Dysfunction of cerebral autoregulation is one of the pathophysiological mechanisms that causes delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH). Pressure reactivity index (PRx) have been confirmed to reflect the level of cerebral autoregulation and used to derive optimal cerebral perfusion pressure (CPPopt). The goal of this study is to explore the associations between autoregulation, CPPopt, PRx, and DCI.Continuous intracranial pressure (ICP), arterial blood pressure (ABP), and cerebral perfusion pressure (CPP) signals acquired from 61 aSAH patients were retrospectively analyzed. PRx was calculated and collected by Pneumatic computer system. The CPP at the lowest PRx was determined as the CPPopt. The duration of a hypoperfusion event (dHP) was defined as the cumulative time that the PRx was > 0.3 and the CPP was <CPPopt. The duration of CPP more than 10 mmHg below CPPopt (ΔCPPopt < − 10 mmHg) was also used to assess hypoperfusion. The percent of the time of hypoperfusion by dHP and ΔCPPopt < − 10 mmHg (%dHP and %ΔCPPopt) were compared between DCI group and control group, utilizing univariate and multivariable logistic regression. It was the clinical prognosis at 3 months after hemorrhage that was assessed with the modified Rankin Scale, and logistic regression and ROC analysis were used for predictive power for unfavorable outcomes (mRs 3–5).p < 0.001) and the %ΔCPPopt < − 10mmHg (p < 0.001) was significantly longer in the DCI group. In multivariate logistic regression model, %ΔCPPopt <− 10 mmHg (p < 0.001) and %dHP (p < 0.001) were independent risk factor for predicting DCI, and %ΔCPPopt <− 10 mmHg (p = 0.010) and %dHP (p = 0.026) were independent risk factor for predicting unfavorable outcomes.Data from 52 patients were included in the final analysis of 61 patients. The mean %dHP in DCI was 29.23% and 10.66% in control. The mean %ΔCPPopt < − 10 mmHg was 22.28%, and 5.90% in control. The %dHP (The increase of duration of hypoperfusion events and duration of CPP below CPPopt over 10 mmHg, evaluated as time of lowered CPP, is highly indicative of DCI and unfavorable outcomes. Cerebral autoregulation (CA) is crucial to maintain a constant cerebral blood flow (CBF) by regulating precisely brain vascular resistance in the context of changes of cerebral perfusion pressure . DysfuncDelayed cerebral ischemia (DCI) is defined as a clinical deterioration along with associated ischemic changes and hypoperfusion . DCI is In our study, we assessed the state of cerebrovascular reactivity and CPPopt in SAH patients, and exploratively investigate the relationship between hypoperfusion identified by PRx threshold and DCI.Aneurysm subarachnoid hemorrhage (aSAH) patients were diagnosed with intracranial aneurysm by DSA or CTA, and treated by microsurgical clipping and intracranial pressure (ICP) monitoring. Traumatic SAH patients or other cerebrovascular diseases were excluded. Arterial blood pressure (ABP) and ICP obtained in 61 patients were collected at the neuro-intensive care unit (NICU) at the First Affiliated Hospital of Chongqing Medical University between January 2018 and September 2019. All data were analyzed retrospectively. A standardized treatment protocol was used, focusing on early detection and treatment of secondary insults . PropofoAll patients with a diagnosis of aSAH were strictly followed by a standardized imaging protocol in all cases. Brain CT scan, CTA, and a CT perfusion study were performed on admission and/or prior to transfer to the First Affiliated Hospital of Chongqing Medical University. Patients after microsurgical clipping were admitted and managed in NICU. Brain CT scan were performed on the first day after surgery and before being transferred out of the NICU in all patients. The determination of performing additional CT in NICU depended on level of consciousness in patients and associated complications. Brain MR scan were performed in all patients before discharge.Diagnosis of DCI was based on standard definition including clinical deterioration and cerebral infarction : clinicaICP was monitored with an intraparenchymal probe . ABP was monitored through the radial artery with the aid of a standard pressure monitoring kit and was zeroed at the level of the Monro. Data were sampled at 100 Hz with Pneumatic computer for proprietary data acquisition and analysis . ABP andx-axis and mean of PRx on the y-axis in all patients. The CPPopt were defined as CPP associated with the lowest values of PRx in “U-shaped curve”  were calculated using waveform time integration over 10-s intervals. CPP-PRx curve was calculated with the method proposed by Steiner . CPP valPrevious studies have found that both low and high CPP resulted decline of cerebral vascular reactivity, so that threshold method was used to identify poor CPP. A similar index by Hakseung Kim  which wat test and rank sum test were used to analyze the differences measurement data between groups. Univariate and multivariable logistic regression were used to analyze in the end. According to modified Rankin score (mRs) at 3 months, and logistic regression and ROC analysis were used for predictive power for unfavorable outcomes (mRs 3–5). Age (years), Hunt-Hess Score, mFisher Score [dHP and time with ΔCPPopt < − 10mmHg was compared between DCI group and control group, utilizing univariate and multivariable logistic regression. Pearson’s chi-squared test and continuity-adjusted chi-squared were used for comparisons of the rate in four-fold table data. er Score , and dHPp = 0.009).In a total over 3300 h, median total monitoring time was 52 h  continuous bedside monitoring was performed on 61 patients  at NICU at the First Affiliated Hospital of Chongqing Medical University between January 2018 and September 2019. The mean initial time of monitoring was 4 days after aneurysm rupture. The mean age was 53.57 years, median CT Fisher score was 2 (range 1–4), and median Hunt-Hess grade was 3 (range 1–4). Four patients were excluded by reason of decompressive craniectomy. CPPopt could not be calculated in 5 patients. Data from the 52 patients were used for further analysis finally (Table p = 0.002). The monitoring time in NICU was significantly longer in those that DCI . The mean PRx was suggestive for impaired pressure reactivity defined as PRx > 0.3 in 9 patients (17%), but there was no significant difference between DCI and control . Figure p = 0.006).The mean ICP was significantly higher in those that DCI  and ΔCPPopt < − 10 mmHg (p < 0.001) was significantly longer in the DCI group.We calculated separately percent of the time of hypoperfusion by dHP and ΔCPPopt < − 10 mmHg in each patient. Hypoperfusion events were found in every single patient. The mean % dHP in DCI was 29.23%, and 10.66% in control. The mean %ΔCPPopt < − 10 mmHg was 22.28% and 5.90% in control. The time of hypoperfusion defined as dHP (p = 0.004), mFisher Score (p = 0.006), Hunt-Hess Score (p = 0.020), %ΔCPPopt <− 10 mmHg (p < 0.001) and % dHP (p < 0.001) were significantly associated with DCI. In the covariate-adjusted logistic regression model, %ΔCPPopt <− 10 mmHg (p = 0.006) and % dHP (p = 0.047) were significantly associated with DCI. The odds ratio (OR) for dHp% was 1.055 (95% CI 1.001–1.112); the OR for ΔCPPopt% was 1.114 (95% CI 1.030–1.204). Furthermore, %ΔCPPopt <− 10 mmHg  was found to have the highest AUC over % dHP , indicating that it had better discriminative ability.In univariate logistic regression, ICP (p = 0.010) and % dHP (p = 0.026) were significantly associated with unfavorable outcomes (mRs 3–5). The OR for dHp% was 1.091 (95% CI 1.010–1.178); the OR for ΔCPPopt% was 1.133 (95% CI 1.034–1.242). Unfavorable outcomes at 3 months was predicted by %ΔCPPopt < − 10 mmHg  or % dHP . Age (years), Hunt-Hess Score, and mFisher Score were included as adjusted variables.In the covariate-adjusted logistic regression model, %ΔCPPopt <− 10 mmHg  are routinely used to improve the outcome in aSAH . CalciumFinally, our study with a small sample size; therefore, we have some caveats regarding significance testing. The results must be interpreted critically. For example, there is also an increased risk of significant findings being false positives, and we can decrease these risks by increasing the sample size. Practically, the present study is to be considered the generation of a hypothesis rather than hypothesis testing and needs more researches to test.Our study demonstrates that PRx can assess cerebrovascular reactivity and be used to calculate CPPopt in aSAH patients. The increase of duration of hypoperfusion events and duration of CPP below CPPopt over 10 mmHg, evaluated as time of lowered CPP, is highly indicative of DCI and unfavorable outcomes.


