Differentiation of multiple system atrophy with predominant parkinsonism (MSA-P) and Parkinson's disease (PD) is important, but an effective tool for differentiation has not been identified. We investigated the efficacy of the composite autonomic symptom scale 31 (COMPASS 31) questionnaire as a tool for evaluating autonomic function in parkinsonism patients. In this study, we enrolled drug-naïve patients with MSA-P and PD, and administered the COMPASS-31 and an objective autonomic dysfunction test (AFT). Demographic and clinical data, including parkinsonism and autonomic dysfunction, were compared between the two groups. Additionally, we determined the optimal COMPASS 31 cut-off score to differentiate MSA-P from PD for use as a screening tool. In this study, 27 MSA-P patients and 41 PD patients were recruited. The total COMPASS 31 score was well correlated with the objective AFT results. When we compared the COMPASS 31 score between the two groups, MSA-P patients showed higher total scores and sub-scores in the orthostatic intolerance, gastrointestinal, and bladder domains compared with PD patients. Similarly, MSA-P patients had more abnormalities in expiration to inspiration ratio, Valsalva ratio and pressure recovery time than PD patients in objective AFT. With 13.25 as the cut-off score for diagnosis of MSA-P, the total COMPASS-31 score demonstrated high sensitivity (92.6%) and moderate specificity (51.2%) with an area under the curve of 0.765. Based on our results, the COMPASS 31 is an effective tool for evaluation of autonomic function in patients with parkinsonism. The COMPASS-31 could be used as a sensitive and convenient screening tool, especially for the differentiation between MSA-P and PD. Multiple system atrophy with predominant parkinsonism (MSA-P) and Parkinson’s disease (PD) are different in terms of disease progression and survival. Nevertheless, because MSA-P and PD share similar motor symptoms, differential diagnosis at an early stage is difficult. Although autonomic dysfunction is a characteristic symptom of MSA , autonomThe composite autonomic symptom scale 31 (COMPASS 31) questionnaire is a self-rating questionnaire evaluating six domains of autonomic function: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor domains . The COMIn addition, previous studies enrolled PD and MSA-P patients irrespective of dopaminergic medications, thus failing to eliminate the possible confounding effects of such –8. BecauIn this study, we investigated the diagnostic significance of the COMPASS 31 score in patients with parkinsonism by comparing the total score and domain scores between drug-naïve patients with MSA-P and PD, and determining the correlation between COMPASS 31 score and AFT results.18F-FP-CIT positron emission tomography (PET). Probable MSA-P was determined based on the Second Consensus diagnostic criteria for MSA [DSM-IV criteria for dementia), psychiatric disorders requiring medication, malignancy, or musculo-skeletal problems mimicking parkinsonism were excluded. In addition, we also excluded subjects with medical conditions which could affect AFT results including diabetes mellitus or cardiac arrhythmia. Demographic and clinical data were collected for all patients. Motor symptoms were evaluated with the Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 and by Hoehn and Yahr stage [This study was approved by the Institutional Review Board of Samsung Medical Center, Seoul, Korea and all enrolled subjects provided written informed consent. We recruited drug-naïve patients with PD and probable MSA-P from January 2015 to October 2015 from the movement disorders clinic at Samsung Medical Center. PD was diagnosed based on the UK Brain Bank Criteria for PD , and 18FAll enrolled subjects received the COMPASS 31, which is a questionnaire of autonomic symptoms and consists of six domains: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder and pupillomotor . The sixAll enrolled subjects discontinued medications that could affect the AFT results at least 24 hours before the AFT, and refrained from drinking coffee or tea and smoking on the day of the test. Both MSA-P and PD patients underwent our standardized autonomic test battery which included heart rate response to deep breathing (HRDB), the Valsalva maneuver, blood pressure and heart rate response to head-up tilt test (HUT), and sympathetic skin response (SSR). Continuous BP monitoring using the Finometer® , and ECG and respiratory movements were obtained during the HRDB test, Valsalva maneuver, and HUT.The HRDB test was performed with the patient in a supine position. Patients were asked to breathe deeply by repeatedly inhaling for 5 seconds and exhaling for 5 seconds for 1 minute at a rate of 6 breaths per minute. The difference in heart rate between the end of expiration, end of inspiration and the expiration to inspiration ratio (E:I ratio) were calculated to evaluate cardiovagal function.The Valsalva maneuver was performed with the patient in a supine position. The patient breathed into a mouthpiece connected to a manometer with an expiratory pressure of 40 mmHg for 15 seconds. Pressure recovery time (PRT) and Valsalva ratio were measured for the assessment of adrenergic and cardiovagal functions, respectively; PRT was defined as the time interval from the bottom of phase III to the complete return of systolic blood pressure to baseline during the Valsalva maneuver . The ValHUT was performed on patients after 30 minutes of resting in a supine position on an electrically driven tilt table. Patients were tilted up to 70 degrees for 10 minutes while their blood pressure, heart rate, and the presence of any discomfort, chest pain, dyspnea, dizziness, or syncope was monitored. The presence of orthostatic hypotension (OH) was evaluated as an adrenergic function parameter, which was defined as a fall of at least 30 mmHg in systolic blood pressure and/or a 15 mmHg fall in diastolic blood pressure within two to five minutes of HUT .Sudomotor function was assessed with SSR. SSR was recorded from the palm of the hand and sole of the foot using a Nicolet Viking IV electromyography machine  according to a previously reported protocol . The SSR2 or Fisher’s exact test for categorical variables. To determine the relationship between COMPASS 31 score and AFT results, we performed Spearman’s correlation analysis. Receiver operating characteristic (ROC) curve analysis