The management of hypertensive disorders of pregnancy (HDP) during hospitalization requires an accurate blood pressure (BP) measurement, mainly by invasive intra-arterial reading. Nevertheless, little is known about the precision of non-invasive (NI) central BP measurements in HDP. We aimed to assess the accuracy of NI central BP assessment in comparison to invasive BP measurement in HDP.This cross-sectional study included all patients with HDP that were admitted to university hospitals for high BP control, from December 2018 till December 2019, and 10 healthy matched non-hypertensive controls. Patients were compared for demographic, anthropometric, and echocardiographic data. In all subjects, invasive BP assessment was done by radial arterial cannulation and NI assessment of BP was performed by an oscillometric automated device (Mobil-O-Graph); the comparison was done after initial control of BP.p = 0.5) and diastolic BP  among the total studied population. A strong positive correlation was found between NI central and invasive SBP . HDP was associated with an increase in arterial stiffness, left ventricular diastolic dysfunction, and complications.One hundred patients were included and divided into 3 groups (pre-existing hypertension (HTN), gestational HTN, and pre-eclampsia). There was no statistically significant difference between NI central and invasive methods in measuring both systolic BP (SBP) . Hypertensive disorders of pregnancy (HDP), an umbrella that includes pre-existing and gestational hypertension, pre-eclampsia, and eclampsia, complicate up to 10% of pregnancies and represent a significant cause of maternal and perinatal morbidity and mortality [The definition of hypertension (HTN) in pregnancy is based only on office  BP values [systolic BP (SBP) ≥ 140 mmHg and/or diastolic BP (DBP) ≥ 90 mmHg]. However, the pathophysiology of HTN in pregnancy leading to a significant difference between central and peripheral hemodynamics all through pregnancy, thus necessitating the use of other methods to follow up HDP , 3. BracInvasive blood pressure measurement via arterial cannulation, commonly from a major artery, is considered to be the most accurate method of blood pressure measurement in those patients that need intensive care admission for control of high BP during pregnancy . HoweverIn this study on pregnant women with different types of HTN, we studied the accuracy of non-invasive central blood pressure assessment by an oscillometric automated device (Mobil-O-Graph) in comparison to the standard invasive blood pressure measurement.This cross-sectional study was conducted between the 1st of December 2018 to the 1st of December 2019 at a university hospital. The study was approved by our university institutional review board (RD no. = 17101032) and complied with the Declaration of Helsinki. Written informed consent was obtained from all patients .We included all pregnant women admitted to our university women’s health hospital during this period and diagnosed to have HDP that necessitate hospital management by anti-hypertensive medications. Exclusion criteria were patients with a history of cardiac diseases, chronic kidney disease, endocrine diseases such as hyperthyroidism, and conditions that prevent arterial cannulation as severe bleeding disorders or peripheral arterial disease. One hundred seventeen patients were recruited; 17 patients were excluded . Another group of 10 healthy non-hypertensive non-pregnant women, with matched age, weight, and height, were also included in the study as a control group to validate BP measurements’ accuracy, both invasive and central non-invasive techniques. We divided our patients into 3 groups according to recent 2018 ESC guidelines of HTN [All patients were subjected to a full medical and an obstetric history taking and clinical examination, including BP measurement by 3 different methods and echocardiographic examination. Exclusion of albuminuria was done at the time of hospital admission as routine work to all participants using the dipstick method owing to its sensitivity, convenience, and being widely available.A)Office blood pressure measurement using sphygmomanometer: According to ESC guidelines of hypertension 2018, BP was measured in the sitting position  with an appropriately sized arm cuff at heart level and using Korotkoff V for DBP, and an average of 3 readings was done [B)Non-invasive central BP monitoring in a quiet, temperature-controlled examination room: Three measurements with a 2-min break between them were taken to all patients in a sitting position with an adequately sized cuff. The Mobil-O-Graph 24 h NG  with inbuilt ARC Solver  and its blood pressure detection unit is validated according to the British Hypertension Society and European Society of Hypertension recommendations , 10. AlgC)Invasive blood pressure measurement through percutaneous radial artery cannulation by 20-gauge Teflon cannula under aseptic conditions after palpation of the artery as a guide. Cannulation was done by a single experienced operator. The arterial cannula was connected to a disposable tubing system and flushed frequently with a heparinized 0.9% saline solution. The tubing liquid was connected to a transducer . The transducer was kept horizontally at the level of the patient’s 4th intercostal anterior axillary line, and the radial access was at the same height of the cuff. We perform zeroing by opening the transducer to the atmospheric pressure and electronically zeroing the system. We recorded the arterial blood pressure signals by using a bedside monitor .In the blood pressure assessment in all studied groups, BP measurement was done after control of initial blood pressure on the 3rd or 4th day of hospital admission by 3 different methods including:P = 0.001).The BP measurements using the three mentioned methods were conducted by 2 different clinicians (A.G and M.K) in 2 different occasions using the standardized measuring procedures and reported their reading separately to the data collecting hub nurse. The inter-observer agreement was calculated with weighted Kappa statistics and showed good agreement  was performed on all patients before discharge from the hospital. ECHO was performed in the left lateral decubitus position using VIVID S5 instrument, GE Medical Systems, Horten, Norway, based on the recommendations of the European Association of Echocardiography (EAE) and American Society of Echocardiography (ASE) . Assessmt test. Analysis of variance (ANOVA) test was used to compare differences between more than two groups. The inter-observer agreement was calculated with weighted Kappa statistics. Correlations were done by Spearman correlation coefficient test. All P values are two-tailed, and statistical significance was defined if P < 0.05. Our analyses were performed with SPSS version 22.0 statistical software .We presented the categorical variables as counts and percentages then compared by Pearson chi-square analysis or Fisher’s exact test. We tested the normal distribution of our continuous data by Kolmogorov-Smirnov test. We presented continuous and normally distributed data as mean ± SD and were compared by unpaired The current study examined 117 patients for eligibility. Seventeen patients were excluded . Finally, the study included 100 pregnant participants and 10 healthy controls (non-hypertensive and non-pregnant women) who were seen and examined at a Women Health Hospital and a University Heart Hospital. We divided our patients into 3 main groups, defined according to 2018 ESC guidelines of hypertension [The mean age of the study population was 29.16 ± 6.6 years with no significant difference between all 3 groups. The lowest number of previous pregnancies was seen in the pre-eclampsia group (2 ± 2) as shown in Table p = 0.5) and DBP  among the total studied population. The same non-significant difference was noted among the studied groups, including the control, as shown in Table Results showed no significant difference between non-invasive central and invasive methods in measuring both SBP . Moreover, noninvasive central DBP and invasive DBP showed moderate positive correlation  as shown in Fig. Using Spearman correlation test, a strong positive correlation was found between noninvasive central SBP and invasive SBP (Table p < 0.001 for AIx and 0.03 for PWV) in the control group, as shown in Fig. Both are considered indicators of arterial stiffness and were recorded from the non-invasive oscillometric device ( Mobil-O-Graph). Both parameters were compared between the three different hypertensive groups and the control group. AIx and PWV were significantly lower , passed their pregnancy smoothly without complications. most complications were noticed in the pre-eclampsia group including (intrauterine growth retardation (IUGR) = eight patients, oligohydramnios = 4 patients, and HELLP syndrome = 13 patients). Eclampsia was found in 4 patients in the pre-existing hypertension group and 6 cases in the gestational hypertension group.Little is known about the accuracy of non-invasive central blood pressure by an oscillometric automated device (Mobil-O-Graph) to the invasive blood pressure measurement by arterial cannulation conducted on the same population in hypertensive pregnant women.Key findings of our study are as follows: (1) there was no difference between non-invasive BP readings by oscillometric automated devices (Mobil-O-Graph) and invasive BP readings, and (2) hypertension in pregnancy was associated with an increase in arterial stiffness, left ventricular diastolic dysfunction, and complications.Regarding the main aim of the study, to assess the accuracy of non-invasive central BP measurements in comparison to invasive BP measurement, results showed no statistically significant difference between SBP and DBP measurements by the two methods between the different studied groups indicating that central blood pressure measured