Long-term exposure to excessive aldosterone secretion from the adrenal gland may cause renal damage in patients with primary aldosteronism (PA). The aldosterone-to-renin ratio (ARR) may be significantly affected by renal function, especially in patients with renal damage related to long-term PA. The objective of this study was to investigate the association between the estimated glomerular filtration rate (eGFR) and ARR as well as its effect on screening for PA.  This study was performed in Zhongshan Hospital, Fudan University, China. 803 patients with hypertension were consecutively recruited from 2012 to 2015. All participants underwent routine biochemical measurements, including plasma renin activity (PRA) and plasma aldosterone concentration (PAC). In all patients with a PAC higher than 10 ng/dl, a saline perfusion test was conducted, and a CT scan or adrenal venous sampling was also performed if needed. Receiver operating characteristic (ROC) analysis was conducted in all eGFR < 90 and eGFR ≥ 90 groups separately to determine the optimal cut-off values of ARR. 2, and 18 ng/dl per ng/ml.h in subjects with an eGFR lower than 90 ml/min/1.73 m2. Patients with an eGFR higher than 90 ml/min/1.73 m2 had significantly lower PRA and higher ARR levels than patients with an eGFR lower than 90 ml/min/1.73 m2 (P < 0.05).  The optimal cut-off point for PA was an ARR of 40 ng/dl per ng/ml.h in the whole population, 52 ng/dl per ng/ml.h in subjects with an eGFR higher than 90 ml/min/1.73 m Unsuppressed renin and lower ARR levels were associated with decreased eGFR in patients with primary aldosteronism. Diagnostic criteria of ARR by stratified eGFR may be an optimal strategy for the screening of primary aldosteronism. Primary aldosteronism (PA) is one of the most common causes of secondary hypertension in adults, with prevalence ranging from 3.2 to 20% in different populations . The aldRenal function and glomerular filtration rate are closely associated with the regulatory role of renin synthesis and secretion  and the Considering the use of ARR in screening for PA, the effects of renal function on the PRA and ARR values need to be further clarified. In the present study, we will use estimated glomerular filtration rate (eGFR) as the major indicator of kidney function. The eGFR-associated change in ARR values may lead to an increased risk of a false diagnosis of PA in a hypertensive patient if the criteria are determined using patients with normal renal function. On the other hand, a lower threshold could result in too many false positives in the normal renal function group. An ideal optimized cut-off for initial outpatient screening for PA would have high sensitivity, be stable and simple to use, and be cost-effective.This study was aimed to investigate the association between eGFR and PRA and ARR values in PA patients and to determine the optimal eGFR-dependent screening thresholds.Patients with hypertension were consecutively enrolled from the Hypertension Clinic of Zhongshan Hospital, Fudan University, Shanghai, China, from 2012 to 2015. All of the hypertension patients met the 1999 WHO/ISH criteria . WrittenClinical data including age, gender, and duration of hypertension, the status of BP control, numbers, and dosage of all medications and history of other chronic diseases, including primary kidney disease, were obtained from the clinical documents of the Hypertension Clinic. According to the routine protocol, the results of a complete physical examination including height, weight, waist circumference, body mass index (BMI), and BP were recorded. After 5 min of rest in a sitting position, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured in participants by a nurse using a mercury sphygmomanometer adapted for arm size.BP was measured twice with a 5 min interval, and the mean was used for the analysis. Resistant hypertension was defined in our study as the following criteria: on each of three measurements obtained on different days, with hypertension (BP > 140/90) resistant to three conventional antihypertensive drugs (including a diuretic), or controlled BP (>140/90) on four or more antihypertensive drugs. The general laboratory tests included measurements of serum sodium, potassium, blood urea nitrogen (BUN), and serum creatinine (Scr) levels. eGFR was calculated using the abbreviated Modification of Diet in Renal Disease Study Group (MDRD) equation. Patients were divided into two groups according to the median value of eGFR.Venous blood was sampled in the morning two hours after waking, after 5–10-minute rest in a sitting position. Plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were measured by radioimmunoassay. PRA was measured by indirect assay involving the generation of angiotensin I . The lower limit of detection for PRA in EH and PA subgroup is 0.02 ng/ml/h. Saline perfusion test (SPT) was conducted in all patients with a PAC higher than 10 ng/dl shown in  17]. A . A 17]. Among patients with positive saline perfusion tests, a diagnosis of PA was further considered. For subtyping, the diagnosis of aldosterone-producing adenoma required fulfillment of all of the following criteria: unilateral excessive aldosterone secretion confirmed by AVS and evidence of a unilateral adrenocortical nodule on CT scan, pathologically confirmed adenoma after surgery, and complete biochemical success during the postadrenalectomy follow-up. Patients for whom surgery was not indicated received spironolactone treatment. Idiopathic hyperaldosteronism (IHA) was diagnosed in patients with bilateral hyperplasia of the adrenal gland by CT scan, normokalemia and the normalization of BP (140/90 mmHg without the aid of antihypertensive agents) after spirolactone treatment, or significant improvement of hypertension (decrease in mean BP by 20% and fewer antihypertensive agents taken to control BP after spirolactone treatment at follow-up).t-test, one-way ANOVA, or χ2 test for continuous or categorical variables. Spearmen correlations were performed to investigate the possible correlation between ARR and eGFR in PA patients. Sensitivity and 1 − specificity for different cut-offs of the ARR were plotted in receiver operating characteristic (ROC) curves. The optimal cut-off point was assessed using Youden's J statistic. The analyses were performed using SPSS software for Windows, version 13.0 . P value <0.05 was considered to be statistically significant.Normally continuous variables were expressed as the mean ± standard deviation (SD); the non-normally-distributed variables were expressed as the median and interquartile range. Non-normally-distributed values were log-transformed before analysis. Comparisons between the groups were performed with Student's As shown in P < 0.05). In each group, all subjects were divided into two subgroups according to the median eGFR  and higher borderline ARR levels (P=0.06) than patients with lower eGFR. In the PA group, patients with higher GFR were younger, were younger at onset of hypertension, had lower SBP, DBP, and PRA levels, and had significantly higher ARR levels than patients with lower eGFR (P < 0.05). The differences in ARR levels remained significant after adjustment for age, gender, and hypertension duration (P < 0.05). In this study, correlations were performed and our results indicated that eGFR significantly correlated with ARR levels in PA cases .The differences in ARR levels remained significant after adjustment for age, gender, and hypertension duration (P < 0.001) in all (P < 0.001) in eGFR < 90 (P < 0.001) in eGFR ≥ 90 patients  in all , 0.996  in PA cases. The variation of ARR may be significantly affected by renin levels among these patients. Renin is synthesized by juxtaglomerular epithelioid cells in the medial layer of renal afferent arterioles. Renal function and glomerular filtration rate are the major factors influencing renin synthesis and secretion in normal and pathophysiological situations. Under prolonged hypertension and high aldosterone levels, decreased eGFR may also stimulate the synthesis and secretion of renin in PA patients. Accordingly, unsuppressed PRA may contribute to lower ARR values in PA cases with renal damage. Our results showed that decreased eGFR was strongly associated with substantially increased PRA and earlier onset of hypertension in PA cases, which might reflect the natural history in patients with long-term PA.2 (18 ng/dl per ng/dl/h) and patients with an eGFR above 90 ml/min/1.73 m2 (52 ng/dl per ng/dl/h) will improve the accuracy of using ARR. It is strongly recommended to use a decreased cut-off point (18 ng/dl per ng/dl/h) instead of using the single cut-off point (40 ng/dl per ng/dl/h) in patients with eGFR below 90 ml/min/1.73 m2; otherwise, the sensitivity would dramatically decrease to 85.2%, which would lead to the misdiagnosis of 8  PA patients whose eGFR was below 90 ml/min/1.73 m2.Considering the significant key findings on the correlation between ARR and eGFR, it is evident that eGFR-specific diagnostic criteria can be used to optimize the sensitivity and specificity of screening for PA. The proposed decision limits of patients with an eGFR below 90 ml/min/1.73 mThe protocol used in our study tried to ensure an accurate diagnosis of PA. Confirmation tests were conducted in every hypertension case with PAC higher than 10 ng/dl to fully ensure no PA cases were missed, regardless of the ARR value. PA was carefully diagnosed in cases with positive confirmation test results and clinical outcomes. The strict diagnosis criteria used here strongly support the diagnosis among PA patients.There were still several limitations in our study: (1) confirmation tests for PA were not conducted in all cases; (2) we only used eGFR to evaluate renal function; it would be more accurate enough if we included more parameters; (3) this study was a monocentric study and we only enrolled patients from one medical institution. At present, we are not yet able to perform any external validity due to lack of participants elsewhere. We would explore the internal validity and external validity in the future to make the results of our study be more broadly applicable; (4) our study was retrospective; therefore, we could not identify cause-and-effect relationship of PA and renal damage. Follow-up data remained to be included to further investigate the relationships of plasma renin and aldosterone levels with pre- and posttreatment renal function; (5) the current literature does not identify a gold-standard confirmatory test for PA, so we have also taken the operative diagnosis, effective surgery, and medication together into account to obtain a final diagnosis of PA.2) and 52 ng/dl per ng/dl/h (eGFR ≥ 90 ml/min/1.73 m2) can be recommended as optimized cut-off points.ARR must now be regarded as an initial test, with further diagnostic confirmation tests for PA in patients with hypertension. Using eGFR-dependent decision limits will optimize the diagnostic accuracy of using ARR; decision values of 18 ng/dl per ng/dl/h (eGFR < 90 ml/min/1.73 m


According to the new hypertension treatment guidelines blood pressure (BP) readings need to be kept below or equal to 130/80 mmHg in patients aged less than 65 years old. This study shows the change in proportion of identified cases of uncontrolled blood pressure in light of these changes.The data was collected from 248 hypertensive patients who had visited an outpatient clinic at the Department of Family Medicine, Faculty of Medicine, Chiang Mai University, Thailand. Patients were classified into three groups: The 3 groups were: 1) controlled BP group (BP is 130/80 mmHg or lower); 2) newly identified uncontrolled group (BP between 130/80 mmHg and 140/90 mmHg) and 3) existing uncontrolled group (BP higher than 140/90 mmHg). Health behaviors, past history related to hypertensive disease and current pharmacological treatments were compared.p = 0.043). While the average number of medication taken was similar across the three groups, it was poor medication adherence (p < 0.013) which was associated with the uncontrolled disease.Of the total 248 patients, 56% were female and the mean age was 58.8 (sd 5.99) years old. Following application of the new guidelines, the group designated as uncontrolled increased from 21.7 to 74.2%, an additional 52.4% due to new BP targets. Higher BMI was associated with uncontrolled HT (Lower BP targets will increase the number of identified hypertensive patients. While intensifying pharmacological treatment may be considered, our study suggests that two behavioral factors should not be overlooked. Weight reduction and enhancement of medication adherence remains an important mainstream treatment strategy. Hypertension (HT) is a chronic disease which is of a great concern as it is one of the cardiovascular risk factors and leads to the disease burden on cardiovascular diseases (CVD) morbidity and mortality . The WorGuidelines from the 2018 American College of Cardiology (ACC) and the American Heart Association (AHA) recommends a lower blood pressure goal for treatment strategies in hypertension, the blood pressure goal is decreased from 140/90 mmHg to 130/80 mmHg in every patient aged less than 65 years old. Following the Systolic Blood Pressure Intervention Trial (SPRINT) , it was The Thai Guidelines on The Treatment of Hypertension 2019  was launThis study aims to determine the prevalence of newly identified uncontrolled patients in accordance with the new BP goals. The patient characteristics, background health behaviors and pharmacologic treatment were investigated resulting in comparisons between three groups consisting of 1) BP controlled group, 2) a group in which the BP had already been acknowledged as not controlled and 3) a new group in which the BP was