Kidney transplantation is the best option for end-stage chronic kidney disease. Transplant viability is conditioned by drugs’ nephrotoxicity, ischemia–reperfusion damage, or acute rejection. An approach to improve graft survival is the identification of post-transplant renal function prognostic biomarkers. Our objective was to study three early kidney damage biomarkers  in the initial period after transplantation and to identify possible correlations with main complications. We analysed those biomarkers in urine samples from 70 kidney transplant patients. Samples were taken on days 1, 3, 5, and 7 after intervention, as well as on the day that renal function stabilised (based on serum creatinine). During the first week after transplant, renal function improved based on serum creatinine evolution. However, increasing levels of biomarkers at different times during that first week could indicate tubular damage or other renal pathology. A relationship was found between NGAL values in the first week after transplantation and delayed graft function. In addition, higher NAG and NGAL, and lower KIM-1 values predicted a longer renal function stabilisation time. Therefore, urinary NAG, NGAL, and KIM-1 could constitute a predictive tool for kidney transplant complications, contributing to improve graft survival rates. Kidney transplantation has been a great medical milestone that has increased the life expectancy of patients with end-stage chronic kidney disease (CKD). For this reason, it is the best option for renal replacement therapy (RRT), and it also contributes to reduce the high socioeconomic costs associated with dialysis ,2.Between the main factors that affect kidney viability after transplantation are the immunosuppressive drugs. Calcineurin inhibitors (cyclosporine A and tacrolimus) are included in this group of drugs. Their nephrotoxic effects are dose dependent and show great heterogeneity between individuals and insufficient correlation with immunosuppressant plasma levels ,4,5,6. KPost-transplant kidney damage can also occur due to acute tubular necrosis (ATN), which clinically manifests as delayed graft function (DGF) and requires RRT during the first week post-transplant . ATN canOther causes of impaired renal function after transplantation are acute rejection (AR), graft vascular complications , urinary tract obstruction, pyelonephritis, cytomegalovirus or polyomavirus infections, or underlying disease recurrence .The existence or co-existence of the aforementioned factors make the patient particularly susceptible to the graft viability. In these circumstances, one of the most effective tools would be early diagnosis. In clinical practice, monitoring of transplanted kidney function is based on the determination of serum creatinine. However, it has an important limitation: when an increase is observed, more than 70% of the kidney function has been lost . FurtherIn recent decades, some urinary biomarkers have been developed, even clinically validated, to diagnose acute kidney injury (AKI) in a more sensitive, precise, and early manner than serum creatinine or glomerular filtration (which is largely based on serum creatinine) ,19. ThesOur objectives in this work were (i) to study the post-kidney transplant evolution of the urinary biomarkers NAG, NGAL, and KIM-1 in relation to the renal function evolution (determined by serum creatinine); and (ii) to evaluate the capacity of these biomarkers to predict possible complications in the initial evolution of kidney transplantation.A prospective longitudinal study was proposed in which patients who were to receive a kidney transplant at the University Hospital  were included . The proThe inclusion criteria were the following: patients older than 18 years who underwent surgery to receive a kidney transplant, or a double kidney and pancreas transplant, from a living or cadaveric donor. The only exclusion criterion was that the patients did not agree to participate in the study (patients who did not sign the informed consent).The patient inclusion period was between July 2013 and January 2015, inclusively. The follow-up time was 3 months from the transplant.Concentration and urinary excretion of NAG, NGAL, and KIM-1  were analysed in the post-transplant first week , as well as on the day on which renal function was considered to have stabilised in each patient . Evolution of urinary biomarkers was compared with the evolution of serum creatinine. In addition, associations of these markers with some post-transplant factors or complications were studied: type of transplant , cold ischemia time of the graft, nephrotoxic agents’ administration, AR, DGF, and stabilisation time in post-transplant renal function .The following data were collected from each patient : age, seg, 4 °C, 8 min) to eliminate possible sediments. Subsequently, they were frozen in several aliquots that were stored at −80 °C until use.From the excreted urine for 24 h, 10 mL samples were collected on days 1, 3, 5, and 7 after transplantation; subsequently, once a week for 3 months. The samples were processed and stored in the Samples Biobank of University Hospital . Once in the Biobank, the urine samples were centrifuged  for Windows program was used. Quantitative variables were expressed as mean plus/minus standard error. Qualitative variables were expressed in patients’ percentages and in absolute numbers. To analyse the relationship between the biomarkers and the different events that occur in the immediate post-transplant period, statistical analyses were performed with the χSeventy patients who had received cadaveric, double renal–pancreatic cadaveric, or living donor transplants were recruited for the study. In addition, cadaveric transplants were divided into two groups: donors aged 55 or older, and under than 55. This division is based on the different protocol applied in our hospital  for transplant patients with donors over 55 years of age, in whom a delayed introduction of the anticalcineurin inhibitor was performed. Patient numbers in each group, age, and sex of both donors and recipients, as well as the cold ischemia time, are shown in For cadaveric donors, the most common cause of death was stroke (68%), followed by traumatic brain injury (25%). Other causes of death were asphyxia, drowning, and aortic dissection.Regarding recipients, CKD causes were very diverse. The most common were diabetic nephropathy (29%), glomerular diseases (22%), and vascular pathology  (15%). Other causes were unknown CKD, autosomal dominant polycystic hepatorenal disease, interstitial nephropathies, Alport syndrome, urological pathology, and hemolytic uremic syndrome.Immunosuppressive therapy was based on the administration of the following drugs: basiliximab or thymoglobuline (induction), tacrolimus, mycophenolate mofetil, and corticosteroids .Living-donor transplant recipients began taking the medication (tacrolimus and mycophenolate mofetil) three days before intervention. Day 0 is considered the day of transplantation.Incidence of the main post-transplant complications (AR and DGF) are shown in Finally, 19% of transplant recipients received some nephrotoxic agent (not immunosuppressive drugs) , such asThe mean of the markers in the set of patients was calculated to compare the urinary biomarker evolution with serum creatinine evolution on the established days see  after trUrinary biomarker concentrations (i) at the highest point of the first week after transplantation and (ii) on the day on which each biomarker showed an increasing trend , living transplant, and double kidney–pancreas transplant. Groups differ in the immunosuppression regimen received , which cTo study the biomarker  evolution after transplantation, their progression was compared with that of serum creatinine during the first week post-transplantation and at the time of renal function stabilisation . While sIt is important to note that at renal function stabilisation time (based on serum creatinine), NGAL presents lower values than those found on day 1 after transplant, while NAG and KIM-1 present similar values to the initials (day 1). Data from our lab indicate that levels of both NAG and KIM-1 are within the normal range  on the first post-transplant day and at the time of stabilisation. However, NGAL values on day 1 after transplantation are about six times higher than in healthy individuals, and decrease to the normal range at stabilisation time. It suggests that NGAL could be a more sensitive biomarker at the beginning of the transplant.We have not found significant differences in the biomarker evolution of experimental groups, which could be due to the low “n” in living donor and double transplant groups, as well as the greater variability in cadaveric donors younger than 55 years old. Salazademh et al.  neither Moreover, no major differences have been observed between the biomarker evolution expressed as urinary concentration and as daily excretion . TherefoWhen analysing the relationship between urinary NAG and complications that occur in the immediate post-transplant period , we obseRegarding NGAL , we haveAs in other previous publications ,48, in oOne of the most relevant results of our study is that high NGAL values during the first week after transplant are associated with a greater probability of suffering from DGF. This result is consistent with those of the meta-analysis published by Haase-Fielitz et al.  in whichDespite the fact that various publications indicate that KIM-1 could be a good tool for the prognosis of kidney transplant viability ,60,61,62Our results significantly show that patients with high urinary NAG or NGAL in the first week take longer to stabilise their renal function . RegardiOne of the main limitations of our study is the lack of a sufficient number of biopsies to establish correlations between the biomarkers and the anatomopathological findings observed in the biopsy. Research in this sense is of great interest because by establishing these correlations, urinary biomarkers could mean avoiding having to perform many biopsies. While it is true that, in our study, AR was confirmed by biopsy.In conclusion, our results show that the urinary biomarkers NAG, NGAL, and KIM-1 rise during the first post-transplant week; in addition, their concentrations/excretions during that first week correlate with some post-transplant events; it is worth noting that the relationship was found in the three biomarkers with renal function stabilisation time, since this event is probably influenced by others such as DGF or cold ischemia time. Therefore, our work provides evidence about the possible use of NAG, NGAL, and KIM-1 as prognostic tools for kidney transplantation. These results are a proof of concept and constitute a first step in the development of a clinical decision support system (CDSS) in the context of kidney transplant evolution. The second step will be to confirm and characterise the utility of each biomarker, and later it will be possible to propose the scientific-technological development of a rapid and precise diagnosis that allows the clinician to make decisions. The present work lays the foundations to carry out a broader analysis in terms of included biomarkers, combined analysis of biomarkers, number of patients, and post-transplant time studied.