non-invasively by the oscillometric automated device (Mobil-O-Graph) is accurate as of the invasive assessment of blood pressure, and the strong positive correlation between non-invasive central blood pressure measurements and invasively measured both systolic BP and diastolic BP confirm this conclusion.r = 0.763, p < 0.001) and diastolic  central blood pressures and non-invasive BP readings.In agreement with our results, Gotzmann and colleagues  conducter = 0.89) and women (r = 0.917).In the same context, another study, by Sanchez and colleagues , in 20 sr= 0.899, p < 0.001) central blood pressure in agreement with our results.Another study, by Weber and colleagues , includeOf note, central hemodynamics recorded by the oscillometric device (Mobil-O-Graph) uses in the current study showed that AIx and PWV were higher in the pre-existing hypertension group with a significant difference when compared to non-hypertensive control.p value 0.001, and the PWV values were higher in the preeclamptic groups but with a non-significant difference.Concordant to our results, Franz and colleagues  conductep value < 0.05.Furthermore, in Elvan-Tasšpinar and colleagues’  study ofDespite being used routinely, sphygmomanometer BP has many limitations, as it does not represent real-life BP, in addition to the discrepancy between brachial BP and central BP with its predictive value for cardiovascular events . CentralIn our study, we found a significant difference between sphygmomanometer and central methods in both SBP and DBP readings in patients with HDP, including pre-eclampsia. This was in concordance with Langenegger et al. who found discordance between readings collected by direct intra-arterial monitoring and peripheral methods by both manual and automated devices, and they concluded that invasive central BP monitoring is mandatory in patients with severe pre-eclampsia .Regarding diastolic dysfunction, we found that diastolic dysfunction was more frequent in patients with HDP, including pre-eclampsia. In concordance with these results, Guirguis et al. found more frequent diastolic dysfunction in patients with pre-eclampsia. Furthermore, we demonstrated that other variants of HDP were also associated with diastolic dysfunction .The invasive maneuver used  was refused by some patients, failed in other ones, and was an obstacle. We depended on radial cannulation  rather than advancing catheters into the aorta for accurate central BP assessment for comparison. The small number of non-pregnant, non-hypertensive matched the control due to logistic reasons. Lack of BP measurement, using the oscillometric automated device (Mobil-O-Graph), before and after BP control, could elucidate its role in an emergency. In this study, we did not evaluate the effect of different drugs used in HDP on BP control centrally or on pregnancy outcomes.Non-invasive measurement of central BP using oscillometric automated devices is as accurate as of the invasive methods, and it is a practical, safe method in pregnant women with hypertensive disorders. HDP was associated with an increase in arterial stiffness, left ventricular diastolic dysfunction, and complications.


BackgroundAround 10% patients with hypertension have resistant hypertension (RH). Older age, Black race, obesity, diabetes mellitus (DM) and chronic kidney disease (CKD) are the common risk factors for RH. The present study was done to find out the prevalence and factors associated with RH.MethodsThis cross-sectional study was done between December 2018 and February 2020. Adult patients registered with the hypertension clinic and on care for more than three months were included in the study. History was noted and blood pressure (BP) was measured using standard precautions. The patients were divided into two groups - resistant and non-resistant hypertension. Chi-square test was done to check the significance of the differences between the two groups. Binary logistic regression was done for the risk factors with a p-value < 0.2 in the Chi-square test.ResultsA total of 275 patients were included. The mean age was 56 ± 10 years and 61% were females. The mean duration of hypertension was 7 ± 5 years; 77% of patients were overweight or obese. A family history of hypertension was present in 30% and 18% had diabetes mellitus. History suggestive of secondary hypertension was present in 13%. BP was controlled (<130/80 mm of hg) in 145 (53%), uncontrolled in 130 (47%) and resistant hypertension was seen in 31 [(11%) 95% CI 8-16%] patients. Duration of hypertension, obesity, and elevated fasting blood sugar were significantly associated with RH. ConclusionsRH was found in 11% of hypertensive patients. Longer duration of hypertension, obesity, and higher fasting blood glucose were associated with RH. High blood pressure (BP) has a graded association with increased cardiovascular disease (CVD) risk . Twenty Resistant hypertension (RH) is defined as elevated BP above-goal despite the concurrent use of three antihypertensive drug classes, commonly including a long-acting calcium channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. The antihypertensive drugs should be administered at maximum or maximally tolerated daily doses. RH also includes patients whose BP achieves target values on ≥ four antihypertensive medications. .Meta-analysis of data from 3.2 million patients has estimated that the global prevalence of true resistant hypertension is 10%, which was lower than the prevalence of apparent treatment-resistant hypertension (when pseudo-resistant hypertension is not excluded) .Common risk factors for resistant hypertension include older age, obesity, chronic kidney disease (CKD), Black race, and diabetes mellitus (DM). All the available studies so far have taken BP control target of < 140/90 mmHg but the American Heart Association revised the control target to < 130/80 in 2017 . It is eWe undertook this study to find out the prevalence of RH among patients attending a hypertension clinic at a tertiary care referral hospital in South India and also studied the factors associated with RH using the newer control target as there were no previous such studies in this region. SettingThis was a cross-sectional, analytical study conducted in the Hypertension Clinic of Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, a tertiary care referral hospital in South India catering to patients mainly from Puducherry, neighbouring districts of Tamil Nadu, Kerala, and Andhra Pradesh, between December 2018 and February 2020. The hypertension clinic at JIPMER runs every Tuesday between 14.00 and 16.30 hours and around 100 to 150 patients attend the clinic every week. Patients are given free medicines every month during follow-up visits. The study was approved by the Institute Ethics Committee (JIP/IEC/2018/0187).ParticipantsAdult (> 18 years of age) patients registered with hypertension clinic and on treatment for more than three months were included in the study. There were no exclusion criteria used for our study. A list of patients attending the clinic for a two-month period was prepared and consecutive patients were included from the line list till the sample size was achieved.Sample size calculationwww.OpenEpi.com).Assuming the proportion of patients with resistant hypertension as 20% based on a study done in a similar setting as ours in Sri Lanka  with absProcedureEligible patients were enrolled in the study after taking written informed consent. Demographic details , lifestyle-related information , treatment-related information , oral contraceptive pills, cyclosporine, erythropoietin, etc.), family history of hypertension and features suggestive of secondary hypertension  were noted in a predesigned proforma. The presence of diabetes mellitus, ischemic heart disease (IHD), chronic kidney disease, dyslipidemia, and thyroid disorders were confirmed from the previous records of the patients.Measurement of BPStandard precautions were used while measuring blood pressure. Participants were advised to empty the bladder if needed and asked to sit relaxed with feet on the floor and arm and back supported for five minutes. No smoking, exercise, or intake of caffeine within 30 minutes preceding the measurement was ensured. Arm circumference was measured and appropriate cuff size was used accordingly. BP was measured with a mercury sphygmomanometer in both arms and in the standing position to check for orthostatic hypotension. BP was rechecked after few minutes in the arm with higher recording. The second reading was taken as the actual blood pressure of the patient.Other relevant physical examinations and investigations were done to identify secondary hypertension and target organ damage. Adherence to antihypertensive medications was assessed using the Morisky Green Levine adherence scale . A scoreDefinitionsUncontrolled hypertension was defined as blood pressure ≥ 130/80 mm of Hg. Uncontrolled resistant hypertension was defined as blood pressure ≥ 130/80 mm of Hg on three or more antihypertensive drugs with optimal doses including a diuretic. Controlled resistant hypertension was defined as blood pressure < 130/80 on more than three antihypertensive drugs with maximal/maximally tolerated doses including a diuretic. Excess alcohol consumption included binge drinking, heavy drinking, and any drinking below 21 years of age. Physical activity was defined as 30 minutes of aerobic exercise five times per week for a total of 150 minutes per week. BMI was categorized according to 2004 WHO classification for the Asian population. Overweight is defined as BMI of 23-24.9 kg/m2 and obese is defined as BMI ≥ 25 kg/m2.Estimation of salt intakeThe following formula was used for the estimation of 24-hour urinary sodium excretion from spot urinary sodium and creatinine values ..The predicted 24-hour urinary creatinine was calculated using the following formula:The daily salt intake was estimated by multiplying 2.54 