was performed to establish the optimal cut-off value for the differentiation of MSA-P from PD. A p-value < 0.05 was considered significant. Statistical analyses were performed with a commercially available software package .All data were presented as medians and interquartile ranges (IQR). Demographic and clinical data were compared between groups using the Student t-test or Mann-Whitney U-test for continuous variables, and Pearson’s χWe recruited 41 patients with idiopathic PD and 27 patients with probable MSA-P. Demographic and clinical details of the enrolled subjects are presented in To investigate the efficacy of using the COMPASS 31 for evaluation of autonomic dysfunction in patients with parkinsonism, we performed correlation analyses between COMPASS 31 score and objective AFT results. The total COMPASS 31 score was well-correlated with all objective AFT results, including the E:I ratio, Valsalva ratio, PRT, SSR and OH . Among tMSA-P patients demonstrated more autonomic involvement than PD patients in both COMPASS 31 score and objective AFT results . In termThe sensitivity and specificity of COMPASS 31 total score for discriminating MSA-P from PD  were 92.This is the first study to investigate the COMPASS 31 for differential diagnosis between MSA-P and PD. Because parkinsonism and autonomic dysfunction are common to both MSA-P and PD, it is difficult to differentiate one from the other. Therefore, precise evaluation of autonomic dysfunction is important and helpful. In this study, COMPASS 31 scores were well-correlated with objective AFT results in patients with parkinsonism. Furthermore, there was a significant difference in COMPASS 31 score between MSA-P and PD patients, and COMPASS 31 total score showed high sensitivity for the diagnosis of MSA-P. Based on these results, the COMPASS 31 could be a convenient and useful tool for screening MSA-P in patients with parkinsonism even from an early stage.Classically, the objective AFT was regarded as the main tool for diagnosing autonomic dysfunction, but an expensive immovable device and a trained operator are required for this evaluation. Moreover, there is still controversy on the efficacy of using the objective AFT to differentiate between MSA and PD –8. HowevWhen we compared autonomic dysfunction between MSA-P and PD patients using the COMPASS 31, MSA-P patients showed a higher total COMPASS 31 score than patients with PD. Similarly, previous studies also revealed more severe autonomic involvements in MSA-P compared to PD patients , 7, 8. PWhen we examined the sensitivity and specificity of the COMPASS 31 for the differentiation of MSA-P from PD, COMPASS 31 total score showed high sensitivity but moderate specificity. A previous study using a scoring system based on the objective AFT reported a sensitivity of 89% and specificity of 70% , and anoDespite high sensitivity, the COMPASS 31 demonstrated moderate specificity. Relatively low specificity could result from the recruitment of early, drug-naïve patients in this study, ir from the limitation of COMPASS 31. Considering it is difficult to distinguish PD from MSA-P, especially in early stage, we aimed to investigate the clinical implications of COMPASS 31 for differentiation in patients with early stage. Additionally, to overcome the possible limitation of COMPASS 31, we need instruments/biomarkers with high specificity. In previous studies, the objective AFT showed relatively high specificity compared with our results , 5, and MSA is usually divided into two subtypes based on the predominant symptoms: parkinsonism (MSA-P) and cerebellar ataxia (MSA-C). Unlike previous studies , 7, we oThis study has some limitations. First, our sample size was relatively small. However, even with a small sample size, we found that the COMPASS 31 was a useful tool for evaluating autonomic function in patients with parkinsonism and could be used as a screening tool for MSA-P. Additionally, we enrolled drug-naïve, early stage subjects with MSA-P and PD. Considering clinical diagnosis could be changed with follow up, there is a possibility for changed diagnosis. However, all the PD patients in our study showed excellent response to dopaminergic medication and were also confirmed with dopamine transporter PET. Another limitation is that our study was cross-sectional. Since autonomic involvement could be more prominent with disease progression, it is important to investigate further with longitudinal follow-up studies. In this study, we focused on the utility of the COMPASS 31 in patients with parkinsonism since the differential diagnosis between MSA-P and PD is usually difficult in the early stages of these diseases. Moreover, we recruited drug-naïve MSA-P and PD patients so we could eliminate possible confounds due to medications or disease severity. Lastly, we did not enroll normal controls. In this study, our primary objective was to determine the efficacy of the COMPASS 31 in patients with parkinsonism, thus we enrolled patients with MSA-P and PD, two of the most common and dominant diseases in parkinsonism.In conclusion, the COMPASS 31 was a convenient and effective tool for the evaluation of autonomic function in patients with parkinsonism along with the objective AFT. Furthermore, considering that the total COMPASS 31 score showed high sensitivity for differentiating between MSA-P and PD, this questionnaire could be a helpful tool for screening MSA-P from parkinsonism.S1 FigSpearman correlation analysis was performed to determine the relationship between the total COMPASS 31 score (y-axis) and E:I ratio, Valsalva ratio, and pressure recovery time (x-axis). The total COMPASS 31 score showed negative correlations with the E:I ratio (A) and Valsalva ratio (B). A significant positive correlation was observed between the total COMPASS 31 score and pressure recovery time (C).(TIF)Click here for additional data file.S1 Tablep-values below 0.029 are considered significant and marked with an asterisk based on Bonferroni corrections.E:I ratio, expiration:inspiration ratio; PRT, pressure recovery time; OH, orthostatic hypotension; SSR, sympathetic skin reflex. (DOCX)Click here for additional data file.S2 TableCOMPASS 31, composite autonomic symptom scale 31 questionnaire; MSA-P, multiple system atrophy with predominant parkinsonism; PD, Parkinson’s disease; CI, confidence interval; AUC, area under the curve.(DOCX)Click here for additional data file.


