Small vessel disease is associated with age, mean blood pressure (MAP) and bloodpressure pulsatility (PP). We used data from the UK Biobank cohort study todetermine the relative importance of MAP versus PP driving white matter injurywithin individual white matter tracts, particularly in the anterior andposterior vascular territory. The associations between blood pressure anddiffusion indices in 27 major tracts were analysed using unadjusted andfully-adjusted general linear models and mixed-effect linear models. Bloodpressure and neuroimaging data were available for 37,041 participants . In unadjusted analyses, MAP and PP were similarlyassociated with diffusion indices in the anterior circulation. In the posteriorcirculation, the associations were weaker, particularly for MAP. Infully-adjusted analyses, MAP remained associated with all diffusion indices inthe anterior circulation, independently of age. In the posterior circulation,the effect of MAP became protective. PP remained associated with greater meandiffusivity and extracellular free water diffusion in the anterior circulationand all diffusion indices in the posterior circulation. There was a significantinteraction between PP and age. This implies discordant mechanisms for chronicwhite matter injury in different brain regions and potentially in the associatedstroke risks. Progression of SVD and its neuroimaging markers is strongly associated with age andhypertension.59 In middle-aged people, thesechanges are strongly associated with an increase in both systolic and diastolicblood pressure represented by mean arterial blood pressure and reflecting thesteady-state component of the blood flow; however, later in life the effect dependson the difference between the systolic and diastolic blood pressure corresponding tothe pulsatility of the blood flow. However, the effect of blood pressure on white matter integrity may varyacross the brain regions due to differences in the location of white matter tractsrelative to vascular supply and watershed regions. In particular, the importance ofdifferences in blood pressure and its pulsatility between the anterior and posteriorcerebrovascular circulation due to the damping effect of the blood pressure at thelevel of the carotid siphon is uncertain. Differences in haemodynamic mechanisms of injury between theanterior and posterior circulation may require adaptation of treatment to preventfuture stroke and progression of white matter injury depending on the location ofsmall vessel disease in individual patients.Small vessel disease (SVD) is associated with an increased risk of stroke, However, early microstructural white matter damage that is evident ondiffusion-weighted magnetic resonance imaging (dMRI) as altered diffusion of watermolecules within and around neurites. It may be characterised as an increase in meandiffusivity (MD) and reduction in anisotropy13 reflecting the loss ofstructural integrity of white matter tracts. Diffusion changes precede the development of macrostructural changes in SVDand may provide a sensitive tool to investigate disease mechanisms in its early stages, for example, the relative contribution of different haemodynamicmeasures.Macrostructural white matter injury manifests as lacunar strokes, white matterhyperintensities (WMH), microbleeds, and enlarged perivascular spaces.Therefore, in the UK Biobank cohort, we determined whether associations of meanarterial blood pressure or pulse pressure with individual white matter tractsdiffered and whether these associations varied between tracts located predominantlywithin the anterior versus posterior cerebrovascular circulation.http://www.ukbiobank.ac.uk/ethics) and the IRB approval wasobtained from the North West Multi-centre Research Ethics Committee.UK Biobank is a large, prospective cohort study including demographic, lifestyle,clinical, and imaging data of 502,540 middle-aged community-based peoplerecruited from 22 centres across the UK. Informed consent was obtained from allUK Biobank participants. The details regarding the ethical approval andgovernance are described on the UK Biobank website  volume and diffusion-weighted imaging(dMRI), and systolic and diastolic blood pressure measurements (SBP and DBP).People with a condition potentially associated with cerebral white matterdamage, such as multiple sclerosis or other demyelinating disorders, cerebralinfarction, encephalitis or brain abscess, brain tumour or systemic lupuserythematosus, were excluded on the basis of the codes from the 10th revision ofthe International Statistical Classification of Diseases and Related HealthProblems (ICD-10).https://biobank.ctsu.ox.ac.uk/crystal/crystal/docs/brain_mri.pdf. T1-weighed 3D MPRAGE, FLAIR,and dMRI data were pre-processed and analysed by the UK Biobank brain imagingteam using FMRIB Software Library (FSL) tools (http://www.fmrib.ox.ac.uk/fsl).UK Biobank brain MRI data were acquired on a single Siemens Skyra 3 T scanner,and the sequence parameters are available at , DTI indices are sensitive to myelination and structural integrity ofwhite matter but cannot distinguish between changes in the neurite density andchanges in neurite arrangement. NODDI overcomes these limitations and provides estimates of neuritedensity as the ICVF and the variability of neurite orientation as OD as well asestimates of diffusion in the extracellular free water as ISOVF., In the UK Biobank, DTI data were analysed using FSL tools and the NODDI indices were derived by AMICO (Accelerated MicrostructureImaging via Convex Optimization). The white matter tracts were defined using the Juelich (JHU ICBM-DTI-81)atlas and presented for reference in Supplementary Figure 1. The tract-averageDTI and NODDI measures were derived for 27 major white matter tracts.Analysed dMRI variables included diffusion tensor imaging (DTI) measures inindividual white matter tracts, such as fractional anisotropy (FA) and meandiffusivity (MD) as well as neurite orientation dispersion and density imaging(NODDI) measures such as Intracellular Volume Fraction (ICVF), the IsotropicCompartment Volume Fraction (ISOVF), and the Orientation Dispersion (OD).The main explanatory variables were the mean arterial pressure (MAP) and pulsepressure (PP) calculated from the automated systolic (SBP) and diastolic (DBP)blood pressure measures. In the UK Biobank, blood pressure was measured twice bytrained nurses after the participant had been at rest for at least 5 minutes inthe seated position with a digital sphygmomanometer  with a suitably sized cuff. Whenautomated blood pressure values were not available, manual blood pressure wasused, and when it also was missing, values from Pulsewave Analysis (PWA) wereused. Measures of SBP and DBP were averaged within a visit. and the volumes of segmented white matter (WM) was estimated using FAST; both algorithms are a part of FSL. The WMH volume was divided by the total volume of WM andlogit-transformed to normalise and stabilise the variance; this measure wasfurther referred to as WMH load.As diffusion measures are affected by white matter lesions, the volume of whitematter hyperintensities (WMH) was used as a covariate and used to stratify theanalyses. In the UK Biobank, the volume of WMH was calculated from theT1-weighted and T2-FLAIR images using BIANCA,To compare the explanatory variables with different units of measurement,continuous variables were centred and scaled before being entered intoregression analyses. The effect of MAP and PP on DTI and NODDI dMRI measureswithin individual white matter tracts was analysed with sequential addition ofcovariates to assess the impact of adjustment, first, using unadjusted models(dMRI ∼ PP or dMRI ∼ MAP), then, after adjusting for age and sex(dMRI ∼ PP + age + sex OR dMRI ∼ MAP + age + sex), and, finally, after adjustingfor the other blood pressure measures and cardiovascular risk factors(dMRI ∼ MAP + PP + age + sex + smoking + diabetes + antihypertensives + BPmeasure + centre).The same covariates were included in all the multivariable models. The effectswere also investigated using mixed-effects models, where we had to allow forrandom effects due to multiple regions being included from the same individual(dMRI ∼ circulation + age + sex + MAP + PP + antihypertensives + smoking + diabetes + BPmeasure + centre + antihypertensives:MAP + antihypertensives:PP + age:MAP + age:PP + circulation:PP + circulation:MAP + (1|eid) + (1|roi)).The effect of MAP and PP on DTI and NODDI dMRI measures within individual WMtracts was analysed, first, using unadjusted models, then, after adjusting forage and sex, and, finally, after adjusting for the other blood pressure measure,age, sex, WMH load, smoking status, diagnosis of diabetes, the source of bloodpressure measurement, and an assessment centre. All modelling was performedusing the concurrent explanatory variables, i.e. acquired at the same time asthe MRI. Standardised coefficients between the dMRI measures and blood pressurewere presented in tables, forest plots, and brain maps. The tables and plotssummarised both, left and right hemisphere tracts together whereas the mapspresented standardised coefficients for MAP and PP within each white mattertract separately. On the brain maps and forest plots, the strength ofassociations was represented on a saturation scale with red corresponding topositive associations, and blue to negative associations; for the interactionsthat did not reach significance the coefficients were set to zero and renderedas white. In the forest plots, the WM tracts were presented in thesuperior/anterior to inferior/posterior order.The analyses were also stratified by age decade  and tertilesof WMH load. In order to investigate the interactions between age and bloodpressure and the effect of vascular territory on dMRI, a mixed-effect analysiswas performed using participants and tracts as fixed factors, and adding abinary variable encoding whether a tract was within the anterior or posteriorcirculation; the analysis was stratified by tertiles of WMH load. The tractssupplied predominantly by the posterior circulation included: splenium of thecorpus callosum, the hippocampal part of the cingulum, cerebral peduncle,corticospinal tract, pontine crossing tract, medial lemniscus, inferior, middle,and superior cerebellar peduncle. Analysed tracts and used abbreviations arepresented in Supplementary Figure 1 and the list of abbreviations.data.table package version 1.13.6, themagrittr package version 2.0.1, the lme4package version 1.1.26, and the mfp package version 1.5.2. Figures were plottedusing ggplot2 version 3.3.3 and annotated usingcaptioner version 2.2.3. Additionally,stringr version 1.4.0 and fst 0.9.4packages were used for data management. The manuscript was typeset usingknitr version 1.30 in RMarkdown.Modelling assumptions were checked using diagnostic plots of residuals.Fractional polynomials terms were used to determine the presence of anystatistically significant non-linear relationships, with Bayes informationcriterion (BIC) used to determine whether model fit had been improved orworsened through the addition or removal of any