| Neurogenic orthostatic hypotension (NOH) is one of the most main reason of orthostatic hypotension (OH). The diagnosis of NOH can be basicly clear when the others causes of OH were eliminated, such as endocrine metabolic disease, cardiovascular system diseases, chronic wasting disease, insufficient blood volume, iatrogenic secondary factors. NOH occupy large proportion in patients with OH. And other secondary factors of OH were rare and complicated. This task aimed at the majority of the OH objects, of which the condition were relatively fixed Recognized in clinical, diagnosis of NOH is remarkably instructive. First, NOH may be the omen of cerebrovascular hypoperfusion and multisystem diseases. The second, NOH might be a risk factor of falling. The third, OH might be a sign of a weakening and dying. The forth, categorized diagnosis of OH is helpful for further remedy. Currently OH diagnosis is based on the criteria set by the American Autonomic Society (AAS) and the American Academy of Neurology (AAN) in1996. OH is defined as a persistent, consistent,orthostatic fall in systolic blood pressure of more than20mmHg or diastolic blood pressure of more than10mmHg, combined or not combined with various clinical symptom of hypoperfusion within3minnutes of standing up. In the past10years or so, the criteria have been widely applied. The criteria rely greatly on current measurement on blood pressure and key point is screening patients and timing of blood pressure measurement. According to the criteria, the repeatability of OH tests is poor. There has been argument that the criteria should be revised and there were evidence showing the criteria need to be revised. The main revisions should be involved in range of blood pressure decrease, time for reaching threshold value and how many times of measurement for a fixed OH diagnosis. Further problem is coming from the application of diagnosis criteria. Can an orthostatic test be applied to different patients from various clinical environments? Are there different OH threshold associated with changing clinical conditions, causes and complications of patients? Which test has the best predicted effect on the prevalence and mortality of the OH? Are there other objective laboratory parameters instead of blood pressure variation indicators? In our country, NOH large-scale epidemiological studies are few. This research aimed to analyze the prevalence of OH and arteriosclerosis index characteristics in different age groups, through studying orthostatic changes in blood pressure and arteriosclerosis index in healthy population of different age class. At the same time, this research also selected crowd of OH-related symptoms. Symptoms were graded and rated, and orthostatic blood pressure changes and the arteriosclerosis index were checked at the same time, for analyzing the relationship of symptoms, orthostatic changes in blood pressure and arteriosclerosis index. The relation among repeatability of current OH diagnostic criteria, different intervals of standing, and diagnose of OH were judged. As there was argument on criteria of diagnosis, most researches resulted in different prevalence rate, dangerous factors and remedies. At present, there is no proved instruction or solution for OH remedy. Although some scholars believe that asymptomatic OH patients can be recovered without the treatment, but little evidence-based medical experiments are proven. The asymptomatic population with orthostatic blood pressure changes according with the OH diagnostic criteria were performed non-drug treatment for orthostatic blood pressure changes. The same time, all the objects with symptoms have been carried out the intervention. The different treatment options depending on the orthostatic blood pressure changes were used and the effects were explored. The improvement of protein chip technology allows researchers to grasp phenotypic fingerprint of NOH, and there is one more objective indicator in diagnosis of OH. This research choosed apoptosis related factors antibody chip to detect apoptosis related proteins characteristic of patients with NOH. So that, in high-risk groups, the phenotypic fingerprint could support early intervention to prevent incident of falls, cerebrovascular accident and so on. It can also provide an objective basis for the selection of pilots, astronauts, and other special occupational groups. And efficient, convenient, cheap protein targets for the diagnosis of OH are to be further explored based on phenotypic fingerprint. G protein is a transduction messenger of certain hormones, neurotransmitters and vasoactive substances, being molecular switch in the signal transduction process as mediating many effect of stimulating vasoactive substances and angiogenesis within the cell.It plays an extremely important role in regulating vascular tone and maintenance of the vessel wall. The incidence of NOH is closely related to vasoactive substances, aging, hypertension and atherosclerosis. It is supposed that NOH and GNB3gene C825T polymorphism may have certain relevance. Relevant reports on GNB3gene C825T polymorphism of patients with NOH research have not yet found in China. The research on