to the sodium excretion per day .Statistical analysisData entry was done using Epicollect 5  and analysis was done using SPSS version 19 . Patients were divided into two groups - resistant and non-resistant hypertension. Frequencies with percentage were calculated for all categorical variables. Chi-square test was done to check the significance of the differences between the two groups. P-value < 0.05 was considered as statistically significant. Multivariable analysis (binary logistic regression) was done to identify the factors associated with RH. Those variables with a p-value < 0.2 in the unadjusted analysis were included in the multivariable model.A total of 275 patients were included in the study. The mean age of the patients was 56 ± 10 years (range 28-81 years) and 61% (n=169) of the patients were females. The mean duration of hypertension was 7 ± 5 years (range 1-30 years). The mean BMI of the patients was 25 ± 4 kg/m2 and 77% (n=213) patients were overweight or obese. A family history of hypertension was present in 30% of patients (n=83) and 18% (n=50) patients had diabetes mellitus.History suggestive of secondary hypertension was present in 36 (13%) patients of which eight (3%) patients had a history of recent weight gain, 30 (11%) patients had a history of sleep disturbances which include erratic sleep, reduced sleep (less than four hours), daytime sleepiness and snoring and 14 (5%) patients had a history of other drug intakes which can contribute to secondary hypertension. Left ventricular hypertrophy was present in 42% (n= 106) and hypertensive retinopathy was present in 40% (n=91). The most commonly used antihypertensive drugs were amlodipine (81%) followed by enalapril (53%) and thiazide diuretic (21%).Blood pressure was controlled (< 130/80 mm of Hg) in 145 (53%) patients whereas, it was uncontrolled in 130 (47%) patients. Of 130 patients with uncontrolled hypertension, 81 (29%) patients had uncontrolled hypertension due to therapeutic inertia and 22 (8%) had uncontrolled hypertension due to non-adherence to drug therapy. Treatment-resistant hypertension was seen in 31 [(11%) 95% CI 8-16%] patients. Of these, 27 (10%) had uncontrolled resistant hypertension and four (1%) had controlled resistant hypertension , and fasting blood glucose (FBG) between patients with non-resistant and resistant hypertension  Table .As the duration of hypertension increases, the prevalence of resistant hypertension increased. In the binary logistic regression analysis hypertension duration > 10 years, obesity (BMI ≥ 25), disordered sleep, and FBG> 125 were significantly associated with resistant hypertension Table .Resistant hypertension increases end organ damage, cardiovascular morbidity, and premature death significantly . We condTherapeutic inertia is one of the important causes of uncontrolled hypertension . It is dDuration of hypertension, elevated FBG, and disordered sleep was significantly associated with resistant hypertension. A history of erratic sleep was present in 29% of patients with RH. High salt intake causes uncontrolled hypertension but we could not demonstrate significant association between high salt intake and RH.In a meta-analysis including 91 studies published between 1991 and 2017 with a pooled sample of 3,207,911 patients, the global prevalence of RH was 10.3% . RH prevIn a study done in a secondary care setting in Jaipur, India, the prevalence of RH was found to be 19% , which iEven in the United States, the National Health and Nutrition Examination Survey (NHANES) prevalence estimates suggest that uncontrolled hypertension is a major issue with rates being as high as 51% in men and 45% for women overall and up to 30% among those who are on treatment . AwareneTomaszewsk et al reported higher rates of 25% of nonadherence among patients with uncontrolled hypertension from the UK . Higher Duration of hypertension, obesity, and elevated FBG were significantly associated with RH in this study. A similar association was also demonstrated in many other studies ,7,12,13.A Cochrane review of meta-analysis including 34 trials suggests a modest reduction of salt intake for a longer period of time causes a reduction in blood pressure. Salt intake of 4.4 gm/day on an average reduces BP 5/3 mm of hg in hypertensive and 2/1 mm of hg in normotensive people . The golTo the best of our knowledge, this is the first study from South India on the prevalence of RH. We included an adequate sample size of 275 hypertensive patients attending a hypertension clinic. BP for all patients was measured by a single investigator (RM) with a mercury sphygmomanometer using standard precautions. We also systematically studied the adherence to medications using the Morisky Green Levine scale. However, our study had many limitations. The prevalence of resistant hypertension in our study (11%) might be an overestimation as we could not rule out white coat effect by 24-hour ambulatory BP measurement. It is possible that since we have separate clinics for cardiovascular diseases and kidney diseases, we had less number of patients with these comorbidities where prevalence of RH is found to be high . We coulPrevalence of treatment-resistant hypertension in our study was 11% and longer duration of hypertension, obesity, history of disordered sleep, and elevated fasting blood glucose were associated with RH. Therapeutic inertia among doctors is very high which needs to be addressed with continued education and training.


Mean blood pressure (MBP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse wave velocity  were assessed via a Vicorder device. Asymmetric dimethylarginine (ADMA) was measured via ELISA. Retinal photos were taken via a CR-2 retinal camera, and retinal microvasculature analysis was carried out. T-tests were conducted to compare the disease and control groups. ANOVA and ANOVA—ANCOVA were also used for the correction of covariates. Results: A high prevalence of hypertension was seen in RA (80% of cases) and PSS (40% of cases) compared to controls (only 20% of cases). Significant changes were seen in MBP , SBP , DBP . Patients with PSS showed no significant difference as compared to controls . Increased plasma ADMA was seen in RA (0.45 ± 0.069 ng/mL) and PSS (0.43 ± 0.060 ng/mL) patients as compared to controls (0.38 ± 0.059 ng/mL). ADMA in RA vs. control was statistically significant (p = 0.022). However, no differences were seen in ADMA in PSS vs. controls. PWV and retinal microvasculature did not differ across the three groups. Conclusions: The prevalence of hypertension in our cohort was very high. Similarly, signs of endothelial dysfunction were seen in autoimmune rheumatic diseases. As hypertension and endothelial dysfunction are important contributing risk factors for cardiovascular diseases, the association of hypertension and endothelial dysfunction should be monitored closely in autoimmune diseases.Background: The etiology of autoimmune rheumatic diseases is unknown. Endothelial dysfunction and premature atherosclerosis are commonly seen in these patients. Atherosclerosis is considered one of the main causes of cardiovascular diseases. Hypertension is considered the most important traditional cardiovascular risk. This case-control study aimed to investigate the relationship between autoimmune diseases and cardiovascular risk. Methods: This study was carried out in patients with rheumatoid arthritis, RA ( Autoimmune diseases are diseases in which the immune system loses its tolerance to self-antigen and starts to attack its tissues and organs . The cauThe endothelium is the thin innermost layer in the blood vessels. Endothelial cells secrete chemical mediators that can cause constriction and dilation of blood vessels and ensures smooth blood flow in vessels as part of the body’s homeostasis. One of the most important chemical mediators secreted by the endothelium is nitric oxide, which plays a major role in blood circulation. Nitric oxide is the main vasodilator of blood vessels and prevents atherosclerosis, platelet aggregation, leucocytes adhesion to the vessels wall, and thrombosis ,9. DistuAsymmetric dimethylarginine (ADMA) is a competitive inhibitor of nitric oxide synthases (NOSs), a group of enzymes that catalyze the production of nitric oxide (NO) from L-arginine. ADMA, by its antagonizing action on nitric oxide, plays an important part in the development of endothelial dysfunction ,12. ADMAHypertension is considered the most important traditional cardiovascular risk factor in the development of atherosclerosis and cardiovascular diseases . Up to 9The relation between chronic inflammation in autoimmune diseases, endothelial dysfunction, and atherosclerosis is still unknown . What roRetinal vessel diameter is affected by many factors like age, weight, height, and eye diseases, but the most important factor is blood pressure ,47. UsuaPulse wave velocity is a well-known technique to assess arterial stiffness ,50. It dCardiovascular diseases are the endpoint of endothelial dysfunction, whether in autoimmune diseases or other diseases. The current European League Against Rheumatism (EULAR) guidelines state that the cardiovascular risk in autoimmune disease is 1.5× greater when compared to the cardiac risk in patients not having chronic inflammation . ChronicTo our knowledge, this study is the first study to investigate the relationship between endothelial dysfunction and hypertension in rheumatoid arthritis and Sjögren disease as compared to age-matched healthy persons, as well as whether endothelial dysfunction is already present in autoimmune diseases, and the relation between endothelial dysfunction and hypertension, cause or result.The following is a preliminary case-control study aimed to investigate the relationship between autoimmune disease and cardiovascular risk factors and to study the effect of chronic inflammation on the vascular function that utilized patients with two autoimmune