P = 0.36). Serial serum creatinine in the first two days after surgery in addition to urine volumes during the first day after transplantation was significantly different in the HS group (P ≤ 0.05). The urinary NGAL and IL-18 were significantly lower in HS vs. control, at 24 h after transplantation (P ≤ 0.05). The frequency of adverse reactions was similar between groups. This study did not show any significant benefits from HS administration immediately before allograft reperfusion in terms of reducing DGF, serum creatinine at hospital discharge or length of hospital stay in deceased-donor kidney transplant patients.Ischemia reperfusion injury (IRI) is one of the main causes of delayed graft function (DGF) in deceased-donor kidney transplantation (DDKT). Evidences suggest that hypertonic saline (HS) has beneficial effects on IRI. The objective of the present study is to determine the effect of intraoperative HS, on graft function and urinary biomarkers of interleukin 18 (IL-18) and neutrophil gelatinase-associated lipocalin (NGAL), in patients with DDKT. The design of the study is a randomized, open-label, pilot trial in patients with DDKT. The intervention of the study is administration of 4 mL/kg HS, 5% before graft reperfusion. The primary endpoint was DGF. Fifty-eight (58) adult patients were randomized . There were no significant differences between the two groups in terms of recipient, donor, and transplant characteristics. The rate of DGF was 20% in the HS group compared with 31.8% in the control group (Relative risk 0.63; 95% CI 0.23–1.67;  Kidney transplantation has become a preferred treatment for most patients with end-stage renal disease and is superior to dialysis in terms of quality of life and long-term mortality risk . IschemiAttempts to reducing graft IRI include avoiding hypovolemia and nephrotoxic drugs, minimizing warm and cold ischemia times, using vasodilator, immunosuppressive and anti-inflammatory drugs, as well as antioxidant therapy . AlthougHypertonic saline now is widely used as a resuscitation fluid during critical illness because of its beneficial hemodynamic properties, such as rapid expansion of intravascular volume, reduction of endothelial and tissue edema that improves microcirculation, and increased myocardial contractility , 6. BesiInterleukin 18 (IL-18) and neutrophil gelatinase-associated lipocalin (NGAL), play a pathogenic and protective role for kidney IRI, respectively. Recently, IL-18 and NGAL were proposed as promising biomarkers, hence their measurement in urine samples can be used to detect DGF in kidney transplant patients .Considering the aforementioned facts, HS could be beneficial for attenuating IRI, a key factor in the development of DGF. To the extent of our knowledge, HS has not been studied in kidney transplantation. Therefore, we carried out a pilot randomized clinical trial to evaluate the effect of bolus administration of HS, at the time of graft reperfusion on the early kidney allograft function and urinary biomarkers of kidney injury, including IL-18 and NGAL.PatientsAll consecutive adult deceased donor kidney transplant recipients at Sina hospital , between October 2013 and September 2014 were approached to participate in this randomized, open-label, pilot trial. The study was approved by the Ethics committee of Tehran University of Medical Sciences and registered under the Iranian registry of clinical trials (IRCT2013122815841N19). The inclusion criteria included a first transplantation, deceased-donor kidney transplantation, recipients’ ages between 18 to 65 years, left ventricular ejection fraction >30%, panel reactive antibody <20%, and donor serum creatinine <2 mg/dl. The exclusion criteria included severe acidosis (pH ≤7.2 and/or serum bicarbonate ≤10 mEq/l and/or Base excess (BE) ≤ -15 mEq/l), electrolyte abnormality (k<3.5 mEq/dl or Na<125 mEq/dl or Na>145 mEq/dl), blood product transfusion, colloidal fluid administration, graft anastomosis bleeding or thrombosis.InterventionA computer-generated list with three random-block sizes  was used to randomize patients on a 1 to 1 ratio to HS 5% or normal saline (NS) solutions. The patients in the HS and NS groups received 4 mL/kg of HS 5% or NS within 15 minutes starting 10 min before graft reperfusion. 2O and systolic blood pressure more than 140 mmHg at graft reperfusion time and thereafter. In both groups, patients’ acid-base states were measured after induction of anesthesia, during the vascular anastomosis procedure, before administration of intervention solutions, and after graft reperfusion. As our transplantation protocol, all patients received 5 mg/kg of furosemide just before graft reperfusion. All the transplantation surgeries were performed by the same transplant surgeon.Normal saline approximately at a dose of 20 mL/kg/h administered to all the patients as intra-operative fluid therapy and titrated to keep the central venous pressure between 10 and 15 cm HThe immunosuppressive regimen involved induction with daily ATG at a dose of 1 mg/kg for 5 days, followed by triple-drug immunosuppressive therapy. All patients received methylprednisolone 500 mg during transplantation surgery, 250 and 100 mg on the second and third day post-transplant which was then converted to prednisone and tapered to 5 mg daily for several months. Mycophenolate mofetil was administered at a dose of 1 g twice daily, starting the day of transplantation. Cyclosporine administered after transplantation, when serum creatinine had fallen to an acceptable level, at a dose of 6 mg/kg/day, as divided twice daily.Study endpointsThe primary endpoint was DGF. DGF defined as the need for dialysis within the first week after transplantation. In addition, the early functioning grafts were divided into two groups, slow graft function (SGF) and immediate graft function (IGF). SGF defined as serum creatinine level above 2.5 mg/dl on the fifth day of kidney