correlation of GNB3gene C825T polymorphism and NOH have theoretical and practical significance for the further explore of the pathogenesis and treatment programs in the the clinical work with OH. 1.Method1.1For doing in-depth analysis on prevalence rate of NOH in different groups of people, this reseach set up a test on objects with and without OH relevant symptom respectively. Total of547people were chosen as without OH relevant symptom targets and divided into3groups,259as young people group,176as mid-age group and139as elderly group. For another crowd,193people were chosen as with OH relevant symptom targets and divided into3groups as well,37as young people group,66as mid-age group and90as elderly group.1.2Binding assay needs, the asymptomatic population survey follow-up registration table and the symptoms population survey registration table were designed. Physician checks were perfomed following contents of the table and general information were recorded. Orthostatic blood pressure checks were implemented4times, respectively in two different inspection day at sometime in morning and afternoon. Each check was performed by examining supine blood pressure, blood pressure respectively at1,3,5,10,15,20minutes after standing. Orthostatic changes in systolic blood pressure (OCs) and orthostatic change in diastolic blood pressure (OCd) were calculated. The atherogenic index, CAVI and ABI were examined in two different examination date, and symptom scores were calculated for OH symptomatic crowd.1.3The asymptomatic objects according with OH diagnostic criteria were randomly divided into non-drug treatment group and follow-up group. The symptomatic objects, who did not meet the OH diagnostic criteria, were classified as OH-nagetive groups, and divided into the follow-up subgroup, the non-drug treatment subgroup, placebo treatment subgroup. The symptomatic objects according with OH diagnostic criteria were classified as OH groups, and divided into the non-drug treatment subgroup, the placebo treatment subgroup, the drug treatment subgroup. In follow-up date after treatment for3months, another2times orthostatic blood pressure checks were performed respectively at sometime in morning and afternoon. Each check was performed by examining supine blood pressure, blood pressure respectively at1,3,5,10,15,20minutes after standing. OCs and OCd were calculated and the CAVI and ABI were examined again. Symptom scores were calculated once more.1.4Comply with OH diagnostic criteria and typical OH symptoms,3patients were selected. Similar to the corresponding baseline data of the selected objects,3asymptomatic objects of OH-negative were selected as control. After acquisition serum samples of the six objects, analysis proceeded by apoptosis-related factor antibody chip.1.5Comply with OH diagnostic criteria and typical OH symptoms,84patients were selected. Similar to the corresponding baseline data of the selected objects,100asymptomatic objects of OH-negative were selected as control. After acquisition4-5ml venous blood samples of selected objects, DNA extract were processed. Subsequently, GNB3geneC825T polymorphism analyses were carried through by means of standard PCR-RFLP genotyping technology.1.6After the survey and the quality inspection, the data were entried, and the database was established by using SPSS19.0. The qualitative data were described by percentage, and the quantitative data were described by the mean and standard deviation. Chi-square was used to test the comparison of qualitative data, and T test wad used to test the comparison of two sets of quantitative data. ANOVA (single-factor analysis of variance) or LSD (least significance difference) method was used to compare multiple sets of quantitative data. Welch F test and Dunnett’s T3method were used in unequal variances. The quantitative data before and after the treatment on the same object were compared by paired T test. The method of variance analysis of repeated measurement data was used to analysis repeated measurements data. The method of Logistic regression analysis was used to analyse the relationship of multiple variables and orthostatic hypotension. By bilateral observation, P≤0.05for the difference was statistically significant. ScanAlyze software analysis was applied in the protein chip test results.2.Result2.1There were574objects in the asymptomatic group. However,21objects were matched with OH diagnosis criteria, which meant3.6%of all. Among them,5objects were in young group, accounting for1.9%of the younger group. Representing3.4%of the middle-aged group,6objects were in the middle-aged group. And accounting for7.2%of the older group,10objects were in elderly group. Chi-square was used to test the comparison of the prevalence among the three groups, P>0.05, and no statistically significant difference was found. The orthostatic changes of blood pressure varied in repeated measurements of different measurement schedule. There were significantly different in orthostatic changes blood pressure between different age groups. The orthostatic changes in diastolic blood pressure and systolic blood pressure fluctuated, and no significant regularity was found. Between the