diseases. The diseases studied are RA, as the prototype of rheumatological autoimmune diseases with excessive inflammation on vascular function, and PSS, with mild or moderate inflammation. The specific aim was to assess the effects of these diseases and use this data for bigger epidemiological studies, including with other diseases.A case-control pilot study was carried out at the Rheumatology Clinic at the Medical University of Graz, Austria, between February 2021 and March 2021. There were 3 groups of participants: patients with rheumatoid arthritis, primary Sjögren syndrome, and age-matched healthy controls.Male or female adults above 18 years old who were diagnosed with rheumatoid arthritis by the 2010 ACR/EULAR classification criteria , and priThe study was conducted in accordance with the principles stated in the Declaration of Helsinki of 1964 and its most recent revision (2013), as well as local and national regulations in Graz, Austria. Ethical approval was obtained from the Ethical Committee at the Medical University of Graz (Project identification code: 32-283 ex 19/20). The patients were informed about the study aims and the detailed protocol. Written informed consent was obtained from participants before enrolling them in the study. The study adhered to the standards of reporting and was in accordance with the National Data Protection act, wherein each participant was assigned a code and data samples were stored anonymously.Data related to age, gender, weight, height, diagnosis, medication, lifestyle factors such as smoking, alcohol consumption, or physical activity were recorded.Blood pressure was measured in a quiet room using the Vicorder device . After resting for 10 min, the patients explained the maneuver and consent given. Then participants remained in a supine position for another 10 min prior to measurements. A slandered 7 cm pressure cuff was used to measure systolic blood pressure (SBP), diastolic blood pressure (DBP). Mean blood pressure (MBP) was calculated. Hypertension is defined by patients taking medication for hypertension or blood pressure over 140 systolic and 90 diastolic.PWV measured by the arterial wall stiffness was assessed non-invasively by a Vicorder device. The Vicorder measures the speed of waves transmitted between 2 points through the wall of large carotid and femoral arteries. The device is connected to a laptop software program that analyzes the wave and gives the result of the speed in m/s. Following 20 min of supine relaxation, pulse wave velocity was assessed.This was carried out using the CR-2 Canon automated camera. The software program Mona-Riva was used for analyzing the diameter of the six biggest arterioles and six biggest venules in the retina. Assessed were the central retinal arteriole equivalent (CRAE) and central retinal venule equivalent (CRVE), as well as the A/V ratio (% of CRA to CRV). 10 cm of blood was obtained from the participants. Blood sample taken for measuring lipid profile , low-density lipoprotein (LDL)), serum creatinine, and endothelial dysfunction markers as ADMA. ADMA was assessed by enzyme-linked immunosorbent assay . The normal range for the kits was 0.29–63 ng/mL.p < 0.05 was considered as the level of statistical significance except where an alpha level correction was necessary (Benjamini-Hochberg).Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) software . Statistically, we used t-tests for comparison between the disease and control groups. ANOVA and ANOVA—ANCOVA was used for the correction of significant covariates . Additionally, the Pearson correlations of the parameters with each other were carried out. The descriptive statistics were given as a number, percentage, and mean ± standard deviation, and median (range). A Due to the limited sample size, multivariate models may not be appropriate. However, this pilot study will help us to plan for bigger epidemiological studies, in which we will use a general mixed model to assess these effects across the sexes, over repeated measurements, and across the participant groups.Correlation coefficient (r) results between 1 and −1 with results ±1, indicates a linear correlation in the same or other direction. We took 0–0.3 to be no correlation, 0.4–0.6 as moderate correlation, and 0.7–1 as a significant correlation .To reduce the inter- and intra-rate variability of vascular assessments, we ensured that all the vascular measurements were only carried out by one person each time and across all the patients.The patient’s database stored in the rheumatology department at the Medical University of Graz was examined. Disease activity was 3.5 (median)  in RA and 3  in PSS. All patients were stable during their follow-ups in outpatient clinics at the time of examination.Each of the investigated groups consisted of 10 patients; in RA, there were eight females, two males, age 55.3 ± 7 years, 79 kg (57–140). Only four out of the eight patients were taking antihypertensive medication. As none of the patients were taking vasodilators or diuretics to control their blood pressure, we believe that our results could not have been influenced by the medications of the patients. All the groups were taking biological disease-modified anti-rheumatoid drugs (DMARDS) plus Methotrexate (7 of 10). PSS group ) patients were not known to be hypertensive, and only one patient received mycophenolate mofetil. The healthy control group included two males and eight females of age 50 ± 9 years and weight 72.5 kg (60–105). p-value: 0.007, DBP, p-value: 0.01, and MBP p-value: 0.01) . However, significant values are seen when the autoimmune diseases are compared with the healthy controls . In the RA group, 80% of the patients had elevated blood pressure  while 40% of PSS patients had elevated blood pressure . However, only 20% of the controls showed elevated blood pressure . Statistical analyses showed significant differences between the RA group vs. the control group  . PSS patNo correlation between elevated blood pressure and kidney function in regard to serum creatinine was seen (0.154). With regards to the age of the participants, there is a correlation between age and blood pressure in the diseased group (0.714) but not in the control group (0.408). p = 0.02). However, there were no statistical differences in the ADMA levels of PSS patients as compared to controls . On the other hand, there was a significant correlation between ADMA and weight (0.612) as well as creatinine level  (0.525). However, no significant correlation between ADMA and PWV (0.348) (only in PSS) was observed (0.669).p = 0.02, p = 0.003, respectively) and MBP  but not in DBP . The control group showed significant correlations in SBP (p = 0.02).Pulse wave velocity values varied across the three groups: RA group (10.2 ± 2.31 m/s), PSS (8.74 ± 1.64 m/s), and control group (8.69 ± 1.78 m/s). However, no statistical differences were seen between the patient groups compared to the controls . There iAge and pulse wave velocity: There was a significant correlation between age and PWV  in all the groups (r = 0.703); on the other hand, no correlation between PWV and disease duration was found (r = 0.179).p = 0.125) as compared to the PSS patients  and control group (151 mic ± 21). The retinal vein diameter showed no changes between all groups. Analysis of retinal blood vessels showed no statistically significant differences between the diseased group and healthy controls. However, there was a decrease in retinal arterial diameter in the RA group , height (−0.578), ADMA (−0.517), and BP (−0.465) was seen with CRAE in the diseased group. This was, however, not the case in the healthy controls. Finally, no correlations between cholesterol level values and those of blood pressure (0.252), ADMA (−0.105), PWV (0.13), or CRAE (0.17) were seen.It was surprising to report that even with this limited number of participants in each group, we were able to see statistically significant differences across the populations studied. We also observed a high prevalence of hypertension in patients with the two types of autoimmune diseases. This result is particularly important, as currently, the evidence regarding the true prevalence of hypertension in autoimmune diseases is still not clear. Moreover, our findings also contribute to the ongoing debate regarding hypertension and vascular functional changes in autoimmune patients—is it hypertension that causes endothelial dysfunction, or does the endothelial dysfunction, which accompanies chronic inflammatory states, lead to hypertension. Our paper adds to the exciting and important discussions in this area. However, these data are going to be used for planning and carrying out bigger epidemiological studies in the future.We also agree that a comparison between two diseases can be a problem, especially when a major, very common disease is compared with another less known disease. However, it was not our intention to compare RA and PSS; rather, we compared chronic inflammation in autoimmune disease patients and healthy persons. Our study showed that elevated blood pressure is a very common sign in autoimmune diseases, especially in rheumatoid arthritis. In addition, there appears to be an associated endothelial dysfunction, as shown by elevated plasma ADMA levels but no accompanying effects on macro- or micro-vascular circulation. Arterial stiffness, using pulse wave velocity measurements, was used to assess general vascular function, while the microvascular function was assessed via retinal imaging studies in which central retinal arteriole and central retinal venule diameters were measured. Currently, there is debate about the percentage of hypertension in autoimmune diseases. While some studies reported the occurrence of accompanying hypertension, others did not observe blood pressure differences between those with autoimmune diseases and healthy persons ,29,33.Our results show that hypertension prevalence