| Objective:Orthostatic intolerance(OI)can be defined as having difficulty tolerating an upright posture because of symptoms and signs that can be resolved when returned to supine.Vasovagal syncope(VVS)and postural tachycardia syndrome(POTS)are two common types of pediatric OI.Circadian rhythm dysfunction is involved in developing many diseases,such as hypertension,cardiovascular diseases,obesity,diabetes,and tumors.However,there is little known about the circadian rhythm dysfunction of pediatric OI.This study aims to explore whether circadian rhythm dysfunction exists in pediatric VVS and POTS,to study the specific patterns and the potential mechanism of the circadian rhythm dysfunction,so as to provide the basis for accurate diagnosis and treatment of VVS and POTS.Methods:24-hour ambulatory blood pressure monitoring(24-h ABPM)indicators,standing heart rate(HR)related indicators in the standing tests,and the expressions of clock genes were used to study the circadian rhythms in the children with VVS and the children with POTS.(1)In this part,the research group included 80 children with VVS and 94 children with POTS who were diagnosed in the pediatrics of our hospital from January 2015 to December 2019.80 healthy children were recruited as the control group.We collected and analyzed the baseline data of 24-h ABPM from the control,VVS,and POTS groups.Besides,we depicted the 24 h changes of rate-pressure product(RPP).62 children with VVS and 61 children with POTS completed a follow-up of 3(2,4)months.They were divided into responders and non-responders according to the improvement of OI symptoms.Then,the 24-h ABPM indicators were analyzed to study their impact on the prognosis of VVS and POTS,respectively.(2)In this part,the research group included 56 children with VVS and52 children with POTS who were admitted in the pediatrics of our hospital from July 2019 to March 2021.39 healthy children were recruited as the control group.All children completed standing tests in 3 different time periods(7:00-9:00 in the morning,15:00-17:00 in the afternoon,20:00-22:00 in the evening).Another 21 children with VVS and 20 children with POTS who were admitted in the pediatrics of our hospital were recruited for the external validation study.52 children with POTS completed the short-term follow-up(3 months)and long-term follow-up[9(6,12)months]after the treatment of metoprolol.During the short-term follow-up,the children were divided into responders and non-responders according to the improvement of OI symptoms.The receiver operating curve was used to analyze the predictive value of orthostatic heart rate increment(ΔHR)in the afternoon and evening on the diagnosis and treatment efficacy of POTS.(3)In this part,we enrolled 20 children diagnosed with VVS and 19children diagnosed with POTS who were admitted in the pediatrics of our hospital from July 2020 to May 2021.15 healthy children were served as the control group.Peripheral venous blood was collected at 7:00 and 17:00,and separated into plasma and peripheral blood mononuclear cells(PBMCs).We detected the expressions of circadian clock genes(BMAL1,CLOCK,PER1,PER2,CRY1,CRY2,REV-ERBα)in PBMCs,oxidative stress indicators[the expressions of nuclear factor E2-related factor 2(NRF2),haeme oxygenase 1(HO-1)m RNA in PBMCs,and plasma superoxide dismutase(SOD)activity],and vascular endothelium function[plasma nitric oxide(NO)levels].Due to the excessive increase of standing plasma norepinephrine(NE)levels in the POTS patients,NE treatment of human umbilical vein endothelial cells(HUVECs)simulated a hyperadrenergic state.And the expressions of clock genes were detected in HUVECs.Results:(1)There were abnormal circadian rhythms of blood pressure in the VVS and POTS groups.Non-dipping blood pressure pattern was more prevalent in the VVS and POTS groups than the control group(62.5%vs.66.0%vs.43.8%,P<0.001).The circadian variations of the 24h RPP values in the 3 groups showed similar patterns with peaks roughly occurring approximately 2 h to 3 h after waking up from nocturnal sleep.The RPP values in the POTS group from 1 h to 4 h after waking up were significantly higher than those in the VVS and control groups.The RPP value≥95.3×10~2 bpm·mm Hg at 1 h after waking up to diagnose POTS yielded a sensitivity and specificity of 61.7%and 75.0%,respectively.The RPP value≥107.2×10~2 bpm·mm Hg at 2 h after waking up to diagnose POTS yielded a sensitivity and specificity of 46.8%and 85.5%,respectively.In the follow-up,there was no obvious change in the proportion of non-dipping blood pressure pattern before and after treatment whether in the treatment responders nor the non-responders.(2)The standingΔHR in the VVS and POTS groups were significantly higher in the morning than in the afternoon and evening.However,there was no significant difference of theΔHR in the control group in the 3 time periods(except forΔHR at 10 min).TheΔHR during all the 3 time periods were significantly higher in the POTS group than those in the VVS and control groups.All the POTS children met the diagnostic criteria in the morning standing test[ΔHR≥40 beats/min(bpm)],46.2%in the afternoon,26.9%in the evening.The external validation test showed that the afternoonΔHR≥30 bpm to diagnose POTS yielded sensitivity,specificity,and accuracy of 85.0%,71.4%,and 78.0%,respectively.And the eveningΔHR≥25 bpm yielded sensitivity,specificity,and accuracy of 85.0%,76.2%,and 80.5%,respectively.The circadian variations of the standingΔHR were related to the efficacy of metoprolol to POTS.The afternoonΔHR in the non-responders was significantly higher than in the responders.The afternoonΔHR<44 bpm yielded a sensitivity and specificity of 73.7%and 87.9%in predicting the treatment efficacy of metoprolol.In the long-term follow-up,the cumulative symptom relief rate in the group with the afternoonΔHR<44bpm was significantly higher than the group withΔHR≥44 bpm(χ~2=15.130,P<0.001).(3)The expressions of PER1,CRY1 m RNA at 7:00 in the VVS group were significantly higher than those in the control group.The expressions of CLOCK,PER1,PER2,CRY1,REV-ERBαm RNA at 7:00 in the POTS group were significantly higher than those in the control group,with the most significant difference in PER1.The expressions of NRF2,HO-1m RNA,and plasma NO levels at 7:00 in the VVS and POTS groups were significantly higher than those in the control group.While the plasma SOD activity at 7:00 in the POTS group was significantly lower than that in the VVS and control groups.At 17:00,there was no significant difference in each examined indicator among the 3 groups.In the control and VVS groups,the expressions of clock genes,NRF2 m RNA,plasma SOD activity,and plasma NO levels were significantly different between 7:00and 17:00,respectively.However,in the POTS group,only the expressions of PER1,PER2 m RNA were significantly different between 7:00 and17:00.The other indicators did not change obviously at the two time points in the POTS group.Treatment with NE in HUVECs can induce a transient increase in the expression of PER1 m RNA with a concentration-dependent manner.Conclusions:(1)Abnormal blood pressure circadian pattern is prevalent in children with VVS and the children with POTS.There is excessive increase in the morning of RPP values in the POTS children.(2)The standingΔHR exhibits circadian variations in children with VVS and the children with POTS.The circadian variations ofΔHR may affect the diagnosis and treatment efficacy of POTS.(3)The abnormal expressions of clock genes CLOCK,PER1,PER2,CRY1,REV-ERBαm RNA exist in the children with POTS.And the expressions of clock genes PER1,CRY1 m RNA were abnormal in the children with VVS. |
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