Renal denervation (RDN) exerts sympathoinhibitory effects. No information is available, however, on whether these effects have a regional or a more generalized behavior.In 14 patients with resistant hypertension , we recorded muscle and skin sympathetic nerve traffic  using the microneurographic technique, before, 1 month, and 3 months after RDN. Measurements included clinic blood pressure (BP), heart rate (HR), 24-h BP and HR, as well as routine laboratory and echocardiographic variables. Ten age-matched RHT patients who did not undergo RDN served as controls.P < 0.05). This effect was not accompanied by any significant change in SSNA . No quantitative or, in some cases, qualitative relationship was found between BP and the MSNA reduction induced by RDN. No significant changes in various sympathetic markers were detected in the control group who did not undergo RDN and were followed for 3-months observation.MSNA, but not SSNA, was markedly higher in RHT. RDN caused a significant reduction in MSNA 1 month after RDN, with this reduction increasing after 3 months (from 68.1 ± 2.5 to 64.8 ± 2.4 and 63.1 ± 2.6 bursts/100 heartbeats, These data provide the first evidence that RDN exerts heterogeneous effects on sympathetic cardiovascular drive, inducing a marked reduction in MSNA but not in SSNA, which appears to be within the normal range in this condition.These effects may depend on the different reflex modulation regulating neuroadrenergic drive in these cardiovascular districts. Resistant uncontrolled hypertension (RHT) is characterized by a pronounced sympathetic overdrive, as confirmed by increased urinary normetanephrine levels, augmented renal sympathetic spillover, heightened muscle sympathetic nerve traffic (MSNA) values, and elevated low-to-high frequency ratio of the heart rate variability signal –6. ThereAs previously reported , the stuMeasurements included sphygmomanometric and beat-to-beat finger  systolic and diastolic blood pressure, heart rate [cardiotacograph triggered on R wave of an electrocardiogram (EKG) lead]. They also included routine laboratory measurements  and an echocardiographic evaluation of the left ventricular mass index, calculated by the Devereux formula and normalized to body surface area, whereas left ventricular ejection fraction was measured from the four-chamber apical projection using the product area times length , 18. ColP < 0.05 was taken as statistical significance. References values for normal MSNA and SSNA were taken from a previous study in which a group of healthy normotensive subjects of a similar age was investigated [In the 14 RHT patients undergoing RDN, three experimental sessions were performed. The first session was carried out 24–48 h before the procedure for RDN, whereas the other two sessions were performed 1 and 3 months after the procedure, respectively. In the ten patients with RHT not undergoing RDN and thus serving as controls, three experimental sessions were also performed, with 1- and 3-month time intervals between the initial session and the other two, respectively. In each experimental session, which was carried out in the morning after a light breakfast, patients in the lying position were fitted with an intravenous cannula and devices for measuring sphygmomanometric and finger BP, heart rate, and respiration rate. After a 30-min interval, a blood sample for routine laboratory measurements was drawn from the cannula. Thereafter, three sphygmomanometric BP measurements were performed and then the microelectrode was inserted into a peroneal nerve to obtain MSNA or SSNA, which was recorded together with finger BP, heart rate, and respiration rate during a 30-min period. The microelectrode was then repositioned in the peroneal nerve fascicles to obtain the sympathetic nerve activity (MSNA or SSNA) that was not obtain in the previous recording period. Also in this instance, finger BP, heart rate, and respiration rate were all recorded during a 30-min period. Each protocol step was separated from the following one by a 20-min interval. Bilateral renal denervation was carried out by employing a radiofrequency ablation catheter  according to a protocol previously described . Data westigated .As presented in Table RDN was associated with a significant reduction in office and 24-h systolic and diastolic average BP values when evaluated 1 and 3 months after the procedure  in physiological as well as in pathological conditions, reflexes stemming from arterial baroreceptors modulate MSNA but not SSNA , 20, 21; in physiOther results of our study deserve to be briefly discussed. One, in our RHT patients, we did not find any quantitative or, in some instances, qualitative relationships between the BP reduction associated with RDN and the concomitant MSNA inhibition, which may suggest that the BP lowering effects of the intervention are not necessarily dependent on its sympathomodulatory effects. This finding, which has recently been confirmed by the results of a meta-analysis we performed examining the MSNA effects of RDNA in 11 published microneurographic studies for more than 400 patients , may sugSecond, in our study heart rate did not show any significant change in the 3-month period following RDN. Since heart rate represents a marker of the sympathetic drive to the heart , this fiOur study has some limitations. These include the small sample size and the presence of antihypertensive drugs, which may have affected sympathetic activity. It should be emphasized, however, that the same drug classes employed in the RDN group were used in the control group, with no evidence of any sympathetic change. In addition, SSNA is not affected by antihypertensive drugs , 16, 29,This study has two major new findings: (1) there is evidence that in patients with RHT, the sympathetic overactivity does not uniformly affect the sympathetic cardiovascular drive, because although MSNA is markedly increased, SSNA is in the normal range, and (2) RDN triggers a sympathetic deactivation, which occurs in the muscle but not in the skin vascular district. These differential effects of RDN may be because, while MSNA is under baroreflex mechanisms (which are activated by the RDN), SSNA is modulated by thermoregulatory and emotional mechanisms usually unaffected by RDN , 20, 21.


The study participants were 104 consecutive men aged ≥ 20 years who had been hospitalized or had undergone outpatient care at our hospital for heart failure between February 2019 and January 2023. MWS was measured in a 5-m section with a 1-m run-up before and after the course. Multivariable analysis was used to examine the association between MWS and peak VO2 and AT by CPX. The Pearson correlation coefficient showed that MWS was positively correlated with percent-predicted peak VO2 and percent-predicted AT . In the multiple linear regression analysis employing percent-predicted peak VO2 and percent-predicted AT as the objective variables, only MWS demonstrated a significant positive correlation . Multiple logistic regression analyses, using an 80% cutoff in percent-predicted peak VO2 and AT, revealed that only MWS was identified as a significant factor in both cases . MWS was correlated with peak VO2 and AT in male patients with heart failure. The MWS measurement as a screening test for exercise tolerance may provide a simple means of estimating peak VO2 and AT in heart failure patients.This retrospective observational study aimed to examine the relationships of maximum walking speed (MWS) with peak oxygen uptake (peak VOThe online version contains supplementary material available at 10.1007/s00380-023-02289-y. Two variables were expressed as the number of subjects and proportion. Continuous variables were performed using Welch’s t-test for normally distributed variables and the Mann–Whitney U test for non-normally distributed variables. Comparisons between two variables were performed with the chi-square test. Following confirmation of a distribution with the Kolmogorov–Smirnov test, correlations between continuous variables were assessed with the Pearson correlation coefficient. Additionally, multiple linear regression and multiple logistic regression analyses were performed using explanatory variables that were correlated or tended to be correlated in simple regression analysis with percent-predicted peak VO2 and percent-predicted AT as objective variables.2 and AT in this matched pair was examined using the Pearson correlation coefficient and logistic regression analysis.In addition, we added an examination using propensity score matching (PSM) between the high and low MWS groups to minimize the influence of confounding variables that may lead to biased results. We selected the variables to generate propensity scores based on the results of the pre-matching two-group comparison. With a caliper width of 0.2 × standard deviation and a one-to-one closest neighbor matching algorithm, the propensity score was calculated using a multivariate logistic regression model. The degree of PSM was measured using a standardized mean difference. Furthermore, the relationship of MWS with peak VOp values were two-tailed, with p < 0.05 considered significant.All the statistical analyses were performed with Statflex ver. 7 . All Between February 1, 2019 and January 6, 2023, 145 patients underwent CPX for exercise tolerance assessment at our hospital. Twenty-seven patients were excluded because they were female. An additional 10 patients had an unmeasured MWS, and 4 patients were excluded because of gait difficulty due to orthopedic or neurologic disease. Finally, 104 male patients were enrolled. The flow chart is reported in Fig. Table p = 0.152. Inter-observer reliability evaluated by the Pearson correlation coefficient with 20 randomly selected patients was r = 0.705 (p < 0.001). We could not find any reports of mean MWS in patients with heart failure. Therefore, we divided the participants based on median MWS (2.278 m/s) into the high MWS group (n = 52) and low MWS group (n = 52) to understand the clinical background associated with MWS. The high MWS group was more likely to have younger participants  and had fewer participants with hypertension , as well as higher height  and hand grip strength  than the low MWS group. Only one patient with pacemaker implantation was in the high MWS group. Patients with an implantable cardioverter defibrillator or those who received cardiac resynchronization therapy were not present in this study.MWS was measured by two independent physicians as observers. Intra-observer reproducibility assessed by paired-samples t-test was 2 was 20.78 ± 5.03 ml/kg/min, the mean percent-predicted peak VO2 was 83.54 ± 16.49%, the mean AT was 14.39 ± 3.10 ml/kg/min, the mean percent-predicted AT was 92.37 ± 18.97%, and VE/VCO2 slope was 33.60 ± 6.05. The peak respiratory exchange ratio was 1.15 ± 0.10, while the peak Borg scale score was 16.88 ± 0.63. Median MWS-based group-wise comparisons revealed that the high MWS group demonstrated higher peak VO2 , percent-predicted peak VO2 , AT , and percent-predicted AT . The mean peak respiratory exchange ratio was higher in the high MWS group