different age groups, there were significant differences in the values of CAVI and ABI (P<0.01).The CAVI values of young group were less than the middle-aged group and the elderly group, and the CAVI values of middle-aged group was less than the elderly group.2.2Total of193objects with OH related symptoms were selected, of which63people were according with OH diagnostic criteria, accounting for32.6%of the symptomatic people. Among the OH positive objects, there were12people in the young group, accounting for32.4%of the younger group. There were17objects in the middle-aged group, accounting for25.8%of the middle-aged group. And there were34objects in the older group, accounting for37.8%of the older group. Chi-square was used to test the comparison of the prevalence among the three groups, P>0.05, and no statistically significant difference was found. According to the results of statistical analysis, the orthostatic changes of blood pressure varied in repeated measurements of different measurement schedule. There were significantly different in orthostatic changes blood pressure between different age groups. There were statistically difference between morning and afternoon of OCs1ã€OCs3ã€OCs5〠OCs10ã€OCd3ã€OCd5ã€OCd10ã€OCd15in first inspection day. There were statistically difference between morning and afternoon of OCs3ã€OCs10ã€OCd20in second inspection day. There were statistically difference between the two inspection days of OCs10in morning and OCs5〠OCs15ã€OCd15ã€OCd20in afternoon. And there were no statistically significant difference between changes in blood pressure values of two inspection days, between morning and afternoon in the two respective inspection date.2.3A total of769people were selected for the examination.There were296people in young group, average age20.57±3.88years. There were242people in middle-aged group, average age53.08±4.15years. And there were229people in elderly group, average age77.49±4.30years. Among them, there were84people complied with OH diagnostic criteria through4times of orthostatic blood pressure measurement, as prevalence rate, accounting for10.95%of all objects. There were significant differences among different age groups, P<0.01.The prevalence of the elderly group was higher than the young group and middle-aged group (19.2%vs5.7%,9.5%). There were significantly different in orthostatic changes blood pressure between different age groups(P>0.05) among OH positive objects. There were statistically differences in OCsl, OCs3, OCd3of afternoon in first inspection day comparing with morning, P<0.05. There were statistically differences in OCs3of afternoon in second inspection day comparing with morning, P<0.05. There were no statistically difference in changes of blood pressure values of morning between two inspection days, P>0.05. There were statistically differences in OCs3of afternoon in second inspection day comparing with first inspection day, P<0.05. As so, there were no statistically differences in OCsl, OCd1, OCd3, P>0.05. Anyway, compared with two inspection day for orthostatic changes of blood pressure in OH positive people, the consistency was good in morning, and the consistency was also relatively well in afternoon. But the consistency between morning and afternoon was poor in respective inspection days. The numbers of people accoding with OH diagnostic criteria were various in different inspection schedules. The account of objects should be calculated once if the same object was repeatly positive in different inspection schedules. There were58objects with positive result in the OH inspection in first inspection day, accounting for69.05%of the all the OH positive objects. And there were45objects with positive result in the second inspection day, accounting for53.57%of the all the OH positive objects. Chi-square was used to test the comparison of the diffence between the two insecion days, P>0.05, and no statistically significant difference was found. There were63objects with positive result in the OH inspection in morning of the two inspection days, accounting for75%of the all the OH positive objects. And there were32objects with positive result in afternoon of the two inspection days, accounting for38.01%of the all the OH positive objects. Chi-square was used to test the comparison of the diffence between morning and afternoon, P<0.01and the difference was statistically significant. There were significant differences of CAVI between the different age groups, P<0.01. The CAVI values of the young group were less than the middle-aged group (P<0.05) and the elderly group (P<0.01), and the CAVI values of middle-aged group was less than the older group (P<0.01). There were significant differences of ABI between the different age groups, P<0.05.The ABI values of the young group were less than the elderly group (P<0.01), and the ABI values of middle-aged group were less than the elderly group (P<0.05). There were no significant difference (P>0.05) between the ABI values of the middle-aged group and the young group.2.4There were84people complied with OH diagnostic criteria through4times of orthostatic blood pressure measurement. The intervals in OH diagnostic criteria were treated as