terms. Data management andanalyses were performed using R version 4.0.2 using theAll data is available upon application to the UK Biobank by eligibleresearchers.A total of 38,347 UK Biobank participants had brain magnetic resonance imaging (MRI)data available. After the exclusion of 492 due to diagnoses that could confoundwhite matter assessment, and 822 due to missing blood pressure data, 37,041 wereeligible for inclusion in analyses .In unadjusted analyses, the steady component of blood pressure represented by MAPwas associated with dMRI changes indicative of white matter injury, namely lowerFA, higher MD, lower intracellular (ICVF), higher extracellular (ISOVF)diffusion fraction, and higher directionality of neurites (OD) . The relationships were similar for FA, MD, ICVF, and ISOVF, but therewas some heterogeneity in associations with neurite orientation (OD). Thestrength of associations was stronger in the anterior circulation, with areversal of the direction of the effect for ICVF in the brainstem regions. Afteradjusting for age and sex, the effect size of MAP decreased, but the differencebetween the superior/anterior and inferior/posterior regions remained,especially for MD, ICVF, and ISOVF .In fully adjusted analyses, including the adjustment for PP, MAP remainedstrongly associated with white matter damage reflected by all diffusivitymeasures  were in MAP associations with increased white matter injury were independent of age(Supplementary Table 2). The effect of MAP on dMRI indices was stronger in olderpeople  due to a confounding effect of WMH load as these interactions wereattenuated in those in the lowest tertile of WMH  andenhanced in those in the top tertile of WMH . Theregional interactions between age and the severity of WMH load were complex. Consistent withpredominance of WMH load within the anterior circulation, posterior regions wereassociated with greater microstructural injury in the absence of WMH(Supplementary Table 2).In unadjusted analyses, the effect size of PP on dMRI indices was larger thanMAP. There were marked regional differences and the effect was stronger in thesuperior/anterior regions for MD, ICVF, and ISOVF and in the inferior/posteriorregions for OD . After adjusting for age and sex, therelationship between PP and dMRI indices in the anterior circulation greatlydiminished or was no longer present due to the covariance between PP and age.In fully-adjusted analyses, including an adjustment for MAP, PP was only weaklyassociated with white matter injury within the anterior circulation  for MD  and otheThe steady component of blood pressure represented by MAP and the pulsatile componentrepresented by PP were both associated with microstructural white matter damage,independent of age and the extent of macrostructural white matter damage representedby WMH load. While MAP was associated with all analysed DTI and NODDI markers, bothreflecting neurite density and organisation  and overall diffusion andfree water fraction , PP was predominantly associated with the latter (MDand ISOVF). However, PP was most markedly associated with white matter injury in theposterior circulation for all indices after adjustment for MAP, except for higherneurite density in the brainstem’s long tracts, whereas MAP was generally protectiveagainst white matter injury in the posterior circulation regions, after adjustmentfor pulsatility and other confounders. and higher WMH load, either directly or through the augmented effect of age, but the associations between haemodynamic factors within the anterior andposterior cerebrovascular circulation and white matter injury is well less established., White matter hyperintensities occur both in the supra- and infratentorial location, but at least in middle-aged people, white matter hyperintensities in theinferior/posterior regions are less common and diffusion imaging changes within the posterior circulation have not beenextensively investigated. However, infratentorial cerebral microbleeds, but notlobar cerebral microbleeds, were associated with higher arterial stiffness whilst infratentorial aneurysms tend to have a higher rupture risk thananterior circulation aneurysms due to higher flow rates due to the lack ofprotective effect of the carotid siphon. This reflects anatomical and physiological differences between the anteriorand posterior circulation, with likely less damping and more pulsatile blood flowdue to longer and straighter cerebral vessels, which may be more vulnerable tostiffening with age; therefore, high PP may be more relevant to post circulation injury due to agreater risk of hypoperfusion and greater shear stress.High blood pressure pulsatility is related to lacunar infarcts,, as well as pathology not present in healthy ageing, but the majority of regional effects remained after controlling for age andWMH load, which suggests that most of the dMRI changes represent pathologicalprocesses that are independent of age-related and macrostructural changes.30 Althoughantihypertensive use was associated with greater white matter injury for mostindices, regardless of WMH load, there were no interactions with blood pressure,except for the interaction between PP and ICVF in the absence of WMH. This suggeststhat microstructural damage appears early in the course of hypertension and persistseven if blood pressure is successfully controlled. dMRI measures are potentially useful as an early biomarker of SVD as MD innormal-appearing white matter (NAWM) of patients with SVD correlated with a declinein cognitive performance as well as physical function. The current analysis of the effect of blood pressure on the individual whitematter tracts demonstrated that the negative effect of MAP on white matter integritywas most marked within the anterior circulation. MAP was associated with reducedtract anisotropy (FA) and neurite density (ICVF), indicating damage to the integrityof white matter tracts and with an increase in overall diffusivity (MD) and freewater fraction (ISOVF) suggesting demyelination. In the posterior circulation, MAP was associated with reduced microstructuralinjury, represented by higher neurite density (ICVF) and lower MD, but the increasein FA and reduction in ISOVF were less consistent across the posterior white mattertracts. However, MAP seemed to be linked to higher neurite orientation dispersion(OD) within the posterior circulation. In contrast, PP was not associated with whitematter injury markers of intracellular neurite density and orientation , but only with markers dominated by extracellular free water . Theeffect of PP was independent of WMH severity, but it enhanced the negative effect ofage on MD and the extracellular compartment diffusion fraction (ISOVF). The regionaldifferences in the effects of the steady and pulsatile component of blood pressuremay explain why earlier studies suggested that dMRI changes reflect axonal loss and gliosis, axonal loss or dysfunction, reduction of white matter fibre organisation or an increase in free water due to oedema and demyelination without changesin the tissue compartment or due to plasma extravasation.The association between MAP and white matter injury within the anterior circulationwas stronger in older people and with an increase in WMH load, and WMH loadconfounded the interactions between dMRI with age. For example, the associationsbetween MAP and reduced microstructural damage in the posterior circulation werepresent regardless of WMH load, and diminished with age, but the strong effect ofMAP on MD and ICVF within the anterior circulation was attenuated in people in thelowest tertile of WMH load within their age decade. Age was strongly associated withall indices of white matter injury, to a greater extent than blood pressure, butwhereas associations with MAP were independent of age and did not interact, PPinteracted with age to enhance the association between age and MD or ICVF.Therefore, the observed changes may reflect processes observed in healthy ageing it included both DTI and NODDI measures within individual white mattertracts, which made it possible to assess the interactions between MAP and PP andmicrostructural white matter integrity within specific anatomical regions and tocompare the effect between the regions within the anterior and posterior cerebralcirculation. Mixed effect modelling allowed us to investigate the association withblood pressure accounting for the differences between different types of tracts andfor the different effect of WMH load.The study has several strengths. Firstly, it is based on a large cohort ofmiddle-aged community-based participants. Secondly, the study included not onlynormotensive and hypertensive people, but also those with mildly elevated bloodpressure and with controlled hypertension, which are less often studied. Anotheradvantage of this analysis is, that unlike earlier studies,, However, analyses in patients in the bottom tertile of WMH load confirmed themain findings. Secondly, the automated method for WMH segmentation only results inestimates for cerebral white matter; therefore, an effect of infratentorial WMH ondMRI within the posterior circulation could not be investigated. As this study wasbased on reported mean dMRI values rather than diffusion images, there was noadditional correction for susceptibility and pulsatile motion artefacts, which mighthave particularly affected inferior/posterior regions overlapping with the posteriorcirculation. Moreover, the cross-sectional nature of this study did not allow us toinvestigate the causal relationship between blood pressure and dMRI changes. Inaddition, the information regarding blood pressure lowering medication in the UKBiobank is based on self-reported data, with limited information available toinvestigate interactions between specific clasess of antihypertensives andcerebrovascular dynamics. Finally, the brachial pulse pressure used in this presentstudy may not reflect intracranial arterial pulsatility.It is also important to acknowledge the limitations of this study. Firstly, dMRIvalues included measures both from WMH lesions and NAWM. This might have potentiallyconfounded the analysis and limited interpretation of the results, because, althoughhigh blood pressure is associated with dMRI changes in all white matter, they may bedifferent in WMH and NAWM.This study demonstrated that both steady and pulsatile components of blood pressurewere associated with microstructural white matter damage even in regions that arenot common locations of WMH, with MAP in the posterior circulation having aprotective effect against the negative effects of pulsatile blood pressure. Theseresults showed that dMRI provides a way to study detailed microstructural changesand to better understand the mechanisms responsible for the development of whitematter changes associated with raised blood pressure. These differences between theanterior and posterior circulations imply different haemodynamic mechanisms forchronic white matter injury and may therefore reflect differences in the associatedregional risk of stroke and a need for personalisation of treatment strategies.