but exceeded 1.1 in both groups . The peak Borg scale score did not differ significantly between the two groups .The CPX responses are summarized in Table 2 and between MWS and percent-predicted AT, respectively, in terms of the Pearson correlation coefficient. In both cases, MWS demonstrated a positive correlation .Figure 2 as the objective variable, MWS and hand grip strength were significantly correlated with percent-predicted peak VO2  (Table p < 0.001)  (Table p < 0.001) , while hypertension demonstrated trends toward significant associations  (Table p = 0.004)  (Table p < 0.001)  Table . In the 1) Table .Table 6LIn addition, PSM was examined between the high and low MWS groups to minimize the influence of potentially confounding variables that could lead to biased results Fig. . The var2  and percent-predicted peak VO2  (Online Resource 2). Similarly, AT and percent-predicted AT kept trending higher in the high MWS group , and the percentage of percent-predicted AT ≥ 80% was significantly higher in the high MWS group  (Online Resource 2).Median MWS-based group-wise comparisons after PSM indicated that the high MWS group demonstrated higher peak VO2 and between MWS and percent-predicted AT, respectively. In both instances, a positive correlation was observed for MWS .Online Resource 3-a and 3-b depict the Pearson correlation coefficient-based correlations after PSM between MWS and percent-predicted peak VO2 and AT, only MWS showed a significant association. The ORs for MWS were 1.311  for percent-predicted peak VO2 and 1.559  for percent-predicted AT (Online Resource 4-a and 4-b).In logistic regression analyses conducted after PSM using an 80% cutoff in percent-predicted peak VO2 and AT by CPX in male patients with heart failure. We found that MWS demonstrated significant positive correlations with percent-predicted peak VO2 and percent-predicted AT. Medications, medical history, underlying heart disease, left ventricular ejection fraction, height, or blood test findings, such as N-terminal pro-B-type natriuretic peptide, did not affect these correlations. Our results also indicated that the representative CPX indicators percent-predicted peak VO2 and percent-predicted AT can be predicted with MWS. Additionally, similar results were also obtained after PSM. To our knowledge, this is the first-ever study to demonstrate that a 5-m walking speed is associated with peak VO2 and AT in patients with heart failure.In the present study, we assessed the relationships of MWS with peak VO2 and AT, are consistent with those reported by the abovementioned studies.Exercise capacity predicts survival in patients with cardiovascular disease, including heart failure , while g2 and AT, it can only be performed at a limited number of centers since it requires staff with specialized skills and knowledge and specialized equipment and takes 1 h to perform. Consequently, simpler alternatives for estimating peak VO2 and AT are sought, such as the 6MWT [2 dynamics, it can assess cardiopulmonary function in the same manner as the 6MWT without major differences [2 and AT with MWS makes the 5-m walk test effective as a simple test for estimating exercise tolerance. Further, although the 6MWT and the shuttle walking test are representative tolerance tests and remain important, MWS can be conducted easily at any facility in a short time without the need for specialized knowledge, meaning that measurement of MWS over 5 m may be important as an initial screening test. Furthermore, the patients experienced little anxiety, did not refuse the test thanks to its short duration, and did not demonstrate any adverse events. These points may also make the 5-m walk test effective as an initial screening test. Additionally, in light of a previous study that reported that grading based on peak VO2, AT, and VE/VCO2 slope enables stratification of the risks of mortality and heart failure [Although CPX is practically the only test that accurately measures peak VOthe 6MWT , 12 and the 6MWT , 14. Howferences . However failure , 29, 30,Cardiac rehabilitation is a well-established non-pharmacological treatment for many patients with cardiac disease. Especially for patients with ischemic heart disease and heart failure, cardiac rehabilitation is considered a Class I therapy by the American Heart Association and European Society of Cardiology guidelines –35.The recommended exercise for cardiac rehabilitation is aerobic exercise, such as walking and cycling. Aerobic exercise does not cause intramuscular lactate accumulation and does not lead to acidosis ; it alsoTherefore, the estimation of AT, the limiting value of aerobic exercise, is an important indicator in safe and effective cardiac rehabilitation. Contrarily, it is practically difficult to perform CPX on all patients, and AT cannot be measured in medical facilities that do not have CPX.2. MWS is a simple, safe, inexpensive, and repeatable test that can be performed by non-physician staff. Therefore, screening for exercise tolerance and risk in cardiac rehabilitation, similar to CPX, can be possible in facilities that do not have specialized equipment. Furthermore, the results are expected to contribute to greater social recognition and dissemination of cardiac rehabilitation, similar to frailty and sarcopenia.However, the results of this study indicate the possibility of using MWS as a screening test to estimate AT and peak VO2 and AT after PSM. The results also showed that MWS had a significant positive correlation with predicted peak VO2 and predicted AT as well as before PSM.There are limitations to consider in this study. First, this is a single-center, retrospective observational study with small sample size. The clinical background of this study differs from that of Japanese registry studies of heart failure, such as ATTEND Registry and JCARE-CARD , 39. The2 and AT in patients with heart failure. Moreover, the ability to estimate peak VO2 and AT in a simple fashion with MWS as a screening test was suggested to be extremely effective in providing safe cardiac rehabilitation.Second, it is unclear whether endurance and response to long-term loading were properly assessed in the measurement of gait speed over the course of a few seconds. In particular, it is unclear whether the risk of myocardial ischemia was sufficiently assessed; thus, we inspected participants’ medical records and conducted diagnostic interviews regarding their conditions before testing. In the 5-m walk test and CPX, none of the participants presented with findings indicative of ischemia. However, despite these limitations, this is the first significant report showing a positive correlation of MWS with peak VO2 and AT in male patients with heart failure. Measurement of MWS as a screening test for exercise tolerance may provide a simple means of estimating peak VO2 and AT in heart failure patients. A prospective multicenter study needs to be conducted based on the results of the present study.We found MWS to be strongly correlated with peak VOSupplementary file1 (PDF 2482 KB)Below is the link to the electronic supplementary material.


Patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are prone to diaphragmatic dysfunction. However, dynamic assessment of diaphragmatic function is complex and difficult, and whether the assessment of diaphragmatic function can reflect clinical indicators such as lung function in AECOPD patients remains unclear. We studied diaphragm stiffness and diaphragm stiffening rate (DSR) in AECOPD patients with acute exacerbations ≥ 2 times within 1 year and their correlation with clinical data, the diaphragmatic thickening fraction (DTF), lung function, and blood gas values.In total, 112 AECOPD patients in group C and Group D who had acute exacerbations ≥ 2 times within 1 year in the Global Initiative for Chronic Obstructive Lung Disease Guideline A , B , C , D  grouping system were included in the study. Their general clinical data, chronic obstructive pulmonary disease assessment test (CAT), modified medical research council (mMRC), number of acute exacerbations in 1 year, DTF, lung function, and blood gas analysis were collected. The diaphragm shear wave elasticity at functional residual capacity (DsweFRC) and DSR were measured by ultrasound.P < .05). DsweFRC, DSR were negatively correlated with DTF, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and FEV1/FVC , and positively correlated with CAT score, mMRC score, and arterial carbon dioxide pressure  in both groups; the correlation coefficients of DsweFRC, DSR and DTF, FEV1/FVC in group D were greater than those in group C. There was no correlation between DsweFRC, DSR and arterial oxygen partial pressure in both groups (P > .05). The DsweFRC, DSR increased with the number of acute exacerbations per year in both groups.The DsweFRC and DSR of Group D were higher than those of Group C (We found that diaphragmatic stiffness in AECOPD patients increased with the number of acute exacerbations within 1 year, correlated with DTF, CAT, mMRC, lung function, and arterial carbon dioxide pressure and provides a simple and practical method for dynamically assessing diaphragmatic function and disease severity in AECOPD patients. The diaphragmatic dysfunction in COPD patients is caused by airway obstruction, lung hyperdistension due to increased respiratory resistance, decreased protein synthesis, malnutrition, increased muscle apoptosis, and other factors.–4 The diaphragmatic dysfunction affects respiratory function and ultimately increases the risk of respiratory failure and mortality. Antenom et al found that the diaphragm function of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) decreased continuously with the development of the disease. Therefore, dynamic evaluation of diaphragm function in AECOPD patients is very important.According to the World Health Organization, chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide after coronary heart disease and stroke. Ultrasound measurement of the diaphragm thickening fraction (DTF) is a feasible method to evaluate diaphragm function in COPD patients. Because there is a strong linear relationship between muscle shear modulus and muscle strength,,10 muscle strength and muscle function can be evaluated by ultrasonic shear wave elastography (SWE) measurement of the muscle tissue shear modulus. Therefore, ultrasound SWE is an alternative method to evaluate the diaphragm function.The transdiaphragmatic pressure is the Global Initiative for Chronic Obstructive Lung Disease (GOLD) standard for evaluating diaphragmatic function, which is the pressure difference between the esophagus and the stomach cavity. However, it is difficult to perform it on a large scale in clinical practice, because the measurement of transdiaphragmatic pressure is invasive and has technical limitations. The International Primary Care Respiratory Group published a “User Guide for COPD Health Tools,” which ranked various health status questionnaires in terms of validity and reliability, pointed out that the CAT was the preferred questionnaire. Several studies have found that diaphragmatic dysfunction is associated with pulmonary function in patients with stable COPD.