myocardial injury.

It has been demonstrated that excessively activated endoplasmic reticulum stress (ERS) is related to myocardial injury. The study was designed to explore the possible role of sulfur dioxide (SO(2)) in protecting excessively activated ERS in rats with isoproterenol (ISO)-induced myocardial injury. Wistar rats were randomly divided into control, ISO, and ISO + SO(2) groups. Cardiac catheterization-derived hemodynamic parameters and myocardial enzymes in plasma were measured. Microstructure changes in myocardial tissues were examined. Cardiomyocyte apoptosis was detected by TUNEL method. Myocardial SO(2) content and aspartate amino transferase (AAT) activity were detected. Meanwhile, protein and mRNA expressions of myocardial AAT1, AAT2, and ERS markers (GRP78, caspase-12, and CHOP) were evaluated. The results showed that cardiac function was decreased, myocardial microstructure was damaged, and myocardial enzyme levels and cardiomyocyte apoptosis were increased with a downregulated endogenous AAT/SO(2) pathway, and that ERS markers were upregulated at transcriptional and translational levels in ISO-treated rats. However, the administration of an SO(2) donor, resulting in an increased SO(2) content in myocardial tissues, improved cardiac function and myocardial structure, and ameliorated myocardial enzyme levels and cardiomyocyte apoptosis associated with a downregulation of excessively activated ERS. In conclusion, the endogenous AAT/SO(2) pathway was probably responsible for the inhibition of excessively activated ERS, which might be involved in the mechanism of ISO-induced myocardial injury.

Endogenous sulfur dioxide protects against isoproterenol-induced myocardial injury and increases myocardial antioxidant capacity in rats.

Recently, sulfur dioxide (SO(2)) was discovered to be produced in the cardiovascular system and to influence important biological processes. Here, we investigated changes in endogenous SO(2)/glutamic oxaloacetic transaminase (GOT) pathway in the development of isoproterenol (ISO)-induced myocardial injury in rats and the regulatory effect of SO(2) on cardiac function, myocardial micro- and ultrastructure, and oxidative stress. Wistar male rats were divided into control, ISO-treated, ISO+SO(2), and SO(2) groups. At the termination of the experiment, parameters of cardiac function and hemodynamics were measured and the micro- and ultrastructure of myocardium and stereological ultrastructure of mitochondria were analyzed. Myocardial SO(2) content was detected by high-performance liquid chromatography. GOT (key enzyme for endogenous SO(2) production) activity and gene (GOT1 and GOT2) expressions were measured, and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), hydrogen peroxide, and superoxide radical levels were assayed. SOD (SOD1 and SOD2) and GSH-Px (GSH-Px1) gene expressions were also detected. The results showed that SO(2) donor at a dose of 85 mg/(kg day) did not impact the cardiac function and structure of rats, but exerted a subtle influence on myocardial redox status. ISO-treated rats exhibited decreased cardiac function, damaged myocardial structures, and downregulated endogenous SO(2)/GOT pathway. Meanwhile, myocardial oxidative stress increased, whereas antioxidative capacity downregulated. Administration of SO(2) markedly improved cardiac function and ISO-induced myocardial damage by ameliorating the pathological structure of the myocardium and the mitochondria. At the same time, myocardial products of oxidative stress decreased, whereas antioxidative capacity increased. These results suggest that downregulation of the endogenous SO(2)/GOT pathway is likely involved in the pathogenesis of ISO-induced myocardial injury. SO(2) protects against ISO-induced myocardial injury associated with increased myocardial antioxidant capacity in rats.

Effect of sulfur dioxide preconditioning on rat myocardial ischemia/reperfusion injury by inducing endoplasmic reticulum stress.