identified as uncontrolled using the new stricter guidelines. Understanding the patient characteristics and potential differences between the three groups will be beneficial for further interventions and health care service planning such as reducing modifiable risk factors and guide clinical practices in countries such as Thailand where new BP targets are being adopted.We conducted a cross-sectional study of patients with hypertension who had visited the out-patient clinic of the Department of Family Medicine, Faculty of Medicine, Chiang Mai University. Sample size calculation was based on a prior population based study from Thailand that the prevalence of controlled hypertension was estimated at approximately 20% . AllowinThe interviews consisted of assessment of current health behaviors, past history related to hypertensive disease and current pharmacological treatments. Health behaviors assessed included taking alcohol consumption, and smoking in past 3 months, a history of adequate exercise (moderate intensity aerobic exercise more than 150 min per week in the past 3 months), sodium consumption . These were assessed by yes or no answers. A history of illness related to hypertensive disease include family history of HT, family history of CVD or IHD, co-morbidities such as diabetes and dyslipidemia. For pharmacological therapy related to HT treatment, information was collected on the number of years diagnosed with HT, duration (years) for taking anti-hypertensive drugs, the class of drugs currently taken, the types of anti-hypertensive drugs currently taken per day, the number of times taking anti-hypertensive drugs, combined drugs currently used, experience of side effects from anti-hypertensive drug. Research assistants directly measured height and weight by using the same stadiometer and electronic scale throughout the study. Self-reported medication adherence using the Thai version of the four-item Morisky Green Levine (MGL) Medication Adherence Scale  were alsAfter the patient has rested for at least 30 min, we measured each person’s blood pressure twice, 15-min apart, using an automatic sphygmomanometer. The average value of the two readings was used for analysis. Based on the BP readings, patients were categorized into three groups using the new goals for BP control described in the Thai Hypertensive Guidelines 2019 . The ThaThe data was analyzed using STATA 15.1. Descriptive statistics were used to summarized patient characteristics, past medical history, current behavior and treatment. Chi – square or Fischer’s exact test and analysis of variance (ANOVA) were used to compare qualitative and quantitative variables respectively in order examine potential differences between the three groups of patients.Out of the 248 hypertensive patients, 141 were female (56%) and the mean age was 58.8 (sd 5.99) years old. The patients had been diagnosed with hypertension for 8.1 (sd 4.69) years. According to the new Thai Hypertensive Guidelines 2019, the controlled group was 25.8% of the sample, the new uncontrolled group was 52.4% and the pre-guidelines uncontrolled group was 21.7%.2, 27.8 ± 4.52 kg/mg2, and 27.4 ± 4.75 kg/mg2, respectively (p = 0.043). While all BMI of all these groups was considered high, the BMI in the controlled BP group was the lowest. In all three groups, there was no evidence for any differences in co-morbidities and family history of cardiovascular diseases (Table 2).As shown in Table ). However, high medication adherence was statistically significantly different and was highest in the BP control (p = 0.013).In regard to behavioral aspects, Table 4This study showed tremendous increase in the identified prevalence of uncontrolled BP patients from 21.7 to 74.2% based on the new BP criteria. In the newly identified uncontrolled BP group, there are significant differences in modifiable risk factors compared to the controlled BP group, specifically BMI and medication adherence.The prevalence of overall uncontrolled patients was increased by 52.4% (the post-guidelines uncontrolled group). A prior study conducted in the two countries, United States and China, give similar results to our study –14. ThesHigher BMI is associated with hypertension , 16. As In regard to pharmacological factors, interestingly, the average number of the anti-hypertensive medication taken was similar in all groups, but it was medical adherence that was significantly higher among the controlled group. It is a potential cause for concern. Our data suggest that even if pharmacological treatment were to be intensify, there might not be a direct benefit due to poor adherence. A systematic review shows that adherence to prescribed medication leads to significantly lower blood pressure and lower mortality compared with suboptimal adherence . Non-adhIn low adherence patients, there are many ways to improve medication adherence such as exploring and addressing the barriers to medication adherence for the patient, finding common ground and improving the patient’s health literacy. In addition self-monitoring of blood pressure will help improve the awareness of patient and encourage good self-care . CognitiBase on the results, we can expect an increase workload and burden of uncontrol hypertension due to new treatment targets. It has been estimated that less than 1% of cases with hypertension in Thailand are on lifestyle management alone  as accesThere were some limitations of this study. Firstly, using a single site may limit the generalizability of results of other settings. Our study is limited to patients who are less than 65 years of age. The systolic BP should be targeted at between 130 and 140 mmHg, and diastolic BP to less than 80 mmHg for patients ages 65 and older . HoweverDespite its limitation, the study gave some insights which has clinical implications. Adopting guidelines with lower BP targets such as the new Thai Hypertensive Guidelines 2019 will increase the number of identified hypertensive patients which will increase the work and resource load on hospitals and staff. While intensifying pharmacological treatment may be considered, our study suggests that two behavioral factors should not be overlooked. Weight reduction and enhancement of medication adherence remains an important mainstream treatment strategy which will help conserve resources in the long term.Additional file 1.


Cardiac biomarkers Troponin T (TnT) and N-terminal pro-B-type natriuretic peptide (proBNP) and abdominal aortic calcification score (AAC) are associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). The effects of cardiac biomarkers and AAC on maximal exercise capacity in CKD are unknown and were studied.One hundred seventy-four CKD 4–5 patients not on maintenance dialysis underwent maximal bicycle ergometry stress testing, lateral lumbar radiograph to study AAC, echocardiography and biochemical assessments.p = 0.02), AAC  and diabetes  remained significantly associated with WMAX% in the multivariable model. Maximal ergometry workload (in Watts) was similarly associated with TnT and AAC in addition to age, male gender, hemoglobin and diastolic blood pressure in a respective multivariate model.The subjects with proportional maximal ergometry workload (WMAX%) less than 50% of the expected values had higher TnT, proBNP, AAC, left ventricular end-diastolic diameter, left ventricular mass index, E/e’ and pulse pressure, and lower global longitudinal strain compared to the better performing patients. TnT (β = − 0.09, AAC and TnT showed fair predictive power for WMAX% less than 50% of the expected value with AUCs of 0.70 and 0.75, respectively.TnT and AAC are independently associated with maximal ergometry stress test workload in patients with advanced CKD.http://www.ClinicalTrials.gov NCT04223726.The online version contains supplementary material available at 10.1186/s12882-021-02251-y. Cardiovascular disease is the prevailing cause of morbidity and mortality in patients with chronic kidney disease (CKD). Alterations in cardiac and vascular structure and function may lead to exercise intolerance. Impairment of maximal exercise performance is well-established in CKD –3, but lElevated troponin T has been shown to be associated with increased cardiovascular mortality in end stage kidney disease (ESKD) –6. The FCurrent guidelines recommend the evaluation of abdominal aortic calcification (AAC) score in CKD . AAC is Deteriorating exercise capacity has great importance on the quality of life, morbidity and mortality. Evaluating physical performance in CKD patients not yet on dialysis might provide valuable data on health-related risks, and result in improved care, if the causes of declined exercise capacity are better comprehended.We aimed to study maximal physical performance and its determinants including cardiac biomarkers, AAC and echocardiography in patients with stage 4–5 CKD not on maintenance dialysis.http://www.ClinicalTrials.gov NCT04223726) is an ongoing prospective follow-up study protocol assessing arterial disease, quality of life and mortality in patients with CKD stage 4–5. Two hundred ten consecutive patients referred to the predialysis outpatient clinic of Kidney Center, Turku University Hospital between 2013 and 2017 were recruited to the study. Inclusion criteria for the study participants were ≥ 18 years of age and CKD stage 4–5 with an estimated glomerular filtration rate (eGFR) < 30 ml/min per 1.73 m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation  for skewed variables. Skewed variables were logUnivariable associations between the study variables were analyzed by calculating Spearman’s correlation coefficients. Multivariable analysis was done using linear regression technique. Potential existence of multicollinearity was assessed by examining variance inflation factors. Variables with significant univariable correlations with WMAX% , as well as diabetes and previous coronary artery disease were included as covariates in stepwise multivariable linear regression models. The multivariable associations between exposure variables and WMAX were also studied using the similar analyses. However, for WMAX (expressed in Watts), age, height and gender were also included as covariates in the initial stepwise multivariable model. To make the multivariable results easily comparable, variables were included in the final models without transformation.Receiver operating characteristics (ROC) curve analyses were conducted to estimate the area under the curve (AUC) as a measure of discriminative capacity of TnT and AAC for WMAX% < 50%. Generally, we consider an AUC > 0.90 outstanding, an AUC 0.80–0.90 excellent, an AUC 0.70–0.80 acceptable and an AUC < 0.70 poor discrimination .P < 0.05 was considered statistically significant.All statistical analyses were performed using statistical analysis system, SAS version 9.3 . 2 underwent a maximal bicycle stress test, echocardiography and lateral lumbar radiography for AAC assessment. Nearly half (43) had diabetes and 21 (12) had coronary artery disease. All, but one were on antihypertensive medication. The mean workload of the last 4 minutes of maximal stress (WMAX) was 83.7 ± 36.5 W and the proportional maximal workload (WMAX%) 55.7 ± 21.5% of the age predicted normal value. The baseline clinical and laboratory characteristics of the study groups (WMAX% < 50 vs. ≥50%) are shown in Table A total of 174 patients with a mean age of 60.9±13.7 years and median eGFR 12.9 ± 3.4 ml/min/1.73 mn = 36) to those who did (n = 174). Those not attending were more often women, had a higher proportion of coronary artery disease (CAD), were older and had higher TnT but no differences were observed in AAC or proportion of diabetics  LVEF.p < 0.0001 for both comparisons).Univariable correlates of relative exercise performance are shown in Table p = 0.02), AAC  and diabetes  remained as significant predictors for WMAX% in the stepwise multivariable linear regression model. When WMAX (in Watts) was included as the dependent variable in the multivariable model (instead of WMAX%) the significant explanatory variables were TnT , AAC , age , male gender , hemoglobin , leukocytes  and diastolic blood pressure  and diabetes  , E/e’ , GLS  and creatinine  but not with LVEF or eGFR. AAC was significantly associated with E/e’ . TnT and AAC showed fair predictive power for WMAX% less than 50% in ROC curve analyses. TnT exhibited an AUC of 0.75 (95%CI 0.68–0.83) and AAC an AUC of 0.70 (95%CI 0.62–0.79)  and diastolic dysfunction in CKD but not with systolic dysfunction . In lineAAC is independently associated with cardiovascular events in the general population and in dialysis patients and the KDOQI Work Group recommends the assessment of AAC for risk stratification in CKD –12. TherThe present study has limitations. The data included in this current report are cross-sectional and from a single center which may increase the possibility of residual confounders and limit the generalizability of the findings. The study sample was somewhat limited. There was a degree of expected selection bias in attending stress ergometry as the patients not attending were more often women and had CAD, were older and had higher TnT but no differences were observed in AAC or proportion of diabetics  score assessment in plain lateral lumbar radiograph. AAC score is the sum of scores of anterior and posterior wall calcific deposits of L1 through L4 shown in the figure. Severe AAC (AAC score 20/24) in a > 60-year-old male with CKD stage 5 (Panel A) and no aortic calcific deposits (AAC score 0/24) in a < 40-year-old female with CKD stage 5 (Panel B). L = lumbar vertebra.Additional file 3: Supplemental Table 1. Comparison between patients included in the study and patients excluded due to missing stress ergometry data.