–15 In a prospective clinical trial conducted by Xu et al, it was found that ultrasonic SWE could quantitatively assess the diaphragmatic stiffness in patients with stable COPD, and it was found that the diaphragmatic stiffness in patients with stable COPD was correlated with the CAT score and pulmonary function. However, it is not clear whether diaphragmatic stiffness changes with the progression of AECOPD or whether diaphragmatic stiffness is correlated with pulmonary function, CAT, mMRC score or other clinical data during acute exacerbation.The severity evaluation of COPD patients includes lung function and quality of life. The committee of the Global Initiative for Chronic Obstructive Pulmonary Disease points out that the classification of COPD patients into groups A, B, C, and D based on their chronic obstructive pulmonary disease assessment test (CAT), modified medical research council (mMRC score) and history of acute exacerbations can guide the evaluation of disease severity, disease course, and efficacy.In this study, diaphragm shear wave elasticity at functional residual capacity (DsweFRC) was considered the diaphragm stiffness. The primary objective of our study was to detect the characteristics of DsweFRC and diaphragm stiffening rate (DSR) in C and D groups of AECOPD patients; the secondary objective was to detect the correlation of DsweFRC and DSR with clinical characteristics such as pulmonary function and blood gas analysis. This study provides a new method for the real-time dynamic assessment of diaphragm function and disease severity in AECOPD patients.This prospective study was approved by the Ethics Committee of Baoji High-tech Hospital (No. 2022-002), and each participant signed informed consent. Patients with AECOPD admitted to the Department of Respiratory and Critical Care Medicine of Baoji High-tech Hospital from October 2021 to October 2022 were recruited. The COPD patients were divided into groups A, B, C, and D according to CAT score, mMRC score and the number of acute exacerbations within a year using the GOLD guideline A , B , C , D  grouping system, as shown in Table 2), and arterial carbon dioxide pressure (PaCO2).The study inclusion criteria were as follows: confirmed AECOPD patients who met the criteria of the GOLD diagnosis and had an acute exacerbation; the patient was conscious and could complete the CAT and mMRC questionnaires; each AECOPD patient could cooperate with the pulmonary function test and diaphragm ultrasound examination; and the patient’s forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) was <70% after the application of a bronchodilator. The exclusion criteria were as follows: severe heart, liver and renal organ dysfunction, pneumonia and bacterial infection in other organs, bronchial asthma, severe bronchiectasis, digestive tract diseases, active pulmonary tuberculosis, malignant tumors, and other consumptive diseases. Patients with disorders such as anxiety, depression and cognitive dysfunction were excluded for accuracy. The clinical data collected included age, sex, body mass index, systolic blood pressure, diastolic blood pressure, white blood cell count, C-reactive protein, CAT score, mMRC score, number of acute exacerbations within 1 year, FEV1, FVC, FEV1/FVC, arterial oxygen partial pressure (PaODTF and diaphragm SWE were measured using a GE S8 ultrasonic system and a 9 L linear array transducer (9 MHz). All ultrasound examinations were performed by a physician with more than 5 years of ultrasound experience. /DsweFRC.  was used to analyze and process all data. The Kolmogorov–Smirnov method was used to test the normality of the measurement data. Variables with a normal distribution were expressed as the mean ± SD, comparisons between the groups were analyzed by the t test, and the correlation between 2 variables was analyzed by Pearson correlation analysis. Nonnormally distributed data were presented as medians , comparisons between the groups were performed using the nonparametric Wilcoxon rank-sum test, and correlations between variables were analyzed by Spearman correlation analysis. The chi-square test was used for comparison of enumeration data. Interclass correlation coefficients (ICC) were used to assess the intra-assessor and inter-assessor reliability of the DsweFRC measures. When P < .05, the difference was statistically significant. A scatter plot was drawn using GraphPad Prism 5.This was an observational study using ultrasound SWE to measure diaphragm stiffness, so we referred to previous studies, and a sample size of 50 patients per group was sufficient.P = .007).The general clinical data of groups C and D are shown in Table P = .000, 95% CI 0.584–0.915), and the external reliability of the variables measured by the different examiners was also good .The internal reliability of the values measured by the same examiner at different times was good . There was a tendency for DsweFRC and DSR to increase with the number of acute exacerbations within 1 year in both groups. , and weak negative correlation with FEV1 ; low positive correlation with CAT score, PaCO2 , weak positive correlation with mMRC score , and no correlation with PaO2; DSR showed low negative correlation with DTF, FEV1/FVC, FEV1, FVC , and low positive correlation with CAT score, mMRC score and PaCO2  had a low positive correlation, and no correlation with PaO2. , and low negative correlation with FEV1 and FVC ; low positive correlation with CAT score, mMRC score, PaCO2 , and no correlation with PaO2. , and low negative correlation with FEV1 and FVC ; low positive correlation with CAT score, mMRC score, PaCO2 , and no correlation with PaO2 . and many changes in the systems of the local microenvironment. Other studies have found that the length of the diaphragm is related to the degree of lung distension, and the higher the ratio of gas volume and residual volume to the total lung volume, the shorter the length of muscle. All the above factors make the diaphragm muscle fiber adaptively change, eventually leading to greater metabolic capacity and resistance to fatigue.,21 Therefore, in COPD patients, the number of diaphragm type I muscle fibers increase, and the number of type II fiber muscle fibers decrease. Testelmans D and Barreiro E found that COPD patients had more type I fibers than type II muscle fibers in the diaphragm than healthy people. Several studies have found that type I muscle fibers are stiffer than type II fibers.–26 Xu et al found that severe COPD patients had stiffer diaphragms than patients with mild-to-moderate COPD. In this study, we found that the DsweFRC and DSR in group D was significantly higher than that in group C (P < .05), which confirmed that the stiffness of the diaphragm increased with the aggravation of the disease. After further study, we also found that the DSR of AECOPD patients also increased with aggravation of the disease. There has been no report on DSR in previous studies.COPD patients have stiffened diaphragms. The diaphragmatic muscle fibers mainly contain type I and type II muscle fibers. The type I muscle fibers resist fatigue, and the type II muscle fibers generate strength. and Eryuksel et al reported that the measurement of the diaphragm thickening rate by ultrasound can accurately and quickly evaluate the diaphragm function. Brown et al found that the mitochondrial density of type I muscle fibers in the diaphragm was higher than that of type II muscle fibers. With the exacerbation of AECOPD, the diaphragm muscle strength decreases, DTF decreases, type I muscle fibers increase, diaphragm mitochondrial density increases, and fiber density increases. According to the shear modulus calculation formula, the higher the tissue density, the higher the shear modulus.Elnemr, found that with the exacerbation of AECOPD, dyspnea increased, the mMRC score increased, the diaphragmatic activity decreased, and the diaphragmatic function decreased. Therefore, with the increase in the CAT and mMRC scores in AECOPD patients, DsweFRC and DSR also increase.The CAT scores included cough, phlegm, chest tightness, feeling of going up a flight of stairs or climbing a hill, housework activities, going out, confidence, and sleep and energy, which reflected the severity of the symptoms. The CAT scores increased, the symptoms worsened, the type I fibers increased in the diaphragm, and DsweFRC and DSR increased. Paulin et al found that the airway obstruction in COPD patients increases the workload of the respiratory muscles, especially the diaphragm, resulting in diaphragm fatigue and reduced diaphragm function. With the exacerbation of AECOPD, the degree of airflow obstruction increases, FEV1/FVC%, FEV1, FVC decrease, diaphragm function further decreases, type I fibers increase, diaphragm mitochondrial density increases, and diaphragm stiffness and DSR increase. Therefore, DsweFRC and DSR increase with decreasing FEV1/FVC%, FEV1 and FVC in AECOPD patients.Some common indicators of airway obstruction include FEV1/FVC%, FEV1, and FVC. The higher the above lung function indexes, the better the pulmonary ventilation capacity; the lower the value, the more serious the airflow obstruction. Scheibe et al2 and DsweFRC and DSR, suggesting that the PaO2 index could not directly reflect the diaphragm function and airway obstruction in patients with AECOPD. PaCO2 was positively correlated with DSR and DsweFRC, which may be related to decreased diaphragm function, reduced CO2 output and significantly higher partial pressure of CO2 in patients with AECOPD. The decrease in diaphragm function is accompanied by an increase in diaphragm type I fibers and an increase in mitochondrial density, which leads to an increase in diaphragm stiffness.There was no correlation between PaOOur study also has some limitations. First, the patients in Group A and Group B in the GOLD A , B , C , D  grouping system had a low risk of acute exacerbation, so we did not include them in the study, which may bias the results of the study. Second, the ultrasound imaging of the left diaphragm was not ideal due to gastric gas interference, and we only studied the stiffness of the right diaphragm. Third, we only studied the diaphragm stiffness at functional residual capacity, and the characteristics of the diaphragm stiffness at total lung capacity are not clear and need to be further studied.Ultrasound SWE measurement of diaphragmatic stiffness in AECOPD patients can evaluate diaphragmatic function in different risk groups, evaluate disease progression, and provide a basis for individualized treatment of AECOPD patients. Therefore, it is a good prospect for clinical application.Conceptualization: Jingfeng Zhang, Chunfeng Zhang.Data curation: Yanping Wan, Jinzhi Xu.Funding acquisition: Jingfeng Zhang.Formal analysis: Chunfeng Zhang.Investigation: Chunfeng Zhang, Lei Zhang.Methodology: Jingfeng Zhang, Peng Wang.Project administration: Jingfeng Zhang, Chunfeng Zhang.Resources: Lijuan Yan, Peng Wang.Supervision: Qi Wang.Writing – original draft: Jingfeng Zhang, Yanping Wan.Writing – review & editing: Lijuan Yan, Lei Zhang.