is high in autoimmune diseases, especially in rheumatoid arthritis. From the foregoing discussion, it appears that the occurrence of hypertension in autoimmune diseases has been poorly studied and underreported. This is really alarming as it is important to assess and manage hypertension correctly. Moreover, there are currently no guidelines for the treatment of hypertension in autoimmune diseases. When hypertension is seen in autoimmune patients, most doctors only use the traditional antihypertensive drugs to control hypertension . TherefoAll studies have identified hypertension as one of the traditional cardiovascular risk factors affecting the atherosclerosis process and have compared traditional versus nontraditional risk factors as a cause of premature atherosclerosis. An interesting question put forward is whether hypertension associated with autoimmune diseases arises due to a chronic state of inflammation of blood vessels due to low-grade vasculitis, immune complex deposition , medications , or whether it is a co-incidental finding ,59. SimiWith regards to pulse wave velocity changes in autoimmune diseases, our study showed that there was a tendency to have a higher PWV in rheumatoid patients than in healthy controls; however, it did not reach statistical significance. The patients who showed higher PWV also had hypertension, so it is not known whether this high PWV was due to the accompanying high inflammatory state in autoimmune patients or due to hypertension? Other studies have also reported increased arterial stiffness in RA patients . FurtherWith regards to the ADMA plasma levels, our results are similar to the other studies, which showed that ADMA is higher in rheumatologically autoimmune diseases . Erre anOnly a few studies have examined the retinal vessel diameters in autoimmune diseases, especially in rheumatoid arthritis and primary Sjögren syndrome. One study reported that there is an increase in CRVE in the rheumatoid group . SimilarUntil now, there is still controversy about the percentage of hypertension in autoimmune diseases, and, as we mention in our article, the difference in the prevalence of hypertension is big. We found that nearly all the RA patients had hypertension, although they are young, and there was no explanation of hypertension as kidney function was normal, and no steroids were used. Thus, no definite cause of hypertension in this patients group other than endothelial dysfunction .Limitations: The sample size is rather limited. Despite the low number of patients, we obtained excellent results. Moreover, the pilot study data will be used as a basis for sample size calculations in future epidemiological studies.Flow-mediated dilatation (FMD), which is the standard method used to non-invasively assess endothelial cell reactivity will be incorporated in future studies ,81,82,83Autoimmune diseases affect vascular function due to the chronic inflammatory process. The inflammation affects endothelial cells, followed by a disturbance and change in cytokines and chemical mediators (vasoconstrictor and vasodilator), and leads to changes in the homeostasis of the vascular system. Based on our results, we speculate that nontraditional risk factors, in the form of chronic inflammation, initiate or potentiate atherosclerosis through the traditional risk factors . Hypertension is a major traditional risk that is considered an early sign in the process of atherosclerosis . The eleWe recommend awareness and early detection of arterial hypertension in rheumatic autoimmune diseases. Future studies are needed to confirm the relationship between hypertension and endothelial dysfunction in rheumatoid arthritis and primary Sjorgren syndrome. Finally, we recommend that patients with other autoimmune diseases such as systemic lupus physiology of hypertension and a great majority of SLE patients have accompanying hypertension) and scleroderma should be included in future studies.


Salivary and serum toxins  concentrations were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Urinary proteins, hemoglobin, and glucose were measured using a semi-quantitative strip test. Salivary IS (odds ratio (OR) = 1.19), and proteinuria (OR = 3.69) were demonstrated as independent factors for the prediction of DoGF. Satisfactory discriminatory power (area under the receiver operating characteristic curve (AUC) = 0.71 ± 0.07) and calibration of the model were obtained. The model showed that categories of the increasing probability of the risk of DoGF are associated with the decreased risk of graft survival. The non-invasive diagnostic biomarkers are a useful screening tool to identify high-risk patients for DoGF.Acute kidney injury (AKI) is a significant risk factor for developing chronic kidney disease and progression to end-stage renal disease in elderly patients. AKI is also a relatively common complication after kidney transplantation (KTx) associated with graft failure. Since the lifespan of a transplanted kidney is limited, the risk of the loss/deterioration of graft function (DoGF) should be estimated to apply the preventive treatment. The collection of saliva and urine is more convenient than collecting blood and can be performed at home. The study aimed to verify whether non-invasive biomarkers, determined in saliva and urine, may be useful in the prediction of DoGF in kidney transplant recipients (KTRs) ( Acute kidney injury (AKI) is a significant risk factor for developing chronic kidney disease (CKD) and progression to end-stage renal disease (ESRD) in elderly patients . Both diThe prediction and prevention of loss or deterioration of graft function are essential for patients and the effectiveness of medical care. Long waiting times for renal transplantation results in dialysis have lasted up to 11 years . AnotherThis study aimed to assess the utility of variables tested in non-invasively collected materials  for predicting the deterioration of graft function in KTRs beyond 1-year KTx. The pre-transplant data are suggested to influence only short-term survival, whereas long-term survival can be predicted using laboratory tests and other parameters determined with the use of post-transplant data. Therefore, we used only the data obtained at the time of the patient enrolment. In the previous study, we showed a correlation between serum and salivary concentrations of pCS and IS  in chronic kidney disease (CKD) patients . In thisn = 77), and M12 (n = 73) are shown in The baseline study group included 37 Caucasian females and 55 Caucasian males, with the median (M) age of 53 (IQR = 19) years. The time after kidney transplant ranged from 279 to 1828 days . The clinical blood, urinary, and salivary parameters for the study population of the 92 kidney recipients at M1, M6 , diabetic nephropathy (10%), and polycystic kidney disease (28%). Other reasons included another type of nephritis, hypertensive kidney disease, Alport syndrome, and kidney cancer. For most of the patients, it was a primary (87%) or secondary transplant (12%) from a deceased donor (90%). For one patient it was the third transplantation. The duration of follow-up ranged from 354 to 1958 days , from baseline (M1) to about 41 (12) months after the last collection.p = 0.00807).The median concentration of IS and pCS in serum and saliva, as well as for eGFR, during study follow-up, was calculated . There wThere was a significant correlation at M1, between both toxins in serum and saliva with eGFR for all subjects , for thes = 0.81, p < 0.00001), and between salivary and serum pCS at M1   .rejection process) during follow-up. Lack of contact with patients (1 out of 92) was an exclusion criterion from the final calculations. Two variables were found to be associated with the deterioration of graft function: salivary IS (10 ng/mL) and the presence of proteinuria. Salivary pCS, presence of hematuria, and presence of glucosuria were not risk factors for the deterioration of graft function. The influence of change of concentration, both pCS and IS in saliva, during the observation period were also analyzed; however, the univariate logistic analysis showed that analyzed variables were statistically insignificant .To identify salivary and urinary biomarkers associated with the deterioration of graft function the univariate regression analysis was applied . The detp < 0.05) were included in the multivariate logistic regression analysis. The most suitable variables for our model were selected using a backward elimination algorithm. According to the algorithm used, salivary IS and proteinuria were identified as independent predictors of deterioration of graft function  [The Hosmer–Lemeshow goodness-of-fit test showed that the model received adequate calibration (χ 0.5000) . The accp < 0.00001) .A Kaplan–Meier analysis was performed to investigate the association between the predicted probabilities of deterioration of graft function as calculated from the received multivariable logistic model and graft failure in our cohort. The cut-off values for predicted probabilities to group the patients were chosen as: <10% risk of deterioration of graft function, 10–40% risk, and >40% risk. The log-rank test showed a significant association between high predicted probabilities of deterioration of graft function and deterioration of graft function (0.00001) a. Since teinuria b.p = 0.07142) and glucosuria (p = 0.05781) are not risk factors for the deterioration of graft function. When other end-points were established  hematuria was included in the model (data not published). However, due to a small number of events per variable, that model was not applied. Hematuria frequently occurs following Ktx, mostly due to urologic malignancy and urinary tract infection [We have demonstrated that monitoring of kidney functioning is feasible using non-invasive tests and easily available diagnostic material, i.e., saliva and urine. We have shown that salivary