Publications by authors named "Chaoshu Tang"

218 Publications

Compensatory role of endogenous sulfur dioxide in nitric oxide deficiency-induced hypertension.

Redox Biol 2021 Nov 18;48:102192. Epub 2021 Nov 18.

Department of Pediatrics, Peking University First Hospital, Beijing, China. Electronic address:

Objective: This study aimed to determine the communicational pattern of gaseous signaling molecules sulfur dioxide (SO) and nitric oxide (NO) between vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs), and elucidate the compensatory role and significance of endogenous SO in the development of hypertension due to NO deficiency.

Approach And Results: Blood pressure was monitored by the tail-cuff and implantable physiological signal telemetry in L-nitro-arginine methyl ester (l-NAME)-induced hypertensive mice, and structural alterations of mouse aortic vessels were detected by the elastic fiber staining method. l-NAME-treated mice showed decreased plasma NO levels, increased SO levels, vascular remodeling, and increased blood pressure, and application of l-aspartate-β-hydroxamate, which inhibits SO production, further aggravated vascular structural remodeling and increased blood pressure. Moreover, in a co-culture system of HAECs and HASMCs, NO from HAECs did not influence aspartate aminotransferase (AAT)1 protein expression but decreased AAT1 activity in HASMCs, thereby resulting in the inhibition of endogenous SO production. Furthermore, NO promoted S-nitrosylation of AAT1 protein in HASMCs and purified AAT1 protein. Liquid chromatography with tandem mass spectrometry showed that the Cys192 site of AAT1 purified protein was modified by S-nitrosylation. In contrast, dithiothreitol or C192S mutations in HASMCs blocked NO-induced AAT1 S-nitrosylation and restored AAT1 enzyme activity.

Conclusion: Endothelium-derived NO inhibits AAT activity by nitrosylating AAT1 at the Cys192 site and reduces SO production in HASMCs. Our findings suggest that SO acts as a compensatory defense system to antagonize vascular structural remodeling and hypertension when the endogenous NO pathway is disturbed.
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http://dx.doi.org/10.1016/j.redox.2021.102192DOI Listing
November 2021

Sulfur Dioxide: Endogenous Generation, Biological Effects, Detection, and Therapeutic Potential.

Antioxid Redox Signal 2021 Sep 20. Epub 2021 Sep 20.

Peking University First Hospital, 26447, Beijing, China;

Significance: Previously, sulfur dioxide (SO) was recognized as an air pollutant. However, it is found to be endogenously produced in mammalian tissues. As a new gasotransmitter, SO is involved in regulating the structure and function of blood vessels, heart, lung, gastrointestinal tract, and nervous system, etc. Recent Advances: Increasing evidence showed that endogenous SO regulates cardiovascular physiological processes, such as blood pressure control, vasodilation, maintenance of the normal vascular structure, and cardiac negative inotropy. Under pathological conditions including hypertension, atherosclerosis, vascular calcification, aging endothelial dysfunction, myocardial injury, myocardial hypertrophy, diabetic myocardial fibrosis, sepsis-induced cardiac dysfunction, pulmonary hypertension, acute lung injury, colitis, epilepsy-related brain injury, depression and anxiety, and addictive drug reward memory consolidation, endogenous SO protects against the pathological changes via different molecular mechanisms and the disturbed SO/aspartate aminotransferase pathway is likely involved in the mechanisms for the abovementioned pathologic processes.

Critical Issues: A comprehensive understanding of the biological effects of endogenous SO is extremely important for the development of novel SO therapy. In this review, we summarized the biological effects, mechanism of action, SO detection methods, and its related prodrugs.

Future Directions: Further studies should be conducted to understand the effects of endogenous SO in various physiological and pathophysiological processes and clarify its underlying mechanisms. More efficient and accurate SO detection methods, as well as specific and effective SO-releasing systems should be designed for the treatment and prevention of clinical related diseases. The translation from SO basic medical research to its clinical application is also worthy of further study.
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http://dx.doi.org/10.1089/ars.2021.0213DOI Listing
September 2021

Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation.

J Adv Res 2021 03 8;29:55-65. Epub 2020 Sep 8.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Introduction: Mast cell (MC) degranulation is an important step in the pathogenesis of inflammatory reactions and allergies; however, the mechanism of stabilizing MC membranes to reduce their degranulation is unclear.

Methods: SO content in MC culture supernatant was measured by HPLC-FD. The protein and mRNA expressions of the key enzymes aspartate aminotransferase 1 (AAT1) and AAT2 and intracellular AAT activity were detected. The cAMP level in MCs was detected by immunofluorescence and ELISA. The release rate of MC degranulation marker β-hexosaminidase was measured. The expression of AAT1 and cAMP, the MC accumulation and degranulation in lung tissues were detected.

Objectives: To exam whether an endogenous sulfur dioxide (SO) pathway exists in MCs and if it serves as a novel endogenous MC stabilizer.

Results: We firstly show the existence of the endogenous SO/AAT pathway in MCs. Moreover, when AAT1 was knocked down in MCs, MC degranulation was significantly increased, and could be rescued by a SO donor. Mechanistically, AAT1 knockdown decreased the cyclic adenosine monophosphate (cAMP) content in MCs, while SO prevented this reduction in a dose-independent manner. Pretreatment with the cAMP-synthesizing agonist forskolin or the cAMP degradation inhibitor IBMX significantly blocked the increase in AAT1 knockdown-induced MC degranulation. Furthermore, in hypoxia-stimulated MCs, AAT1 protein expression and SO production were markedly down regulated, and MC degranulation was activated, which were blunted by AAT1 overexpression. The cAMP synthesis inhibitor SQ22536 disrupted the suppressive effect of AAT1 overexpression on hypoxia-induced MC degranulation. In a hypoxic environment, mRNA and protein expression of AAT1 was significantly reduced in lung tissues of rats. Supplementation of SO elevated the cAMP level and reduced perivascular MC accumulation and degranulation in lung tissues of rats exposed to a hypoxic environment .