Median CVP increased from 13 mmHg at baseline to 14.5 mmHg (p < 0.001) at steady state. CVP increased by more than 20% in eight patients. Median VEDP increased from 10 mmHg at baseline to 11.5 mmHg (p < 0.001). Ten patients had elevated VEDP at steady state, and in 21, VEDP increased more than 20%. The transpulmonary pressure difference (CVP‒VEDP) and CVP were consistently higher in patients with right ventricular morphology across repeated measurements. CVP at any stage was associated with VO2peak and VT. VEDP after volume expansion was associated with VT. Preload challenge demonstrates the limitations beyond baseline measurements. Elevation of both CVP and VEDP are associated with impaired CRF. Transpulmonary flow limitation was more pronounced in right ventricular morphology. Ventricular dysfunction may contribute to functional impairment after Fontan operation in young adulthood.The role of dysfunction of the single ventricle in Fontan failure is incompletely understood. We aimed to evaluate hemodynamic responses to preload increase in Fontan circulation, to determine whether circulatory limitations in different locations identified by experimental preload increase are associated with cardiorespiratory fitness (CRF), and to assess the impact of left versus right ventricular morphology. In 38 consecutive patients , heart catheterization was supplemented with a rapid 5-mL/kg body weight volume expansion. Central venous pressure (CVP), ventricular end-diastolic pressure (VEDP), and peak systolic pressure were averaged for 15‒30 s, 45‒120 s, and 4‒6 min (steady state), respectively. CRF was assessed by peak oxygen consumption (VOClinicalTrials.govidentifier NCT02378857 Palliative operations for univentricular congenital heart defects are among the most frequently performed procedures in pediatric open-heart surgery. Fontan-type palliation has saved many lives during the last four to five decades . HoweverLong-term failure of the low-energy/low-flow Fontan circulation is inevitable . During Sudden increase in preload during right heart catheterization has previously been used by other groups to evaluate the hemodynamic changes and limitations of the Fontan circulation , 6. HoweThe present experimental study was part of the Norwegian Fontan Project at Oslo University Hospital, which is a multi-disciplinary observational study involving a national cohort of adolescents living with Fontan circulation.All patients were recruited between March 2015 and December 2018 during routine clinical work-up before transition to adult care. In Norway, which has 5 million inhabitants, Oslo University Hospital is the only surgical center that performs cardiac surgery and catheter-based interventions in patients of all ages with congenital heart disease. Transition to adult health care usually occurs at 18 years of age. During the last 2 years prior to transition, we routinely admitted patients with Fontan circulation for a comprehensive diagnostic work-up. On two separate days of admission, all patients underwent heart catheterization and a cardiopulmonary exercise test (CPET). The inclusion criterion for the present study was pre-transitional hospital admission. Patients with other severe sensory or neurodevelopmental health problems, for whom the expected diagnostic gain was considered small when compared with the procedural burden, were excluded. Heart catheterization was performed in all enrolled patients unless they had recently undergone a clinically indicated catheterization.Heart catheterization was performed under either conscious sedation or general anesthesia depending on the patient’s request or feasibility. The patients were prepared for the procedure by an initial infusion of 5 mL of 0.9% saline solution/kg body weight which equals 50% of the preprocedural volume support in Fontan patients per institutional protocol. Femoral arterial and venous access were used. Hemodynamic assessments were performed as triplet pressure measurements with liquid-filled catheters after blood sampling from each of the following locations: descending aorta, ascending aorta, ventricular cavity, superior vena cava, right pulmonary artery, left pulmonary artery, inferior vena cava, bilateral pulmonary wedge position, and hepatic venous wedge position. All pressure readings were obtained at the end of expiration, from maximum pressures in patients with spontaneous breathing and from minimum pressures in ventilated patients.For the preload challenge, we performed rapid volume expansion (RVE) manually by rapidly (over 15‒30 s) infusing 5 mL of 0.9% saline solution/kg body weight at room temperature. Saline was simultaneously infused through at least two venous access sites.Serial pressure readings (mmHg) were recorded simultaneously at precise time intervals after the onset of saline infusion: every 15 s for the first 2 min, every 30 s for the next 2 min, and every minute until 6 min after infusion. Pressure readings were averaged for 15‒30 s, 45‒120 s, and 4‒6 min (steady state), and the maximum pressure at any stage after baseline was identified. Pressure measurements before and after RVE were obtained from the ventricular cavity in systole (VSP) and end-diastole (VEDP), the inferior vena cava (CVP), and the hepatic wedge position. The difference between CVP and VEDP (CVP‒VEDP) was calculated and considered as indicative of, but not equal to, the transpulmonary pressure gradient.There is no generally accepted definition of the limits of normal pressure in Fontan circulation. Based on clinical experience and published invasive pediatric data , 11, we 2peak) [All patients performed a maximal symptom-limited CPET on a treadmill  using the Oslo test protocol —the same2peak) . The pat2peak [mL × kg−1 × min−1], and oxygen consumption at the ventilatory threshold (VO2@VT). VT was calculated using a combined method with the ventilatory equivalent and the V-slope method [2peak. We chose VO2peak due to its prognostic impact and VO2@VT because it reflects the circulatory (aerobic) component of the total functional reserve of the body [The primary outcome during CPET was CRF, expressed as VOe method  to assesthe body .All study participants provided informed consent before enrollment. The study protocol was approved by the Regional Committee for Medical and Health Research Ethics  and registered with ClinicalTrial.gov (identifier: NCT02378857).t-test for normal distribution and otherwise by Mann–Whitney U test or one-way repeated-measures analysis of variance (ANOVA) as appropriate for the number of groups and variables. Normality tests were performed using the Shapiro–Wilk test. Variable relationships were analyzed with univariate and multivariate linear regression analyses.Continuous variables were presented as mean ± standard deviation for normal distribution; otherwise, median/range and interquartile range (IQR) were provided. Comparisons were made using paired or non-paired two-tailed Student’s p < 0.05. Statistical analysis was performed using IBM Statistical Product and Service Solutions for Windows (SPSS), versions 26.0 and 27.0 .To analyze group differences and account for the individual variation across the repeated measurements , we applied linear mixed-effect models. Specifically, we accounted for individual variability by unique random intercepts for each patient. To adjust for the impact of ventricle type and/or sedation type on the measurements, ventricle type and/or sedation type were included as a fixed effect. Model parameters and confidence intervals were estimated using the restricted maximum likelihood estimation. Model selection was done using the Schwarz’s Bayesian criterion. Statistical significance was set at The Norwegian Association for Children with Congenital Heart Disease was involved in designing the study and planning organization of the enrollment phase. The sequence of study tests was revised based upon invited feedback from participants. A representative of the Norwegian Association for Adults with Congenital Heart Disease participated in continuous safety surveillance with the study monitoring group.During the study period, we included 38 patients who gave their informed consent to undergo experimental intravenous saline infusion during routine catheterization. The inclusion and general characteristics of the study population are shown in Fig. Data from complete hemodynamic assessment at baseline and after RVE, including group differences, are provided in Table Heart rate reduced significantly in 30 of the 31 non-pacemaker patients (97%) within the first minute after RVE Fig. .Fig. 2HeEight patients (21%) had > 20% increase in CVP after RVE. Four patients had elevated CVP at both baseline and steady state, and in two additional patients, CVP became elevated at steady state Fig. . There wTwenty-one patients (55%) had > 20% increase in VEDP after RVE. Seven patients had elevated VEDP levels at the baseline. Six of these and four additional patients had elevated VEDP at steady state Fig. . There wp = 0.004), at 45‒120 s after RVE , and at steady state .Nine patients had elevated CVP–VEDP at baseline, of which four were still elevated at steady state. There were no differences between stages detectable by one-way repeated-measures ANOVA. Self-breathing patients had lower CVP–VEDP than anesthetized patients at baseline .There was a trend toward approximately 10 mmHg higher VSP in self-breathing patients than in anesthetized patients, and this difference reached statistical significance at steady state  had abnormal CVP at baseline.Of the nine patients with elevated CVP–VEDP at baseline, only two had elevated CVP. Of 11 patients with elevated CVP–VEDP after RVE, only two had elevated CVP at baseline. Only 2/6 patients had elevated CVP and CVP–VEDP but normal VEDP at steady state after RVE; in contrast, 6/10 patients with elevated VEDP at steady state after RVE did not have simultaneously elevated CVP–VEDP or CVP.Cardiopulmonary exercise data were available for 36 out of the 38 study patients, as one patient refused CPET due to fatigue, and another refused to use a face mask during CPET. In one patient, VT could not be determined.2peak and VO2@VT, including comparison of results for LV and RV morphology, are displayed in Table Thirty-six patients underwent CPET with an exercise test duration until termination of 9.5 ± 2.4 min. The median respiratory exchange ratio at test termination was 1.15 (1.10‒1.20). The maximum heart rate was 177 ± 17.0 beats per minute. VO2peak and CVP at all stages, and no association between VEDP or CVP‒VEDP and VO2peak. For VO2@VT, the same association was shown for CVP at all stages. Similarly, VEDP at all stages was associated with VO2@VT, whereas CVP‒VEDP was not  = 5.514, p = 0.035, R2 = 0.298), maximum CVP  = 10.672, p = 0.006, R2 = 0.451), and CVP at steady state  = 5.929, p = 0.03, R2 = 0.313), but not for baseline CVP.Separate univariate analysis for patients with LV morphology did not reveal an association between VOp = 0.022) and 2.53 mmHg higher CVP‒VEDP  than patients with left ventricular morphology. No significant differences between the two morphologies were found for VEDP , ventricular systolic pressure , and heart rate (non-pacemaker patients) .Mixed-effect model analyses comparing groups with different ventricular morphologies revealed that patients with right ventricular morphology have, on average, 2.30 mmHg higher CVP . This effect was still significant having controlled for ventricular morphology . Conversely, no significant differences between the different sedation groups were found for CVP , ventricular systolic pressure , and heart rate (non-pacemaker patients) .Mixed-effect model analyses comparing patient groups with different sedation showed that ventilated patients have, on average, 3.28 mmHg higher CVP-VEDP than self-breathing patients (1.28–5.28, In this study, we aimed to characterize hemodynamic responses to acute preload increase by rapid saline infusion in a representative sample of adolescent patients with Fontan circulation. Our volume expansion experiment demonstrated cardiac and circulatory responses to a sudden preload increase, and thereby challenges the reserves in terms of transpulmonary blood flow and functional reserve in a single ventricle. We were able to identify characteristics of preload response and to unmask circulatory limitations that were not detected by baseline pressure assessment.We observed a uniform decrease in heart rate immediately after preload increase, which is counterintuitive and contradicts the normal volume-induced increase in heart rate in biventricular physiology . To our 2peak and VO2@VT. However, CVP alone does not permit conclusions about the location of downstream restrictions, either in the pulmonary vessels or in the single ventricle.Many patients had a significant increase in CVP after RVE, which on a group level is in line with the physiological increase of CVP in the biventricular circulation in young adults . Our datBaseline VEDP was comparable with the reference pressure conditions in young adults . Most ofDespite preload challenge and increased transpulmonary blood flow, CVP‒VEDP was remarkably stable, and it was not associated with CRF, which contributes to the above-mentioned paradigm challenge. The lack of association with CRF might explain the general disappointing effect of pulmonary vasodilators on CRF , 20. TheWe found unfavorable hemodynamic conditions in our subgroup with single RV, compared with single LV. The RV patients had higher pressures in the Fontan circuit at baseline, maximum pressure, and steady state after RVE. Not surprisingly, we found a non-significant trend toward lower CRF in patients with RV than in those with LV morphology, as expected from previous data , 21. It De May et al.  performeAverin et al.  also incWhile pulmonary vascular resistance has been the focus of non-invasive interventions, our data suggest the equal importance of impaired ventricular function for long-term function of Fontan circulation. Hence, it will be of interest if the pressure rise in the preload-stressed Fontan circulation corresponds with the directly measurable limitations of myocardial contractile reserve.Our study design did not include some known factors that influence hemodynamics and/or CRF in patients with Fontan circulation, including veno-venous collaterals , echocarThe pressure difference CVP‒VEDP does not equal the transpulmonary pressure gradient, which must be calculated from simultaneously measured pre- and post-capillary mean pressures; our experimental position of catheters did not allow such measurement.Preload challenge by rapid saline infusion unmasked occult limitations of Fontan circulation indicated by the elevation of both CVP and VEDP. Baseline abnormality and volume-induced elevation of both CVP and VEDP were associated with impaired CRF. Transpulmonary flow limitation was more pronounced in RV morphology. Our findings suggest that ventricular dysfunction might play an important role in functional impairment after Fontan operation in young adults as pulmonary vascular resistance.