This study investigated neutrophil activation and neutrophil-derived extracellular traps formation in coronary artery ectasia.We enrolled 90 patients who underwent coronary angiography, and included 30 patients with coronary artery ectasia (CAE), 30 patients with obstructive coronary artery disease (CAD) and 30 patients with normal coronary arteries (CON). Intra-neutrophil mean myeloperoxidase index (MPXI) was determined using an automated blood cell counter (ADVIA2120 Hematology System). Serum concentrations of plasma adhesion molecules, cytokines, and neutrophil-derived extracellular traps were quantified.p = 0.016 and CAE vs CON, p = 0.007). Multiple logistic regression analysis showed that MPXI and dsDNA were independent factors that predicted the presence of CAE. CAE patients had higher levels of plasma adhesion molecules  and interleukin 1 beta levels. Neutrophil extracellular trap concentrations were significantly higher in the CAE group compared to CAD and CON patients (284.31(258.33–449.91) ng/mL, 225.12(203.34–257.13) ng/mL, and 247.37(231.04–273.01) ng/mL, respectively; CAE vs CAD, p = 0.000 and CAE vs CON, p = 0.001).The intra-neutrophil mean myeloperoxidase index was reduced in CAE patients compared to CAD and CON patients (1.02 ± 3.01, 3.22 ± 3.03, 3.52 ± 4.25, respectively; CAE vs CAD, Peripheral neutrophils from CAE patients were activated and neutrophil extracellular traps were elevated in the plasma. IL-1β and soluble adhesion molecules may be the causal factors for neutrophil activation. Coronary artery ectasia (CAE) is a rare condition that forms a bulge in the coronary arteries that exceeds 1.5 times or more of the normal artery diameter. The underlying pathophysiology remains to be deciphered , 3. TherWe prospectively performed a case-control study that included 90 patients without any of the conditions listed in the exclusion criteria between 2015 and 2017 in the catheter room in the Peking Union Medical College Hospital. Blood samples were collected after written informed consent was obtained. Of these patients, 30 patients had coronary artery ectasia and constituted the CAE group. During the study period, 30 patients with obstructive coronary artery and 30 patients with normal coronary angiograms were randomly selected to comprise the CAD and CON group respectively  . The incPatients were excluded from the study if they had acute coronary syndromes, acute decompensated heart failure, cardiomyopathy, severe valvular heart disease or pulmonary arterial hypertension. Patients with acute infectious diseases, autoimmune diseases , renal failure or cancer were also excluded from this study.Blood samples were obtained through the peripheral vein using a K2EDTA tube. Blood serum samples were immediately separated by centrifugation and stored at − 80 °C for future experiments. Demographic data and laboratory results were collected from the electronic medical record system. Intra-neutrophil mean myeloperoxidase index (MPXI), which represents the myeloperoxidase content of neutrophils, was determined using an automated blood cell counter  .We quantitatively determined the serum concentration of E-selectin , P-selectin glycoprotein ligand-1 (PSGL-1) (eBioscience), L-selectin (eBioscience), interleukin 1 beta (IL-1β) , interleukin 8 (IL-8) (BOSTER), interleukin 17 (IL-17) (BOSTER), and tumor necrosis factor alpha (TNFα) (BOSTER) in 90 patients using commercial ELISA kits. With regards to NET concentrations, PicoGreen  was used to measure cell-free DNA, which was mainly derived from NETs based on previous publications , 16. Sinp-value < 0.10 were included for multivariate logistic regression analysis. A final model using multivariate logistic regression was constructed to examine the influence of the following variables on CAE: Diastolic blood pressure, BMI (Body mass index), MPXI and dsDNA. p < 0.05 was considered statistically significant.Statistical analyses were performed using IBM SPSS statistics 22.0 . Numerical variables with normal distribution were presented as mean ± standard deviation. Non-normal data were presented as median with interquartile range (25th–75th percentile). Categorical data were presented as frequencies and percentages (%). We analyzed the normal distribution of numerical variables using the Kolmogorov-Smirnov test (sample number ≥ 50) or Shapiro-Wilk (sample number < 50) test together with a Q-Q map. We compared continuous variables using t-test and one-way analysis of variance (ANOVA). We compared different variances based on their heterogeneity using the least significant difference (LSD) test or Dunnett T3 test. In addition, we used the Mann-Whitney U test or Kruskal-Wallis H test to determine non-normal distribution variables, and ANOVA with LSD or Dunnett T3 were used in multiple comparison of the rank of non-normal distribution variables. Pearson’s chi-squared test was used to compare frequencies between categories. Univariate logistic regression analysis was used to identify risk markers for CAE. Variables with p = 0.559). Patients with CAE had a lower MPXI value (1.02 ± 3.01) compared to patients in the CAD or CON groups  (Table p = 0.999). The area under the curve (AUC) of MPXI in receiver operating characteristic (ROC) analysis was 0.716   showed that the ANOVA test of MPXI achieved a power of 0.88. Second, we did not perform follow-up on our study cohort. Additional studies are required to determine the prognostic value of neutrophil activation markers and neutrophil extracellular traps for CAE patients. Third, we only used peripheral blood rather than coronary blood samples. Neutrophil activation is theoretically more predominant in samples obtained around the ectasia area. However, direct sampling from coronary arteries is an invasive procedure and may cause complications. Fourth, this study lacked preclinical data to support the selectins-IL-1β-neutrophil activation-NETs axis. Finally, there may be more accurate markers for neutrophil activation and NET formation, i.e., neutrophil CD11b and CD66b are direct markers for neutrophil activation, however, measurement of these markers requires rapid isolation of neutrophils .In conclusion, our study demonstrated activation of peripheral neutrophils and NETs formation in CAE patients. The underlying causative factors for neutrophil activation may include IL-1β and soluble adhesion molecules.