Conclusion: SO serves as an endogenous MC stabilizer via upregulating the cAMP pathway under hypoxic circumstance.
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http://dx.doi.org/10.1016/j.jare.2020.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020161PMC
March 2021

Endogenous SO-dependent Smad3 redox modification controls vascular remodeling.

Redox Biol 2021 05 18;41:101898. Epub 2021 Feb 18.

Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China; Key Laboratory of Cardiovascular Sciences, Ministry of Education, China. Electronic address:

Sulfur dioxide (SO) has emerged as a physiological relevant signaling molecule that plays a prominent role in regulating vascular functions. However, molecular mechanisms whereby SO influences its upper-stream targets have been elusive. Here we show that SO may mediate conversion of hydrogen peroxide (HO) to a more potent oxidant, peroxymonosulfite, providing a pathway for activation of HO to convert the thiol group of protein cysteine residues to a sulfenic acid group, aka cysteine sulfenylation. By using site-centric chemoproteomics, we quantified >1000 sulfenylation events in vascular smooth muscle cells in response to exogenous SO. Notably, ~42% of these sulfenylated cysteines are dynamically regulated by SO, among which is cysteine-64 of Smad3 (Mothers against decapentaplegic homolog 3), a key transcriptional modulator of transforming growth factor β signaling. Sulfenylation of Smad3 at cysteine-64 inhibits its DNA binding activity, while mutation of this site attenuates the protective effects of SO on angiotensin II-induced vascular remodeling and hypertension. Taken together, our findings highlight the important role of SO in vascular pathophysiology through a redox-dependent mechanism.
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http://dx.doi.org/10.1016/j.redox.2021.101898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933484PMC
May 2021

Cartilage oligomeric matrix protein is an endogenous β-arrestin-2-selective allosteric modulator of AT1 receptor counteracting vascular injury.

Cell Res 2021 Jul 28;31(7):773-790. Epub 2021 Jan 28.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China.

Compelling evidence has revealed that biased activation of G protein-coupled receptor (GPCR) signaling, including angiotensin II (AngII) receptor type 1 (AT1) signaling, plays pivotal roles in vascular homeostasis and injury, but whether a clinically relevant endogenous biased antagonism of AT1 signaling exists under physiological and pathophysiological conditions has not been clearly elucidated. Here, we show that an extracellular matrix protein, cartilage oligomeric matrix protein (COMP), acts as an endogenous allosteric biased modulator of the AT1 receptor and its deficiency is clinically associated with abdominal aortic aneurysm (AAA) development. COMP directly interacts with the extracellular N-terminus of the AT1 via its EGF domain and inhibits AT1-β-arrestin-2 signaling, but not Gq or Gi signaling, in a selective manner through allosteric regulation of AT1 intracellular conformational states. COMP deficiency results in activation of AT1a-β-arrestin-2 signaling and subsequent exclusive AAA formation in response to AngII infusion. AAAs in COMP or ApoE mice are rescued by AT1a or β-arrestin-2 deficiency, or the application of a peptidomimetic mimicking the AT1-binding motif of COMP. Explorations of the endogenous biased antagonism of AT1 receptor or other GPCRs may reveal novel therapeutic strategies for cardiovascular diseases.
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http://dx.doi.org/10.1038/s41422-020-00464-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249609PMC
July 2021

Persulfidation of transcription factor FOXO1 at cysteine 457: A novel mechanism by which HS inhibits vascular smooth muscle cell proliferation.

J Adv Res 2021 Jan 1;27:155-164. Epub 2020 Jul 1.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Introduction: The proliferation of vascular smooth muscle cells (VSMCs) is an important physiological and pathological basis for many cardiovascular diseases. Endogenous hydrogen sulfide (HS), the third gasotransmitter, is found to preserve vascular structure by inhibiting VSMC proliferation. However, the mechanism by which HS suppresses VSMC proliferation has not been fully clear.

Objectives: This study aimed to explore whether HS persulfidates the transcription factor FOXO1 to inhibit VSMC proliferation.

Methods: After the proliferation of VSMC A7r5 cells was induced by endothelin-1 (ET-1), FOXO1 phosphorylation and proliferating cell nuclear antigen (PCNA) expression were detected by Western blotting, the degree of FOXO1 nuclear exclusion and PCNA fluorescent signals in the nucleus were detected by immunofluorescence, and the persulfidation of FOXO1 was measured through a biotin switch assay.

Results: The results showed that ET-1 stimulation increased cell proliferation, FOXO1 phosphorylation and FOXO1 nuclear exclusion to the cytoplasm in the cells. However, pretreatment with NaHS, an HS donor, successfully abolished the ET-1-induced increases in the VSMC proliferation, FOXO1 phosphorylation, and FOXO1 nuclear exclusion to the cytoplasm. Mechanistically, HS persulfidated the FOXO1 protein in A7r5 and 293T cells, and the thiol reductant DTT reversed this effect. Furthermore, the C457S mutation of FOXO1 abolished the HS-induced persulfidation of FOXO1 in the cells and the subsequent inhibitory effects on FOXO1 phosphorylation at Ser256, FOXO1 nuclear exclusion to the cytoplasm and cell proliferation.

Conclusion: Thus, our findings demonstrated that HS might inhibit VSMC proliferation by persulfidating FOXO1 at Cys457 and subsequently preventing FOXO1 phosphorylation at Ser256.
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http://dx.doi.org/10.1016/j.jare.2020.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728583PMC
January 2021

Hydrogen sulfide and vascular regulation - An update.

J Adv Res 2021 Jan 16;27:85-97. Epub 2020 May 16.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Background: Hydrogen sulfide (HS) is considered to be the third gasotransmitter after carbon monoxide (CO) and nitric oxide (NO). It plays an important role in the regulation of vascular homeostasis. Vascular remodeling have has proved to be related to the impaired HS generation.

Aim Of Review: This study aimed to summarize and discuss current data about the function of HS in vascular physiology and pathophysiology as well as the underlying mechanisms.