transplantation and the remaining was considered as IGF . The secTo measure urinary biomarkers, 5 mL urine samples were collected directly from the patients› urinary catheter at 2, 24, and 48 h after graft reperfusion. Urine samples were centrifuged at 5000×g for 5 min at room temperature and stored at 80 °C. Interleukin 18 and NGAL levels were measured using Human IL-18 ELISA Kit and Human NGAL ELISA Kit purchased from Shanghai Crystal Day Biotech Co, China. The coefficient of variation (inter-assay variability) for both biomarkers was less than 12%. Urinary biomarkers were normalized to urinary creatinine concentration in order to account for the differences in the glomerular filtration rate and resultant urinary flow.Serum creatinine was measured daily until discharge and urine volume recorded at two, six, and 24 h after transplantation, then daily within the first week after transplantation.Baseline recipient characteristics such as age, sex, body mass index, length of hemodialysis, time of last hemodialysis session before transplant surgery and donor characteristics of age, sex, serum creatinine, warm, and cold ischemia time recorded for all patients.Statistical Analysist-tests or cross-tables and Fisher’s exact test. If the statistical assumptions for parametric analysis of interval variables were not met, Mann–Whitney’s two-independent samples test was used. Different variants of multiple measurements were separately analyzed using repeated measurement analysis. The rates of DGF and AR were compared using cross-tables and Fisher’s exact test. A value of P < 0.05 was considered statistically significant. Analyses were conducted using the SPSS software package version 19. We used the method described by Cocks. et al to estimate the sample size for this pilot randomized trial  potential deceased-donor kidney transplant recipients were identified and screened for eligibility criteria . Four paIn the intra-operative period, five patients in the HS group were excluded with severe acidosis before (n = 4) or after HS administration (n = 1). Three patients in the control group were excluded with severe acidosis (n = 2) or blood product transfusion (n = 1). In the follow up period, one patient in the control group and two patients in the HS group were excluded because of graft vein thrombosis. Twenty-five  patientsThe baseline characteristics of the recipient and donor are summarized in P = 0.02). The average cold ischemia time was 4.91 h  in the HS group and 4.72 h  in the control group. Patients in the HS group received 4 mL/kg HS 5% as bolus administration. Although the baseline acid-base state did not differ between the two groups, the arterial blood pH and BE 10 min after graft reperfusion, were lower in the control group compared to HS group (7.29 (0.03) vs 7.34 (0.04), P = 0.25). In addition, mean of BE was statistically lower in the control group (-8.5 (-3.1) vs -10.2 (-3.4), P = 0.36). Generally, the donor and recipient characteristics were not different among patients with various graft functions (P=0.5). However, the incidence of AR was lower in the subgroup of patients with IGF (P=0.043).The rate of DGF, SGF, and IGF occurrences after transplantation are shown in unctions . MultivaP=0.24).Early post-transplant graft function in terms of serum creatinine and urine volume significantly improved in patients who received HS . HoweverP=0.002) and 24 h after graft reperfusion (P=0.001). In addition, the difference for NGAL/Cr levels between patients with DGF and IGF was significant at 24 h (P=0.0047), and 48 h after graft reperfusion (P=0.001). Urine IL-18 to creatinine ratio (IL-18/Cr) and NGAL to creatinine ratio (NGAL/Cr) in the HS group were lower at all sampling times. These differences for urine IL-18/Cr at 2 and 24 h and for urine NGAL/Cr at 24 h after graft reperfusion, achieved statistical significance . The uriThe infusion of HS was generally well tolerated. Only, two patients experienced severe hyperchloremic metabolic acidosis after HS administration. Nonetheless, no clinically significant electrolyte or hemodynamic abnormalities such as pulmonary edema and cardiac arrhythmias were observed in the patients. This is the first randomized, case-controlled, trial that evaluated the efficacy of HS in improving early graft function, in patients receiving kidney transplantation from a deceased donor. Our findings did not show a significant reduction in DGF occurrence after HS administration starting 10 min prior to allograft reperfusion. Serum creatinine at hospital discharge and length of hospital stay were not significantly different between HS and control groups.In this study, we observed that HS administration shortly prior graft reperfusion improved early graft function in terms of urine output and serum creatinine. These results may be explained by osmotic and hemodynamic effects of HS. The endothelial cell (EC) injury and swelling initiated during the ischemia phase is the key to the microcirculatory disturbance after reperfusion . By estaIn our study, HS infusion was at the time of high-dose furosemide administration. Studies in acute decompensated heart failure patient shown that combination of HS and high dose furosemide was associated with increased urine output and enhanced weight loss as well as significantly smaller increase in serum creatinine . HS enhaIL-18 and NGAL are early markers of tubular damage that their serum and urine levels reflect degree of tubular damages due to IRI. Urinary levels of these biomarkers were measured to determine whether HS improves allograft function by attenuating tubular damage caused by ischemia-reperfusion, in addition to modulation of renal hemodynamics. Furthermore, these biomarkers were measured to evaluate subtle reduction of kidney damage caused by HS that clinical tests are not able to detect. In this study, the urinary levels of both biomarkers were significantly lower 24 