Sulfur dioxide has recently been found to be produced endogenously in the cardiovascular system and have important positive biological effects. However, it is unknown whether sulfur dioxide preconditioning has a protective effect on rat myocardial ischemia/reperfusion (I/R) injury and whether this process involves endoplasmic reticulum stress (ERS). In this study, we showed that preconditioning with sulfur dioxide 10 min before ischemia (with a low concentration of sulfur dioxide of 1-10 µmol/kg) could reduce myocardial infarct size and plasma activities of lactate dehydrogenase and creatine kinase in rats with I/R in vivo. Sulfur dioxide preconditioning also reduced myocardium apoptosis induced by I/R. In addition, sulfur dioxide preconditioning increased cardiac function in vitro. Sulfur dioxide preconditioning induced expression of myocardial glucose-regulated protein 78 (GRP78) and phosphorylated eukaryotic initiation of the factor 2α-subunit (p-eIF2α) prior to myocardial I/R but suppressed expression of myocardial GRP78, C/EBP homologous protein, and p-eIF2α during myocardial I/R, in association with improved myocardial injury in vivo and in vitro. Pretreatment with dithiothreitol, an ERS stimulator mimicked the above cardioprotective effect. However, pretreatment with the ERS inhibitor 4-phenylbutyrate reversed the cardioprotection provided by sulfur dioxide preconditioning. These data indicated that sulfur dioxide preconditioning reduced I/R-induced myocardial injury in vivo and in vitro, and that augmenting ERS by sulfur dioxide preconditioning prior to I/R contributed to protection against myocardial I/R injury.

Sulfur Dioxide Protects Against Collagen Accumulation in Pulmonary Artery in Association With Downregulation of the Transforming Growth Factor ß1/Smad Pathway in Pulmonary Hypertensive Rats.

BACKGROUND: We aimed to explore the role of endogenous sulfur dioxide (SO2) in pulmonary vascular collagen remodeling induced by monocrotaline and its mechanisms. METHODS AND RESULTS: A rat model of monocrotaline-induced pulmonary vascular collagen remodeling was developed and administered with l-aspartate-ß-hydroxamate or SO2 donor. The morphology of small pulmonary arteries and collagen metabolism were examined. Cultured pulmonary arterial fibroblasts stimulated by transforming growth factor ß1 (TGF-ß1) were used to explore the mechanism. The results showed that in monocrotaline-treated rats, mean pulmonary artery pressure increased markedly, small pulmonary arterial remodeling developed, and collagen deposition in lung tissue and pulmonary arteries increased significantly in association with elevated SO2 content, aspartate aminotransferase (AAT) activity, and expression of AAT1 compared with control rats. Interestingly, l-aspartate-ß-hydroxamate, an inhibitor of SO2 generation, further aggravated pulmonary vascular collagen remodeling in monocrotaline-treated rats, and inhibition of SO2 in pulmonary artery smooth muscle cells activated collagen accumulation in pulmonary arterial fibroblasts. SO2 donor, however, alleviated pulmonary vascular collagen remodeling with inhibited collagen synthesis, augmented collagen degradation, and decreased TGF-ß1 expression of pulmonary arteries. Mechanistically, overexpression of AAT1, a key enzyme of SO2 production, prevented the activation of the TGF-ß/type I TGF-ß receptor/Smad2/3 signaling pathway and abnormal collagen synthesis in pulmonary arterial fibroblasts. In contrast, knockdown of AAT1 exacerbated Smad2/3 phosphorylation and deposition of collagen types I and III in TGF-ß1-treated pulmonary arterial fibroblasts. CONCLUSIONS: Endogenous SO2 plays a protective role in pulmonary artery collagen accumulation induced by monocrotaline via inhibition of the TGF-ß/type I TGF-ß receptor/Smad2/3 pathway.

Risk factors for postural tachycardia syndrome in children and adolescents.

BACKGROUND: Postural tachycardia syndrome (POTS) is prevalent in children and adolescents and has a great impact on health. But its risk factors have not been fully understood. This study aimed to explore possible risk factors for children and adolescents with POTS. METHODS AND FINDINGS: 600 children and adolescents (test group) aged 7-18 (11.9 ± 3.0) years old, 259 males and 341 females, were recruited for identifying its risk factors. Another 197 subjects aged from 7 to 18 (11.3 ± 2.3) years old were enrolled in the validation group. Heart rate (HR) and blood pressure (BP) were monitored during upright test. Risk factors were analyzed and sensitivity and specificity for predicting POTS were tested via receiver operating characteristic curve. Among 600 subjects, 41 were confirmed with POTS patients (6.8%) based on clinical manifestation and upright test. The results showed a significant difference in daily water intake, the daily sleeping hours, supine HR, HR increment and maximum HR during upright test between POTS and the unaffected children (P<0.05). Likelihood of POTS would increase by 1.583 times if supine HR was increased by 10 beats/min (95%CI 1.184 to 2.116, P<0.01), by 3.877 times if a child's water intake was less than 800 ml/day (95%CI 1.937 to 7.760, P<0.001), or by 5.905 times (95%CI 2.972 to 11.733, P<0.001) if sleeping hours were less than 8 hours/day. Supine HR, daily water intake and sleeping hours showed the capability of predicting POTS in children and adolescents with an AUC of 83.9% (95% CI: 78.6%-89.1%), sensitivity of 80.5% and specificity of 75%. Furthermore, in validation group, predictive sensitivity and specificity were 73.3% and 72.5%. CONCLUSION: Faster supine HR, less water intake and shorter sleeping hours were identified as risk factors for POTS.