Key Scientific Concepts Of Review: Endogenous hydrogen sulfide (HS) as a third gasotransmitter is primarily generated by the enzymatic pathways and regulated by several metabolic pathways. HS as a physiologic vascular regulator, inhibits proliferation, regulates its apoptosis and autophagy of vascular cells and controls the vascular tone. Accumulating evidence shows that the downregulation of HS pathway is involved in the pathogenesis of a variety of vascular diseases, such as hypertension, atherosclerosis and pulmonary hypertension. Alternatively, HS supplementation may greatly help to prevent the progression of the vascular diseases by regulating vascular tone, inhibiting vascular inflammation, protecting against oxidative stress and proliferation, and modulating vascular cell apoptosis, which has been verified in animal and cell experiments and even in the clinical investigation. Besides, HS system and angiotensin-converting enzyme (ACE) inhibitors play a vital role in alleviating ischemic heart disease and left ventricular dysfunction. Notably, sulfhydryl-containing ACEI inhibitor zofenopril is superior to other ACE inhibitors due to its capability of HS releasing, in addition to ACE inhibition. The design and application of novel HS donors have significant clinical implications in the treatment of vascular-related diseases. However, further research regarding the role of HS in vascular physiology and pathophysiology is required.
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http://dx.doi.org/10.1016/j.jare.2020.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728588PMC
January 2021

Hydrogen sulfide regulates insulin secretion and insulin resistance in diabetes mellitus, a new promising target for diabetes mellitus treatment? A review.

J Adv Res 2021 Jan 26;27:19-30. Epub 2020 Feb 26.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Background: Insulin resistance and impaired insulin secretion lead to disorders of glucose metabolism, which contributes to the development of diabetes. Hydrogen sulfide (H2S), a novel gasotransmitter, is found to play important roles in regulation of glucose metabolism homeostasis.

Aim Of Review: This study aimed to summarize and discuss current data about the function of H2S in insulin secretion and insulin resistance regulation as well as the underlying mechanisms.

Key Scientific Concepts Of Review: HS could be endogenously produced in islet β cells, liver, adipose, skeletal muscles, and the hypothalamus, and regulates local and systemic glucose metabolism. It is reported that HS suppresses insulin secretion, promotes or reduces the apoptosis of islet β cells. It plays important roles in the regulation of insulin sensitivity in insulin responsive tissues. HS inhibits glucose uptake and glycogen storage, and promotes or inhibits gluconeogenesis, mitochondrial biogenesis and mitochondrial bioenergetics in the liver. In adipose tissue, several investigators indicated that H2S promoted glucose uptake in adipocytes, while other studies reported that HS inhibits this process. HS has also been shown to promote adipogenesis, inhibit lipolysis, and regulate adiponectin and MCP-1 secretion from adipocytes. In skeletal muscle, HS increases glucose uptake and improves insulin sensitivity. It is also observed that HS modulates circadian-clock genes in muscle. Hypothalamic CBS/HS pathway reduces obesity and improves insulin sensitivity via the brain-adipose interaction. Most studies indicated plasma HS levels decreased in diabetic patients. However, the mechanisms by which HS regulates systemic glucose metabolism remain unclear. Whether HS acts as a new promising target for diabetes mellitus treatment merits further studies.
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http://dx.doi.org/10.1016/j.jare.2020.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728586PMC
January 2021

Author Correction: Catestatin attenuates endoplasmic reticulum induced cell apoptosis by activation type 2 muscarinic acetylcholine receptor in cardiac ischemia/reperfusion.

Sci Rep 2020 Nov 5;10(1):19543. Epub 2020 Nov 5.

Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, Beijing, P.R. China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-76697-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645768PMC
November 2020

CD4 T-Cell Endogenous Cystathionine γ Lyase-Hydrogen Sulfide Attenuates Hypertension by Sulfhydrating Liver Kinase B1 to Promote T Regulatory Cell Differentiation and Proliferation.

Circulation 2020 11 9;142(18):1752-1769. Epub 2020 Sep 9.

Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing, P.R. China (C.C., Z.C., W.W., S.y.L., Jun Cai, B.G.).

Background: Hydrogen sulfide (HS) has antihypertension and anti-inflammatory effects, and its endogenous-generation key enzyme cystathionine γ lyase (CSE) is expressed in CD4 T cells. However, the role of CD4 T-cell endogenous CSE/HS in the development of hypertension is unclear.

Methods: Peripheral blood lymphocytes were isolated from hypertensive patients or spontaneously hypertensive rats, then HS production and expression of its generation enzymes, cystathionine β synthase and CSE, were measured to determine the major HS generation system changes in hypertension. Mice with CSE-specific knockout in T cells (conditional knockout, by CD4 mice hybridization) and CD4 null mice were generated for investigating the pathophysiological relevance of the CSE/HS system.

Results: In lymphocytes, HS from CSE, but not cystathionine β synthase, responded to blood pressure changes, supported by lymphocyte CSE protein changes and a negative correlation between HS production with systolic blood pressure and diastolic blood pressure, but positive correlation with the serum level of interleukin 10 (an anti-inflammatory cytokine). Deletion of CSE in T cells elevated BP (5-8 mm Hg) under the physiological condition and exacerbated angiotensin II-induced hypertension. In keeping with hypertension, mesenteric artery dilation impaired association with arterial inflammation, an effect attributed to reduced immunoinhibitory T regulatory cell (Treg) numbers in the blood and kidney, thus causing excess CD4 and CD8 T cell infiltration in perivascular adipose tissues and kidney. CSE knockout CD4 T cell transfer into CD4 null mice, also showed the similar phenotypes' confirming the role of endogenous CSE/HS action. Adoptive transfer of Tregs (to conditional knockout mice) reversed hypertension, vascular relaxation impairment, and immunocyte infiltration, which confirmed that conditional knockout-induced hypertension was attributable, in part, to the reduced Treg numbers. Mechanistically, endogenous CSE/HS promoted Treg differentiation and proliferation by activating AMP-activated protein kinase. In part, it depended on activation of its upstream kinase, liver kinase B1, by sulfhydration to facilitate its substrate binding and phosphorylation.

Conclusion: The constitutive sulfhydration of liver kinase B1 by CSE-derived HS activates its target kinase, AMP-activated protein kinase, and promotes Treg differentiation and proliferation, which attenuates the vascular and renal immune-inflammation, thereby preventing hypertension.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.045344DOI Listing
November 2020

Sitting-induced hemodynamic changes and association with sitting intolerance in children and adolescents: a cross-sectional study.