IS (OR = 1.19) and proteinuria (OR = 3.69) are the independent factors for long-term predicting of the deterioration of graft function in KTRs, beyond 1 year of kidney transplantation. Proteinuria showed the strongest correlation with the deterioration of graft function (OR = 3.69). Mottola C. et al. also showed a strong correlation between proteinuria and poor graft survival but measured only within 1 year of Ktx . Proteinnfection ,25. Hemanfection , but notnfection .Contrary to the salivary IS, salivary pCS was not useful to predict the deterioration of graft function. Lack of correlation between salivary pCS and the deterioration of graft function might indicate that pCS was involved in the pathogenesis of another disease in KTRs. For instance, pCS is associated with a cardiovascular event in patients with CKD  and diabThe calibration and discriminating power for the deterioration of graft function of our preliminary prediction model were assessed. Firstly, the discrimination was quantified with an ROC analysis. This analysis confirmed the good discriminatory power and identified the presence of the deterioration of graft function, with an AUC of 0.71 ± 0.07. A systematic review including 31 studies on risk prediction models for graft failure after KTx showed that the discriminatory power of presented models ranged from 0.55–0.90 . SecondlCompared to the existing solutions, our model is very straightforward and requires the use of only two variables. Some other models for long-term predictions (>1 year of follow-up) of graft loss obtained satisfactory results using complex recipients’ tests and including as many as 48  or 38 clOur model includes variables collected only during patients’ enrolments at different times after KTx. Models for long-term follow-up are usually very heterogeneous . Some ofThere is a limited number of prognostic models based only on easily collected material. Some models include urinary markers like CCL2 (other parameters: recipient age and delayed graft function) , albumins ≥ 0.81) and our previous paper (rs ≥ 0.70) [In our study, only the two uremic toxins were analyzed. IS and pCS are uremic toxins produced by the gut microbiota from dietary tryptophan and tyrosine , respectively . Their h ≥ 0.70)  we prove ≥ 0.70) .Reports on the levels of uremic toxins in KTRs are scarce. In this paper, we showed that both IS and pCS are good markers for kidney functions above 1 year after KTx. The correlation coefficient between eGFR and toxins was about two-fold higher for IS than for pCS at each point: M1, M6, and M12. Other studies on the group of KTRs after 5.3 ± 4.9 years from transplantation revealed the association between the stage of CKD and IS, as well as pCS concentration in serum . A similIn this study, we demonstrated a preliminary model for detecting the deterioration of graft function which can be used as a screening tool to identify high-risk patients for long-term graft loss/deterioration of graft function. Facing limited access to the clinical laboratory, the collection of saliva and urine is much more convenient than collecting blood and can be performed even by patients themselves at home. Moreover, the preparation of the analytical sample from saliva is faster and safer for medical staff. Our preliminary model might be very helpful for the decision-making process to prolong the survival of KTRs, following further studies.The convenient and non-invasive model can be useful to predict long-term deterioration of graft function in patients beyond 1 year following KTx. Salivary IS (OR = 1.19), and proteinuria (OR = 3.69) can be considered as independent predictors for the deterioration of graft function (AUC = 0.71 ± 0.07). Our model might be implemented in the clinical decision support system following further studies.The experimental group included 97 individuals after KTx was randomly selected from patients at the Infant Jesus Teaching Hospital in Warsaw, Poland. The inclusion criterion was renal transplantation conducted between September of 2010 and January of 2015 (from 1 to 5 years before inclusion into this study). Five patients were excluded from the study due to not collecting enough saliva at every time point of the study. Written informed consent was obtained from each subject included in the study and the study design was approved by the Bioethics Committee of the Medical University of Warsaw (No. KB/68/A/2015).At baseline (M1), all participants completed a questionnaire concerning weight, height, and smoking habits. Smoking status was categorized as: never a smoker, current smoker, former smoker, and passive smoker. BMI was calculated as the ratio of weight (kilograms) to the square of height (meters).Blood, saliva, and urine collecting were performed at baseline (M1) after 6.0  months (M6) from M1 and after 7.0 (IQR = 2.0) months (M12) from M6. Additionally, the deterioration of graft function was prospectively collected until November of 2020.g for 3 min at 4 °C to obtain the saliva samples. Fasting blood was obtained from the cubital vein onto a tube without anticoagulants. The serum was obtained via centrifugation at 340× g for 10 min at 20 °C. Then, all samples were stored at −80 °C, until further analysis.Following the overnight fasting, unstimulated saliva samples were collected using a Salivette device  with a cotton swab (5 min under the tongue). After collecting, a swab was placed in the Salivette tube and was centrifuged at 750× v/v) and the internal standard to a final concentration of 80 ng/mL. Next, samples were vortexed, incubated at −20 °C for 20 min, and centrifuged at 9300× g for 10 min at 4 °C. The supernatant was transferred to a glass vial and analyzed.Saliva samples were mixed with acetonitrile . Next, samples were incubated at −20 °C for 20 min and centrifuged at 9300× g for 10 min at 4 °C. The diluted supernatant (6-fold with mobile phase) was transferred to a glass vial and then analyzed.Serum samples were mixed with the internal standard  and methanol , equipped with a degasser, autosampler, and binary pump coupled to a QTRAP 4000 hybrid triple quadrupole/linear ion trap mass spectrometer . Chromatographic separation was achieved with a Kinetex C-18 column  with a guard column supplied by Phenomenex . The chromatographic and mass spectrometric conditions for s report .All biochemical parameters were determined using the standard manufacturer’s procedures. Blood hemoglobin level was evaluated on XN-2000 . Urinary proteins, hemoglobin, and glucose were quantified using the semi-quantitative automated reagent strip test Iris iRICELL2000 . The dipstick urine test detects hemoglobin at four levels: 0.03, 0.10, 0.50, and ≥1.0 mg/dL; proteins at three levels: 10, 50, and 100 mg/dL; and glucose at three levels: 50, 100, and 200 mg/dL. Detection and quantification of the BK virus (BKV) and Cytomegalovirus (CMV) in the plasma were assessed with the real-time PCR method, using the diagnostic test R-gene Kit . The number of virus copies was automatically calculated by the ABI 7500 Fast Dx Real-Time PCR Instrument  relative to the standard curve. The creatinine concentration in serum was measured on a Cobas6000 . Next, eGFR was estimated from creatinine concentration, age, and sex of the subject using the chronic kidney disease epidemiology collaboration (CKD-EPI) equation according to the current 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines .p < 0.05) were included in the multivariate model. Variables were selected with backward elimination algorithms. To validate the model, 10-fold cross-validation was performed. Model calibration was estimated by the Hosmer–Lemeshow “goodness-of-fit” test [Normally distributed data were expressed as mean and standard deviation, non-normally distributed data as median and interquartile range, and binary data as number and percentage. The statistical evaluation of the results was performed with STATISTICA software version 13.3 for Windows . To evaluate the normal distribution of the results, the Shapiro–Wilk test was performed. The patients’ characteristics at different time points were compared in a test for repeated variables, post hoc Dunn’s test with Bonferroni correction, and Tukey’s HSD test, as appropriate. Correlations were studied using the Spearman rank test. The logistic regression was used to build the model. Qualitative variables were coded as 0–1 dummy variables. Variables identified as statistically significant in the univariate analysis (it” test . The preit” test . Logistiit” test . Due to