The close relationship between kidney and heart is well known. Cardiovascular impairment contributes to the worsening of renal function and kidney failure worsens cardiovascular health. Atrial fibrillation (AF) is a frequent issue in patients with Chronic Kidney Disease (CKD) and several studies have demonstrated that AF impacts negatively on their quality of life and outcomes. Understanding the mechanisms leading to the progression of CKD, new-onset AF and acute myocardial infarction (AMI) is a key issue. The evaluation of Glomerular Filtration Rate (GFR) could make the difference in this equilibrium and suggests specific strategies in the treatment of the population at major risk of cardiovascular events. This intriguing connection paves the way for necessary further investigations. The close relationship between kidney and heart is well known. Cardiovascular impairment contributes to worsening of renal function and kidney failure worsens cardiovascular health. Atrial fibrillation (AF) is a frequent issue in Chronic Kidney Disease (CKD) patients, and several studies have demonstrated that this condition impacts negatively on their quality of life. AF, in turn, is associated with an increased risk of Acute Myocardial Infarction (AMI), having similar long-term prognosis despite these two conditions having a quite different pathogenesis ,2.The reason can be explained by mechanisms leading to CKD and AF and their pathophysiology. One of the altered pathways, common in both diseases, involves the renin–angiotensin–aldosterone system (RAAS). RAAS dysregulation is widely associated with hypertension and CKD progression and also to AF . While aMoreover, a genetic link has been demonstrated between angiotensin-converting enzyme (ACE) polymorphisms and AF: ACE polymorphisms are associated with an increased risk of AF, together with vasoconstriction, an increased secretion of aldosterone and antidiuretic hormone, fibrosis and the structural remodeling of the atrial myocardium. These mechanisms facilitate the induction and maintenance of AF . AF operates on heart pro-fibrotic effects and on the decline of left ventricular systolic and diastolic function ,8, and tIncident AF in patients with CKD is also independently associated with an increased risk of developing End-Stage Renal Disease (ESRD) . MoreoveThe reason could be partially found in the systemic inflammation and increased oxidative stress caused by AF that contributes to the development and progression of CKD ,13. CKD,AMI directly affects the glomerular filtration rate (GFR), with a marked and rapid decrease after the cardiac event . Other aEven for AMI, the RAAS pathway is a crucial mechanism, establishing a link between heart and kidney. As mentioned for AF and CKD, ACE inhibitors (ACE-I) play more important roles beyond being a fundamental first-line antihypertensive drug. ACE-I could also represent a protective factor against AKI after AMI. A clinical study of >6000 patients showed that RAAS inhibition, in patients with CKD and ACS, could improve 90-day mortality rates . This isIn line with these results, Cosentino and colleagues  performeThese evidences are supported by a recent systematic review and meta-analysis that demonstrated AF to be associated with an increased risk of death and cardiovascular and renal morbidity: AF patients had a 64% higher risk of CKD and a 96% higher risk of a major cardiovascular event .Understanding the mechanisms leading to CKD progression, AF, and AMI is a key issue. Cardiovascular diseases are the main cause of death in CKD patients and the combination of AMI and AF may become a life threatening condition. The study by Cosentino and colleagues  provides


The observed decrease in the cerebral oxygenated hemoglobin level was larger in children with orthostatic headaches (Left: 6.3 (3.2–9.4) vs. 4.1 (0.8–6.1); p < 0.01, Right: 5.3 (3.1–8.6) vs. 4.0 (0.8–5.9); p < 0.01). Conclusion: Fluctuations in cerebral blood flow were associated with orthostatic headaches in children, suggesting that the headaches are due to impaired intracranial homeostasis. As orthostatic headache can have multiple causes, the term “head and/or neck pain attributed to orthostatic  hypotension” should be replaced with a more inclusive term.Background and aim: Although head and/or neck pain attributed to orthostatic hypotension is included in international guidelines, its mechanisms and relevance remain unknown. This study examined the term’s relevance and aimed to elucidate the associated clinical features. Methods: An active stand test was performed to evaluate fluctuations in systemic and cerebral circulation in children and adolescents reporting complaints in the absence of a confirmed organic disorder. The subjects were categorized based on orthostatic headache presence/absence, and their characteristics and test results were compared. Results: Postural tachycardia syndrome was observed in 50.0% of children with, and 55.1% without, orthostatic headache. For orthostatic hypotension, the respective values were 31.3% and 30.6%. A history of migraine was more prevalent in children with orthostatic headaches (64.1% vs. 28.6%;  Headaches are common in childhood and adolescence, with approximately 20% of children reporting having a headache at least once a year . In chilChronic headaches may greatly interfere with daily life. Children with orthostatic headaches experience difficulties in daily life. However, their condition is difficult to treat because, being induced by postural changes such as standing, it does not meet the diagnostic criteria for either primary or secondary headaches. When moving from the supine to a standing position, the volume of blood that returns to the heart decreases by approximately 30%, lowering cardiac output and systemic blood pressure and triggering the baroreceptor reflex. Although this reflex maintains adequate, blood pressure in healthy people, those with an abnormal baroreceptor reflex or decreased plasma volume experience a severe drop in blood pressure upon standing. In adults, orthostatic hypotension (OH) is diagnosed when a decrease in systolic blood pressure ≥ 20 mmHg or diastolic blood pressure ≥ 10 mmHg occurs within 3 min of changing from the supine or sitting to the standing position. Low et al. published a study of postural tachycardia syndrome (POTS) in 1995 . POTS coA disorder termed “head and/or neck pain attributed to orthostatic  hypotension” was included in the third edition of the International Classification of Headache Disorders (ICHD3). This concept, which has yet to become established, is defined as “pain, mostly in the back of the neck but sometimes spreading upwards to the occipital region (“coat hanger” distribution), attributed to postural hypotension presenting only in upright posture”  . ImpaireThe present study examined the relevance of the term, “head and/or neck pain attributed to orthostatic  hypertension,” as included in the ICHD3 by investigating the mechanisms of orthostatic headaches in children based on clinical features and cerebral blood flow fluctuations.Pediatric patients who visited our hospital between January 2017 and March 2019 due to three or more concurrent complaints disrupting daily life and school attendance and lasting more than two months, such as headache, malaise, palpitations, morning fatigue, daily nausea, face pallor, umbilical colic, and orthostatic dizziness, were identified. Patients with an obvious, posttraumatic headache were excluded at the initial visit. The eligible patients underwent an examination which included detailed history taking, neurophysical tests, thoracoabdominal radiography, head magnetic resonance imaging (MRI), echocardiography, 12-lead electrocardiography, and blood analysis, including thyroid hormone measurement. If no clearly organic disorder was found, the subjects and their parents were asked to submit their verbal and written informed consent to participate. All participating subjects underwent the active stand test (described below), and their cerebral blood flow was simultaneously assessed. None of the subjects received any drug affecting their blood pressure or modifying their NE level, such as selective serotonin reuptake inhibitor (SSRI) or atomoxetine, before the test. The participants were divided into those who either did or did not experience a headache induced by the active stand test (the orthostatic headache vs. non-orthostatic headache groups). The groups were compared in terms of their characteristics, background factors, and systemic and cerebral circulatory responses. In addition, the association between the presence/absence of pulsatility in induced headaches and headache sites and other factors were examined.The patient characteristics of age, sex, height, weight, body mass index (BMI), and cardiothoracic ratio (CTR) were examined. The background factors assessed included the presence/absence of migraine and morning fatigue. Migraine was diagnosed based on the ICHD3 criteria.The subjects were admitted on the day before the active stand test. They underwent the test before breakfast on the following day between 8:00 and 9:30 a.m. in a quiet room with an ambient temperature between 23–24 degrees Celsius and no external light. After resting in the supine position for 10 min, they were asked to stand up in 3 s and remain standing for 10 min. Subsequently, they were asked to return to the supine position and rest for 5 min. Readings were taken continuously throughout this procedure. Blood pressure, pulse, and blood pressure recovery time were measured using a continuous noninvasive pressure system  with a small to medium-sized probe placed on the left middle finger . To determine the timing of subjective symptom onset, the subjects were asked by the examiner whether they had a headache before standing and at every minute until the conclusion of the test. None of the subjects had a headache while in the supine position. Their responses were recorded. After the conclusion of the test, the subjects were asked about the site and features of their headache, if any, and the presence or absence of pulsatility. If the subject felt severe orthostatic intolerance or presyncope symptoms, the test was terminated, and the point was recorded, but there were only few such instances. In addition, to measure the blood norepinephrine (NE) level, an indwelling needle was inserted and fixed to the left cubital vein at least 30 min before the start of the active stand test. Flashback blood samples were collected before, and 10 min after, standing. POTS was diagnosed if a sustained heart rate increase of 40 bpm within 10 min of standing was recorded in the absence of OH.The probes of an infrared oximeter  were attached to the left and right sides of the frontal region, and a hairband was used to fix the probes and prevent light leakage. Highly permeable light at 700 to 900 nm was used, and the light scattered in the body was automatically measured with a detector. The oxygenated hemoglobin (OxyHb) concentrations in the bilateral frontal cerebral cortices were measured using the Modified Beer–Lambert method ), followed by the temporal region (16 [25%]) and the frontal or occipital region (11 [17.2%]). In 18 of the 64 (28%) children with orthostatic headaches, the headaches induced by the active stand test were pulsatile. No statistical difference was observed in the site of headaches between subjects with and without pulsatile orthostatic headaches (= 0.214) A. Neitheheadache B. All suOrthostatic headaches have traditionally been associated with intracranial hypotension. In 2003, Mokri et al. reported that many patients with orthostatic headaches did not, in fact, exhibit features of cerebrospinal fluid leak; moreover, many of them received the diagnosis of POTS following an evaluation of their autonomic nervous system . As a reIn the present study, 64 of the 113 subjects experienced an orthostatic headache. However, the proportion of normal subjects and those with POTS or OH did not differ significantly between the groups with and without orthostatic headaches. Previously, Deb et al. reported that 87% of patients with POTS experienced headaches in daily life . In the Thieben et al. reported no association between excretion of urinary sodium (Na), which reflects the circulating blood volume, and increase in noradrenaline level, which reflects sympathetic nervous activity after standing . The autMeanwhile, the renin-angiotensin-aldosterone system is an important system for maintaining the circulating blood volume. A previous study reported low renin levels in patients with POTS despite hypovolemia , drawingOjha et al. reported that the incidence of concomitant migraine in patients with POTS was 41% in adolescents and 61% in adult patients . LikewisThe limitation of this study is that the symptoms, aura, nausea, and photosensitivity associated with orthostatic headache were not assessed, and the association with migraine was not fully investigated. More research is needed on these points in the future.Our study found that orthostatic headaches in children were associated with fluctuations in cerebral blood flow and were induced by impaired intracranial homeostasis. In some children, the features of orthostatic headaches were found to be similar to those of migraine. However, in almost all the cases, the headache improved upon assuming the supine position sooner than described in the criteria for migraine diagnosis. Special attention should be paid in clinical practice to this similarity, as the treatment can differ. As orthostatic headaches occur in patients with OH and POTS, the description, “head and/or neck pain attributed to orthostatic  hypotension” in the ICHD3 should be replaced with a more inclusive, diagnostic term that better defines the condition or differentiates between disparate entities on the basis of head/neck pain attributed to orthostatic hypotension and orthostatic headache associated with impaired intracranial vascular homeostasis. Reconceptualizing orthostatic headaches may help clinicians find more effective treatments and contribute to progress in the research on the disease.