Sci Rep 2020 08 18;10(1):13921. Epub 2020 Aug 18.

Department of Pediatrics, Peking University First Hospital, No. 1, Xi'an-men Street, West District, Beijing, 100034, China.

Hemodynamic alteration with postural change from supine to sitting has been unclear in the young. In the cross-sectional study, 686 participants (371 boys and 315 girls, aged 6-18 years) were recruited from 4 schools in Kaifeng city, the central area of China. The active sitting test was performed to obtain heart rate (HR) and blood pressure (BP) changes from supine to sitting in children and adolescents. Hemodynamic change-associated sitting intolerance was analyzed. In the study participants, the 95th percentile (P) values of changes in HR and BP within 3 min from supine to sitting were 25 beats/min and 18/19 mm Hg, respectively. Sixty-six participants had sitting intolerance symptoms. Compared with participants without sitting intolerance symptoms, those with symptoms more frequently had HR increase ≥ P or BP increase ≥ P within 3 min from supine to sitting (P < 0.001). Risk factors for sitting intolerance were age (odds ratio 1.218, 95% confidence interval 1.072-1.384, P = 0.002) and changes in HR or BP ≥ P within 3 min after sitting (odds ratio 2.902, 95% confidence interval 1.572-5.357, P = 0.001). We firstly showed hemodynamic changing profiles from supine to sitting and their association with sitting intolerance in children and adolescents. Sitting tachycardia is likely suggested with a change in HR ≥ 25 beats/min and sitting hypertension with a change in BP ≥ 20/20 mm Hg when changing from supine to sitting within 3 min. The age and changes in HR or BP were independent risk factors for sitting intolerance.
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http://dx.doi.org/10.1038/s41598-020-70925-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435175PMC
August 2020

Sulfur Dioxide: An Endogenous Protector Against Myocardial Injury.

J Cardiovasc Pharmacol 2020 10;76(4):389-396

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Sulfur dioxide (SO2) was previously known as a harmful gas in air pollution. Recently, it was reported that SO2 can be endogenously generated in cardiovascular tissues. Many studies have revealed that endogenous SO2 has important physiological and pathophysiological significance and pharmacological potential. As a novel gasotransmitter, SO2 has important regulatory effects on the heart. It has a dose-dependent negative inotropic effect on cardiac function, in which L-type calcium channels are involved. SO2 can also attenuate myocardial injury caused by various harmful stimuli and play an important role in myocardial ischemia-reperfusion injury and myocardial hypertrophy. These effects are thought to be linked to its ability to reduce inflammation and as an antioxidant. In addition, SO2 regulates cardiomyocyte apoptosis and autophagy. Therefore, endogenous SO2 plays an important role in maintaining cardiovascular system homeostasis. In the present review, the literature concerning the metabolism of endogenous SO2, its cardiac toxicological effects and physiological regulatory effects, mechanisms for SO2-mediated myocardial protection and its pharmacological applications are summarized and discussed.
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http://dx.doi.org/10.1097/FJC.0000000000000882DOI Listing
October 2020

Sympathetic Overactivation From Supine to Upright Is Associated With Orthostatic Hypertension in Children and Adolescents.

Front Pediatr 2020 21;8:54. Epub 2020 Feb 21.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

There are no prior publications or submissions with any overlapping information, including studies and patients. The study data have not been presented as an abstract or poster before the submission. The study was conducted to analyze the changes of baroreflex sensitivity and heart rate variability from supine to upright standing in children and adolescents with orthostatic hypertension to explore whether and how the autonomic nerve regulation was involved in the development of pediatric orthostatic hypertension. This case-control study included twenty-five children with orthostatic hypertension (the patient group) and twenty-six healthy controls (the control group). All subjects underwent a standing test, during which their hemodynamic parameters were continuously monitored by a Finapres Medical System, and baroreflex sensitivity and heart rate variability were calculated. The demographic characteristics, supine baroreflex sensitivity, and supine heart rate variability including time domain and frequency domain indices did not differ between the patients with orthostatic hypertension and healthy subjects ( > 0.05). However, a more obvious drop of baroreflex sensitivity and a greater increase of low frequency/high frequency ratio from supine to upright were observed in subjects with orthostatic hypertension compared with those in the healthy children ( < 0.001 and < 0.01, respectively). Changes of baroreflex sensitivity were negatively related to mean arterial pressure changes from supine to upright in all subjects ( < 0.01), and the increases in low frequency/high frequency ratio from supine to standing were positively correlated with those in mean arterial pressure in the study subjects ( < 0.001). Upright sympathetic overactivation is associated with pediatric orthostatic hypertension.
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http://dx.doi.org/10.3389/fped.2020.00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047410PMC
February 2020

Endothelin-1 Downregulates Sulfur Dioxide/Aspartate Aminotransferase Pathway via Reactive Oxygen Species to Promote the Proliferation and Migration of Vascular Smooth Muscle Cells.

Oxid Med Cell Longev 2020 28;2020:9367673. Epub 2020 Jan 28.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

The regulatory mechanisms for proliferation and migration of vascular smooth muscle cells have not yet been clear. The present study was designed to investigate whether and how endothelin-1 (ET-1) impacted the generation of endogenous sulfur dioxide (SO) in rat vascular smooth muscle cell (VSMC) proliferation and migration. Primary VSMCs and purified aspartate aminotransferase (AAT) protein were used in this study. We found that in the presence of ET-1, the expression of PCNA and Ki-67 was upregulated and the migration of VSMCs was promoted, while the AAT activity and SO levels in VSMCs were reduced without any changes in AAT1 and AAT2 expression. SO supplementation successfully prevented the ET-1-facilitated expression of PCNA and Ki-67 and the migration of VSMCs. Interestingly, ET-1 significantly increased reactive oxygen species (ROS) production in association with SO/AAT pathway downregulation in VSMCs compared with controls, while the ROS scavenger N-acetyl-L-cysteine (NAC) and the antioxidant glutathione (GSH) significantly abolished the ET-1-stimulated downregulation of the SO/AAT pathway. Moreover, the AAT activity was reduced in purified protein after the treatment for 2 h. However, NAC and GSH blocked the hydrogen peroxide-induced AAT activity reduction. In conclusion, our results suggest that ET-1 results in the downregulation of the endogenous SO/AAT pathway via ROS generation to enhance the proliferation and migration of VSMCs.
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http://dx.doi.org/10.1155/2020/9367673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008293PMC
September 2020

Negative auto-regulation of sulfur dioxide generation in vascular endothelial cells: AAT1 S-sulfenylation.