In addition, blood pressure categories failed to recognize between-group differences in endothelial dysfunction (p = 0.88) and arterial stiffness (p = 0.26). An increase in myocardial contractility and a parallel decrease in afterload was associated with the decline of vascular dysfunction. Systemic Hemodynamic Index (SHI), as a surrogate marker, demonstrated a significantly negative correlation with vascular damage index . These findings illustrate that systemic hemodynamics underlying hypertensives provides more vascular information. The SHI/VDI score may be a feasible tool for cardiovascular function assessment.Vascular dysfunction is a key hallmark of hypertension and related cardiovascular outcomes. As a well-known hemodynamic disease, hypertension is characterized by abnormal ventricular-vascular interactions. Complementing non-invasive systemic hemodynamics in hypertensive vascular risk assessment is of promising significance. We aimed to investigate the effects of abnormal hemodynamic states other than elevated blood pressure on vascular damage and establish a united index of systemic hemodynamics for generalized vascular risk evaluation. Non-invasive systemic hemodynamics, assessed by impedance cardiography, was compared among blood pressure stages. Vascular function was evaluated by flow-mediated dilation (FMD) and brachial-ankle pulse wave velocity (baPWV). Systemic hemodynamics was obtained from a total of 88 enrollees with a mean (±SD) systolic blood pressure 140 (±17) mm Hg, and aged 17 to 91 years. Both stroke systemic vascular resistance index and left stroke work index exhibited a significant alteration among blood pressure stages ( Approximately 1.13 billion people worldwide suffer from hypertension –4. GuideHemodynamics, reflecting ventricular-vascular structure and function interaction, is responsible for the pathophysiology of hypertension , 21. As In this study, overall non-invasive hemodynamic parameters, assessed by ICG technique, were presented to estimate alteration of vascular dysfunction. We aimed to construct synthetic surrogate markers, VDI and SHI, by principal component analysis (PCA)-based method, and explore their correlations in both controlled and uncontrolled hypertensives.In this retrospective, cross-sectional study, we recruited 88 enrollees, aged 17–91 years, who underwent an ICG test at the Department of Hypertension and Cardiovascular Disease, the First Affiliated Hospital of Sun Yat-sen University from March 2016 to December 2016. Participants with new-onset hypertension (0–5 years duration) and more than 5 years of history of hypertension were included. Among these participants, 46 were on antihypertensive treatments before enrollment. Patients who had secondary hypertension, untreated diabetes, acute infectious diseases, active malignant tumor, chronic renal failure, acute cardiovascular diseases , or peripheral artery disease were excluded. For individuals who participated in ICG, baPWV, and FMD tests, these exams were sequentially performed on the same day. The study protocol was approved by the Ethics Committees of the First Affiliated Hospital of Sun Yat-sen University.The noninvasive hemodynamic parameters were assessed by the HOTMAN system . Studies have validated the device for hemodynamic assessment in hypertensives –30. BefoFlow-mediated dilation was measured by high-resolution ultrasonography equipment  on the same day following guidelines of the American College of Cardiology (ACC)/American Heart Association (AHA) . MeasureArterial stiffness was evaluated using baPWV assessed by oscillometry-based technique . Measurements were performed in a room with a set temperature. Before measurement initiation, participants were obliged to rest for at least 5 min in a supine position. Four appropriate blood pressure cuffs were placed on bilateral fossa cubitalis and ankles by trained technicians according to the instruction of the manufacturer. Electrocardiograms were synchronously measured by limb leads and thoracic sensors. Bilateral baPWV values were then simultaneously recorded and automatically calculated by the device. BaPWV was defined as the ratio of pulse wave distance divided by the transit time between brachial and posterior tibial arteries. The higher-side baPWV value of each participant was used in further analysis.U test, or the chi-squared tests accordingly. Post-hoc comparisons of effects across groups were tested, and Bonferroni correction was used to determine significance. The relationship of FMD, baPWV, and hemodynamic parameters was tested by Pearson's correlation coefficients.Demographic characteristics and ICG parameters were described among blood pressure categories. Mean and SD, median and interquartile range for continuous variables with or without normal distribution, and percentages for categorical variables were calculated appropriately. Between-group differences were compared using the ANOVA, non-parametric Mann–Whitney Then, the PCA-based approach , 36 was p < 0.05 was considered statistically significant. All statistical analyses were performed in SPSS version 23 , Origin version 8.5 , and Graphpad Prism version 8 .A two-tailed To evaluate the systemic hemodynamic parameters variations in different blood pressure categories, a non-invasive ICG technique was performed in volunteers to obtain real-time results. Discrepancies of these parameters among defined groups were summarized in However, we discovered distinct alterations of CI, LSWI, and SSVRI within similar degrees of blood pressure elevation . Similarp = 0.88), in accordance with the correlation analysis result  and FMD .A PCA-based approach was employed to generate a combined SHI as a surrogate marker of hemodynamic states. SHI was comprised of a series of hemodynamic parameters obtained from the ICG test. In this study, PC1, the biggest contributor to hemodynamic states variation . The loadings and composition of VDI are further illustrated in r = −0.49, p < 0.001; r = −0.52, p < 0.01; r = −0.56, p < 0.01, respectively) were also observed  that inversely correlates with vascular dysfunction and provides information for cardiovascular function assessment tailored for hypertension.Hypertension correlates with elevated perfusion blood flow, systemic resistance, or both. Our results extend findings of previous researches , 37 illuUnderlying hemodynamic abnormalities in hypertension are responsible for cardiovascular deterioration both in structure and function. Therefore, it suggests that hemodynamics provides more information for vascular risk stratification beyond blood pressure values. Hypertension imposes on the vascular system and damages vascular endothelium and elasticity to various extents. Endothelial dysfunction and arterial stiffness, namely, vascular function impairment, are independent risk factors of cardiovascular events , 40, 41.The PCA-based approach allows us to construct comprehensive indices for systemic hemodynamics and vascular damage evaluation, which are subsequently utilized to explore the relationship between changes in hemodynamics and vascular risks on the largest scale. Potential risk predictors, including age, SBP, hypertension duration, number of antihypertensive agents, baPWV, and FMD are chosen as PCA inputs, with the combination of age, hypertension duration, baPWV, and FMD being recognized as VDI, which explains 40.95% of overall variations. Considering the role of blood pressure as hemodynamic formulas parameter and antihypertensive agents' use, SBP is excluded from PCA in this study. Also, other traditional risk factors  are not available in this study. Thus, the initial concept of VDI should be cautiously interpreted. In this case, our study provides the first evidence that SHI is negatively correlated to vascular damage. It sheds light on the applicable systemic hemodynamics score for hypertensive vascular risk stratification in clinical practice. Further, SHI may become a potential factor for VDI upgrade, along with other vascular risk confounders, and function as a surrogate marker of cardiovascular outcomes which should be investigated in further large-scale, long-term studies.There are several limitations to this study. First, due to its cross-sectional design in nature, it is challenging in causality investigation between SHI and vascular dysfunction. Hence, large-scale, prospective, longitudinal studies are required in the future. Second, this study did not report cardiovascular events in the following years. Further researches exploring the correlation between systemic hemodynamics, VDI, and cardiovascular outcomes are warranted. Note that, ICG technique is not applicable in patients with obesity, atrial fibrillation, and severe aortic valve diseases, and shock, which may limit its clinical practice . Third, In this study, we confirm the heterogeneity of systemic hemodynamics states under blood pressure levels. Of note, the initial SHI and VDI scores may function as feasible tools for vascular damage assessment in clinical practice. Furthermore, the following step is learning to extrapolate potential cardiovascular risk appraisal with solid biomarkers. Future validations in population-based studies are needed.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Ethics Committees of the First Affiliated Hospital of Sun Yat-sen University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JZ, JL, and XZ conducted enrolment of patients and clinical measurements. JZ designed and conducted the statistical analysis, and wrote the original draft of the manuscript. CS and JH helped design the study and review the manuscript. YQ, ZZ, and ZW collected clinical data and provided information on statistical analysis and methodology. BD and QT helped revise the manuscript. SX, WX, and JT participated in the initial study design, wrote and revised the manuscript, and provided guidance in statistical analysis. All the authors have read and agreed to the published version of the manuscript.This study was supported by the National Key Research and Development Program of China (No. 2020YFC2008005), the National Natural Science Foundation of China , the Natural Science Foundation of Guangdong Province (No. 2021A1515010914) and the Science and Technology Program of Guangzhou (No. 202002020030).