the dependent variable. As so, the prevalence of3minutes orthostatic interval was10.92%. Diagnosis of threshold in orthostatic changes in blood pressure remaining unchanged, the prevalence of5minutes orthostatic interval was15.91%. As so, the prevalence of10minutes orthostatic interval was16.82%. The prevalence of15minutes orthostatic interval was17.86%. And the prevalence of20minutes orthostatic interval was19.04%. There were more and more people compliance with blood pressure change threshold of the OH diagnostic criteria with prolonged standing intervals. Compared with3minutes orthostatic interval, there was a statistically difference in prevalence of5minutes orthostatic interval. The number of people matched the OH diagnostic criteria in3minutes orthostatic interval in morning was more than that in afternoon. The fluctuation curves of orthostatic changes of blood pressure in different standing intervals were different and with respective laws.2.5A total of21asymptomatic OH patients had been treated. There were no statistically differences between the non-drug treatment group and the follow-up group in variations of changes in orthostatic blood pressure after treatment. The values of CAVI and ABI were not significant before and after the treatment.2.6There were a total of130symptomatic objects with OH nagetive diagnose. There were43people in follow-up subgroup, of which6objects (14.0%) according with OH diagnostic criteria once in two time’s orthostatic blood pressure measurement after the treatment. There were45people in non-drug treatment subgroup, of which5obj ects (11.1%) according with OH diagnostic criteria after the treatment. And there were42people in placebo treatment subgroup, of which2objects (4.8%) according with OH diagnostic criteria after the treatment. There were no statistically differences among diagnostic rate of the three subgroups. Based on the method of variance analysis of repeated measurement data, there were statistically differences in OCsl (P<0.01), OCdl and OCd3(P<0.05) between follow-up subgroup and placebo treatment subgroup, as no statistically differences in OCs3. There were no statistically difference in changes of blood pressure values of non-drug treatment subgroup and others two subgroups respectively, P>0.05. The improvement of symptom scores was0.42±1.05in follow-up subgroup,1.18±1.35in non-drug treatment subgroup,1.76±1.28in placebo treatment subgroup. The improvement of follow-up subgroup was the least of the three subgroups. And the improvement of placebo treatment subgroup was better than non-drug treatment subgroup. Based on bivariate variation Pearson correlation analysis results, there was relationship between improvement of symptom scores and OCd1mVariation, as were no relationship between improvement of symptom scores and the others variations value of orthostatic changes of blood pressure (P>0.05)2.7There were63symptomatic OH objects, and21objects in each and every subgroup. After treatment for3months, orthostatic blood pressure measurements were performed twice. There were9(42.9%) objects in the non-drug treatment subgroup of which orthostatic changes of blood pressure were up to OH diagnostic criteria at least once. There were4(19.0%) objects as to the drug treatment subgroup and5(23.8%) as to the placebo subgroup. There were no statistically differences among diagnostic rate of the three subgroups (P<0.05). In line with the curves of the values of OCs and OCd in the third inspectionday after treatment, the placebo treatment subgroup and drug treatment subgroup were obviously located in below the non-drug treatment subgroup. The curve of OCs was relatively stable, which shew that the orthostatic blood pressures of drug treatment subgroup were improved the most obviously among the three subgroups. The orthostatic blood pressures of the placebo treatment subgroup were improved more than that of the non-drug treatment subgroup.But the curves of OCd were fluctuant, which shew that the orthostatic blood pressures of the drug treatment subgroup and the placebo treatment subgroup were improved more obviously than that of the non-drug therapy subgroup. But the effect of improvement was not stable and of different degrees. The values of CAVI and ABI were not significant before and after the treatment in the three subgroups. The improvement of symptom scores was0.57±0.60in the non-drug therapy subgroup,1.57±1.40in the placebo treatment subgroup,1.48±0.93in the drug treatment subgroup.The symptom scores improvement of the drug treatment subgroup and the placebo treatment subgroup were more than that of the non-drug therapy subgroup(P<0.05). There were no statistically difference in the symptom scores improvement between the drug treatment subgroup and the placebo treatment subgroup, P>0.05. Based on Pearson correlation analysis results, there was no relationship between improvement of symptom scores and OCdlmVariation, as were no relationship between improvement of symptom scores and orthostatic changes of blood pressure mostly.2.8A total of193objects with related OH symptom were involved in the research. The symptom scores improvement of the4treatment methods were analysed by LSD method. The symptom scores improvement of non-drug treatment, placebo treatment and medicine treatment were more than that of follow-up treatment (P<0.01or P<0.05). The symptom scores improvement of placebo treatment was more than that of non-drug treatment. There were no statistically difference in the symptom scores improvement between the non-drug treatment, the placebo treatment and drug treatment, P>0.05. 