Biochem Biophys Res Commun 2020 Feb 19. Epub 2020 Feb 19.

Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China. Electronic address:

Recently, endogenous sulfur dioxide (SO) has been found to exert an important function in the cardiovascular system. However, the regulatory mechanism for SO generation has not been entirely clarified. Hence, we aimed to explore the possible auto-regulation of endogenous SO generation and its mechanisms in vascular endothelial cells. We showed that SO did not affect the protein expression of aspartate aminotransferase 1 (AAT1), a major SO synthesis enzyme, but significantly inhibited AAT activity in primary human umbilical vein endothelial cells (HUVECs) and porcine purified AAT1 protein. An AAT1 enzymatic kinetic study showed that SO reduced the Vmax (1.89 ± 0.10 vs 2.55 ± 0.12, μmol/mg/min, P < 0.05) and increased the Km (35.97 ± 9.54 vs 19.33 ± 1.76 μmol/L, P < 0.05) values. Furthermore, SO induced S-sulfenylation of AAT1 in primary HUVECs and purified AAT1 protein. LC-MS/MS analysis indicated that SO sulfenylated AAT1 at Cys192. Mechanistically, thiol reductant DTT treatment or C192S mutation prevented SO-induced AAT1 sulfenylation and the subsequent inhibition of AAT activity in purified AAT1 protein and primary HUVECs. Our findings reveal, for the first time, a mechanism of auto-regulation of SO generation through sulfenylation of AAT1 at Cys192 to suppress AAT activity in vascular endothelial cells. These findings will greatly deepen the understanding of regulatory mechanisms in the cardiovascular homeostasis.
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http://dx.doi.org/10.1016/j.bbrc.2020.02.040DOI Listing
February 2020

Macrophage-derived sulfur dioxide is a novel inflammation regulator.

Biochem Biophys Res Commun 2020 04 10;524(4):916-922. Epub 2020 Feb 10.

Department of Pediatrics, Peking University First Hospital, Beijing, China. Electronic address:

Macrophage-mediated inflammation is a key pathophysiological component of cardiovascular diseases, but the underlying mechanisms by which the macrophage regulates inflammation have been unclear. In our study, we, for the first time, showed an endogenous sulfur dioxide (SO) production in RAW267.4 macrophages by using HPLC and SO-specific fluorescent probe assays. Moreover, the endogenous SO generating enzyme aspartate aminotransferase (AAT) was found to be expressed by the macrophages. Furthermore, we showed that AAT2 knockdown triggered spontaneous macrophage-mediated inflammation, as represented by the increased TNF-α and IL-6 levels and the enhanced macrophage chemotaxis; these effects could be reversed by the treatment with a SO donor. Mechanistically, AAT2 knockdown activated the NF-κB signaling pathway in macrophages, while SO successfully rescued NF-κB activation. In contrast, forced AAT2 expression reversed AngII-induced NF-κB activation and subsequent macrophage inflammation. Moreover, treatment with a SO donor also alleviated macrophage infiltration in AngII-treated mouse hearts. Collectively, our data suggest that macrophage-derived SO is an important regulator of macrophage activation and it acts as an endogenous "on-off switch" in the control of macrophage activation. This knowledge might enable a new therapeutic strategy for cardiovascular diseases.
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http://dx.doi.org/10.1016/j.bbrc.2020.02.013DOI Listing
April 2020

Baroreflex Sensitivity Predicts Response to Metoprolol in Children With Vasovagal Syncope: A Pilot Study.

Front Neurosci 2019 13;13:1329. Epub 2019 Dec 13.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

To explore the role of baroreflex sensitivity (BRS) in the head-up tilt test (HUTT) in predicting the therapeutic response of vasovagal syncope (VVS) patients to metoprolol. Vasovagal syncope patients treated with metoprolol were enrolled in this study and were classified as responders or non-responders according to changes in their symptom scores before and after metoprolol treatment. Values of BRS in the supine position and at positive response occurrence in the HUTT were obtained, and BRS changes from supine to positive response occurrence were calculated. Differences between responders and non-responders were analyzed. Receiver operating characteristic curve analysis was performed to assess the value of BRS for predicting the therapeutic efficacy of metoprolol in pediatric patients with VVS. Forty patients (14 boys; 11.8 ± 2.5 years) diagnosed with VVS were recruited in the study, 28 of whom were verified to be responders to metoprolol and 12 of whom were verified as non-responders. They did not show any differences in baseline characteristics and hemodynamics in the HUTT ( > 0.05). However, the responders had an obviously increased supine BRS value compared to the non-responders (16.9 ± 7.7 ms/mmHg vs. 7.6 ± 3.8 ms/mmHg; < 0.01). No difference in BRS at positive response occurrence was observed between the two groups (8.9 ± 8.5 ms/mmHg vs. 10.6 ± 9.8 ms/mmHg; > 0.05). Accordingly, the changes in the BRS of responders were more obvious than in non-responders (8.0 ± 7.8 ms/mmHg vs. -3.0 ± 10.4 ms/mmHg; < 0.01). The area under the receiver operating characteristic curve for the predictive value of supine BRS was 0.887 (95% CI, 0.779-0.995; < 0.01). A cut-off value of 10 ms/mmHg yielded a sensitivity and specificity of 82 and 83%, respectively, in predicting the therapeutic efficacy of metoprolol in pediatric VVS patients. The area under the receiver operating characteristic curve for the predictive value of BRS changes was 0.827 (95% CI, 0.693-0.962; < 0.01). A cut-off value of 4 ms/mmHg yielded a sensitivity and specificity of 71 and 83%, respectively. Baroreflex sensitivity may predict the response of children with VVS to metoprolol.
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http://dx.doi.org/10.3389/fnins.2019.01329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923178PMC
December 2019

L-Cystathionine Protects against Homocysteine-Induced Mitochondria-Dependent Apoptosis of Vascular Endothelial Cells.