This paper presents the feasibility of automated and accurate in vivo measurements of vascular parameters using an ultrasound sensor. The continuous and non-invasive monitoring of certain parameters, such as pulse wave velocity (PWV), blood pressure (BP), arterial compliance (AC), and stiffness index (SI), is crucial for assessing cardiovascular disorders during surgeries and follow-up procedures. Traditional methods, including cuff-based or invasive catheter techniques, serve as the gold standard for measuring BP, which is then manually used to calculate AC and SI through imaging algorithms. In this context, the Continuous and Non-Invasive Vascular Stiffness and Arterial Compliance Screener (CaNVAS) is developed to provide continuous and non-invasive measurements of these parameters using an ultrasound sensor. By driving 5 MHz (ranging from 2.2 to 10 MHz) acoustic waves through the arterial walls, capturing the reflected echoes, and employing pre-processing techniques, the frequency shift is utilized to calculate PWV. It is observed that PWV measured by CaNVAS correlates exponentially with BP values obtained from the sphygmomanometer (BPMR-120), enabling the computation of instantaneous BP values. The proposed device is validated through measurements conducted on 250 subjects under pre- and post-exercise conditions, demonstrating an accuracy of 95% and an average coefficient of variation of 12.5%. This validates the reliability and precision of CaNVAS in assessing vascular parameters. According to the World Health Organization (WHO), cardiovascular diseases (CVD) are the leading cause of global mortality, affecting approximately 17.9 million individuals annually. Hypertension has impacted an estimated 1.13 billion people worldwide, with the majority residing in low- and middle-income countries. Those with hypertension are at a higher risk of developing severe medical complications, including brain, heart, and kidney diseases, among others. Disturbingly, reports indicate that 1 in 4 men and 1 in 5 women suffer from hypertension, making it a significant contributor to premature mortality on a global scale. Physiologically, pulse wave velocity (PWV), blood pressure (BP), arterial compliance (AC), and stiffness index (SI) are closely related vascular parameters and play an important role in maintaining blood flow to all vital organs ,3. StudiAll these devices monitor PWV, BP, AC, and SI parameters individually or collectively, either by causing discomfort to the subject with continuous measurements or image-guided ultrasound modalities with complex algorithms. Also, these devices require a large set-up for monitoring in intensive clinical environments, which makes it more complex for implementation in basic healthcare units in remote areas. Computer- and image-assisted methods of diagnosis have high accuracy, but repeatability remains a big area to be worked on. Many researchers have discussed carotid stiffness indices, which depend on the relationship between the pressure and the diameter of arterial distension from the diastolic to the systolic phase, giving deep insight into the relationship between geometrical parameters of the blood vessel and clinical values ,27,28,29A survey of the literature indicates that existing modalities employed to find blood pressure and arterial parameters have many impediments. Frequent usage of cuff-based devices may lead to damage of the blood vessels, and a skilled technician is required to detect the Korotkoff sound to evaluate BP. Employing separate modalities like imaging algorithms for finding arterial parameters and invasive catheter methods to detect continuous blood pressure leads to an increase in complexity and a potential clinical hazard that is unavoidable during long-term surgical procedures.Clustering all of these important parameters into a single continuous non-invasive device without a complex imaging algorithm would benefit clinical specialists to successfully carry out prolonged and lifesaving surgeries. In this context, the aim of this research is to develop a device that will measure said parameters continuously and non-invasively using an ultrasound sensor. This paper provides additional confirmation of the potential clinical application of a Continuous and Non-Invasive Vascular Stiffness and Arterial Compliance Screener (CaNVAS) device by demonstrating the feasibility of automated and precise in vivo measurements of these parameters using a straightforward and innovative methodology. This validation paves the way for the device’s potential use in clinical settings in the near future.This device focuses on deriving the blood pressure value from PWV; in addition, AC and SI are computed, making it a suitable alternative for existing modalities. Nonionizing ultrasound waves are passed through the blood vessel to obtain the reflected echoes to evaluate the PWV using the Doppler shift. The relationship between PWV and BP is established, which helps in the automated estimation of BP from PWV. AC and SI are formulated by extracting the derived systolic and diastolic diameter and blood pressure. To validate the entire experimental set-up in its working, two checkpoints with the artery diameter value as an indicator are programmed to indicate any deviation on device placement in the region of interest. A vessel finder is utilized to trace the artery position or to correct the CaNVAS position whenever needed. CaNVAS is developed to monitor vascular parameters under a single roof in a feasible manner without involving any complex algorithm, making it extendable to be employed as a point-of-care device for CVD patients.(i)A sensor positioning module equipped with infrared illumination to mark the artery’s position.(ii)An embedded ultrasound sensor module housing a piezoelectric crystal oscillator with an appropriate frequency.(iii)A transmitter unit, receiver unit, and pre-processing module encompassing an acquisition unit, operational amplifier, and high-pass filter.(iv)A microprocessor and signal processing module responsible for extracting vascular parameters.(v)A display module featuring a manual setting mode and an output display unit.s), diastolic blood pressure (Pd), pulse wave velocity (PWV) (which includes peak systolic velocity (Vs) and end diastolic velocity (Vd)), arterial compliance (AC), and stiffness index (SI).It is important to note that the term “vascular parameters” encompasses systolic blood pressure . The device transmits acoustic waves at a predetermined frequency across the blood vessel interface to capture reflected waves from the vessel’s surface, causing a frequency shift in the receiver module. Both the transmitter and receiver modules are positioned adjacent to each other on the skin’s surface, aligned with the direction of blood flow towards the receiver module. A crystal oscillator embedded in the sensor activates the ultrasonic transmitter module, generating waves at a specific frequency that interact with the blood vessel. After being absorbed, the waves are reflected back and detected through the oscillator crystal in the receiver module. The programmed microprocessor controls the crystal oscillator, producing specific frequencies tailored to the targeted arterial site. More specifically, the transmitting frequency Ft is generated in a range between 1.5 and 3.5 MHz for the brachial artery, 4 and 7 MHz for the radial artery, and 7 and 10 MHz for the carotid artery (with an ultrasound sensor with 98% accuracy with a resonant frequency variation of ±5%) to measure the vascular parameters. The range of frequencies is provided to allow for the selection of a specific frequency that is appropriate for the individual subject being examined. The CaNVAS device is tailored for three specific arteries: radial, brachial, and carotid. Each artery is outfitted with its ultrasound sensor and a corresponding algorithm, guaranteeing the emission of acoustic waves at precise frequencies targeted to the specific arterial site.A sensor positioning module is provided with an artery tracing circuit to support the non-invasive device in marking the correct position of the target artery on the skin’s surface, thereby illuminating the infrared source at a wavelength of 620 nm to visualize the target artery. O is converted to an electrical signal by a receiver crystal. That electrical signal is amplified by an operational amplifier with a bandwidth greater than 200 MHz and a slew rate of, at a minimum, 4100 Vµs−1. The operational amplifier can amplify the electrical signal by a gain value beyond 25. Furthermore, the receiver module is coupled to a high-pass network with a cut-off frequency of 3 MHz to filter the fluctuations on the amplified electrical signal, allowing the sharp amplified electrical signal to microprocessor. This module is programmed with a structural algorithm to extract vascular parameters from the detected reflected acoustic waves. Two checkpoints, Young’s modulus validation to compute the vessel diameter and a diameter-varying function to correct the device position, are included within the algorithm to verify the results obtained simultaneously. The validation unit is also incorporated to validate the pressure value from CaNVAS by the operator. A display module continuously provides the data to the user or attender. The data include the instantaneous systolic blood pressure PS, the instantaneous diastolic blood pressure Pd, the pulse wave velocity, which comprises vs. and Vd, the arterial compliance, the stiffness index of the user, the artery position marking, and the device validation report.The driver circuit is designed in such a way that it guides to transmit the ultrasound acoustic wave at the appropriate frequency towards the target arterial site; the pre-processing module comprises an operational amplifier and a high-pass filter, wherein the received acoustic frequency FA unique methodology is carried out in CaNVAS to determine the constants α and β, which are fed into the predetermined Equation (1), expressing the nonlinear relationship between the pulse wave velocity and the pressure.s, which is computed using the received echo signal from the receiver, is taken as an input for Equation (2) to derive the PWV [−1.