Lipid metabolism factors may play an important role in the progression of nonalcoholic fatty liver disease (NAFLD) and its related cardiovascular dysfunctions. The study aims to assess whether Apolipoprotein A-1 (ApoA1) was associated with vascular stiffness in NAFLD patients.From 2012 to 2013, we included 2,295 non-alcohol users with fatty liver disease  and completely excluded subjects who drank any alcohol ever to eliminate the effect of alcohol intake. The serum ApoA1 levels and the brachial-ankle pulse wave velocity (baPWV) were measured.P < 0.001). ApoA1 level was positively associated with baPWV odd ratio (OR), 4.18; 95% confidence interval (CI) [1.16–15.1], P < 0.05) in patients with AST/ALT < 1 and  in patients with AST/ALT ≥ 1 respectively. Only arterial stiffness in men was associated with ApoA1  in logistics regression models adjusted for age, gender, body mass index, education attainment, physical activity, smoking, history of hypertension and high-density lipoprotein. The relationship between ApoA1 and baPWV in male NAFLD patients remained significant  in the fully adjusted linear regression model.The baPWV in men was much higher than in female patients (1,412.79 cm/s vs. 1,358.69 cm/s, The serum ApoA1 was associated with arterial stiffness in male NAFLD patients. Increased ApoA1 level should be considered as an independent risk factor for arterial stiffness in male NAFLD patients, suggesting that NAFLD may alter arterial stiffness by “ApoA1-related” mechanism in men. Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as a major chronic liver disease not only in Western countries but also in Asian countries like China in which 15–30% of the general adult population suffers from NAFLD . NAFLD, Pulse wave velocity is a valuable tool for assessing arterial stiffness by measuring the pulse propagation time and the travel distance between the studied arterial site, which is associated to abnormal vascular tone, thickening of smooth muscle and changes in blood viscosity . TherefoArterial stiffness could be progressive due to lipid metabolism . LipoproIn this study, we addressed the question of whether the serum ApoA1 concentration was associated with or was a risk factor for NAFLD and whether ApoA1 was associated with arterial stiffness; also, the relationship between ApoA1 and PWV in NAFLD was examined.People were recruited in the Health Management Center of The Third Xiangya Hospital from March 2012 to December 2013. The study was approved by the Institutional Review Board of Central South University (R18030) and informed oral consent was obtained from all subjects. Evidence including non-alcoholic users NAFLD and NAFLD is based on the following items: (1) The diffusion of near-field echoination in the hepatic region increases (stronger than that in the kidney and spleen) and the far field echo is gradual attenuated; (2) Intra-hepatic lacuna structure is not clear; (3) Mild to moderate hepatomegaly, with round and blunt border; (4) Color Doppler ultrasound shows a decrease or even difficulty in showing blood flow signals in the liver, but the distribution of blood flow is normal. If any one or more matches in items 1 and 2–4 are made, the NAFLD is diagnosed. Hepatic ultrasound is carried out blindly by trained ultrasoundists .The exclusion criteria were as follows: (1) patients with hepatotoxic drug treatment; (2) history of heart failure, stroke, arteriosclerosis, and diabetes; (3) participants with hepatitis C virus (HCV), hepatitis B virus (HBV) and any chronic liver disease; (4) participants with other chronic diseases: human immunodeficiency virus (HIV), cancer and end-stage kidney disease; (5) incomplete data information.2). Weight and height were measured after participants had removed their shoes and heavy clothing. They were measured in meters using a scale from the G-TECH Company. Blood pressure measurements were done with a mercury sphygmomanometer with the participants in a chair using the right arm after 5 min in rest. The average value of three readings was accepted as SBP and DBP.Anthropometric factors include height, weight, systolic blood pressure (SBP), diastolic blood pressure (DBP) and the brachial-ankle pulse wave velocity (baPWV). Body mass index (BMI) was calculated as weight (kg) divided by height squared .The definition of social behavior factors has also been reported in our previous study . EducatiThe brachial-ankle pulse wave velocity values were assessed using an automatic, non-invasive vascular screening device Omron Health Medical (China) LTD., Wuhan, China calculated as the distance travelled by the pulse wave divided by the time taken to travel the distance. The baPWV values were measured by the average of the left side baPWV and right side baPWV. The baPWV value is measured by the average of the baPWV on the left and the baPWV on the right. This is obtained by measuring blood pressure levels and pulsewaves in the arms and legs with four pneumatic pressure cuffs around the four limbs. Measurements were taken between 7:30 and 9:00 in the morning on the examination day. All the data was collected after the participants had 5 min of bed rest.Since the reference value of baPWV up to 1,400 cm/s was used as an indicator of the severity of arteriosclerosis vascular damage, increased arterial stiffness was defined as baPWV of 1,400 cm/s or higher .T-test for continuous variables. Multivariate logistic regression was used to assess the association between ApoA1 and baPWV totally and separately by gender. Linear regression analysis was used to determine the correlation between ApoA1 and baPWV in male NAFLD patients. The analysis was conducted after adjusted for age, gender, BMI, education, physical activity, smoking, history of hypertension, HDL and LDL level. As serum AST/ALT ratio is a good index to assess fibrosis advances. Patients can be divided into two groups by comparison of the ratio to 1. Adjusted odds ratio and 95% confidence intervals (CIs) were calculated. An odds ratio (OR) >1 was considered a risk factor, and an OR <1 was considered as a protective factor.Values for continuous variables are presented as mean ± SD. Comparisons between female NAFLD patients and male NAFLD patients were performed using Pearson’s Chi-square analysis for categorical variables and P < 0.05 were considered statistically significant. All the data analyses and figure were performed using STATA software version 14.0.For exploratory purposes, the adjusted relationship between ApoA1 and the incidence of arterial stiffness was also assessed by a multivariate logistic regression model with restricted cubic splines. The relationships were depicted based on this model in which ApoA1 levels were categorized into 0.5 g/L increment from <1 to >3 g/L and were adjusted for age, gender, BMI, education, physical activity, smoking, history of hypertension, HDL and LDL level. Values of 2. The means of systolic and diastolic blood pressure were 124.65 ± 16.54 and 78.13 ± 11.35 mmHg. The average HDL and LDL were 1.58 ± 0.4 mmol/L and 3 ± 0.88 mmol/L. The means of ApoA1 and baPWV were 1.51 ± 0.28 g/L and 1,389.48 ± 273.5 cm/s. There were significant differences in education attainment, smoking, and history of hypertension prevalence between male and female NAFLD patients (P < 0.05). Female NAFLD patients are older and had lower BMI, blood pressure, baPWV and predominantly had higher HDL and ApoA1 level  were enrolled the baseline characteristics of the study participants grouped by gender are shown in P < 0.001) (P < 0.001). In model 2 which adjusted for age, gender, BMI, education attainment, physical activity, smoking, and history of hypertension, the overall ApoA1 level in NAFLD patients was positively associated with baPWV ; ApoA1 level in male NAFLD patients was significantly associated with baPWV . No statistically significant association was observed between female NAFLD patients’ ApoA1 level and baPWV. In model 3, adjusted for model 2 and HDL and LDL, the overall ApoA1 level in NAFLD patients was significantly associated with baPWV ; ApoA1 level in male NAFLD patients was significantly associated with baPWV . No statistically significant association was observed between ApoA1 and baPWV in female patients (P < 0.05). In model 3, the overall ApoA1 level in two subgroups was positively associated with baPWV  in AST/ALT<1 subgroup and  in AST/ALT ≥ 1 subgroup respectively.The total prevalence of arterial stiffness is 41.56%, the prevalence for men is much higher than that for women  . A multipatients . In the P < 0.001). In model 2, after adjusting for age, gender, BMI, education attainment, physical activity, smoking and history of hypertension, the relationship between ApoA1 and baPWV in male patients was statically significant . In model 3, which adjusted for model 2 and HDL and LDL, the relationship between ApoA1 and baPWV in male NAFLD patients remained significant . ApoA1 is associated with the incidence of arterial stiffness only in male NAFLD patients.As shown in The relationship between ApoA1 and the incidence of arterial stiffness in male patients followed a J-shaped curve, with increased odds ratio at low and high ApoA1. In a multivariable logistic regression model, using ApoA1 as a covariate, adjusting for baseline covariates, the risk for the incidence of arterial stiffness increased with ApoA1 .The major finding of this study is that risk of arterial stiffness increased with increasing ApoA1 after adjusting for multi-confounders in NAFLD subjects. The relationship between arterial stiffness and ApoA1 was statistically significant only in male NAFLD population.P < 0.001) than Chinese population with an equal age level (P = 0.066)   . NAFLD iHepatic steatosis arises from an imbalance between triglyceride (TG) acquisition and removal. Many studies have demonstrated that hepatic TG accretion from increased dietary intake, repartitioning of TG from adipose tissue to the liver, or increased de novo lipogenesis result in hepatic steatosis . ApoA1 iAccording to previous studies, lower ApoA1 may have positive effect on atherosclerosis or high-risk plaque features , which iP < 0.05), which is exactly consistent with the results from other populations.The difference in ApoA1 level in different gender groups implied that sex hormones may play an important role in serum ApoA1 level. Both basic and bench research may be designed to test hypothesis and the internal mechanisms.In our study on NAFLD subjects, men had significantly higher level of baPWV levels and arterial stiffness than women, consistent with the results of some multicenter studies on the general population . Many faFatty liver was diagnosed by ultrasonography rather than liver biopsy pathology. Liver biopsy is the “gold standard” for defining fat accumulation, inflammation and fibrosis in liver, but it is not suitable as a screening method for population-based epidemiological studies due to the invasiveness of liver biopsy. Additionally, this current study only investigated the relationships on NAFLD patients in a cross-section research, to clarify the impact of ApoA1 on CVD risks, further longitudinal study should be performed. Despite these limitations, this study conducted a meaningful study of the relationship between ApoA1 and arterial stiffness in NAFLD subjects.Unlike the protective effect of ApoA1 on atherosclerosis, the serum ApoA1 was associated with arterial stiffness in male NAFLD patients, suggesting that NAFLD may alter arterial stiffness by “ApoA1-related” mechanism in male NAFLD population.10.7717/peerj.9757/supp-1Supplemental Information 1Click here for additional data file.