Oxid Med Cell Longev 2019 25;2019:1253289. Epub 2019 Nov 25.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

The study was aimed at investigating the effects of L-cystathionine on vascular endothelial cell apoptosis and its mechanisms. Cultured human umbilical vein endothelial cells (HUVECs) were used in the study. Apoptosis of vascular endothelial cells was induced by homocysteine. Apoptosis, mitochondrial superoxide anion, mitochondrial membrane potential, mitochondrial permeability transition pore (MPTP) opening, and caspase-9 and caspase-3 activities were examined. Expression of Bax, Bcl-2, and cleaved caspase-3 was tested and BTSA1, a Bax agonist, and HUVEC Bax overexpression was used in the study. Results showed that homocysteine obviously induced the apoptosis of HUVECs, and this effect was significantly attenuated by the pretreatment with L-cystathionine. Furthermore, L-cystathionine decreased the production of mitochondrial superoxide anion and the expression of Bax and restrained its translocation to mitochondria, increased mitochondrial membrane potential, inhibited mitochondrial permeability transition pore (MPTP) opening, suppressed the leakage of cytochrome c from mitochondria into the cytoplasm, and downregulated activities of caspase-9 and caspase-3. However, BTSA1, a Bax agonist, or Bax overexpression successfully abolished the inhibitory effect of L-cystathionine on Hcy-induced MPTP opening, caspase-9 and caspase-3 activation, and HUVEC apoptosis. Taken together, our results indicated that L-cystathionine could protect against homocysteine-induced mitochondria-dependent apoptosis of HUVECs.
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http://dx.doi.org/10.1155/2019/1253289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899331PMC
May 2020

Heart Rate Variability Predicts Therapeutic Response to Metoprolol in Children With Postural Tachycardia Syndrome.

Front Neurosci 2019 12;13:1214. Epub 2019 Nov 12.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Purpose: To improve the metoprolol therapeutic effectiveness, we aimed to explore whether baseline heart rate variability (HRV) indicators before metoprolol treatment were useful for predicting its efficacy for postural tachycardia syndrome (POTS).

Methods: We recruited 45 children with POTS who received metoprolol and 17 healthy controls. All children underwent a standing test or basic head-up tilt test and 24-h dynamic electrocardiography before treatment. After 3 months of metoprolol, therapeutic responsiveness was evaluated. The usefulness of baseline HRV parameters in predicting the effectiveness of metoprolol was studied and the long-term cumulative symptom rate was analyzed.

Results: The baseline HRV frequency domain indicators for power, ultra-low frequency, very-low frequency, low frequency (LF), high frequency (HF), and total power (TP) as well as time domain indicators were significantly lower for responders than non-responders to metoprolol; however, low-frequency normalized units and LF/HF ratio were markedly greater for responders than non-responders. On series-parallel analysis, combined baseline triangular (TR) index ≤ 33.7 and standard deviation of all normal-to-normal intervals (SDNN) index ≤ 79.0 ms as cut-off values yielded sensitivity, specificity and accuracy of 85.3, 81.8, and 84.4%, respectively, to predict therapeutic responsiveness to metoprolol. On long-term follow-up, the cumulative symptom rate was significantly higher with TR index > 33.7 and SDNN index ≤ 79.0 ms, TR index ≤ 33.7 and SDNN index > 79.0 ms or TR index > 33.7 and SDNN index > 79.0 ms than TR index ≤ 33.7 and SDNN index ≤ 79.0 ms ( < 0.05).

Conclusion: Combined TR index ≤ 33.7 and SDNN index ≤ 79.0 ms were useful preliminary measures to predict therapeutic response to metoprolol in pediatric POTS.
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http://dx.doi.org/10.3389/fnins.2019.01214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861190PMC
November 2019

Endogenous hydrogen sulfide sulfhydrates IKKβ at cysteine 179 to control pulmonary artery endothelial cell inflammation.

Clin Sci (Lond) 2019 10;133(20):2045-2059

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Background: Pulmonary artery endothelial cell (PAEC) inflammation is a critical event in the development of pulmonary arterial hypertension (PAH). However, the pathogenesis of PAEC inflammation remains unclear.

Methods: Purified recombinant human inhibitor of κB kinase subunit β (IKKβ) protein, human PAECs and monocrotaline-induced pulmonary hypertensive rats were employed in the study. Site-directed mutagenesis, gene knockdown or overexpression were conducted to manipulate the expression or activity of a target protein.

Results: We showed that hydrogen sulfide (H2S) inhibited IKKβ activation in the cell model of human PAEC inflammation induced by monocrotaline pyrrole-stimulation or knockdown of cystathionine γ-lyase (CSE), an H2S generating enzyme. Mechanistically, H2S was proved to inhibit IKKβ activity directly via sulfhydrating IKKβ at cysteinyl residue 179 (C179) in purified recombinant IKKβ protein in vitro, whereas thiol reductant dithiothreitol (DTT) reversed H2S-induced IKKβ inactivation. Furthermore, to demonstrate the significance of IKKβ sulfhydration by H2S in the development of PAEC inflammation, we mutated C179 to serine (C179S) in IKKβ. In purified IKKβ protein, C179S mutation of IKKβ abolished H2S-induced IKKβ sulfhydration and the subsequent IKKβ inactivation. In human PAECs, C179S mutation of IKKβ blocked H2S-inhibited IKKβ activation and PAEC inflammatory response. In pulmonary hypertensive rats, C179S mutation of IKKβ abolished the inhibitory effect of H2S on IKKβ activation and pulmonary vascular inflammation and remodeling.