−1; FS is the doppler shift, because the sensors are placed adjacently; and t is a transmitter frequency, which is selected in the specific range from about 1.5 MHz to 10 MHz based on the target artery, wherein the target arteries are characterized as the radial artery, the brachial artery, and the carotid artery. The instantaneous pulse wave velocity obtained from the subject is used to extract the peak systolic velocity (Vs) and the end diastolic velocity (Vd). The minimum and maximum PWV in one cycle duration is determined, of which 70% of the maximum value is taken as vs. and 10% of it is taken as Vd. The reference blood pressure (Pr) parameter from a multitude of 995 random subjects, which included divergent age groups from 21 to 55 (38 ± 17) with various physiological condition  was measured by means of an external blood pressure measuring device, Diamond Deluxe BPMR-120. Furthermore, the reference pulse wave velocity (Vr) from the same random subjects using an initial CaNVAS experimental set-up is programmed to compute only the PWV . These reference pressure values (Pr) and pulse wave velocity values are plotted on a graph, as depicted in The Doppler shift F the PWV  measure Exponential approximation is employed to analyze the increasing nature of the pressure value to the corresponding increase in the velocity value. From the graph, it is noted that α constant is the slope of the exponential equation, and the y-intercept is calculated when x is zero and the value is taken as β constant. The α constant 0.1857 kPa and the β constant 2.3 kPa values are observed from the curve and set as a standard constant for Equation (1) to calculate the blood pressure value computed from the pulse wave velocity embedded in the non-invasive device CaNVAS. Furthermore, the arterial diameter, arterial compliance, and stiffness index are computed with an appropriate equation, which is embedded in the processor to find the vascular parameters of the user using CaNVAS. Hereafter, the terms “user” and “attendant” refer to the one whose vascular or clinical parameters are specifically measured using the non-invasive device. A sequential algorithm is carried out in the processor, as shown in o) is calculated by a frequency counter as step 1.Initially, user inputs are received from the choice of either data acquisition or validation. The pre-processed received echoes are fed into the microprocessor and digitized, and the reflected frequency (Fs in kilo hertz (KHz) is calculated using Equation (3), where Fs will be positive because the blood flows towards the receiver. The pulse wave velocity, which comprises the peak systolic velocity (Vs) and the end diastolic velocity (Vd), is computed in step 3 with the same procedure as carried out for finding the reference velocity values using Equation (2). The blood pressure value is derived by applying the velocity values obtained in step 3 and with the derived constants α (0.1857) and β (2.3). The systolic (Ps) and diastolic blood pressures (Pd) in kPa are calculated with the corresponding systolic and diastolic velocity values by the two Equations (4) and (5).In step 2, the Doppler shift FsD and the diastolic arterial diameter dD in millimeters (mm) of the target artery of the user, using Equations (6) and (7).The processor is programmed with a diameter equation to calculate the systolic arterial diameter 3. The variables Ps, Pd, Vs, and Vd represent the instantaneous systolic and diastolic blood pressures and the velocity values obtained in previous steps. The initial elasticity of the artery (oE) is set to 13.33 kPa, which will be adjusted according to each subject in subsequent steps. The elasticity property of the artery is determined by its capacity to compress and extend during systole and diastole in one cycle, as reflected in the frequency shift obtained from the receiver. The ratio of the systolic and diastolic diameters is compared to the ratio of the maximum frequency shift to the minimum frequency shift recorded during one cycle. Any differences in these values are considered errors. If the error exceeds a certain threshold, the elasticity value (oE) is modified from the initial set value, and step 5 is repeated until the error is minimized. Consequently, the final value of oE is used as the appropriate elasticity value for the user. To ensure system performance, the non-invasive device includes a checkpoint to verify the derived diameter using the diameter equation against the respective arterial site. This derived diameter is correlated with the thickness–diameter function (T/D), allowing for the detection of deviations beyond 0.3 ± 40%. If the deviation of the thickness–diameter value exceeds 40%, it indicates improper device positioning, and this information is displayed on the display module.The algorithm used in CaNVAS incorporates various constants. The arterial constant (k) is set to 0.017. The thickness of the artery is predetermined based on the target artery: 0.25mm for the radial artery, 0.29 mm for the brachial artery, and 1.5mm for the carotid artery. The density of blood (ρ) is assigned a value of 1060 kg/m2kPa−1 and the stiffness index (SI), where If the input received from the user matches the condition described in step 2, the device will execute all the preceding steps exactly as it did for choice 1, including the validation process. Otherwise, it will skip step 8. During the validation phase, only the blood pressure parameter is validated using an external device. This parameter is crucial for calculating the arterial diameter, arterial compliance, and stiffness index, which are the key parameters used to validate the integrated device. The reference blood pressure value obtained from a gold standard BP apparatus, as measured by the user, is compared with the values provided by CaNVAS. The device will display the error value if it exceeds ±0.67 kPa, as is clinically acceptable. Equations (8) and (9) are employed to derive the arterial compliance (AC) in mmThe individual will utilize the user-friendly and non-invasive device CaNVAS to continuously obtain the specified vascular parameter details without any time gaps. A display unit will show the user’s ongoing measurements, including the instantaneous systolic pressure (SYS), instantaneous diastolic pressure (DIA), peak systolic velocity (PSV), end diastolic velocity (EDV), arterial compliance (AC), and stiffness index (SI). Additionally, the device’s validation status will be displayed. The statistical analysis conducted in this study utilized a linear regression model in Microsoft Excel 2016.For the performance analysis of CaNVAS, a group of 300 participants was selected. This group consisted of both healthy individuals and individuals with a history of hypertension, hypotension, and cardiovascular disorders. Additionally, subjects undergoing regular renal dialysis were included. The age range of the participants was 21 to 55 years, with an average age of 38 ± 17. Among the participants, 65% were female and 35% were male. This study conducted on an educational campus included a significant number of adolescent students and faculty members as participants. To measure the vascular parameters and blood pressure of these individuals, both CaNVAS and Diamond Deluxe BPMR-120  were used simultaneously. The institute’s ethics committee approved this study, and all participants were provided with a clear explanation of the experimental procedure. Informed consent was obtained from each participant before data acquisition. The typical time required for one set of readings was under two minutes. All subjects underwent comprehensive measurements. In certain cases, a few additional minutes were necessary for the initial device set-up to accurately trace the artery due to the associated challenge. The BPMR-120 cuff was applied to the brachial artery, ensuring it covered at least 80% of the arm’s circumference. CaNVAS was positioned over the target artery  using the self-evaluation position correcting unit. During the assessment, all subjects were seated in a relaxed position with their feet resting on the floor and their arms supported at heart level. The measurements were repeated for the same subjects after engaging in physical exercise (Rapid Steps Climbing). Two trials were conducted under each condition to assess the repeatability of CaNVAS. Blood pressure data obtained from CaNVAS were compared to those measured using the gold standard blood pressure device, Diamond Deluxe BPMR-120. Among the total of 600 data points collected for both conditions , a few data points were considered outliers due to movement artifacts and powerline interference. These suspected cases of erratic data differences were excluded from the analysis, resulting in a remaining dataset of 556 data points, which accounted for 90% of the total.In order to evaluate the agreement between blood pressure values obtained from CaNVAS and the gold standard device under two conditions, Bland–Altman plots were generated with limits of agreement set at ±2 standard deviations (SD), as depicted in The mean difference between the blood pressure values obtained from the two devices was observed to be −0.123 ± 2.756, indicating minimal distortion in measurements. The graphical representation illustrates that the differences in measurements are randomly distributed, with 98% of the data falling within the range of agreement.The correlation matrix is estimated within the vascular parameters , Mean Pulse Wave Velocity (MPWV), Mean Diameter (MD), arterial compliance (AC), and stiffness index (SI)) calculated using CaNVAS for all subjects. The correlation coefficients value depicted in During this study, two trials were conducted to assess the repeatability of CaNVAS. The frequency of differences between the two trials for blood pressure (BP), pulse wave velocity (PWV), arterial compliance (AC), and stiffness index (SI) values is depicted in This paper presents a novel device called CaNVAS, along with its methodology, for non-invasively evaluating continuous vascular parameters. CaNVAS utilizes ultrasound technology to measure pulse wave velocity (PWV) based on the reflected frequency shift signal from the artery. This method shows promise and is employed for deriving blood pressure (BP) as well as for estimating arterial compliance (AC) and stiffness index (SI). In a previous device developed by Drzewiecki et al. (1992), an arterial tonometer was used to non-invasively measure continuous blood pressure by identifying the center of the blood vessel . The devThis paper provides a comprehensive description of the hardware and algorithm of the CaNVAS device. The performance of the device was assessed using approximately 300 subjects from various age groups, ranging between 18 and 35 years old, with an average age of 26 ± 9. The blood pressure values measured by CaNVAS were compared to those obtained from a sphygmomanometer (BPMR-120), demonstrating an accuracy rate of 95%. The reliability of other parameters, such as arterial compliance (AC) and stiffness index (SI), measured by CaNVAS was evaluated using a self-correlation technique. Because these parameters are interconnected with blood pressure, even a slight error in blood pressure measurement can impact AC and SI values. It was observed that AC and SI measured by CaNVAS are influenced by age. Similar to the findings of Jayaraj et al. in their ARTSENS device, there is a gradual decrease in arterial compliance and an increase in stiffness index with advancing age.To ensure the repeatability of CaNVAS, linear regression analysis and Bland–Altman plots were employed. The results demonstrated an average coefficient of variability of 12.5%, which is consistent with previous research and indicates a comparable level of repeatability.The obtained results provide strong evidence that CaNVAS is a promising device for measuring vascular parameters comparable to existing modalities. Its compact size, affordability, repeatability, and user-friendly nature make CaNVAS suitable for medical applications, such as measuring continuous blood pressure during dialysis procedures and monitoring the health status of subjects after cardiac surgery. However, it is important to note the limitations of this study. The hysteresis behavior of psychobiological variables during exercise was not considered, and this aspect will be investigated in future research. Additionally, the study population mainly consisted of adolescent students and middle-aged faculty members due to its location on an educational campus. This demographic bias represents a limitation, and a demographic analysis of CaNVAS will be explored in future studies.