Chronic kidney disease (CKD) is a major and serious global health problem that leads to kidney damage as well as multiple systemic diseases. Early diagnosis and treatment are two major measures to prevent further deterioration of kidney function and to delay adverse outcomes. However, the paucity of early, predictive and noninvasive biomarkers has undermined our ability to promptly detect and treat this common clinical condition which affects more than 10% of the population worldwide. Despite all limitations, kidney function is still measured by serum creatinine, cystatin C, and albuminuria, as well as estimating glomerular filtration rate using different equations. This review aims to provide comprehensive insight into diagnostic methods available for early detection of CKD. In the review, we discuss the following topics: (i) markers of glomerular injury; (ii) markers of tubulointerstitial injury; (iii) the role of omics; (iv) the role of microbiota; (v) and finally, the role of microRNA in the early detection of CKD. Despite all novel findings, none of these biomarkers have met the criteria of an ideal early marker. Since the central role in CKD progression is the proximal tubule (PT), most data from the literature have analyzed biomarkers of PT injury, such as KIM-1 (kidney injury molecule-1), NGAL , and L-FABP (liver fatty acid-binding protein). Kidney duration . CVD areduration . In clinduration . Serum cduration ,10,11. Mduration . Furtherduration . Becauseduration . Therefoduration . This reDiabetic nephropathy and nephroangiosclerosis due to arterial hypertension are the most common causes of chronic kidney disease. The rapid rise of common risk factors such as diabetes, hypertension, obesity, and glomerular diseases in high-income countries, as well as infections especially among the poor, will result in even greater and more profound burdens associated with CKD. A kidney biopsy is a golden standard in the diagnostic algorithm of kidney disease because it determines a pathohistological diagnosis and also a proportion of acute and chronic changes relevant to the prognosis . The perDendrin is a proline-rich protein originally identified in telencephalic dendrites of sleep-deprived rats . In addiThe expression of dendrin in podocyte nuclei has been reported by studies on different glomerulopathies: focal segmental glomerulosclerosis, lupus nephritis, membranous nephropathy, IgA nephropathy (IgAN)/IgA vasculitis, and minimal change disease ,23,24,25Nephrin is a 180 kD transmembrane protein expressed in glomerular podocytes where it has a pivotal role in glomerular filtration barrier formation and in maintaining its function . It is ePodocin is a 43 kDa membrane-associated protein, which is a crucial component of the glomerular slit diaphragm. It plays an important role in nephrin-mediated cellular signaling and assures podocyte structure and function . PodocinMollet et al. discovered that podocin knockout mice had a gradient of glomerular lesions that demonstrated a developmental stage dependence of renal histologic patterns of injury . SignifiPodocalyxin (PCX) is an anionic transmembrane sialoglycoprotein, which is a member of the CD34 protein family . It is eFurthermore, in other glomerular diseases, the level of urinary podocalyxin and the number of urinary podocytes were associated with the proportion of segmental sclerosis . ExpressImmunoglobulin G (IgG) antibody is a 150 kDa globular protein, which is a major component of humoral immunity. There are structural differences among four human IgG subclasses meritorious for different biologic effector functions. In kidney disease, due to its size, when the selectivity of the glomerular capillary wall is severely disrupted, IgG will be filtered from the blood and excreted in the urine . Becausec-Myb is a DNA-binding transcription factor. Postnatally, it is included in the normal control of differentiation and regulation of hematopoietic and epithelial cells in many organs, including the kidneys, but mutated c-Myb has a role in tumorigenesis . c-Myb rKidney injury molecule-1 (KIM-1) is a 38.7 kDa type I transmembrane glycoprotein, with an extracellular immunoglobulin-like domain . KIM-1 aIn the context of chronic kidney disease, KIM-1 is also a sensitive biomarker for chronic proximal tubular injury, which is correlated with the incidence, progression, and prognosis of CKD . ContinuNeutrophil gelatinase-associated lipocalin (NGAL) , or lipocalin) is a ubiquitous 21–25 kD iron-carrying protein of the lipocalin superfamily, highly expressed in the tubular epithelium of the loop of Henle and collecting ducts . InitialEarly release of NGAL from tubular epithelial cells occurs following damage ,65. The Liver fatty acid-binding protein (FABP), also known as L-FABP or FABP1 is a 14 kDa soluble protein found predominately in the cytoplasm of hepatocytes, enterocytes, renal proximal tubular cells, and alveolar epithelium . InteresIn CKD patients, fatty acids overload the proximal tubule, and massive proteinuria is found . L-FABP Interleukin (IL)-18, also known as the interferon-gamma inducing factor, is a member of the IL-1 superfamily. It is a proinflammatory cytokine that strongly induces a Th1 response. IL-18 can modulate both innate and adaptive immunity and its dysregulation can cause autoimmune or inflammatory diseases. IL-18 is stored intracellularly as a biologically inactive 24 kDa precursor and is secreted extracellularly as an 18 kDa bioactive mature molecule after being cleaved by caspase-1 . DiffereAccording to data from the literature, an elevated IL-18 level was associated with diabetic nephropathy, and has been reported to be a predictive marker for the development of disease, degree of albuminuria, and decline of kidney function ,77,78. IUromodulin or Tamm–Horsfall protein is a glycoprotein expressed only by renal tubular cells of the thick ascending limb of the loop of Henle and distal tubule . It is pUromodulin activates specific components of the immune system, and thus, may act as a signaling molecule for renal tubular damage . EstimatVascular non-inflammatory molecule-1 (vanin 1) is a glycosylphosphatidylinositol-anchored ectoenzyme with pantetheinase activity ,87. It hGalectin-3 is a 32–35 kDa member of the galectin family of β-galactoside-binding lectins, which is characterized by a carbohydrate recognition domain . It is dRespecting the fact that standard laboratory markers of deteriorated kidney function are scarcely affected in early stages, several targeted strategies have been designed to search for novel early specific biomarkers of CKD diagnosis. Although not routinely, omics techniques are slowly being recognized for their roles in early CKD diagnosis. For instance, proteomics has already been found to be valuable for identifying anti-M-type phospholipase A2 receptor autoantibody in the diagnosis of primary membranous nephropathy (as many as 70% of cases) . Omics tIn an extensive study by Romanova et al., the results showed that blood levels of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, Eotaxin, FGFb, G-CSF, GM-CSF, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-1bb, RANTES, TNF-α, and VEGF were significantly higher in patients with CKD as compared with a control group, and they were positively correlated with kidney function . The mulNevertheless, implementation of omics in the contemporary diagnostic pathway of early CKD diagnosis also bears some notable limitations. Firstly, since a sample collected for proteomics is just a snapshot of an active ongoing process, repeated sample collection might be required to ensure consistency. Furthermore, as proteomics methods are multilayered, appropriate analytical approaches and external validation in separate cohorts are paramount to verify findings from omics studies before implementation to clinical practice. Finally, perhaps the most important consideration for translation of proteomics to clinical use is high cost. In this sense, it is valuable to address that health economic analyses have indicated the cost-effectiveness of CKD273, however, no strategies exist to cover the costs for widespread applications of this method.Lactobacillus, Prevotella, and Bacillus bifidus) is lower in CKD patients, while the numbers of optionally pathogenic bacteria (Enterobacteria and Pseudomonas) or Firmicutes, Actinobacteria, and Proteobacteria are increased [Ruminococcus and Roseburia display the highest diagnostic values for distinguishing an early-stage CKD patient from healthy controls [Human intestines contain over 1014 microorganisms that can be classified as beneficial, harmful, or neutral, and are more than 10 times the total number of human cells . Intestincreased ,103. Forcontrols . FurtherEscherichia-Shigella, Parabacteroides, Roseburia, rectale_group, Ruminococcaceae_NK4A214_group, Prevotellaceae_UCG-001, Hungatella, Intestinimonas, and Pyramidobacter, as distinguishers between CKD and a control group [Proteobacteria phylum, Gammaproteobacteria class, as well as Enterobacteriaceae and Pseudomonadaceae families were more abundant in the CKD population as compared with the control group, and GFR correlated negatively with the amount of Proteobacteria [Maladaptation of microflora to intestinal environmental changes can be detected at an early stage of CKD . Such guol group . Furtherol group . The intol group . The mosbacteria .MicroRNA (miRNA) is a short single-stranded non-coding RNA molecule involved in RNA silencing and post-transcriptional regulation of gene expression . MicroRNUrinary miR-216a has also been reported to be significantly lower in all patients with type 1 diabetes, with the lowest levels among the microalbuminuria group. Further, positive correlations have been found between urinary miR-377 and albumin to creatinine ratio, while urinary miR-216a was negatively correlated to this variable . AccordiIn a subpopulation of chronic glomerulonephritis (CGN) patients, there was a higher level of expression in the urine of hsa-miR-155-5p, hsa-miR 214-3p, hsa-miR-93-5p, and hsa-miR-196a-5p in CGN with daily protein excess <3.5 g. Increased levels of expression of hsa-miR-155-5p, hsa-miR-214-3p, hsa-miR-200a-5p, and hsa-miR-29-5p have been found in CGN patients with eGFR > 60 mL/min . AlthougAt first, it seems obvious that finding a specific biomarker that reflects an early stage of CKD and confirming a timely diagnosis would enable improved treatment and reduce the medical and financial burdens associated with CKD. However, multiple experts agree that the problem is much deeper and that pursuing that goal may be a double-edged sword, such as in population screening employed for colorectal cancer screening. In theory, CKD detection at the asymptomatic phase would result in prevention of kidney failure. However, detection of CKD may not lead to changes in management of the patient. Tonelli et al. even provided us with factors that would diminish the putative benefits of implementing an early CKD detection strategy . NeverthDespite the considerable progress that has been made and the limitations that standardized kidney function estimation offers, currently, the biomarkers of kidney function that are most often used are creatinine and microalbuminuria. Why is it so? From the bench to the bedside, biomarker translation is rather challenging and a tedious process. Nevertheless, perhaps, the biggest setback of CKD biomarker evaluation is the lack of a reliable comparator . Most clinicians argue that a kidney biopsy is, for the most part, suitable, however, they are well aware of the associated risks of this invasive procedure, and also the “trap” of a diagnosis that does not affect management. Hence, comparing biomarker serum/urine levels with kidney changes assessed by biopsy is relatively rarely performed and, most commonly, an analysis is performed with creatinine (in the form of eGFR) and microalbuminuria as reference points. This is very problematic for the establishment of reliable biomarkers, simply because neither eGFR nor microalbuminuria are reliable indicators of kidney function, especially at the early phase of CKD. For instance, we previously mentioned that 30% of patients with diabetic kidney disease have normal urine albumin levels . In addiIn this review article, several biomarkers were listed. The review of the relevant literature identified hundreds of biomarkers, some of which have been thoroughly examined, however, there is still no biomarker that has been incorporated into routine clinical practice as a unique biomarker. Owing to multiple aforementioned limitations, it is probable that this goal will not be achieved in the near future. Although an omics analysis provides a novel approach to personalized medicine and has promising results in CKD, it also bears substantial limitations, especially with respect to high costs. From a clinical standpoint, perhaps the first step should be to determine the population of individuals at high-risk for developing CKD based on integrative and critical assessments of patients, whereas from a preclinical standpoint, the first goal is to use an appropriate comparator  for assessing the use of putative biomarkers in the early diagnosis of CKD.