Conclusion: Collectively, our in vivo and in vitro findings demonstrated, for the first time, that endogenous H2S directly inactivated IKKβ via sulfhydrating IKKβ at Cys179 to inhibit nuclear factor-κB (NF-κB) pathway activation and thereby control PAEC inflammation in PAH.
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http://dx.doi.org/10.1042/CS20190514DOI Listing
October 2019

Long-Term Outcomes of Children and Adolescents With Postural Tachycardia Syndrome After Conventional Treatment.

Front Pediatr 2019 27;7:261. Epub 2019 Jun 27.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

To explore the long-term outcomes of children and adolescents with postural tachycardia syndrome receiving conventional interventions. A total of 121 patients were recruited, but 6 (5.0%) of them were lost at follow-up. The detailed clinical data were collected, and the reoccurrence and frequency of orthostatic intolerance symptoms were evaluated with a mean followed-up period of 18.7 months (range, 14-74 months). The Kaplan-Meier curve was used to show the cumulative symptom-free rate of patients over time. Factors influencing the long-term outcomes were examined using the Cox's proportional hazards models. The cumulative symptom-free rate was gradually increased over time. It was 48.4% at the 1-year follow-up and increased to 85.6% at the 6-year follow-up. The duration of symptoms before treatment and the maximum upright heart rate in standing-up test were identified as independent indicators for the long-term outcomes. Each 1-month prolongation in the duration of symptoms before treatment was associated with a 1.2% decrease in the cumulative symptom-free rate. However, each 1-bpm increase in the maximum upright heart rate in standing-up test was associated with a 2.1% increase in the cumulative symptom-free rate. The long-term outcomes of postural tachycardia syndrome patients who received conventional interventions are benign and the cumulative symptom-free rate was gradually increased over time. The prolonged duration of symptoms before treatment and the reduced maximum upright heart rate in standing-up test are the independent risk indicators.
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http://dx.doi.org/10.3389/fped.2019.00261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610301PMC
June 2019

Angiotensin II downregulates vascular endothelial cell hydrogen sulfide production by enhancing cystathionine γ-lyase degradation through ROS-activated ubiquitination pathway.

Biochem Biophys Res Commun 2019 06 10;514(3):907-912. Epub 2019 May 10.

Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China. Electronic address:

The interactions between vasoactive peptides and gasotransmitters have attracted considerable attention from scientists. However, the impact of angiotensin II (AngII) on the endogenous hydrogen sulfide/cystathionine γ-lyase (HS/CSE) pathway in vascular endothelial cells remains unclear. In this study, we found, for the first time, that AngII downregulated the endogenous HS/CSE pathway in a time-dependent manner. Mechanistically, AngII accelerated the degradation of the CSE protein and shortened its half-life in endothelial cells. AngII significantly induced Lys48 (K48)-linked CSE ubiquitination and subsequent CSE degradation but did not affect Lys63 (K63)-linked CSE ubiquitination in vascular endothelial cells. Treatment with the proteasome inhibitor MG132 and mutation of Lys48 to Arg in ubiquitin successfully blunted the inhibitory effects of AngII on the endogenous HS/CSE pathway in vascular endothelial cells. Furthermore, we found that superoxide anion levels were significantly increased in AngII-treated endothelial cells compared with controls and that the ROS scavenger N-acetyl-l-cysteine (NAC) significantly abolished CSE ubiquitination. Taken together, our data suggested that AngII inhibited endogenous HS generation through ubiquitination-mediated CSE degradation via the ROS pathway in vascular endothelial cells.
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http://dx.doi.org/10.1016/j.bbrc.2019.05.021DOI Listing
June 2019

Autonomic Nervous Function in Vasovagal Syncope of Children and Adolescents.

Neurosci Bull 2019 Oct 27;35(5):937-940. Epub 2019 Apr 27.

Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China.

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http://dx.doi.org/10.1007/s12264-019-00383-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754486PMC
October 2019

Sulfur Dioxide Activates Cl/HCO Exchanger via Sulphenylating AE2 to Reduce Intracellular pH in Vascular Smooth Muscle Cells.

Front Pharmacol 2019 27;10:313. Epub 2019 Mar 27.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Sulfur dioxide (SO) is a colorless and irritating gas. Recent studies indicate that SO acts as the gas signal molecule and inhibits vascular smooth muscle cell (VSMC) proliferation. Cell proliferation depends on intracellular pH (pH). Transmembrane cystein mutation of Na- independent Cl/HCO exchanger (anion exchanger, AE) affects pH. However, whether SO inhibits VSMC proliferation by reducing pH is still unknown. Here, we investigated whether SO reduced pH to inhibit the proliferation of VSMCs and explore its molecular mechanisms. Within a range of 50-200 μM, SO was found to lower the pH in VSMCs. Concurrently, NHCl pre-perfusion showed that SO significantly activated AE, whereas the AE inhibitor 4,4'-diisothiocyanatostilbene- 2,20-disulfonic acid (DIDS) significantly attenuated the effect of SO on pH in VSMCs. While 200 μM SO sulphenylated AE2, while dithiothreitol (DTT) blocked the sulphenylation of AE2 and subsequent AE activation by SO, thereby restoring the pH in VSMCs. Furthermore, DIDS pretreatment eliminated SO-induced inhibition of PDGF-BB-stimulated VSMC proliferation. We report for the first time that SO inhibits VSMC proliferation in part by direct activation of the AE via posttranslational sulphenylation and induction of intracellular acidification.
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http://dx.doi.org/10.3389/fphar.2019.00313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446831PMC
March 2019

Neutrophil-to-Lymphocyte Ratio Predicts Intravenous Immunoglobulin-Resistance in Infants Under 12-Months Old With Kawasaki Disease.

