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.

Sulfur Dioxide Inhibits Extracellular Signal-regulated Kinase Signaling to Attenuate Vascular Smooth Muscle Cell Proliferation in Angiotensin II-induced Hypertensive Mice

Background： Clarifying the mechanisms underlying vascular smooth muscle cell （VSMC） proliferation is important for the prevention and treatment of vascular remodeling and the reverse of hyperplastic lesions. Previous research has shown that the gaseous signaling molecule sulfur dioxide （SO2） inhibits VSMC proliferation, but the mechanism for the inhibition of the angiotensin Ⅱ （Angll）-induced VSMC proliferation by SO, has not been fully elucidated. This study was designed to investigate if SO2 inhibited VSMC proliferation in mice with hypertension induced by Angll. Methods： Thirty-six male C57 mice were randomly divided into control, Angll, and Angll ＋ SO2 groups. Mice in Angll group and Angl I ＋ SO2 group received a capsule-type Angll pump implanted under the skin of the back at a slow-release dose of 1000 ng-kg^-1min In addition, mice in Angll ＋ SO2 received intraperitoneal injections of SO., donor. Arterial blood pressure of tail artery was determined. The thickness of the aorta was measured by elastic fiber staining, and proliferating cell nuclear antigen （PCNA） and phosphorylated-extracellular signal-regulated kinase （P-ERK） were detected in aortic tissues. The concentration of SO~ in serum and aortic tissue homogenate supernatant was measured using high-performance liquid chromatography with fluorescence determination. In the in vio＇o study, VSMC of A7R5 cell lines was divided into six groups： control, Angll, Angll ＋ SO2 PD98059 （an inhibitor of ERK phosphorylation）, Angll ＋ PD98059, and Angll ＋ SO, ＋ PD98059. Expression of PCNA, ERK, and P-ERK was determined by Western blotting. Results： In animal experiment, compared with the control group, Angll markedly increased blood pressure （P 〈 0.01 ） and thickened the aortic wall in mice （P 〈 0.05） with an increase in the expression of PCNA （P 〈 0.05）. SO2 however, reduced the systemic hypertension and the wall thickness induced by AnglI （P 〈 0.05）. It inhibited the increased expression of PCNA and P-ERK induced by AnglI （P 〈 0.05）. In cell experiment, PD98059, an ERK phosphorylation inhibitor, blocked the inhibitory effect of SO, on VSMC proliferation （P 〈 0.05）. Conclusions： ERK signaling is involved in the mechanisms by which SO, inhibits VSMC proliferation in Angll-induced hypertensive mice via ERK signaling.

Hydrogen Sulfide Regulating Myocardial Structure and Function by Targeting Cardiomyocyte Autophagy

Objective： Hydrogen sulfide （H2S）, a gaseous signal molecule, plays a crucial role in many pathophysiologic processes in the cardiovascular system. Autophagy has been shown to participate in the occurrence of many cardiac diseases. Increasing evidences indicated that H,S regulates myocardial structure and function in association with the altered autophagy and plays a ＂switcher＂ role in the autophagy of myocardial diseases. The airn of this review was to summarize these insights and provide the experimental evidence that H2S targets cardiomyocyte autophagy to regulate cardiovascular function. Data Sources： This review was based on data in articles published in the PubMed databases up to October 30, 2017, with the following keywords： ＂hydrogen sulfide,＂ ＂autophagy,＂ and ＂cardiovascular diseases.＂ Study Selection： Original articles and critical reviews on H,S and autophagy were selected for this review. Results： When autophagy plays an adaptive role in the pathogenesis of diseases, H2S restores autophagy; otherwise, when autophagy plays a detrimental role, H2S downregulates autophagy to exert a cardioprotective function. For example, H2S has beneficial effects by regulating autophagy in myocardial ischemia/reperfusion and plays a protective role by inhibiting autophagy during the operation of cardioplegia and cardiopuhnonary bypass. H2S postpones cardiac aging associated with the upregulation of autophagy but improves the left ventricular function of smoking rats by lowering autophagy. Conclusions： H2S exerts cardiovascular protection by regulating autophagy. Cardiovascular autophagy would likely become a potential target of H2S therapy for cardiovascular diseases.

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

Background： Myocardial fibrosis is an important pathological change has not yet been fully elucidated. The study was designed to examine fibroblast proliferation and migration inhibitor. in many heart diseases, but its pathogenesis is very complex and whether endogenous sulfur dioxide （SO2） is a novel myocardial Methods： Primary rat myocardial fibroblasts were isolated and transfected with aspartate aminotransferase （AAT1 and AAT2） knockdown lentivirus or empty lentivirus. SO2 content in the supematant was determined with high-performance liquid chromatography, and the expressions of AATI, 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 AATI and AAT2 knockdown significantly reduced SO2 levels （F = 31.46, P 〈 0.01） and AATI/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 SO： rather 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 （AATI, 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 SO2 might be a novel myocardial fibrob/ast proliferation and migration inhibitor via inhibiting the ERK signaling pathway.

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(DSS).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%±4.44%vs.67.17%±4.88%,t=2.789,P=0.008)and LVFS values(40.00[38.00,42.00]%vs.36.79%±4.11%,Z=2.542,P=0.010)than the non-responders.The baseline LVEF and LVFS were positively correlated with DSS(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.