Perioperative change to the autonomic nervous system (ANS) in spine surgery is an uncommon occurrence but has a wide range of possible presentations including blood pressure, heart rate, and heart rate variability changes collectively referred to as dysreflexia. Increased sympathetic tone and decreased vagal output are believed to be the underlying causes of these autonomic manifestations and pose an important question as to effective treatment of these dysfunctions. Spinal nerve root decompression has shown to be a valuable tool in normalizing autonomic tone by increasing parasympathetic output, most notably to the cardiovascular system, leading to the resolution of the aforementioned cardiovascular complications. Here we report a patient with elevated blood pressure with complaints of upper extremity paresthesias. MRI showed nerve root compression, and anterior cervical discectomy was performed. Post-operatively the patient had a decrease in both systolic and diastolic blood pressure which was maintained two months after surgery and allowed for discontinuation of one anti-hypertensive medication. The autonomic nervous system (ANS) consists of a collection of afferent and efferent fibers located throughout the body which allows for immediate response to stimuli. Any cause of insult to these fibers either through trauma, impingement, or other causes leads to an imbalance between sympathetic and parasympathetic tone leading to characteristic features . ClinicaDysautonomia is the abnormal alteration of the ANS due to chemical or structural neurological insult and is broadly classified into traumatic and atraumatic causes. Traumatic nerve compression has a wide variety of presentations based on the position, speed, and location at the time of injury. While the presenting cause of atraumatic spinal cord or nerve root compression widely varies as well, the underlying cause is more routine in presentation and is typically caused by herniated discs, arthritic changes of the spine, facet joint narrowing, or spinal stenosis ,4. ManagA 56-year-old white male presented for evaluation of numbness and tingling in his right hand. He stated he first noticed the pain while golfing four months earlier, but was able to manage the pain with acetaminophen and stretching. He has a past medical history of elevated blood pressure managed with metoprolol and lisinopril for two years. He states his blood pressure when measured at home is usually around 140/95. A blood pressure reading in the office showed a value of 142/91 on two separate readings. On physical exam decreased sensation was noted over the lateral forearm and proximal hand with no thenar muscle atrophy. The range of motion of the wrist, elbow, and shoulder was 5/5 bilaterally with minimal pain. A positive Hoffman sign was present on the right side, but Tinel and Phalen tests were negative bilaterally. Anterior and lateral cervical X-rays were taken showing moderate arthritic changes in the cervical spine with no obvious deformities, including lack of vertebral fracture and spondylolisthesis. An MRI of the cervical spine was ordered showing moderate lateral recess stenosis at the C5-C6 level. The patient was counseled on their options for management and chose to pursue an epidural nerve block before considering surgical intervention.One month after the epidural block was performed, the patient returned with the complaint of reoccurring pain and consented to surgical decompression of the impinged nerve. A blood pressure reading taken pre-operatively before induction of anesthesia, in the hospital setting, showed a value of 141 mmHg systolic and 90 mmHg diastolic. The patient underwent anterior cervical discectomy and fusion (ACDF) at the C5-C6 level without complication. During operation, a 12mmHg and 9mmHg decrease in systolic and diastolic blood pressure respectively was noted at the time of nerve root decompression. The patient remained stable and no treatment or intervention was required at this time. The patient was discharged the same day with instructions not to perform a strenuous activity and acetaminophen for pain control per the patient’s request. Blood pressure and surgical scar were evaluated one week and four weeks after the operation revealing a well-healing scar and blood pressure values of 129/86 and 128/86 respectively. The patient reported he had stopped taking the metoprolol previously prescribed for his elevated blood pressure at the suggestion of his primary care physician due to an episode of hypotension, but has continued to take lisinopril. One additional follow-up with the patient at two months post-operation showed minimal scarring at the incision site, resolution of “90 percent” of his pain, and a blood pressure value of 128/87.Primary hypertension is one of the most commonly diagnosed medical conditions and is typically managed with pharmacologic therapy. The vast majority of cases of hypertension are related to diet and poor lifestyle choices, however rarer causes of elevated blood pressure, such as spinal nerve root impingement, should be included in the differential . There aPatients with elevated blood pressure have historically experienced a decrease in both systolic and diastolic blood pressure following surgical decompression of nerve root impingement. This association has led to more investigation of the effects of nerve root compression on blood pressure. A review of the literature showed five major studies evaluating the relationship between nerve root impingement and hypertension, including a total of 964 patients with an average age of 55.42 years old [Because of these results nerve root impingement should be considered as a possible cause of elevated blood pressure with management by cervical decompression. It should also be noted that while nerve root decompression surgery may significantly lower blood pressure it should not replace the current pharmacologic anti-hypertensive treatments and should only be performed in those who are surgical candidates regardless of blood pressure level. While a statistically and clinically significant decrease in blood pressure was reported after surgical decompression was performed more information is needed to explore this relationship, as well as the long term effects this drop in blood pressure has on typical hypertension related complications such as stroke, and decreased life span -6.Elevated blood pressure and other cardiovascular disease are one of the leading causes of morbidity in the United States and is most commonly caused by lifestyle choices such as poor diet and a sedentary lifestyle. Hypertension is typically managed solely with pharmacotherapy such as angiotensin-converting-enzyme (ACE) inhibitors and beta-blockers, however, surgical correction of neurologic structural disorders such as cervical nerve root impingement may also play a role. While surgical correction is currently not recommended as a treatment for patients with hypertension alone, there is evidence that those who have concurrent elevated blood pressure and nerve root impingement may achieve long-term relief of both neurologic and cardiovascular morbidities, with a small subset of patients being able to decrease or stop taking their anti-hypertensive medications altogether, as described in this case.