Front Pediatr 2019 19;7:81. Epub 2019 Mar 19.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

We evaluated the ability of peripheral blood neutrophil-to-lymphocyte ratio (NLR) to predict the intravenous immunoglobulin (IVIG) resistance in Kawasaki disease (KD) patients under 1-year of age. A total of 92 KD patients under the age of 1-year and who were hospitalized in Peking University First Hospital from June 2007 to August 2016 were recruited in this study. The clinical and laboratory data were analyzed to see if peripheral blood NLR was useful for predicting the IVIG-resistance in KD. Totally 81 out of 92 patients were IVIG responders while 11 resistant to IVIG, with no significant difference in age, gender, ratio of the number of the incomplete to the number of complete KD, and the number of patients with coronary artery lesion between two groups ( > 0.05). Peripheral blood NLR was increased significantly in IVIG-resistant children compared to the IVIG responders [2.6 (interquartile range: 1.4, 3.8) vs. 1.7 (interquartile range: 0.9, 2.3), = 0.039]. A cut-off value of NLR of 2.51 in KD patients younger than 1-year old yielded a sensitivity of 0.545 and specificity of 0.840, respectively, in the prediction of IVIG resistance. An area under the curve of 0.692 (95% confidence interval 0.526-0.859, = 0.039) was determined. The peripheral blood NLR ≥ 2.51 is useful to predict the IVIG resistance in KD patients younger than 1-year old.
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http://dx.doi.org/10.3389/fped.2019.00081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433842PMC
March 2019

Plasma Homocysteine Level in Children With Postural Tachycardia Syndrome.

Front Pediatr 2018 3;6:375. Epub 2018 Dec 3.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

The study was designed to evaluate the changes of plasma homocysteine (Hcy) level in children with postural tachycardia syndrome (POTS) and explore its significance. A total of 65 subjects were recruited in our study, of whom 35 children were in the POTS group and 30 healthy children were in the control group. Plasma Hcy levels were determined in all subjects. The relationship between the plasma Hcy level and the symptom score was analyzed in the 35 POTS patients. The relationship between the plasma Hcy level and the change in heart rate from the supine to upright position (ΔHR) and between the plasma Hcy level and the rate of increase in heart rate from the supine to upright position (ΔHR/sHR × 100%) were analyzed in all subjects. The plasma Hcy levels were significantly higher in the children with POTS than those in the control group (9.78 [7.68, 15.31] μmol/L vs. 7.79 [7.46, 9.63] μmol/L, < 0.05). The plasma Hcy levels were positively correlated with symptom scores in the POTS patients ( = 35, = 0.522, < 0.01). The plasma Hcy levels were also positively correlated with ΔHR ( = 65, = 0.332, < 0.01) and ΔHR/sHR × 100% ( = 65, = 0.341, < 0.01) in all the subjects. In conclusion, the plasma Hcy levels were elevated in the children with POTS positively correlated with the severity of POTS, suggesting that Hcy might be involved in the pathogenesis of POTS.
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http://dx.doi.org/10.3389/fped.2018.00375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287046PMC
December 2018

Acceleration Index Predicts Efficacy of Orthostatic Training on Vasovagal Syncope in Children.

J Pediatr 2019 04 7;207:54-58. Epub 2018 Dec 7.

Department of Pediatrics, Peking University First Hospital, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China. Electronic address:

Objective: To explore the value of the acceleration index as a predictor of therapeutic response to orthostatic training in children with vasovagal syncope (VVS).

Study Design: Thirty-three children with VVS were recruited and treated with orthostatic training. The therapeutic response of each patient was evaluated after 3 months of treatment. A Pearson correlation was calculated between the acceleration index and the severity of VVS. The value of the acceleration index in predicting the therapeutic response to orthostatic training was assessed by analysis of the receiver operating characteristic curve.

Results: Among the 33 children with VVS, 20 were found to be responders and the remaining were nonresponders. The mean acceleration index was significantly lower in responders compared with nonresponders (21.10 ± 6.61 vs 31.36 ± 9.00; P = .001) and it was negatively correlated with positive response time in the head-up tilt test, with systolic blood pressure and with diastolic blood pressure at positive response time in the head-up tilt test (P < .05). The receiver operating characteristic curve for the predictive value of the acceleration index showed that the area under the curve was 0.827 (95% CI, 0.676-0.978; P = .002), and a cutoff value of the acceleration index of 26.77 yielded a sensitivity of 85.0% and a specificity of 69.2%.

Conclusions: The acceleration index may be useful for predicting the efficacy of orthostatic training on VVS in children.
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http://dx.doi.org/10.1016/j.jpeds.2018.10.063DOI Listing
April 2019

Value of Immediate Heart Rate Alteration From Supine to Upright in Differential Diagnosis Between Vasovagal Syncope and Postural Tachycardia Syndrome in Children.

Front Pediatr 2018 19;6:343. Epub 2018 Nov 19.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

To explore the predictive value of immediate heart rate alteration from supine to upright in the differential diagnosis between vasovagal syncope (VVS) and postural tachycardia syndrome (POTS) in children. A total of 76 pediatric outpatients or inpatients who visited the Peking University First Hospital from July 2016 to November 2017 were recruited in the study. Among them, 52 patients were diagnosed with VVS and 24 patients were diagnosed with POTS. The differential diagnostic value of acceleration index (AI) and 30/15 ratio was evaluated by the receiver operating characteristic (ROC) curve. An external validation test was performed in another 46 patients. Compared with the cases in the VVS group, patients in the POTS group had a significantly increased AI but a decreased 30/15 ratio (33.495 ± 8.472 vs. 23.440 ± 8.693, < 0.001; 0.962 ± 0.067 vs. 1.025 ± 0.084, = 0.002; respectively). The ROC curves showed that AI and 30/15 ratio were useful for differentiating POTS from VVS. A cut-off value of AI set at 28.180 yielded a sensitivity of 79.2% and a specificity of 73.1%. A cut-off value of 30/15 ratio set at 1.025 yielded a sensitivity of 87.5% and a specificity of 61.5%. A combined use of these two indices improved the sensitivity to 95.8% when either AI or 30/15 was used, and specificity to 80.8% with the use of both AI and 30/15 at the same diagnosis. The external validation test showed that the positive and negative predictive values of the AI and 30/15 ratio were 77.3 and 79.2%, and 72.0 and 81.0%, respectively. The positive predictive value increased to 87.5% when both the AI and 30/15 ratio cut-off values were used together. The AI and 30/15 ratio, which are easy to perform and non-invasive, have proper sensitivity and specificity to differentiate patients with POTS from those with VVS. The combination of these two indices significantly improves the predictive value.
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http://dx.doi.org/10.3389/fped.2018.00343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252323PMC
November 2018
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