After CGC, improvements in BI (p < 0.001), TBGT (p < 0.001), and TUG (p < 0.001) were observed in patients with both normotensive and hypertensive BP profiles. The proportion of patients with outcome improvements did not differ between the two groups . Conclusion: Patients both with and without hypertensive BP profiles benefited from comprehensive geriatric care with comparable outcome improvements. Particularly, normotensive BP was associated with chronic cardiovascular comorbidities, indicating increased awareness of the importance of BP management in patients diagnosed with cardiac diseases.Background: Comprehensive geriatric care (CGC) is a multiprofessional treatment for older people which considers medical conditions and functional status. The aim of the presented study is to investigate the impact of hypertensive blood pressure (BP) on functional outcomes among older adults receiving CGC. Methods: Functional status was documented by the Barthel index (BI), Tinetti test (TBGT), and timed up and go test (TUG) prior to and after CGC. The results were analyzed in relation to hypertensive BP, indicated by mean BP ≥ 130/80 mmHg determined by 24 h blood pressure monitoring (BPM) while hospitalized. Results: In the presented monocentric, retrospective, observational study, 490 patients were included (mean age (SD): 83.86 ± 6.17 years, 72.2% females). Hypertension in BPM was found in 302 (61.6%) individuals. Hypertensive BP was associated with the female sex ( Due to demographic changes, the proportion of older patients with chronic medical conditions and multimorbidity has become increasingly common in developed countries, and is highly associated with health service utilization ,2. ComprThe presented investigation is an observational monocentric retrospective study which was conducted in a large geriatric department (50 beds) in the Diakonie Hospital Jung-Stilling Siegen, in the region of South Westphalia, Germany. The comparison of the baseline data between patients with hypertension in BPM versus those without was conducted using a cross-sectional design. Benefits to functionality after CGC were evaluated using a longitudinal design investigating the cohort of geriatric patients treated in the department.Patients were selected according to the following inclusion criteria:(1)Hospitalization for CGC between May 2019 and April 2020;(2)24-h blood pressure monitoring (BPM) during their hospital stay;(3)Complete documentation of outcome parameters .All patients who fulfilled the inclusion criteria were selected for further analysis, and the study participants were subdivided into two groups, with and without hypertension, in BPM. Scores from geriatric assessments, including defined outcome parameters , demographic data, comorbidities, and short-term adverse events during the hospital stay were compared between both groups.CGC is a multiprofessional inpatient treatment program specially addressed to older adults. The treatment spectrum in our geriatric department is various; patients with acute medical diagnoses, recovering from surgery, and experiencing typical geriatric syndromes  are cared for. Patients are assigned to CGC from in-house departments, the emergency room, external hospitals, or their general practitioners. After admission, patients receive an elaborate assessment evaluating mobility, cognitive and emotional capabilities, coping with basic activities of daily living (ADL), and social conditions. BI, TBGT, and TUG were documented upon hospital admission and at discharge as defined outcome scores. Furthermore, Mini Mental Status Examination (MMSE), Shulman’s Clock Drawing test, and the Geriatric Depression Scale (GDS) were carried out upon hospital admission for evaluation of patients’ cognitive and emotional status ,12,13,14Patients’ ability to cope with basic ADL was expressed by BI that covered 10 items of basic ADL . The scores were weighted according to the patient’s ability to answer each item independently, with assistance, or dependently. The scores allotted for bathing and grooming were 0 and 5 points; for ingestion, dressing, using toilet, bladder/bowel control, and climbing stairs, 0, 5, and 10 points; and for transfer and walking, 0, 5, 10, and 15 points for each item. In total, BI scores ranged from 0 to 100 points, with high scores suggesting better performance in basic ADL .TBGT is a two-component score verifying balance and gait abilities, and fall risk of the older patient. TBGT covers proving balance while sitting and standing; while rising and sitting down on a chair; while a slight nudge given to the patient’s chest; with eyes closed; or while turning 360°, respectively. Gait is assessed by observing gait initiation, the step , path, and trunk stability. TBGT is rated on a 3-point scale, from 0 to 2 points for each item. The maximum possible TBGT score is 28 points. Higher scores indicate better balance and gait abilities .TUG is a widespread assessment tool evaluating walking ability. For TUG, the patient sits in a chair and is asked to stand up, walk three meters, turn around, walk back, and sit down again. The time for TUG completion is measured . In the 24-h blood pressure monitoring (BPM) is a routinely performed diagnostic procedure in hypertension diagnostics in our geriatric department, and is evaluated by a specialist in internal medicine. If necessary, blood pressure medication is initiated or adapted, respectively, in the clinical care routine. BPM was scheduled for 24 h with wearable devices . Data sets were stored and evaluated in the accompanying archiving system . Hypertensive BP was defined by BP values ≥ 130 mmHg systolic and/or ≥80 mmHg diastolic, according to the cut-off values for 24 h mean BP in ambulatory blood pressure monitoring, given by the guidelines for the management of arterial hypertension of the European Society of Cardiology and European Society of Hypertension .t-test was used. Statistical analysis was carried out with PSPP software .Demographic parameters; comorbidities; information on short-term adverse events while hospitalized; and the results from the ADL (BI), mobility , cognitive (MMSE and Shulman’s clock drawing test), and emotional assessments (GDS) were documented during the clinical care routine and evaluated for this retrospective, single-center analysis. Normally distributed datasets were presented as mean ± standard deviation (SD), and non-normally distributed data as medians and interquartile ranges . Categorical variables were shown as counts and percentages and analyzed via Fisher’s exact test. Normal distribution was verified by the Kolmogorov–Smirnov test. An analysis of the nonparametric data was carried out using the Mann–Whitney U-test for unpaired samples and the sign test for paired samples. In case of normal distribution, a We received ethical approval for this retrospective data analysis .p < 0.001), coronary heart disease , atrial fibrillation , urinary tract infection , and hypocalcemia  were more common in patients with normotensive BP, whereas female sex  and current fracture  were associated with hypertensive BP profile  to 17 (IQR: 11–21), p < 0.001; and TUG from a median of 4 (IQR: 3–5) to 3 (IQR: 3–4), p < 0.001. In patients with hypertensive BP, BI improved from a median of 50 (IQR: 35–60) to 65 (IQR: 50–80), p < 0.001; TBGT from a median of 13 (IQR: 5.75–18) to 17 (IQR: 12–21), p < 0.001; and TUG from a median of 4 (IQR: 3–5) to 3 (IQR: 2–4), p < 0.001  : 83.86 ± 6.17 years). Among them, 354 (72.2%) were female. A hypertensive blood pressure profile (mean BP ≥ 130/80 mmHg) in BPM was found in 302 (61.6%) patients during their hospital stay. The mean BP of all included patients was 135.01 ± 19.07 mmHg systolic and 70.36 ± 10.03 mmHg diastolic. In the subgroup of patients with normotension in BPM (BP < 130/80 mmHg), the mean BP was 115.79 ± 9.07 mmHg systolic and 63.05 ± 6.71 mmHg diastolic. In those patients with hypertension in BPM (BP ≥ 130/80 mmHg), the mean BP was 146.98 ± 12.85 mmHg systolic and 74.91 ± 9.03 diastolic. Diagnoses of heart failure  .In the presented retrospective study, hypertensive blood pressure was found in 61.6% of 24 h blood pressure monitoring examinations in older adults receiving comprehensive geriatric care. Irrespective of hypertensive BP, while hospitalized, patients both with and without hypertensive BP showed improvements in their functional status.Hypertension is an age-dependent clinical condition with increasing prevalence in older people. Epidemiological data confirm a high prevalence of more than 70% in older adults aged ≥65 years, and the female sex is the predominant gender associated with hypertension in that age group ,20. CompUnlike the lower prevalence of hypertension in patients with cardiac comorbidities, hypertensive BP was associated with a current fracture in the investigated cohort. This point could be explained by several factors that might trigger hypertension. Sympathetic stimulation after surgery with increasing catecholamine release, pain, anxiety, or volume overload could potentially impact the BP profiles of fracture patients ,27,28,29CGC, as a multimodal treatment strategy, also addresses the physical deficits of older people ,4,5,6. Tp = 0.017). This statistically objectified difference in GDS between both groups needs to be considered from the perspective that only GDS scores > 5 indicate depression [Our results revealed lower GDS scores in hypertension patients (median 3 vs. median 4, pression .A strength of this study is the documentation of extensive information on patients’ morbidity and functional status prior to and after the treatment. However, its limitations should also be mentioned. Our investigation was primarily focused on functional outcomes after CGC in the context of hypertension documented in BPM as our standard procedure for assessing patients’ daily BP profiles. Hypertension treatments, or the question of whether a hypertensive BP profile leads to therapy adaptions, were not investigated and could be considered as a major limitation of the presented study. In our specialized geriatric department, BP management is a very dynamic process in the treatment of multimorbid older adults with various diagnoses and comorbidities. Particularly, in patients recovering from surgery, with acute serious injuries or acute medical illnesses BP underlies disease-related fluctuations; thus, several modifications to antihypertensive medications are usually required during the hospital stay. In addition to BPM, daily manual BP measurements were also integrated into the clinical care routine. Initiation or adjustment of antihypertensive medication took place during daily visits, and was rendered by an individual physician’s judgment. To what extent recurrent manual hypertensive BP measurements or hypertension in BPM, respectively, lead to therapy adjustments is not regularly documented. This point affects all patients included in the study. As the second relevant biasing factor, it could be suspected that the white-coat effect impacts patients’ blood pressure profiles due to BPM being performed in a hospital setting. Overall, BPM seems to be advantageous because of the abundant information provided on patients’ daily blood pressure profiles, including night-time readings and short-term BP variability .Patients both with and without hypertensive BP profiles benefit from comprehensive geriatric care with comparable outcome improvements. Particularly, normotensive BP was associated with chronic cardiovascular comorbidities, indicating increased awareness of the importance of BP management in patients diagnosed with cardiac diseases.