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We performed a single-center double-blinded, randomized trial to investigate the hemodynamic effects of IV paracetamol in patients with chronic liver disease (CLD) undergoing liver transplantation surgery. Patients with CLD are particularly susceptible to hemodynamic derangements given their low systemic vascular resistance state. Accordingly, hypotension is common in this setting. The hemodynamic effects of IV paracetamol in patients undergoing elective liver transplantation are unknown, therefore we evaluated whether the intraoperative administration of IV paracetamol in patients with chronic liver disease undergoing liver transplantation results in adverse hemodynamic effects. The primary end point was a change in systolic blood pressure 30-min after the preoperative infusion.Twenty-four participants undergoing liver transplantation surgery were randomly assigned to receive a single bolus of IV paracetamol (1 g paracetamol + 3.91 g mannitol per 100 mL) (n = 12) or placebo  (n = 12). All participants completed their study intervention, and there were no breaches or violations of the trial protocol. Baseline characteristics were similar in both groups. There were no significant differences regarding surgical duration, intraoperative use of fluids, and intraoperative noradrenaline use. After the administration of paracetamol there were no significant differences observed in blood pressure or other hemodynamic parameters when compared to placebo.The online version contains supplementary material available at 10.1186/s13104-021-05749-8. Paracetamol  is a commonly used drug in the hospital setting to treat fever and mild to moderate pain, with its intravenous (IV) formulation routinely used in surgical and critically ill patients. Despite paracetamol’s reputation as the leading cause of drug-induced liver injury in the developed world, several studies support its safe use in the cirrhotic patient. When administered at the recommended daily dosage, paracetamol appears to be well-tolerated in all etiologies of liver disease including alcoholic cirrhosis and hepatitis C . With itRecent clinical trials have shown that IV paracetamol may cause hypotension in healthy volunteers, the critically ill, and in cardiac surgery patients –5. The h2).Between November 2013 and March 2017, participants were identified from elective liver transplantation surgery waiting lists. Inclusion criteria included adult patients (age > 18 years), with chronic liver disease, undergoing elective liver transplantation surgery. Exclusion criteria included known allergic reaction to IV paracetamol, administration of paracetamol or NSAIDs within 24 h of surgery, caffeine consumption less than 10 h prior to surgery, pregnancy, severe chronic renal impairment (preoperative creatinine > 250 μmol/L) and morbid obesity (body mass index (BMI) > 35 kg/mSample size calculations were based on pilot data of preoperative blood pressure measurements in patients scheduled for liver transplantation at our institution. With an average blood pressure of 110 mmHg, and a standard deviation (SD) of 10 mmHg, to demonstrate a mean difference between the paracetamol group and control group of 10 mmHg, with a power value of 90%, a minimum of 11 participants would be required to be recruited into each group. To allow for violations or breaches in study protocol, 12 participants were recruited in each arm. A statistician generated a computerized sequence of 24 allocation codes, 12 for each group. An independent research nurse sealed the allocation codes into sequentially numbered opaque envelopes. The sequence was decoded after the data was analyzed.2/air mixture (FiO2 = 0.5) and intravenous fentanyl (2–5 μg/kg/hr). All participants had a 18 cm 18G arterial line  inserted into their non-dominant brachial artery and femoral artery. A continuous cardiac output pulmonary artery catheter  was inserted via the right internal jugular vein. After the insertion of invasive lines, participants were placed in 15-degree head-up position, with their head resting on a pillow for comfort. IV fluids, or any other medications were avoided unless clinically required.On the day of surgery, an independent clinical pharmacist prepared one 100 mL IV infusion. All trial drug bottles contained paracetamol (1 g paracetamol + 3.91 g mannitol/100 mL) , or saline 0.9% (100 mL) (placebo)  as a control. Intraoperative data collection was conducted after a standardized induction of anesthesia . Anesthesia was maintained with isoflurane (0.5–1.5 MAC) in OParticipants were given a 15-min stabilization period before baseline hemodynamic measurements were recorded. After the stabilization period, the study drug was infused at room temperature over 15 min. The primary end point was an absolute change in systolic blood pressure (SBP) from the baseline to 30 min. We measured changes in mean and systolic blood pressures, diastolic blood pressures (DBP), cardiac index, pulmonary artery pressures, systemic vascular resistance index (SVRI) and heart rate (HR). Pulmonary artery pressure was measured directly from the pulmonary artery catheter. Cardiac index was measured continuously via the continuous cardiac output pulmonary artery catheter.Measurements were recorded at 5, 8, 15 and 30 min after the start of the preoperative infusion and 15 and 30 min after the start of the postoperative infusions, with hourly measurements for six consecutive hours. Other data collected included baseline patient characteristics, intraoperative use of fluids and vasoactive medications, cardiopulmonary bypass time, aortic cross-clamp time, surgery duration, intraoperative use of fluid and vasoactive medications, ventilator times, and length of ICU and hospital stay.Statistical analysis was performed using commercial statistical software STATA/IC v.13 with a p-value of 0.05 to indicate statistical significance. The primary end point (absolute change in SBP from the baseline to 30 min) was analyzed using an ANCOVA model with the SBP value at 30 min as an outcome, the treatment group as a factor, and the baseline SBP value as a treatment covariate. All other end points were analyzed using random effect generalized least squares regression modelling due to the repeated measures nature of the data. The study adheres to the CONSORT Guidelines for reporting randomized trials .The study CONSORT diagram is presented in Fig. Changes in SBP, DBP and MAP after the paracetamol or Saline infusions from baseline to the 60-min end point are summarized in Fig. Fifteen minutes after the start of infusion, SBP decreased from 114 (11) mmHg to a nadir of 98 (13) mmHg in the paracetamol group, representing a decrease of 14.0% from the baseline. Conversely, 15 min after infusion the Saline group, SBP decreased from 122 (29) mmHg to 109 (22) mmHg. This resulted in a decrease of 10.66% from the baseline. The p-value adjusted for treatment-by-time interaction was 0.57 indicating no statistical significance between the two groups. Over the 60-min study period, there was no statistical or clinically significant decreases in DBP observed between the two groups. DBP dropped from 55 (12) mmHg to a nadir of 45 (9) mmHg) in the paracetamol group, representing a 18.9% decrease from the baseline 60 min after infusion. Saline had a nadir 9.1% decrease in DBP from the baseline 30 min after infusion. The p-value adjusted for treatment-by-time interaction was listed as 0.54. Finally, paracetamol also decreased MAP from 76 (12) mmHg to a nadir of 63 (11) mmHg over the 60-min study period, with a decrease of 17.11% from baseline. This was seen to a lesser extent in the Saline group with an overall decrease of 8.97% from baseline 60 min after infusion. The p-value adjusted for treatment-by-time interaction was 0.61.Analyses of SVRI, cardiac index, pulmonary artery pressures, and HR showed no statistical significance in their interaction between the treatments over time. There were no significant changes in blood pressure between the groups after adjustments for age, BMI, gender and Model for End-stage Liver Disease Score.To date this is the first study providing plausible physiological evidence that intraoperative administration of 1 g of IV paracetamol in patients with CLD undergoing liver transplantation caused no changes in blood pressure when compared with a placebo.The use of paracetamol in the context of liver disease is often avoided due to concerns regarding paracetamol-induced liver toxicity . NAPQI oThe hemodynamic effects of IV paracetamol have largely centered around results from studies conducted in critically ill patients. Whilst these studies suggest IV paracetamol may have the propensity to cause hypotension, many are limited by small patient numbers, retrospective design, lack of randomization and blinding or being anecdotal in nature. In addition, frequent use of vasopressors in this patient cohort may confound the results by masking the effect of the paracetamol-induced hypotension , 11, 12.Krajcova et al. found that repeated administrations of IV paracetamol reduced MAP in 6 critically ill patients . This waIn a randomized blinded trial comparing the hemodynamic effects of IV paracetamol and placebo  in patients with chronic liver disease undergoing liver transplantation, we found that the intraoperatively administration of paracetamol caused no significant changes in blood pressure when compared to placebo. Our findings support the therapeutic benefits of the safe use of the recommended dosage of IV paracetamol within this patient cohort.We provided insights on the hemodynamic effects of paracetamol on a very small cohort of 24 liver transplant recipients. We cannot extrapolate our paracetamol infusion results to different combinations of rate, duration or route. However, the dose and speed of administration in our patients reflect clinical practice and recommendations. The findings with IV paracetamol are likely not relevant to oral or per-rectum paracetamol, where the absorption is slower and any hemodynamic effects that might exist are attenuated. We only explored the hemodynamic effects of IV paracetamol in patients with CLD. Therefore, we did not measure the biochemical effects of paracetamol on liver function tests, nor did we examine the effects of paracetamol and its metabolite NAPQI on liver function or graft outcomes. Moreover, the study was not intended to explore any clinical outcomes.Additional file 1: Table S1. Hemodynamic changes in patients with chronic liver disease undergoing liver transplantation after IV paracetamol administration. Values are mean values (standard deviation) with 95% confidence intervals (95% CI). (SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; sPAP, systolic pulmonary artery pressure; dPAP, diastolic pulmonary artery pressure; mPAP, mean pulmonary artery pressure; CVP, central venous pressure; HR, heart rate; CI, cardiac index; SVRI, systemic vascular resistance index.