h after reperfusion in patients who received HS. This suggests that HS has been able to reduce the tubular damage. At the end of HS 5% administration in this study, the serum sodium level increased by 5.8 mEq/l (from 141.5 to 147.3 mEq/l) and remains elevated for up to 30 min. the occurrence of hypernatremia/hypertonicity during the first minutes of reperfusion may decrease oxidative stress and immune- mediated IRI. It is demonstrated that an increase of 10 to 20 mOsm/kg in plasma osmolality caused by HS modulates local and systemic inflammatory response . HoweverActivation of the innate immune system and oxidative stress during reperfusion are associated with graft IRI . A serieAlthough arterial blood pH and BE were reduced after administration of HS, only one patient recorded severe acidosis. Nonetheless, no electrolyte or hemodynamic abnormalities such as pulmonary edema and cardiac arrhythmias were observed in the patients. Therefore, controlled administration of HS regarding patients› acid-base states not only provides them with beneficial effects, but also minimizes such complications as hyperchloremic metabolic acidosis, electrolyte imbalance, and fluid volume overload. Limitations: Firstly, the small sample size is the main limitation of this study. Secondly, the incidence of DGF in this study was lower in comparison with other reports that have affected the power of study. Thirdly, the clinical judgment of practitioners on the need for dialysis might overestimate the rate of DGF and enter a possible bias. In conclusion, this study did not show any significant benefits from HS administration immediately before allograft reperfusion in terms of reducing DGF, serum creatinine at hospital discharge or length of hospital stay in deceased-donor kidney transplant patients (DDKT). The bolus administration of a single dose of HS shortly before graft reperfusion is safe and associated with a more rapid decrease in serum creatinine, increase in urinary volume and lower levels of biomarkers in patients with DDKT. However, future trials using larger study population is needed to confirm the efficacy and safety of intra-operative administration of HS in kidney transplant patients.


Background: Milk intake has been associated with lower blood pressure (BP) in observational studies, and randomized controlled trials suggested that milk-derived tripeptides have BP-lowering effects. Milk intake has also been associated with body mass index (BMI). Nevertheless, it is unclear whether increasing milk consumption would reduce BP in the general population.Methods: We investigated the association of milk intake with obesity and BP using genetically-defined lactase persistence (LP) based on the rs4988235 polymorphism in a Mendelian randomization design in the 1982 Pelotas (Southern Brazil) Birth Cohort. These results were combined with published reports identified through a systematic review using meta-analysis.Results: In the 1982 Pelotas Birth Cohort, milk intake was 42  and higher odds of overweight-obesity [1.09 ]. There were no reliable associations for BP.Conclusions: Our study supports that LP is positively associated with obesity, suggesting that the negative association of milk intake with obesity is likely due to limitations of conventional observational studies. Our findings also do not support that increased milk intake leads to lower BP. Key MessagesGenetically defined lactase persistence (LP) was associated with more milk intake in the 1982 Pelotas Birth Cohort, and this association was more pronounced among individuals of more European ancestry.Milk intake was negatively associated with obesity and blood pressure in conventional observational analysis in the 1982 Pelotas Birth Cohort.LP was positively associated with BMI and overweight-obesity in our meta-analysis which was based on a systematic literature review.There were no reliable meta-analytical associations between LP and blood pressure, thus not supporting the notion that milk intake is causally associated with lower blood pressure.LCT gene [OMIM: 603202] are functionally associated with adult-type hypolactasia;LCT gene) is one such SNP, whose association with lactase persistence (LP)—maintenance of lactase expression after weaning [MIM: 223100]—was first identified in Finland.,,,,,Single nucleotide polymorphisms (SNPs) in the enhancer region of the ,,Cardiovascular diseases are the leading cause of death worldwide. Ischaemic heart disease and stroke were estimated to have caused around 25% of deaths in the world in 2010.,Some studies also detected associations between dairy consumption and body mass index (BMI), but the literature is controversial. Observational studies in children reported positive associations between milk consumption and BMI, especially in children of 4 years of age or younger.The use of genetic variants as proxies of modifiable exposures can improve causal inference in observational studies through applying the principle of Mendelian randomization.,Associations involving LP status and cardiovascular risk factors have already been reported in the literature. A meta-analysis involving 31 720 Europeans reported that T-allele carriers  had higher BMI than CC individuals (i.e. non-persistents).In the present study, we evaluated whether genetically-defined LP is associated with milk intake, obesity and blood pressure among subjects who have been followed up since birth in a southern Brazilian city. We also combined these results with published data identified through a systematic review of the literature.,IJE online).In 1982, the maternity hospitals in Pelotas, a southern Brazilian city (current population 330 000), were visited daily by trained interviewers, who were health professionals with an academic degree. The 5914 liveborns whose families lived in the urban area were examined and their mothers interviewed. We were able to get information of more than 99% of