Long-term preservation of kidney function after liver transplantation (LT) has not been well studied. We thus evaluated the rates of kidney function preservation and long-term survival after pediatric LT. We also investigated the risk factors associated with the progression of chronic kidney disease (CKD). We conducted a retrospective study of 184 pediatric patients who had undergone LT from 2003 to 2018 at a university hospital. We collected demographics, primary indications for LT, liver disease scores, renal function test results, immunosuppressive drug prescriptions, and diagnosis of post-LT complications. The 15-year survival rate was 90.8%. Furthermore, the rate of kidney function preservation at 14 years post-LT in patients at high risk of renal disease was 79.3%, and that in those with less risk of kidney diseases was 96.0%. Arterial hypertension was an independent risk factor associated with CKD progression. However, when arterial hypertension was excluded, the use of cyclosporine and liver disease with renal involvement were risk factors for CKD progression. We found that kidney function after pediatric LT was well preserved. We encourage the early detection of underlying kidney involvement, routine monitoring of renal function for high-risk patients, active control of hypertension, and appropriate immunosuppressive regimens for pediatric patients with LT. Congenital liver diseases, such as biliary atresia and metabolic liver disease, are some of the major indications for pediatric liver transplantation (pLT). pLT has become the treatment of choice for pediatric liver diseases that possess a high potential risk of complications, such as acute liver failure and progression of end-stage liver diseases. Over the last few decades, advancements in surgical techniques, effective immunosuppressive regimens, and multidisciplinary management and monitoring strategies have been recognized for their contributions to decreased long-term complications and prolonged survival in the pediatric population after pLT ,2. With Renal dysfunction is a major post-pLT complication, and its prevalence was reported to be about 17.6% in a cross-sectional study from the Studies in Pediatric Liver Transplantation (SPLIT) registry . AnotherThis study evaluated the kidney function preservation rate in patients who survived at least a year after pLT for up to 15 years of follow-up and the long-term survival of all pediatric patients who received pLT. Moreover, the risk factors of CKD progression associated with pLT were also assessed.This was a retrospective cohort study of patients aged ≤18 years who underwent pLT for the first time. Patient data were collected from electronic medical records (EMRs) at the Seoul National University Hospital in Seoul, South Korea, for 2003–2018. Patients who had a history of pLT at other hospitals and underwent pLT with other organs simultaneously were excluded.Demographic data included age at the time of pLT surgery, sex, height, weight, donor type, primary diagnosis, and estimated glomerular filtration rate (eGFR) at the time of LT. A sex-and age-based standard deviation (SD) score with reported height and weight was assigned by the Lambda–Mu–Sigma (LMS) method ,14. PediTacrolimus was dosed based on the target trough levels in the range of 8–12 ng/mL in the first month after pLT, and the dose was reduced to maintain the range of 6–8 ng/mL for the next six months. It was titrated down to 5 ng/mL thereafter. For cyclosporine (CsA), the initial target trough level was decreased from 250 (200–300) ng/mL to 225 (200–250) ng/mL within the first three months. Then, it was titrated down to 100–200 ng/mL within a year of pLT. The target trough level of CsA was set as under 100 ng/mL thereafter. Steroids were usually administered for the first six months and discontinued thereafter.Survival was evaluated by measuring the time from the pLT to death or the end of the study period, whichever was earlier. After survival analysis, the patients were divided into two groups to compare the survival rates between patients with lower risk of renal involvement (non-KD group) and patients who had renal involvement, such as Alagille syndrome, hepatic fibrosis, and primary hyperoxaluria (KD group). A log-rank test was used to compare survival rates between the KD and non-KD groups ,22,25,26For the kidney function preservation analysis, pediatric patients were excluded if they died during the first year following LT, as such deaths were thought to be driven by peri-transplant complications, such as graft dysfunction and hepatic artery complications, rather than kidney disease per se. In addition, those whose height was unmeasured, whose CKD stages were 4 or 5 prior to pLT, or who had acute renal impairment were excluded to analyze long-term results .2 for three months [For the kidney function preservation rate analysis, patients were followed from the time of pLT to the time of renal function decline or the end of the study period, whichever was earlier. Kidney function decline was defined as a sustained decrease of eGFR to below <60 mL/min/1.73 me months .The survival rates and kidney function preservation rates after LT were determined using the Kaplan–Meier method.p-value. The variables with p < 0.05 on univariate analyses were entered into the multivariable analysis (Model 1). For the assessment of other independent risk factors associated with CKD stage 3 (or higher), variables with p < 0.05 on univariate analysis, except the occurrence of arterial hypertension, were separately analyzed in another multivariable analysis (Model 2). In the multivariable analyses, statistically significant variables were estimated by backward elimination to investigate the role of interactions among variables. All statistical analyses were performed using IBM SPSS software version 25.Risk factors associated with progression of stage 3 CKD or higher were analyzed by the Cox proportional hazards model with an unadjusted hazards ratio (HR) in univariate analysis and an adjusted HR (aHR) in multivariable analysis, along with a 95% confidence interval (CI) and This study was reviewed and approved by the Institutional Review Board of Seoul National University Hospital (IRB No. H 2002 061 1100), and informed consent was waived owing to the retrospective nature of this study. The data were retrospectively collected using EMRs, and all datasets were protected in anonymized form.2 . Only eight (4.3%) patients had ever used CsA as an immunosuppressive agent. Fourteen (7.6%) patients received pLT more than once during the follow-up period  were male, with a median age at pLT of 2.7 years old , and the median follow-up duration was 8.5 years . The median height was 87.7 cm , and 44 (23.9%) patients were below −2 SD in the height-for-age Z-score. The median weight was 12.5 kg , and 38 (20.7%) pediatric patients were below −2 SD in weight-for-age Z-score. Living donor recipients accounted for 110 (59.8%) cases. The most common indication for LT was biliary atresia, which was seen in 85 (46.2%) of pediatric patients. Twenty-two point eight percent (n = 42) of patients had liver diseases with concomitant kidney disease. Pre-transplant eGFR was 125 mL/min/1.73 mp period .p = 0.488)  and the KD group (88.1%) (= 0.488) 2 . Biliary atresia was the most common indication for pLT, accounting for 52.3% (n = 80). Twenty-nine patients (19%) had liver disease with a potential risk of the following renal complications: Metabolic disease (glycogen storage disease (n = 9), tyrosinemia (n = 1), Wilson’s disease (n = 7)), cholestatic disease (Alagille disease (n = 8)), and congenital hepatic fibrosis (n = 4). Twenty patients were newly prescribed anti-hypertensive medications during the follow-up period. Ten patients (50%) were administered either calcium channel blockers, angiotensin-converting enzyme inhibitors, or beta blockers, and the rest (n = 10) had a combination regimen that included the above-mentioned drugs , had no height records (n = 3), had stage 4 or 5 CKD before pLT and required renal replacement therapy at most at 2 weeks post-pLT (n = 7), or had acute renal impairment with fluctuation of renal function (n = 7). The median age at pLT was 2.3 years old , and the median follow-up duration was 8.5 years . The median height and weight were 86.8 cm  and 12.0 kg , respectively. The median pre-transplant eGFR was 130.0 mL/min/1.73 med drugs .p = 0.003) (The 14-year cumulative incidence rate of declining kidney function indicated that CKD ≥ stage 3 progression was 7.2% (n = 11). Among the 11 patients, one patient from the non-KD group  underwent kidney transplantation, while in the KD group , one patient underwent kidney transplantation, and the other received hemodialysis. The 14-year kidney function preservation rate was significantly different between the non-KD group  and the KD group  (= 0.003) .p < 0.001). The use of CsA  and liver failure with concomitant renal involvement  were also significantly associated with the development of stage 3 CKD or higher  data from 2000–2015, the 15-year survival rate was 85.5% . Conside2 for three months, was 96.0% in the pediatric patients who were less likely to have renal involvement prior to pLT. Sato et al., who had a similar endpoint as our study, found that eight-year renal preservation in the non-KD group was 92.4% [Our study showed that the post-transplant kidney function preservation rate, which was defined as no decrease of eGFR to below <60 mL/min/1.73 mas 92.4% . The resas 92.4% . There mas 92.4% ,29,30. I2, and the CKD progression rate was 17.6% at the mean of 5.2 years post-pLT in the multicenter and cross-sectional study of SPLIT [We used eGFR values to assess kidney function rather than measured GFR (mGFR) when evaluating the prevalence of progression of CKD with stage 3 or higher, which was 7.2% during the 14-year follow-up in this study. In contrast, Campbell et al. reported that the prevalence of CKD progression with the primary endpoint measured by mGFR was <90 mL/min/1.73 mof SPLIT .Age did not show statistical significance in the kidney function preservation rate post-pLT when it was adjusted with other variables. This could be because age at transplantation worked as an effect modifier, not a risk factor associated with CKD progression post-pLT. Almost half of the patients in the risk analysis were younger than 12 years old and demonstrated biliary atresia as their indication for pLT . In addition, multivariable analysis revealed that liver re-transplantation was not an independent risk factor of CKD progression in this study. However, Ruebner et al. showed that liver re-transplantation resulted in a 2.7-fold increase in the risk of end-stage kidney disease while noting the outcomes of renal replacement therapy, such as dialysis or kidney transplantation . MeanwhiHarambat et al. verified that potential renal involvement prior to pLT was associated with the occurrence of chronic renal insufficiency in 69 pediatric patients after pLT in 2008 . Our stu2, whereas 60.9% of enrolled patients used CsA within a month after LT [Calcineurin inhibitors of CsA and tacrolimus (FK506) are known to be associated with dose- and efficacy-limiting adverse events, including nephrotoxicity, which may diminish the overall benefits for long-term graft survival. In our Model 2, the use of CsA was an associated risk with CKD progression. In their 10-year study, Harambat et al. reported a 25.4% of incidence of mGFR < 60 mL/min/1.73 mafter LT . The lowafter LT ,33. It iA multicenter prospective cohort study of Korean CKD children is currently in progress . Of the This study has several limitations. First, it is a retrospective single-center study. Some patients in earlier cases had missing values for height and were thus excluded from the analysis. However, we collected the population data of all pediatric patients with pLT surgery at our institution. The study hospital has over 1700 hospital beds and operates a major LT center in Korea with a high number of cases of pediatric LT annually. Another limitation is that eGFR was calculated differently for different age groups due to the retrospective data collection. Even though the CKD-EPI-Cr method showed its superiority over the MDRD formula, one cross-sectional study revealed that the Schwartz equation is more reliable for estimating GFR in adults with mild to moderate kidney impairment up to 40 years old than the CKD-EPI-Cr formula . The traSurvival was analyzed in pediatric patients for a 15-year post-pLT observation period. Increased interest in recent years on long-term outcomes such as physical health-related quality of life issues in the pediatric population has been emphasized by this study’s analysis of kidney function preservation and its association with CKD progression. Our results suggest that aggressive pre- and post-transplant care strategies should be implemented, such as the early detection of renal involvement, arterial hypertension, and optimal medication treatment.The status of survival and kidney function preservation rates were evaluated after pLT. This study suggested the following strategies to improve pediatric patients’ kidney function preservation after pLT: Diligent monitoring and the prevention of arterial hypertension after LT, the proper use of CsA, and the management of concomitant renal involvement.