Sulfur dioxide derivatives improve the vasorelaxation in the spontaneously hypertensive rat by enhancing the vasorelaxant response to nitric oxide.

The present study was designed to explore the role of sulfur dioxide (SO(2)) in the regulation of vasorelaxation in the spontaneously hypertensive rat (SHR). Twenty-two Wistar rats and 15 SHRs were divided randomly into the following groups: Wistar-Kyoto (WKY) control (n = 8), WKY+Na(2)SO(3)/NaHSO(3) (n = 8), WKY+L-aspartic acid-ß-hydroxamate (HDX) (n = 6), SHR control (n = 8) and SHR+Na(2)SO(3)/NaHSO(3) (n = 7). Their blood pressure in vivo was measured by tail plethysmography. The vasorelaxant response of the thoracic aorta to acetylcholine (Ach) and sodium nitroprusside (SNP) in all rats was tested, respectively, in the experiment. At the same time, the SO(2) content of the WKY aorta after incubation with HDX and the vasorelaxant response to Ach after incubation with HDX were quantified. Nitric oxide (NO) production in the aorta of all rats was determined. We also measured the vasorelaxant responses of WKY aorta to different concentrations of SO(2) after incubation with the NO inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME). The blood pressure decreased significantly in SHRs treated with SO(2) derivatives (P < 0.05). Reduction of endogenous SO(2) in WKY vessels resulted in a decrease in the vasorelaxation induced by Ach. Vasorelaxation in response to both Ach and SNP increased in SHRs treated with SO(2) derivatives compared with SHR controls, but decreased in WKY given HDX compared with WKY controls (P < 0.05). The NO level in arterial tissues increased in SHRs treated with SO(2) derivatives (P < 0.05). However, the vasorelaxant response to SO(2) derivatives in the presence of L-NAME decreased markedly compared with WKY controls. The results suggest that SO(2) reduced blood pressure and increased vasorelaxation in SHR arteries via enhancing the vasorelaxant response to NO in isolated aortic rings and increasing the NO level of aortic tissues.

Midregional pro-adrenomedullin as a predictor for therapeutic response to midodrine hydrochloride in children with postural orthostatic tachycardia syndrome.

OBJECTIVES: This study was designed to explore the predictive value of the midregional fragment of pro-adrenomedullin (MR-proADM) in assessing the therapeutic efficacy of midodrine hydrochloride for children with postural orthostatic tachycardia syndrome (POTS). BACKGROUND: Midodrine hydrochloride is an important therapeutic option for children with POTS. However, there has not been any method to predict response to the drug. The MR-proADM is produced in equimolar amounts to adrenomedullin (ADM), and directly reflects levels of the rapidly degraded active peptide, ADM. METHODS: Fifty-seven children with POTS were designated as the POTS group. Twenty healthy children served as the control group. The children in the POTS group received midodrine hydrochloride treatment. The plasma concentration of MR-proADM was measured, using a sandwich immunoluminometric assay. A receiver-operating characteristic curve was used to explore the predictive value of MR-proADM. RESULTS: Plasma levels of MR-proADM were significantly higher in children with POTS (75.0 [62.5 to 96.0] pg/ml) than in the control group (58.5 [50.3 to 69.0] pg/ml). Plasma levels of MR-proADM in responders to midodrine hydrochloride was significantly higher than that of nonresponders (76.0 [66.0 to 91.0] pg/ml vs. 59.0 [54.0 to 65.5] pg/ml, p < 0.01]. A receiver-operating characteristic curve on the predictive value of MR-proADM showed that the area under the curve was 0.879 with a 95% confidence interval of 0.761 to 0.997. Using a cutoff value for MR-proADM of 61.5 pg/ml produced both high sensitivity (100%) and specificity (71.6%) in predicting the efficacy of midodrine hydrochloride therapy for treating POTS. CONCLUSIONS: MR-proADM can help guide midodrine hydrochloride therapy in the management of POTS in children.