Chronic Kidney Disease (CKD) represents a risk factor for fatal and nonfatal cardiovascular (CV) events, including peripheral vascular disease (PVD). This occurs because CKD encompasses several factors that lead to poor prognoses, mainly due to a reduction of the estimated glomerular filtration rate (eGFR), the presence of proteinuria, and the uremic inflammatory milieu. The matrix metalloproteinases (MMPs) are a group of zinc-containing endopeptidases implicated in extracellular matrix (ECM) remodeling, a systemic process in tissue homeostasis. MMPs play an important role in cell differentiation, angiogenesis, inflammation, and vascular damage. Our aim was to review the published evidence regarding the association between MMPs, PVD, and CKD to find possible common pathophysiological mechanisms. MMPs favor ECM deposition through the glomeruli, and start the shedding of cellular junctions and epithelial-mesenchymal transition in the renal tubules. MMP-2 and -9 have also been associated with the presence of systemic vascular damage, since they exert a pro-inflammatory and proatherosclerotic actions. An imbalance of MMPs was found in the context of PVD, where MMPs are predictors of poor prognoses in patients who underwent lower extremity revascularization. MMP circulating levels are increased in both conditions, i.e., that of CKD and PVD. A possible pathogenic link between these conditions is represented by the enhanced production of transforming growth factor-β that worsens vascular calcifications and atherosclerosis and the development of proteinuria in patients with increased levels of MMPs. Proteinuria has been recognized as a marker of systemic vascular damage, and this may explain in part the increase in CV risk that is manifest in patients with CKD and PVD. In conclusion, MMPs can be considered a useful tool by which to stratify CV risk in patients with CKD and PVD. Further studies are needed to investigate the causal-relationships between MMPs, CKD, and PVD, and to optimize their prognostic and predictive (in response to treatments) roles. The Kidialysis) .CV risk is severely increased in patients with CKD, and the impact of CV events in this population is crucial if one considers that the rate of CV events  over time is higher than the risk for kidney disease progression . This st2 or slight increases of albuminuria (>30 mg/g) have been associated with a 1.5 to 4 times higher risk of peripheral artery disease (PAD). This evidence is strong, being derived from patients without PAD at basal visit, and reproducible, being confirmed in the general population, as well as in high-risk populations, regardless of the geographic area. Notably, the rate of PVD among patients with End-Stage Kidney Disease (ESKD) is higher than the incidence of acute myocardial infarction, stroke, and arrhythmias [Among the wide spectrum of CV events, a relevant role is portrayed by peripheral vascular disease (PVD). It has been demonstrated that the presence of mild-to-moderate CKD increases the risk of peripheral artery disease, leg revascularization, leg amputation, and hospitalizations . Either hythmias . Hence, The magnitude of the association is so important that research has recently focused on discovering new biomarkers that are potentially useful in the clinical management of CKD patients at increased risk for PVD. Matrix Metalloproteinases (MMPs) are zinc-containing endopeptidases that are involved in regulating tissue development and homeostasis . AlthougThe purpose of this review is to examine the role of MMPs in increasing the risk of peripheral vascular disease by the specific aggravating condition of Chronic Kidney Disease.The PubMed and ISI Web of science databases were searched for articles by using the following terms: ‘chronic kidney disease”, “chronic renal insufficiency”, “metalloproteinases”, “MMP” “atherosclerosis” “peripheral vascular disease”. Titles and abstracts were screened by three authors  to identify potentially relevant studies. All potentially eligible studies were subsequently evaluated in detail by one reviewer and three authors  through consideration of the full text. Reference lists of retrieved articles were also searched for relevant publications. Clinical trial, meta-analyses, narrative review, and systematic reviews published in the last 10 years were included. Bibliographies of relevant articles and reviews were manually screened to identify additional studies. Studies were excluded if they were not in the English language, if they did not fit the research question, or if they had insufficient data.Initial database searches yielded 180 studies from PubMed and 445 from ISI Web of Science in the last 10 years. After the evaluation of the bibliographies of the relevant articles, we evaluated 67 eligible full text articles. The current evidence on MMP expression and kidney disease, the link between MMPs and CV risk specifically in CKD patients, and the association between MMPs and peripheral vascular disease are described below.MMPs are classified, according to their structure (or function) and the substrate selectivity, into six groups: Collagenases , which cleave native collagen and with possible antifibrotic function; Gelatinases (MMP-2 and MMP-9), whose function is to cleave denatured collagens, type IV collagens in basement membranes and some chemokines; Stromelysins , which degrade a number of substances such as fibronectin, laminin but are unable to cleave native collagen; Matrilysins (MMP-7 and MMP-26) act by degrading ECM components (laminin and entactin); Membrane-type MMPs , so called because they are anchored to the exterior of the cell membrane; and other MMPs that are tissue or cell-type specific . It is rMMPs intervene in all phases of renal fibrosis, from infiltration of mononuclear cells to cells proliferation and scarring. All these processes lead to a progressive decline of renal function in CKD patients. Henger and Colleagues performed a hierarchical clustering analysis to assess the differential gene expression in human kidney fibrosis. Interestingly, they observed that several MMP  genes were upregulated in different degrees of fibrosis . With reThe structural remodeling of ECM, together with the profibrotic effect of MMPs, are detrimental for other organs apart from the kidney. Elevated blood concentrations of TIMP-1 have been associated with an increased risk of developing chronic heart failure (CHF) and, in patients already diagnosed with CHF, they were predictors of poor prognoses ,42. MoreThe CV burden in these patients is significant if one considers that the rate of CV events is similar to that of reaching ESKD ,47. As aMMPs play a role in the pathogenesis and prognosis of arterial and venous disease. With respect to the damage occurring in the arterial tissue, multiple studies have shown that MMPs are involved in one or more steps of atherogenesis and aneurysm development . EvidencRegarding venous diseases, it has been observed that alterations in ECM remodeling are common in the case of varicose veins and chronic venous insufficiency (CVI). With regards to varicose veins, the expression of MMP-1, -2, -3, -7, and -9 is increased, particularly in the smooth muscular cell of the vein wall, both in human and mice models ,66. More2+ in their structure, and have structured as Zn2+ binding globulin (ZBG). Indeed, ZBGs inactivate MMPs by displacing the Zn2+- bound water in the MMPs, and favor the anchorage of the drug to the MMPs substrate binding-pocket [2+ ion, are able to inhibit MMPs. Doxycycline inhibits MMP-2 and-9 [MMP activity is regulated at different levels, including either intracellular  or extracellular (stimulation or inhibition of their enzymatic activity from endogenous or exogenous substrates) process. The net activity of MMPs is a crucial step, since its up- or down- regulation could affect MMP activity, and ultimately lead to metabolic diseases, cancer, cardiovascular, and renal disorders . For theg-pocket . ZBGs eng-pocket . Hence, -2 and-9 . Chemica-2 and-9 . Apart f-2 and-9 . MMPs-Is-2 and-9 . MMPs-I -2 and-9 . A simil-2 and-9 ,80. Inte-2 and-9 ,82.The evidence for how the circulating levels or the expression of MMPs increase cardiovascular risk is well documented in both basic and clinical studies. However, to our knowledge, this represents the first review to encapsulate and describe the dual association between MMPs and CKD and MMPs and PVD.Two large meta-analyses have separately summarized the strength of the relationship between MMP-2, TIMP-1, and subclinical atherosclerosis in CKD patients or between MMPs and vascular risk, regardless of the level of kidney function ,83. TheyAccording to our results, we can also affirm that the CKD condition contributes to reinforcing the risk-pathways oriented from MMPs toward PVD. Numerous pieces of evidence support this: (1) Numerous MMP molecules are likely responsible for both CV (including PVD) and kidney damage and related clinical manifestations. Hence, such biomarkers warrant further investigation. The Gelatinases MMP-2 and MMP-9 are produced by both intrinsic glomerular and tubular cells ,70. It hA further crucial role in the link between metalloproteinases, CKD, and PVD is indicated by NGAL. It has been shown that NGAL levels are increased in atherosclerosis and chronic inflammatory processes, and in particular, are overexpressed in atherosclerotic plaques which are vulnerable to rupture . MoreoveIn addition to clinical trials perspective, further efforts are needed in the context of observational studies and risk stratification. Indeed, risk stratification of CKD patients may improve prevention strategies, acting to slow down CKD progression and reduce the high residual risk in CKD patients. In observational research, it may be useful to evaluate the potential role of MMPs as “prognostic” biomarkers used to identify the likelihood of a patient to develop a clinical outcome, regardless of treatment . Such a measure may improve physicians’ abilities to identify patients with poor prognoses . One app


Background: Orthostatic hypotension (OH) is a common disease of the elderly. It is generally believed that the pathogenesis of OH is related to the impairment of autonomic nerve function and the decreased vascular capacity regulation. This study aims to explore the relationship between OH and heart rate variability (HRV) parameters, which reflects autonomic nerve function; ankle-brachial pressure index (ABI), which reflects the degree of vascular stenosis; pulse wave velocity (PWV) index, which reflects vascular stiffness; and frailty index (FI), which reflects the overall health status of the elderly.Methods: From January to September 2018, 24-h HOLTER monitoring, PWV, and ABI were performed in 108 elderly patients with OH and 64 elderly patients who underwent physical examination in our hospital. Analysis software was used to record the subject's standard deviation of the cardiac cycle (SDNN), the standard deviation of the 5-min average cardiac cycle (SDANN), the square root of the average square sum of consecutive n-interval differences (rMSSD), the percentage of the number of adjacent cardiac interval differences >50 ms (pNN50), low frequency (LF), high frequency (HF), very low frequency (VLF), and low frequency/high frequency ratio (LF/HF). Then, FI was evaluated qualitatively and quantitatively in the form of a scale.Results: There was no statistical difference between the two groups on the basis of age, sex, body mass index (BMI), low-density lipoprotein (LDL), resting heart rate, blood pressure, fasting blood glucose, long-term medication, etc. There were significant differences in PWV, SDNN, LF, VLF, and LF/HF between the two groups (P < 0.05). The risk factor of OH in the qualitative (P = 0.04) and quantitative (P = 0.007) index FI was higher in the OH group than in the control group. The risk factors of OH were PWV, SDNN, VLF, LF/HF, and FI, where FI was positively correlated and LF/HF was negatively correlated.Conclusions: The pathogenesis of OH is related to vascular stiffness, imbalance of autonomic nerve regulation, and its comprehensive health status in the elderly. However, arteriosclerosis has not been confirmed as an independent risk factor.Clinical Trial Registration: Retrospectively registered, http://www.chictr.org.cn. Orthostatic hypotension (OH) is a common disease status of the elderly. Its incidence increases with age. According to American statistics, the prevalence rate of the community population aged over 65 was about 20–30% . In the At present, there are some studies on the pathogenesis of OH. Some studies have shown that non-neurogenic OH was related to autonomic nervous dysfunction and decreased vascular capacity regulation . ClinicaBased on the mechanism of decreased vascular volume regulation, combined with the characteristics of elderly patients, we speculated that there might be a correlation between atherosclerosis and OH, but there were few relevant reports. In consideration of the elderly with multiple mental disorders, we also tried to explore the relationship between the comprehensive state of the elderly and OH. Accordingly, we designed this study.From January to September 2018, 108 cases of OH elderly patients from the Geriatrics Department and Cardiology Department in the eastern district of Wuhan Puai Hospital were screened as observation groups (OH group). In the same period, 64 cases of elderly people from the Physical Examination Department in the eastern district of Wuhan Puai Hospital were taken as control group (CON group). Strobe statements were used for study identification, screening, and inclusion.