the live births. These subjects have been followed-up nine times (five follow-ups targeting subsamples and four targeting the whole cohort). From October 2004 to August 2005, we visited all households located in the urban area of the city. For those not located in this way we used the last known address. Subjects (aged 22–23 years) were interviewed and examined at home and invited to visit the research laboratory to donate a blood sample, collected by venous puncture. DNA and sera were extracted and frozen at −70°C. DNA samples were genotyped using the Illumina HumanOmni2.5-8v1 array.,Exposure variables were rs4988235 SNP and dairy intake. We selected the rs4988235 SNP as a potential genetic proxy of milk consumption due to its role in LP.2), weight and height were measured using portable weighing devices and stadiometers of 100 g and 1 cm of precision, respectively. Overweight-obesity was defined as BMI ≥ 25 kg/m2. Systolic and diastolic blood pressures were measured in mmHg using an Omron HEM-705CPINT digital sphygmomanometer; two measurements were taken and their mean was used for the analyses. Raised blood pressure was defined as systolic BP ≥ 130 mmHg or diastolic BP ≥ 85 mmHg. These variables were measured in the 2012–13 follow-up.Outcome variables were: BMI, overweight-obesity, systolic blood pressure, diastolic blood pressure and raised blood pressure. For BMI , family income at birth, birthweight and gestational age based on the maternal recall of the date of the last menstrual period (measured at birth); self-reported skin colour, genomic ancestry  and leisure-time physical activity  ; and household asset index, achieved schooling in complete years, smoking, alcohol intake, low-density lipoprotein (LDL) and height . Household asset index was obtained by applying principal component analysis to a list of 12 assets and the schooling of the household head.2 tests, respectively. Unadjusted associations of milk intake status (none vs any) with sociodemographic, perinatal, lifestyle and biological variables were evaluated using the χ2 test  or the t test (for continuous variables). The remaining analyses were performed by linear or logistic regression. To account for population stratification, estimates were adjusted for quantitative indicators of genomic ancestry  when indicated. Two genetic effect models were used: codominant (i.e. each genotype is coded as a distinct category) and dominant . The codominant effect is the generic model, whereas the dominant effect is the most strongly supported by the literature regarding the consequences of lactase non-persistence at the distal phenotypic level (e.g. on milk intake).Hardy-Weinberg equilibrium (HWE) and distribution of rs4988235 genotypes according to observed skin colour were evaluated using Fisher’s exact and χhttps://ovidsp.tx.ovid.com/] which allows simultaneously searching the following databases: MEDLINE, Embase, Allied and Complementary Medicine Database, CAB ABSTRACTS, PsycINFO® and The Philosopher’s Index. The following combination of search terms was used: ‘LP’ AND (‘BMI’ OR ‘Blood pressure’ OR ‘Other’). A detailed description of each search term, as well as the number of records retrieved by each in isolation, is provided in IJE online). The resulting records were independently evaluated by two reviewers, and disagreements were resolved by consensus.A systematic review of the literature regarding the association of LP with obesity and blood pressure was performed through Ovid ;cut-off used to determine overweight-obesity or raised blood pressure/hypertension;covariates adjusted for in multivariable models. After data extraction, the following variables were generated to indicate covariates adjusted for in individual studies: sex (either sex-adjusted or sex-specific), age (either age-adjusted or age-specific) and population substructure .mean differences for continuous outcomes, and logistic regression coefficients (and associated standard errors) for binary outcomes  referring to a comparison between CC individuals (reference) and T-allele carriers .The following characteristics of the included studies were extracted:,,,,i and ni are the standard deviation and sample size, respectively, for non-LP (i = CC) and LP (i = LP) individuals.For some studies,,,,μLP is the combined mean, and ni and μi are the sample size and mean, respectively, for CT (i = CT) and TT (i = TT) individuals.For some studies,LP is the combined standard deviation, and ni and si are the sample size and standard deviation, respectively, for CT (i = CT) and TT (i = TT) individuals.Standard deviations were pooled as follows:,P < 0.001 in all cases) in the 1982 Pelotas Birth Cohort, the resulting standard deviation estimate was multiplied by 1.1 (i.e. a 10% increment) to avoid its underestimation due to deviations from the normal distribution.When only the median and interquartile range were available,,,,,For binary outcomes, combining CT and TT into a single group and/or estimating the necessary statistics was performed when necessary,IJE online) and to substantial between-study heterogeneity observed in three studied outcomes. The following variables were explored as heterogeneity sources in stratified analyses and random effects meta-regression models: adjustment for at least sex, age or population substructure, as well as adjustment for each of these covariates individually. The following study characteristics were also evaluated: sample size, mean age, ancestry, continent and prevalence of LP. Publication bias was evaluated through funnel plots and Egger’s regression. Analyses of influence were performed as additional sensitivity analyses by obtaining estimates excluding all studies, one at a time.For meta-analysis, pooled effect estimates were generated using random effects models. We opted to use random effects only due to differences in characteristics of the included studies .http://www.r-project.org/].All