P < 0.0001). In addition, the NLR levels were higher in the non-dipper than in the dipper group . Our findings showed that hypertensive patients had higher level of NLR than normotensive individuals.This study systematically reviewed the evidence regarding differences in the neutrophil to lymphocyte ratio (NLR) level between hypertensive and normotensive individuals as well as between patients with dipper and non-dipper hypertension (HTN). PubMed, Scopus, and Web of Science databases were systematically searched up to 20 December 2021. This was done without any limitation with regard to date, publication, or language. Pooled weighted mean differences (WMD) with 95% confidence intervals (95% CI) were reported. We assessed the quality of studies based on the Newcastle–Ottawa Scale (NOS). In total, 21 studies were included in our study. There was a significant increase in NLR levels for the hypertensive group in comparison to the control group (WMD = 0.40, 95%CI = 0.22–0.57,  Hypertension, a globally prevalent noncommunicable disease, has gained prominence in recent years as medical researchers have discovered some of the inflammatory components that underpins its etiology. In addition, several complications of hypertension, such as retinopathy, neuropathy, and cardiomyopathy, have been linked to the inflammatory response that develops in the arterial walls over time due to consistently elevated pressures. In addition, there is a large volume of published studies reporting the elevated level of inflammatory biomarkers in HTN patients. These studies have shown that inflammation in HTN occurs not only in the arterial walls, but also throughout the whole body. HTN can be divided into two groups, including the dipper and non-dipper groups. In patients with dipper HTN, systolic and diastolic blood pressure dropped by more than 10% during sleep. This diurnal pattern is thought to be a normal variant. Patients whose blood pressure does not show this diurnal pattern are referred to as "non-dippers." Non-dippers have a higher risk of cardiovascular disease and target organ damage than dippers . It is vA large and growing body of literature has investigated the role of inflammatory biomarkers and cytokines in HTN. However, in recent years, there has been increase interest in simple hematologic biomarkers such as the neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). Blood NLR is a simple marker for chronic low-grade inflammation that can be obtained easily from a differential blood count . NeutropThis study systematically reviewed the evidence regarding the differences in the NLR level between hypertensive and normotensive individuals as well as between patients with dipper and non-dipper HTN. The goal was to develop an understanding of the pathophysiology of HTN and explain the risk rise of cardiovascular events in dippers compared to non-dippers using the NLR.We conducted this meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines . PubMed,Population: Patients with HTN (either primary or secondary HTN) in first analysis AND patients with non-dipper HTN in the second analysisIntervention (Exposure): High NLRControl: Healthy control in first analysis AND patients with dipper HTN in the second analysisOutcomes: Diagnostic role of NLRStudies: case–control, cross-sectional, and cohort studiesThe inclusion criteria based on the PICOS principle were as follows.If the study did not report the level of NLR as a mean or standard deviation (SD), Wan et al.’s method was used to calculating the estimated values . In thisWe excluded the incomplete studies and abstracts, reviews, case reports, and animal studies. Two authors independently selected the articles for final inclusion according to these criteria, and if discrepancies existed, a third author resolved any disagreements.The extracted data were as follows: (1) first author; (2) country of origin; (3) year of publication; (4) study design; (5) number of cases and controls; (6) NLR level from cases and controls; (7) drug history; (8) mean age; (9) gender.2 statistics and Q test. The I 2 values showed serious (I 2 = 75–100%), high (I 2 = 50–74.9%), moderate (I 2 = 25–49.9%), low (I 2 = 0.1–24.9%), and no (I 2 = 0) heterogeneity. Furthermore, a significant Q-statistic showed heterogeneity among studies. If heterogeneity was high or serious (I2 ≥ 50%), we used the random-effect model; otherwise, we used the fixed-effect model. In addition, we used meta-regression and subgroup analysis to explore source of heterogeneity. Subgroup analysis was stratified by sample size. The small study was defined as studies with sample size ˂ 150, and studies with ≥ 150 patients were considered large studies. Egger’s and Begg’s tests and funnel plots were used to determine the publication bias. STATA 12.0 software  was used in data analyses. A 2-sided P < 0.05 was considered statistically significant.Pooled weighted mean difference (WMD) with 95% confidence interval (95% CI) was used to assess the differences in NLR levels between the patients with HTN and the controls or between dipper and non-dipper HTN patients. Because different studies used similar methods to measure the NLR, the unit of NLR among included studies was recorded the same. We assessed the quality of studies based on the Newcastle–Ottawa Scale (NOS) , with a Two authors determined the certainty of evidence using the GRADE  approach for two outcomes (HTN and non-dipper HTN)..The literature search gave a total of 2165 articles. After emitting the duplicates, 1794 remained. Among them, 64 were found to be relevant in initial evaluation based on title and abstract. An additional 34 studies were excluded due to lack of data on NLR level, seven due to irrelevant outcomes, and two because they were review articles. Finally, 21 studies –43 invesOf the 21 studies included in this meta-analysis –43, six P < 0.0001, Fig. 2 = 87.5%, p < 0.001); so we used random- effect model. However, the certainty of the evidence was low  or large studies  in comparison to normotensive individuals , publication year , NOS score , gender , mean age of cases , smoking , diabetes , NOS score , or BMI . In addition, use of beta-blocker , calcium channel blockers (CCB) , Angiotensin receptor blockers (ARB)  and diuretics  had no effect on the NLR; so they could not be the source of heterogeneity. However, use of angiotensin-converting enzyme (ACE) inhibitors  had significant effect on NLR; so it could be the source of heterogeneity.In the metaregression analysis, there was no significant effect of total sample size ; so we used a random-effect model. According to GRADE method, the certainty of the evidence was low , but not in small studies  when comparing to patients with dipper HTN  and BMI  could be a source of heterogeneity. However, there was no significant effect of total sample size , publication year , NOS score , gender , mean age of cases , smoking , diabetes , and BMI  on the association between NLR and HTN; so they could not be the source of heterogeneity.In the metaregression analysis, we found that smoking , and between patients with dipper and non-dipper HTN .As seen in Fig. The exact etiology which underlies HTN, a known risk factor for cardiovascular disease, is still unclear , 47. In The inflammation can possibly play a role in the pathophysiology of HTN through an increase in inflammatory markers like IL-1β, IL-6, and TNF-α . Based oNeutrophils, the predominant leukocyte in the blood, are polymorphonuclear granulocytes that play an important role in modulating innate and adaptive immune responses , 53. In A study by Morton et al. strongly suggests a direct involvement of neutrophils in the control of blood pressure. They indicate that decreased neutrophils in normotensive mice can lead to a reduction in endothelial-dependent vasoconstriction and systolic blood pressure .Therefore, according to these aforementioned mechanisms, increased neutrophil counts can likely attribute to high blood pressure.h1 response. These mice had sustained hypertensive responses but were protected from renal damage from chronic angiotensin II provocation [h1 cells can cause kidney injury that is independent of high blood pressure [The leukocyte response seen in increased NLR ratios is lymphocyte dependent. Reduction in the number of lymphocytes results in physiologic stress and poor health status . There avocation . The datpressure .h17 cells. This release plays a role in the pathogenesis of many autoimmune diseases. The effect of Th17 lymphocytes on blood pressure is still controversial. However, the injurious effect of IL-17 or IL-23 deficiency in the DOCA/salt model of hypertension indicates a protective role for Th17 cells [Secretion of IL-17, known as a proinflammatory cytokine, is primarily by T17 cells .h1 and Th17 cells, regulatory T lymphocytes can modulate the anti-inflammatory cellular immune responses [reg cells by mediating the angiotensin II response [reg cells produce IL-10, which is an important cytokine. In addition to immunosuppression, endogenous IL-10 can reduce oxidative stress and vascular dysfunction by a blood pressure-independent mechanism. It has been shown that exogenous IL-10 can reduce blood pressure to the normal range and make the endothelial function normal in hypertensive pregnant mice [reg cells mediated through the IL-10 response warrants further investigation.In opposition to the inflammatory role of Tesponses , 59. An response . Treg ceant mice . Thus, tDespite the fact that additional studies should be done to elucidate the role of CD8 + T Lymphocytes in modulating hypertension, it has been shown that mice deficient in transcription factor inhibitor of differentiation (Id2) have altered CD8 + T cell memory and decreased natural killer cells. These mice do not exhibit hypertension induced by angiotensin II .In summary, different subtypes of T lymphocytes can induce various levels of inflammation, which can either lead to hypertension or protect against it. The protective role of Treg cells was indicated, and it was stated that Th17 might have some protective effect against HTN if appropriately regulated.Another type of lymphocyte is B cells which are necessary for adaptive immunity. The mechanisms by which B cells can play a role in hypertension has not been explored enough. However, it has been indicated by Chan and colleagues that angiotensin infusions induce further increase in B cells as well as plasma cell activation in lymphoid tissues. On the other hand, anti-CD20 antibody administration and genetic deficiency of B cells can cause the protection of mice against the hypertensive effects of angiotensin II . FinallyIn our study, we indicate that in hypertensive patients, the number of neutrophils is increased, and the number of T lymphocytes that have a protective role is decreased. So, the NLR will be higher in hypertensive individuals and lower in normative controls.As it has been stated before that non-dipper hypertensive individuals have a higher cardiovascular disease risk due to myocardial infarction and target organ damage compared with dipper hypertensive patients , 64. TheHigher blood pressure levels in non-dipper hypertensive individuals over the night can cause endothelial damage that triggers the proinflammatory process. Furthermore, inflammation can lead to blood pressure elevation. As a result, increased inflammation and high blood pressure both can feedback on each other contributing to cellular damage , 68. FinSome limitations of our study do exist. First, geographic variability is essential to consider in the context of these results. The majority of current studies on this topic were performed in Turkey. Disparities in both HTN rates as well as HTN outcomes have been shown within different geological locations. It is important to note that the results from the studies on this topic to date may not be as applicable to hypertensive patients located in different geographical regions. Thus, similar prospective and retrospective studies are warranted in wider geographic locations to characterize any potential differences between these populations. Second, heterogeneity in studies was greater than expected due to various treatment regimens, age ranges, and gender differences for included patients. Therefore, widespread validity is a concern, and future larger prospective studies are needed. Third, this review was not registered in PROSPERO. Finally, several studies are limited by bias, whether based on selection or publication, which should be considered.The current study is mainly providing knowledge of pathology of hypertension. Patients with HTN had higher level of NLR than normotensive individuals. In addition, patients with non-dipper HTN had higher NLR than those with dipper HTN. NLR represents a unique inflammatory marker whose elevation in HTN provides implications regarding immune system imbalance in the pathogenesis of the disease. In evaluation of included studies, it can be concluded that there may be association between HTN and NLR. Ultimately, with the development of new biomarkers and therapeutic modalities, we can better prevent and treat delirium to decrease long-term morbidity and mortality.