The task to develop a mechanism for predicting the hemodynamic parameters values based on non-invasive hydrocuff technology of a pulse wave signal fixation is described in this study. The advantages and disadvantages of existing methods of recording the ripple curve are noted in the published materials. This study proposes a new hydrocuff method for hemodynamic parameters and blood pressure values measuring. A block diagram of the device being developed is presented. Algorithms for processing the pulse wave contour are presented. A neural network applying necessity for the multiparametric feature space formation is substantiated. The pulse wave contours obtained using hydrocuff technology of oscillation formation for various age groups are presented. According to preliminary estimates, by the moment of the dicrotic surge formation, it is possible to judge the ratio of the heart and blood vessels work, which makes it possible to form an expanded feature space of significant parameters based on neural network classifiers. This study presents the characteristics accounted for creating a database for training a neural network. The development and implementation of information technologies into medical practice has made it possible to expand the diagnostic prospects for hemodynamic parameters analysis for the purpose of cardiovascular system pathological conditions early diagnosis and adequate therapy conducting. Currently, it is possible to measure more than twenty indicators characterizing the blood through the vessels movement and the cardiovascular system general state.The researchers refer to the primary hemodynamic parameters as heart rate (HR) and blood pressure (BP), while the extended hemodynamic parameters include stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR), and a number of others .The neural networks implementation for diseases diagnosis is an interesting and promising direction. Recent achievements in the field of laboratory diagnostic equipment and the use of computer modeling methods open new possibilities for cardiovascular system (CVS) monitoring. Interest in this topic is growing every year. Research in this field published in scientometric citation databases: Pubmed, Scopus, and Web of Science focus on such aspects as: mathematical modeling of human CVS activity ,3,4,5, bThe problem of hemodynamic parameters monitoring in emergency medicine was successfully solved with the use of resuscitation bedside monitors . If it iResearchers are attempting to solve the task of blood pressure parameters daily monitoring and hemodynamic values by using oscillator-type devices using an air occlusive cuff and photoplethysmography (PPG) ,18. ReceThe artificial neural networks and machine learning technologies implementation for the diseases diagnosis is an interesting and prospective direction ,22,23,24In the paper by Choudhury et al., 2020 , an exteThe article structure is presented as follows: The process of assessing systolic blood pressure (SBP) and diastolic blood pressure (DBP) with various types of devices is associated with a significant influence of factors that reduce the reliability of the values obtained, these primarily include anatomical features.One of the reasons for the need to modernize existing methods for assessing hemodynamic parameters and determining blood pressure values is the significant errors in the data obtained.The existing algorithm underlying the pulsation curve processing is estimated for the average statistical data of patients. It is known that the process of transferring pressure from the artery to the cuff depends on the anatomical features of the forearm or wrist structure.Another reason is related to the influence of breathing on the pulse curve contour as a consequence of a change in the pulse wave signal amplitude (PW) ,28.The third reason is related to the need to form a multiparametric feature space for determining critical conditions and assessing the dynamics of the pathological processes development in the cardiovascular system (CVS) based on neural network technologies.It is not possible to estimate the values of corrections in order to eliminate their influence by traditional filtering methods ,30 and rIn this regard, a technique based on neural network applying is proposed, which allows, on the basis of training, to produce the effective adjustments to the blood pressure values and other hemodynamics parameters. The neural network is based on learning on a multiparametric feature space that characterizes the CVS state.Such parameters can be weight-dimensional anatomical parameters such as: age, gender, height, weight, waist circumference, arm circumference, and body mass index.Another group of indicators forming a multiparametric feature space are hemodynamic parameters: cardiac output, stroke volume, pulse wave propagation velocity, stiffness index and many others. Currently, it is possible to present up to thirty indicators characterizing the CVS state ,32. WhenCurrently, oscillatory methods ,34,35,36The disadvantage of the air compression cuff, widely used in oscillator-type tonometers, is the small amplitude of the generated oscillations (1–3 mm Hg). Against the noise background, it is quite difficult to establish peak values of pulse waves underlying the algorithms for obtaining hemodynamic parameters. The use of filtering procedures, trend removal, and smoothing of the envelope of oscillation peaks lead to significant errors in determining pressure values for characteristic points.The authors of this study upgraded the existing method by applying two chambers of the same type into which liquid is pumped. The oscillations processing is performed on the sensor’s differential activation basis. This makes it possible to implement a direct method of fixing systolic and diastolic pressure levels with a significant reduction in the effect on noise readings, which allows to obtain a more reliable pulse wave contour.The technical result is achieved due to the fact that an incompressible medium, a liquid, is selected as the working medium, which increases the reliability of the qualitative representation of the pulse wave contour and, as a result, the determination of hemodynamic parameters and blood pressure. A more detailed description of hydrocuff technology is undesirable due to the know-how disclosure.The use of a hydrocuff allows to increase the oscillations amplitude up to 20 mm Hg. This creates prerequisites for improving the accuracy of the SBP and DBP assessment. The study included 30 potentially healthy people (15 women and 15 men): average age, 45 ± 2 years; average height, 175.5 ± 5.7 cm; average weight, 80.3 ± 4.2 kg; average heart rate, 80 ± 8 beats/min; average systolic blood pressure, 119 ± 4 mmHg; and the average diastolic blood pressure, 82 ± 4 mmHg. All participants were informed about the study and provided informed consent. The study was developed in accordance with the Helsinki Declaration and approved by the local ethics committee. All measurements were performed during working hours while observing usual lifestyle. The study involved people who did not take any medications.Due to hydrocuff technology oscillation’s formation, these changes in amplitudes have a significant impact on the estimating values of hemodynamic parameters. In this regard, it is necessary to take into account dynamic changes in amplitudes to stabilize the pulsations amplitudes of the pulse wave contour.The third group involved in the formation of a multiparametric feature space includes processes that characterize the formation of pathological changes in hemodynamic parameters, allowing to observe their dynamics and compare the values of the forecast with the values recorded in the early stages. As a result of measurements, an array of data was generated for training and testing a neural network.Taking into account these factors allow to create conditions for the development of systems for assessing the hemodynamics and blood pressure parameters with increased accuracy.This form combines well with the form of the pulse wave in the brachial artery. It allows to present time intervals for characteristic points A, B, B′, C, D, and E which are important parameters in assessing the state of the cardiovascular system and the functions of the left ventricle.Point A characterizes the cardiac cycle beginning. Peak B is the main amplitude of the pulse signal caused by the cardiac discharge of blood from the ventricles during systole. The rate of wave rise characterizes cardiac output, arterial resistance, and the vascular wall elasticity. Peak B′ is often not visible on pulse wave signals; according to a group of authors  this peaFor the early diagnosis of diseases such as hypertension, atherosclerosis, and other vascular pathologies, it is relevant to determine the following amplitude-time parameters of the pulse wave contour.The pulse wave amplitude, has no normative values, is estimated in dynamics, and measured in relative units.The amplitude of the dicrotic wave. Normally, it is ½ of the pulse wave amplitude value, also measured in relative units.The incision height, normally 2/3 of the pulse wave amplitude value, is measured in relative units.The dicrotic wave index is measured as a percentage; the normative value is 63–73%.The duration of the pulse wave anacrotic phase; measurement unit: seconds.The duration of the pulse wave dicrotic phase; measurement unit: secondsThe duration of the exile phase. A parameter reflecting the diastolic activity of blood vessels; measurement unit: seconds.The duration of the exile phase. A parameter reflecting the diastolic activity of blood vessels; measurement unit: seconds.Pulse wave duration; measurement unit: seconds.The rising wave index. This reflects the filling phase in the systolic period of the cardiac cycle. The standard value corresponds to 15–24%.Filling time; measurement unit: seconds. The standard value is in the range of 0.06–0.12 s.The cardiac cycle systole phase duration; measurement unit: seconds.The cardiac cycle diastole phase duration; measurement unit: seconds.The cardiac cycle diastole phase duration; measurement unit: seconds.Pulse wave reflection time; measurement unit: seconds. The standard value is in the range of 0.03–0.04 s.Heart rate; measurement unit: beats per minute.Despite the diagnostic significance of the pulse wave contour with its characteristic points, many normative values of hemodynamic parameters have yet to be determined. The absence of these values is due to the complexity of forming a database of pulse wave contours in normal and pathological conditions. The above-mentioned components of pulse wave signals can be used to evaluate the characteristic points of the pulse wave contour. In this regard, it is important to focus on the study of the pulse wave contour and its characteristics, which make it possible to form a multiparametric feature space for machine learning of neural network classifiers.Pulse wave signals were received using the «Hemodyn1» device. The pressure signal processing algorithm was implemented as a virtual instrument using LabVIEW software. Graphic processing was performed using the MATLAB R2017b software as part of the study, taking into account the age and health status of the participants.To study the process of a multiparametric feature space formation and to prove the possibility of predicting the hemodynamic parameters values based on non-invasive hydrocuff technology using a neural network, the authors used the hydrocuff device «Hemodin1», the block diagram of which is shown in The pressure source contains a reservoir with a given volume of liquid and a device for supplying liquid to the hydrocuff chambers. A two-chamber compression hydrocuff is installed on the patient’s forearm before starting the measurement.When creating pressure, the liquid from the pressure source enters the working chamber through the first control unit. Excessive pressure is created in it and oscillations are formed caused by the passage of pulse waves under the cuff .The figures below show the pulse wave contours of patients from different age groups registered by the «Hemodin 1» hydrocuff device.The factors of formation and diagnostic significance of this peak are to be determined during an extended study of a group of patients 18 to 21 years of age.The maximum amplitude of the presented signal is 8 mm Hg. The amplitude of the dicrotic burst is 3.5 mm Hg, which is 44% of the total amplitude of the signal and indicates a high elasticity of the vessel wall. Having estimated the duration of one cardiac cycle, it can be concluded that 64% of the cardiac cycle time falls on the work of the vessels and only 36% on the work of the heart muscle.Analyzing the treated contour of the pulse wave, it can be stated the high amplitude of the signal, about 12 mmHg, which characterizes such a hemodynamic parameter as cardiac output, it can also be noted a good response of the artery walls to extensibility under the influence of shock volume, as evidenced by a dicrotic surge on a single pulse wave.The amplitude of the dicrotic surge was 41.6% of the total amplitude, there is a decrease in vascular response compared with indicators of a younger age. More detailed calculations and in-depth analysis may offset these discrepancies. The working time of the vessels relative to the total duration of the cardiac cycle was almost the same and amounted to 64%, while the work of the heart accounted for 36%.Analyzing the contour of the pulse wave of an age-related patient in the same way as in previous cases, the shape of the pulse wave resembles the classical one, there are two waves and all the main characteristic points, a distinctive feature can be called a high amplitude of 22 mmHg; however, the amplitude of the dicrotic surge was 5 mm Hg, this is only 22.7%. This indicates the process of reducing the vascular bed elasticity. The