analyses and simulations were performed using R version 3.2.0  and stratifying by self-reported skin colour (P ≥ 0.700). These results corroborate the need to take ethnicity/ancestry into account in associations between rs4988235 and dairy consumption to minimize confounding due to population stratification.In general, dairy consumption was positively associated with socioeconomic status . Reliable associations were not observed for any other dairy product.2 lower BMI, 0.31  and 0.35  mmHg lower systolic and diastolic blood pressure, respectively, as well as with odds ratio of 0.93  and 0.93  for overweight-obesity and raised blood pressure, respectively. There were no reliable associations supporting effect modification by sex  and European genomic ancestry .Milk intake was inversely associated with obesity and blood pressure . After cIJE online) describes the association of genetically-defined LP with potential confounders of the association of milk intake with obesity and/or blood pressure. In unadjusted analyses, LP individuals had 0.4  more complete years of education than non-LP individuals, as well as household asset index higher in 0.1  standard deviation. However, after controlling for genomic ancestry, the respective coefficients were -0.1  and 0.0 . The odds of LP among current smokers was 1.4  times higher in never smokers in adjusted models. There was no strong indication that any of the reported associations differ according to milk intake status, except for alcohol intake: compared with non-LP, LP status was associated with 2.9  g/day less alcohol intake among non-milk drinkers, and 0.5  g/day more among milk drinkers.2 higher in LP individuals. Adjusting for genomic ancestry increased the magnitude of the estimate to 0.44 . These results were directionally consistent with the point odds ratio estimate for overweight-obesity [1.09 ]. Moreover, point estimates of both outcomes were directionally consistent comparing unadjusted and adjusted models, as well as strata of European genomic ancestry and of milk intake status (IJE online). For systolic, diastolic and raised blood pressure, point estimates were inconsistent comparing unadjusted with adjusted models, but all unadjusted 95% CIs included the respective adjusted point estimate and vice versa. Moreover, point estimates for systolic blood pressure and raised blood pressure were directionally inconsistent between strata of European genomic ancestry, with some indication of interaction  for raised blood pressure: odds ratio of 1.20  and 0.87  in individuals with European genomic ancestry ≥ 85% and < 85%, respectively.There were no strong associations of genetically defined LP with obesity or blood pressure , althougIJE online). After accessing the full texts, 16 records were included.,,,,,IJE online). Study-level characteristics and results are displayed in Sheets 2–6 of After duplicate removal, 452 records were screened based on their titles and abstracts, which yielded 30 records . Results for diastolic blood pressure were also suggestive of a positive association with LP, with a mean difference coefficient of 0.02  mmHg comparing LP with non-LP individuals, although the confidence intervals poorly included 0. However, this was inconsistent with the pooled point odds ratio estimate for raised blood pressure (0.98) and the pooled point mean difference for systolic blood pressure (−0.04 mmHg), with both confidence intervals largely including 1 and 0, respectively.Table 4 displays meta-analysis results .I2 statistic suggested considerable heterogeneity for BMI and systolic and raised blood pressure, the number of estimates only allowed exploring potential heterogeneity sources for BMI. Excluding a single small outlying study  reduced the I2 statistic to 30.2% and yielded an estimate of 0.08 . Such exclusion also reduced Egger’s regression intercept from 1.11 —which was suggestive of publication bias, although confidence intervals were wide—to 0.41 .Although forest plots and the Meta-analytical estimates for BMI within subgroups of study characteristics are shown in IJE online) display the expected results of the LP-blood pressure associations assuming that they are entirely mediated by BMI. Even in a sample size of 300 000 individuals, statistical power was low, ranging from 5% to 49% for systolic and 5% to 40% for diastolic blood pressure, depending on LP prevalence and strength of LP-BMI associations. In this sample size, the point effect estimates ranged from 0.016 to 0.192 and 0.007 to 0.088 mmHg, respectively, comparing LP to non-LP (reference group) individuals.In this study, the LP SNP rs4988235 was associated with daily milk consumption in a population-based sample in South Brazil. In conventional observational analysis, there was an inverse association of milk intake with obesity and blood pressure. However, Mendelian randomization analyses based on genetically defined LP did not confirm these associations. Moreover, LP was positively associated with BMI and overweight-obesity in our meta-analysis.The aforementioned meta-analysisn = 98 529) failed to detect an association of LP with blood pressure and hypertension.A recent large study in the Danish population  is the assumption of no effects of the genetic variant on the outcome other than through the exposure of interest . In this regard, we used a genetic variant with strong functional evidence supporting that its phenotypic implications are mediated by milk consumption due to LP status. We tested the association of rs4988235 with intake of different dairy products and observed reliable associations only with milk. Moreover, a recent study on almost 100 000 Danish individuals failed to detect associations with intake of fruit, vegetables, fish, fast food and soda drinks after correcting for multiple testing.P-values were > 0.20). Although this is in accordance with rs4988235 having pleiotropic effects, it