2.9Through apoptosis related factor antibody chip testing, statistical significance was found to have a total of11kinds of target protein down-regulation, and1protein BID up-regulation. The down-regulation target protein included cytoC〠DR6ã€FasLã€IGFBP-3ã€IGFBP-4ã€p21ã€TNF-αã€TNF-βã€TRAILR-3ã€TRAILR-4, a total of10factors.2.10When comparing OH and OH-negative group, there was no statistically difference in genotype frequency and allele frequency distribution. Based on the method of variance analysis of repeated measurement data, the values of blood pressure and the orthostatic changes acted as variables, and the GNB3gene of different genotypes acted as grouping factors. The statistical analysis results shew that, comparing with different genotypes of objects, there were no statistically differences in variation of recumbent blood pressure and orthostatic changes of blood pressure.3.Conclusion3.1The prevalence of OH in no related symptoms people is low. OH was associated with multiple risk factors. The law curve of orthostatic blood pressure change is no significant regularity. Repeated orthostatic blood pressure measurements can improve OH detection rate. The prevalence of OH in people with related symptoms is high.The OH diagnostic of the certain people showed no significant correlation with the multiple OH risk factors. The law curve of orthostatic blood pressure change is no significant regularity. There were no statistically differences among diagnostic rate of the different age groups. There were closely related between prevalence of OH and age, as to atherosclerosis. Repeated orthostatic blood pressure measurements can improve OH detection rate.3.2The increase in frequency was statistically significant between the3minutes and5minutes standing times. With5min of standing, significantly more patients reached the OH diagnostic BP threshold in the morning than in the afternoon, and the number of patients with qualified OCs was greater than that with qualified OCd. Normal distribution curves in OH and OH-negative group’s change in blood pressure when standing were different but regular respectively. It’s more efficient and effective to test the blood pressure in the morning than doing that in the afternoon.3.3Non-medicine treatment was not apparently effective for OH-negative group. But it’s sharply effective in symptom improvement for OH group, but not orthostatic changes in blood pressure. The effect of placebo treatment was better than non-medicine treatment for improvement of symptoms. For symptomatic OH subjects, there were different levels improvements of the orthostatic changes of blood pressure among3different treatments methods. But the improvements were not stable. It is necessary to intervene for patients with related symptoms and OH diagnosis. Placebo treatment can improve symptoms scores, as same as the drug treatment.3.4Arteriosclerosis indexes were highly related to age and cannot be changed by short term treatment. Improvement in symptom and changes in blood pressure had nothing to do with Arteriosclerosis index during short time therapy. Non-medicine treatment can increase the change in blood pressure, but not in improvements of the symptoms scores. There’s no relationship between symptom improvement and the increase of orthostatic blood pressure. Both drug therapy and placebo treatment can significantly improve symptoms and increase orthostatic changes of blood pressure. It meant that the pathophysiological mechanisms of NOH patients were not only related to hemodynamics factors but also mental and psychological factors. And the atherosclerosis indexes had no obvious relationship with that.3.5A very small sample of cytokines can be detected through high flux by means of proteins chip which was the ideal technical methods to screen NOH related cytokines and proteins. This study shew the apoptosis related factors, part of the phenomic fingerprint of NOH patients by means of protein microarray analysis first time. This offers a new lab for NOH diagnosis indicator. The NOH may be related to many apoptosis factors or apoptosis signaling pathways. And death receptor pathway is closely related to up-regulation of the Bid protein, which was suggesting that there should be possible death receptor pathway in the pathogenesis of NOH.3.6When comparing OH and OH-negative group, there’s no statistically difference in genotype frequency and allele frequency distribution. The GNB3gene C825T polymorphisms were not associated with NOH directly. Activity of vascular changes mediated by G protein stimulation and the effects of vascular endothelial change leads to the variations of orthostatic blood pressure may be just one of the many NOH pathophysiologic pathways. |
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