main work is performed by the heart muscle, the weak work of the vessels provides an additional load on the left ventricle of the heart. The same fact confirms the duration of the cardiac cycle, the share of vascular work accounts for 49.4% of the time.The presented results of recording the single pulse waves prove the individuality of the pulse wave contour and the fact that age-related changes in the elasticity of the vascular wall affect the work of the entire CVS.In The use of neural networks when making a diagnosis reduces the time of research and simplifies the task for medical personnel. To form a multiparametric feature space, the authors of this study proposed the structure of an artificial neural network. Determining the sufficient number of neurons in the hidden layers is an important task. A small number of neurons complicates the learning procedure. A large number of neurons leads to an increase in training time and the effectiveness of its tuning. To find the rational number of neurons of the hidden layer of a neural network with the structure of a multilayer perceptron, it is necessary to study the indicators of sensitivity and specificity of all network outputs, which the authors of this study have yet to implement. It is possible that the number of neurons in the hidden layer will decrease as a result of further research. The output layer of the proposed neural network contains information about the normal state and pathologies of the cardiovascular system.To train an artificial neural network, it is possible to use an error back propagation algorithm . The varIn this study, the authors recorded the pulse wave contours of citizens of different age groups and analyzed the characteristic points position of the pulse wave contour. In the study, it was aspired to evaluate the factors influencing the SBP and DBP determination accuracy, as well as to evaluate the possibility of forming a multiparametric feature space based on preliminary collection of information about the patient anatomical features and the pulse wave contour obtained by hydrocuff technology applying . The recDuring the study, the amplitude and time characteristics of the registered signals were evaluated. The obtained preliminary data showed an increase in amplitude with an increase in age, this fact needs to be checked on a larger sample. Moreover, in the conducted research’s result, the task of assessing the effect of pathological changes in the cardiovascular system on the time of a complete cardiac cycle arose. The considered issue of the respiratory organs work influence on the pulse waves contour requires an extended study with the involvement of additional equipment a chest respiratory sensor. The conducted research only confirmed the respiratory system’s effect on the pulse wave contour in all age groups. Studies on the selection of the respiratory component of the signal were not conducted. Hartmann V et al., 2019 , publishIn this study, the authors did not set the task of comparing the developed hydrocuff technology with well-known published works on the assessment of blood pressure and hemodynamic parameters using PPG and ECG signals. The authors propose to use hydrocuff technology to form a high-quality pulse wave contour. This study substantiates the need for the formation of a multiparametric feature space for the purpose of early diagnosis of CVS pathologies. Groups of features are provided that allow forming a large data array for training a neural network. A variant of a multilayer neural network is proposed to increase the prognostic accuracy of the intended diagnosis. The complexity in the formation of a multiparametric feature space is associated with the need to create an extensive database of pulse wave contours characterizing various types of pathologies. The use of hydrocuff technology leads to a complication of the device design compared with PPG, due to the use of expensive microprocessors used to solve neural network classification tasks.As a result of tests, the contours of the pulse waves were obtained and characteristic points were marked. In this study, a reliable, accurate but simple mechanism is proposed that allows to extract clinically significant signs from the pulse wave curve by taking into account the position of characteristic points on the curves.The conducted research results indicated a high sensitivity of perception of pressure changes in the artery under the cuff. This has advantages associated with an increase in the pulsations amplitude of small distortions of the pulse waves contour. High sensitivity makes it possible to capture the influence of the respiratory component on the amplitude characteristics of pulse waves. In this regard, the task of eliminating the modulations of the respiration amplitudes arises. For practical use of the proposed technology, it is necessary to develop an algorithm for extracting respiratory amplitudes from the pulse wave contour. This will allow to isolate and take into account the respiratory component in order to exclude the respiratory system work influence on hemodynamic parameters. It will expand the functionality of hydrocuff devices in the field of diagnostics of the respiratory system for determining the frequency and depth of breathing, which is an urgent problem in pulmonology.


Changes in autonomic function are often caused by spinal cord injuries, which lead to limited orthostatic positioning in these patients.  To investigate the cardiovascular and biomechanical parameters during 90 min of postural elevation equipment usage comparing spinal cord injury and healthy subjects. p < 0.05 for all statistical analyses.  A device was used that allowed patients with spinal cord injuries to remain in an orthostatic posture for 90 min. During this period, the physiological parameters were measured every 15 min. Cardiovascular parameters  and biomechanical parameters of the plantar pressure distribution were evaluated. For blood pressure, heart rate, oxygen saturation, and autonomic nervous system, a two-way analysis of variance was applied. The mixed-effect model was applied to plantar pressure. The significance level was set at F = 0.07), diastolic blood pressure (F = 0.14), heart rate (F = 0.56), and oxygen saturation (F = 0.23) at any of the time intervals throughout the experiment (p > 0.05). No statistical difference was observed in the mean plantar pressure values between the groups (p = 0.35) during the period in which they remained in the orthostatic position.  No differences were observed between the groups in systolic blood pressure ( The present study showed the absence of differences between spinal cord injury patients and control participants using the orthostatic device in terms of cardiovascular and biomechanical parameters over 90 min. Spinal cord injury (SCI) can affect the social participation of individuals, as it leads to motor changes such as paralysis, musculoskeletal injuries, pain, and osteoporosis . IndividAnother factor that contributes to limiting the return of patients with SCI to social and work contexts is the presence of postural hypotension. SCI leads to peripheral and central cardiovascular adaptations such as increased peripheral vascular resistance, reduced capillarization, and decreased artery diameters, which cause static hypotension and limits a standing position . OrthostThis cross-sectional experimental study was approved by the Local Committee of Ethics in Research (number CAAE 07192819.6.0000.5038). Due to the nature of the injury condition, a priori sample calculation was not performed. Thus, the participants were intentionally selected for the study.The following individuals were included in the control and SCI groups: individuals between 18 and 50 years, with a height between 1.55 and 1.75 meters, a maximum weight of 100 kg, of both sexes, healthy, without associated vascular pathologies , and with stabilized BP. Those with any serious cognitive/psychological impairment that could interfere with test performance, such as panic syndrome, major depression or anxiety attacks, and any relevant speech impairment that could impede their communication during the tests.Participants without motor changes were included in the control group. In the SCI group, subjects with medium and lower lesions due to trauma, accidents, gunshot, and others, without associated vascular pathologies , with stabilized BP.The equipment  was deveThe participants were recruited for convenience, and a self-report sleep quality questionnaire and demographic characteristics were collected. The weight of each participant was then checked on a digital scale, and the first measurement of the autonomic nervous system activity in the sitting position was performed. Those to be evaluated were then positioned in the exoskeleton and fixed with belts specifically designed to guarantee user safety. After positioning each subject, they were placed in a condition of elevation with the exoskeleton (standing up position wearing the equipment) and maintained for 90 min. In this condition, the participants performed a battery of tests, which consisted of analysis of their heart rate, oxygen saturation, BP every 15 min, quantification of the activity of the autonomic nervous system, weight distribution on the equipment, and distribution of the plantar pressure on the baropodometry equipment every 30 min. Then, the users were removed from the elevated condition and returned to the sitting position, and the test was finished. Sleep quality data were collected to verify whether patients had any changes since vagal modulation is observed during sleep and sympathetic control is predominant during rapid eye movement (REM) sleep .The participants' cardiovascular parameters  were inspected nine times at intervals of 15 min during and after the intervention. BP was assessed using a manual sphygmomanometer (BIC Brand™) that was properly calibrated and validated . The cufBefore baropodometry, the subjects were weighed using a Renpho (TM) digital scale. Plantar pressure mean analysis was performed using a baropodometer , France). Data of the plantar pressure mean they were collected for 50 s at four different moments during the period when the subjects were in the elevated position: one at Time 0, the second at 30 min, the third at 60 min, and the last at 90 min , 19.t-test for Independent Samples was used. Data on weight and sleep quality showed a non-normal distribution, which is why they were evaluated using the Mann–Whitney U test. The groups were compared at the respective times , and the Shapiro-Wilk normality test was used. For BP, heart rate, oxygen saturation, and ANS, a two-way analysis of variance (ANOVA) was applied. The mixed-effect model was applied to plantar pressure. The significance level was set at p < 0.05 for all statistical analyses. Data are expressed as the mean (SD).Data were analyzed using the statistical software GraphPad Prism 8.0. For the variables age, height, and body mass index, Student's The group samples had similar characteristics at baseline. No statistically significant differences were observed .F = 0.07), diastolic blood pressure (F = 0.14), heart rate (F = 0.56), and oxygen saturation (F = 0.23) at any of the time intervals throughout the experiment (p > 0.05) (No differences were observed between the groups in systolic blood pressure ( > 0.05) . This cop = 0.35) during the period in which they remained in the orthostatic position. p > 0.05).This study aimed to evaluate the influence of the use of orthostatic equipment for 90 min on cardiovascular parameters, ANS, and plantar pressure in patients with SCI compared to controls. Our results showed the stability of cardiovascular parameters throughout using the exoskeleton for postural elevation. Additionally, the ANS responses were similar in both groups, and the plantar pressure mean always remained equal between the groups. In contrast, the time adaptation of this data over time demonstrated a nonspecific intragroup difference.The cardiovascular parameters measured by heart rate, BP, and oxygen saturation in the blood demonstrated that none of the participants presented values that characterized the presence of dysfunction, such as BP . This isThe equipment developed and tested in this study had a circulatory support system. The base of the device, where the patient's feet were supported, was designed to move approximately 15° in ankle dorsiflexion, allowing joint mobility and consequently improving venous return and edema. The same system has already been tested in amputees who practiced physical activity for 90 min and showed favorable BP results . AnotherChanges in the ANS can lead to changes in heart rate variability, as heart–brain interactions are essential for vital functions . In thisThe postural control system works such that the upright posture is maintained with the lowest possible energy expenditure, providing control, stability, and balance . Thus, tThe results in both groups concerning the stability of the cardiovascular parameters during device use for 90 min represent the main strength of this study. Using orthostatic equipment or wheelchair elevation devices could represent a new, safe, and effective technology to help individuals with paraplegia assume a standing position, thus allowing them more mobility . On the This study demonstrates physiological stability for using the exoskeleton by healthy individuals and individuals with SCI for 90 min. Considering that exoskeletons allow overcoming environmental barriers, acting as part of a rehabilitation process , this stThe present study showed the absence of difference between SCI patients and control participants using the orthostatic device in terms of cardiovascular and biomechanical parameters  for 90 min, allowing, in clinical practice, the patient to remain in an orthostatic position for longer than reported so far in the literature.