(1) Age ≥65 years old, able to cooperate with researchers; (2) In the stable stage of the disease, stop intravenous infusion for more than 3 days; (3) OH group meets diagnostic criteria , with or(1) Atrial fibrillation or obvious arrhythmia; (2) Pacemaker implantation; (3) Diabetes; (4) Drugs, such as antidepressants, anti-Parkinson, anti-psychotic, Raas blockers, and Beta blockers that have a significant effect on autonomic nerve function are being taken; (5) At the stage of disease onset, needs clinical treatment, such as intravenous infusion; (6) Those who have not obtained informed consent and cannot cooperate.Refer to the definition in the expert consensus issued by the American Institute of Autonomous Neurology and Neuropathy in 1996: The blood pressure was measured every minute within 3 min after the change from lying position to standing position. The systolic and/or diastolic blood pressure decreased ≥20 mmHg and/or diastolic blood pressure decreased ≥10 mmHg within 3 min .n = 108).From January to September 2018, elderly OH patients from the Geriatrics Department and Cardiology Department of Wuhan Puai Hospital (age ≥65) were screened by the researchers under the condition of stable preexisting disease. The method was as follows: After the patient stayed in bed for 15 min, the researcher used a calibrated mercury sphygmomanometer to measure the blood pressure and heart rate of the lying humeral artery and recorded it. The patient's blood pressure and the heart rate of the same brachial artery were measured every minute after standing upright and recorded to 3 min after standing upright. Patients with reduced systolic pressure ≥20 mmHg and/or diastolic pressure ≥10 mmHg within 3 min were diagnosed as OH. After informed consent was obtained, a total of 108 cases entered the group and completed the study (n = 64).From January to September 2018, the elderly (age ≥65 years old) who came to the Physical Examination Department of Wuhan Puai Hospital for physical examination were enrolled by the researchers after OH detection. Ruling out OH diagnosis and obtaining informed consent, a total of 64 cases were enrolled and completed the study , resting blood pressure, heart rate, and medication. The following routine biochemical tests were performed: blood fat, blood sugar, improved ankle-brachial pressure index (ABI), pulse wave velocity (PWV), and 24-h HOLTER tests. Qualitative and quantitative scores of “frailty” were evaluated and recorded by a specially designated researcher. All data were reviewed and verified by two researchers independently.The ABI and PWV were measured using the VP-1000 automatic arteriosclerosis tester of OMRON Colin of Japan. Resting at least 5 min before the test, all subjects lay on the diagnostic bed on their backs, with the cuff tied to the upper and lower limbs in accordance with the operating rules. The upper arm sleeve belt air bag marked the brachial artery and the lower edge of the cuff was 2–3 cm from the elbow socket. The lower extremity cuff airbag mark was aligned with the inner side of the lower extremity, and the lower edge of the cuff was 1–2 cm from the inner ankle. The cuff was loosened moderately. The electrocardiogram (ECG) sensor was placed in the second left rib, body height parameters were input, the instrument automatically measured ABI and calculated PWV, and the researchers recorded the data.All subjects were monitored using 24-h HOLTER, the device was GE Seer Light Record box, and the heart rate variability (HRV) analysis software used was GE MARS Software. HRV analysis was based on the guidelines of the European College of Cardiology and the North American Pacemaker and Electrophysiological Society. NN intervals were RR intervals in sinus rhythm, and average NN intervals were the mean value of RR intervals in sinus rhythm. Intervals greater than or <30% of the average of the first four intervals are considered artifacts and removed from the analysis record. According to the automatic editing program, each ECG record was manually reviewed by two authors blinded to avoid abnormal QRS complex morphology, ectopic heartbeat, and motion artifacts, and to ensure that the HRV analysis program correctly marks the R wave, so as to accurately detect the R–R interval. Make corrections if necessary. According to the measurement standard, the following HRV measurements were calculated in the time domain and frequency domain .Time-domain related parameters:The standard deviation of normal-to-normal RR interval (SDNN), in ms.The standard deviation of the 5-min average cardiac cycle (SDANN), in ms.The square root of the average square sum of consecutive n-interval differences (rMSSD), in ms.The percentage of the number of adjacent cardiac interval differences >50 ms (pNN50), in%.Frequency-domain related parameters:For frequency-domain HRV analysis, RR time series were interpolated at 250 ms to obtain isometric values. Using fast Fourier transform (FFT), we quantified HRV in four frequency bands. Three characteristic frequencies were identified: LF, HF, and VLF when analyzing 2- to 5-min ECG recordings. ULF bands are identified with VLF bands in a 24-h recording.2.Low frequency (LF) band (LF power in the range of 0.04–0.15 Hz), in ms2.High frequency (HF) band (HF power in the range of 0.15–0.40 Hz), in ms2.Very low frequency (VLF) band (VLF power in the range of 0.003–0.04 Hz), in ms2.Ultra low frequency (ULF) band (ULF power in the range of 0.0001–0.003 Hz), in msWe also considered the LF/HF ratio.In this study, the Groningen frailty indicator (GFI) scale  was seleThe quantitative index of frailty adopted the currently recognized FI proposed by Rockwood et al. . FI is tList the common health deficits reflecting frailty that met the standards and with a score of 0–1 for each item. Each defect can be determined as multiple values according to the situation; for example, there are good, medium, and bad conditions, and the score can be set as 0, 0.5, and 1. You need 4 values to give  four scores. The corresponding individual situation was scored. The FI score was the ratio of the individual's current number of deficits score to the total number of deficits score. For example, consider that a health project data set had 50 variable items, each of which met the criteria considered to be a health deficit. If an individual did not have one, his FI will be 0/50 = 0 . If an individual had 10 deficits of 1 point, the FI index would be 10/50 = 0.20.According to the inclusion criteria of the FI project , referrit-test or a Bonferroni single-factor variance analysis (one-way ANOVA). The percentage of the comparison classification variable was tested using chi square. We determined the relevant risk factors for OH by the multiple logistic regression model. All statistical analysis was performed using SPSS 22.0 software. P < 0.05 was statistically significant.Quantitative data were expressed as mean ± SD, and qualitative data were expressed as the number of cases (percentage). The normal distribution of continuous variables was tested by Kolmogorov–Smirnov. The variance homogeneity test used Levene test. The continuous data of the normal distribution were evaluated by an independent-samples The Medsci sample size tools (MSST) was used to calculate the sample size. According to the matching ratio of 2:1 in the OH group and the CON group, a total of 255 study populations were included according to the results of the OH test. Through the relevant exclusion screening criteria, a total of 78 people failed. Subsequently, five more people were not eligible for the study because they could not cooperate with the experiment. In the end, 172 people entered the study . The steThere was no significant difference between the two groups in age, gender, smoking, drinking wine, BMI, resting blood pressure, resting heart rate, hypertension, hyperlipidemia, hyperuricemia, tumors, and cerebral infarction. There was no significant difference between the two groups in laboratory biochemical indexes, such as fasting blood sugar and LDL .Taking OH as the dependent variable and using age, gender, smoking, drinking wine, BMI, resting blood pressure, resting heart rate, fast blood sugar, LDL hypertension, hyperlipidemia, hyperuricemia, tumors, and cerebral infarction as independent variables, logistic regression analysis showed that the above indicators were not the risk factors of OH .The results showed that there were no significant differences in the DDD of antihypertensive drugs, calcium channel antagonists, alpha receptor antagonists, diuretics, and statins between the two groups . Taking P = 0.14) (P = 0.035)  . PWV was= 0.035) .P > 0.05). Compared with the CON group, SDNN in the OH group decreased significantly (P < 0.05) (P > 0.05). Compared with the CON group, LF, VLF, and LF/HF decreased significantly in the OH group (P < 0.05)  . In the  < 0.05) .P = 0.04) (P = 0.007)  . The qua= 0.007) .Taking OH as the dependent variable and using ABI, PWV, SDNN, SDANN, rMSSD, pNN50, LF, HF, VLF, LF/HF, and FI as independent variables, logistic regression analysis showed that PWV, SDNN, VLF, LF/HF, and FI were all predicted factors of OH. Among them, PWV and FI were positively correlated, and SDNN, VLF and LF/HF were negatively correlated. FI and LF/HF were the most affected .Similar to the literature , researcP > 0.05), while PWV in the OH group was significantly higher than that in the control group (P < 0.05). PWV reflects the degree of vascular stiffness. It was believed that the failure of lower limbs and visceral vessels to contract in time during the body position change of OH patients was related to the damage of sympathetic adrenergic system . In multiple regression analysis, SDNN, LF, VLF, and LF/HF were all predictors of OH (P < 0.05), and LF/HF was strongly correlated. It is suggested that the pathogenesis of OH is related to the imbalance of sympathetic and parasympathetic nerves.In healthy individuals, the periodic changes of HRV were accompanied by respiratory and blood pressure fluctuations . FrequenP = 0.04). In the quantitative index of frailty, there was significant difference between the two groups (P < 0.05). The OH group was significantly higher than the control group, indicating that frailty was related to OH. The results of the subsequent regression equation  also showed that FI is a predictor of OH. The relationship between them was linear and parallel.In clinical practice, we found that the incidence of OH patients was significantly related to their age. Therefore, in this study, we specially set an indicator “frailty” to reflect the comprehensive state of the elderly, and the results were consistent with our assumption. In the qualitative index of frailty, the percentage of frailty in the OH group (55.6%) was higher than that in the control group (39.1%) and had statistical significance . All patients gave informed consent for participation in this study, and written consent was obtained from each participating patient.The study was approved by the ethical committee of Puai Hospital affiliated with Huazhong University of Science and Technology, Wuhan, China  and conducted in accordance with the principles of the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was registered in the Chinese Clinical Trial Register (LL and HL conceived the present study, participated in the design, conducted the data analysis, and drafted the manuscript. HL and HC collected and assembled all the data. YL and LL commented on the manuscript drafts. YL provided the material and technical support and commented on the manuscript drafts. All authors have read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.