is important to note that it was not possible to stratify in never vs ever milk drinkers since this information was not available and, even if it were, the prevalence of never milk drinkers after weaning would most likely be very low. We stratified based on current milk intake status, so it is possible that some individuals stopped drinking milk due to LP-associated symptoms. By conditioning on a potential mediator, we might not only bias downwards the effect estimates associated with LP status, but also introduce collider bias.For some exposures such as alcohol intake, it is possible to perform Mendelian randomization stratifying by never vs ever experimenters to gain insights into potential horizontal pleiotropic effects. This is based on the notion that the effect of genetic variants would be on continuation/addition rather than initiation, so one would expect to see associations only among ever experimenters unless the genetic instruments are associated with the outcome through pathways not mediated by alcohol intake.Another potential source of confounding in Mendelian randomization studies is population substructure, which was reported to interfere with associations of rs4988235 with height in European American populations,It has been suggested that cultural factors associated with acceptance and generality of milk intake influence the association between the latter and genetically defined LP.MCM6 region. This is of special importance given that 26 haplotypes were derived from 10 LP-related SNPs in Southern , North Eastern (n = 262) and Northern (n = 200) Brazilian individuals,MCM6 region. Northern individuals presented the highest variability, whereas Southern individuals (the most similar to the 1982 Pelotas Birth Cohort) presented one case of heterozygozity for each of the rs145946881 and -13779 G > C variants. Importantly, in vitro effects on gene expression are available for the former only.Another potential limitation is the use of a single genetic predictor of LP instead of including other variants at the Considering that obesity and elevated blood pressure are important risk factors for cardiovascular diseases, identifying their determinants is critical for efficient public health interventions aimed at reducing the burden of disease at the population level. In our study, analyses based on genetically defined LP suggested that simply increasing milk intake in the target population would likely increase its BMI and prevalence of overweight-obesity and, at best, not influence blood pressure. Our findings are in accordance with the notion that the results from RCTs evaluating pressure-lowering effects of milk compounds do not imply that simply increasing milk intake in the general population would promote the expected health benefits.This work was supported by different agencies. From 2004 to 2013, the Wellcome Trust supported the 1982 Pelotas Birth Cohort Study. Additional funding was granted from the Brazilian National Research Council (CNPq) and Rio Grande do Sul State Research Support Foundation (FAPERGS). Previous phases of the study were supported by the International Development Research Center, World Health Organization, Overseas Development Administration, European Union, National Support Program for Centers of Excellence (PRONEX) and the Brazilian Ministry of Health.Supplementary DataClick here for additional data file.


Acacia Senegal. Gum Arabic had shown lipid lowering effect in both humans and animals. The aim of this trial was to determine the effect of GA supplementation on anthropometric obesity marker, Visceral Adiposity Index (VAI) and blood pressure in patients with type 2 diabetes mellitus.There is a strong association between cardiometabolic risk and adipose tissue dysfunction with great consequences on type 2 diabetic patients. Visceral Adiposity Index (VAI) is an indirect clinical marker of adipose tissue dysfunction. Gum Arabic (GA) is a safe dietary fiber, an exudate of This randomized, double blinded, placebo controlled trial recruited a total of 91 type 2 diabetic patients , age (mean ± SD) 50.09 ± 9.3 years on hypoglycemic agents and were randomly assigned into two groups, either to consume 30 g of GA or 5 g of placebo daily for 3 months. Anthropometric obesity markers were measured and indices were calculated. Blood pressure was measured and high density lipoprotein (HDL) and triglycerides (TG) were determined in fasting blood samples at the start and end of the study period.P < 0.05) in GA group by 2 and 23.7% respectively. Body adiposity index significantly decreased by 3.9% in GA group while there were no significant changes in waist circumference or waist-to-hip ratio (WHR). Systolic blood pressure significantly decreased by 7.6% in GA group and by 2.7% in placebo group from baseline with no significant changes in diastolic blood pressure in the two groups.After intervention, Gum Arabic decreased BMI and VAI significantly   The incidence of diabetes is increasing globally leading to serious complications . In SudaThe use of oral hypoglycemic drugs is associated with the tendency to gain weight or other side effects; therefore nutritional care is crucial for diabetic patients.Obesity and weight gain play a major role in insulin resistance and development of diabetes. It was recognized that elevated levels of triglycerides lead to elevated levels of free fatty acids which modulate pathways that link insulin receptors with glucose transporters and impair normal function of beta cell. Furthermore, hyperlipidaemia can lead to more difficulties in controlling hyperglycaemia in diabetic patients . The preIn clinical practice, anthropometric measurements such as body mass index could be a predictor for the management of overweight or obesity in patients at high cardiometabolic risk. Unfortunately, there is conflicting evidence in predicting CVD in diabetic patients due to variation in visceral adipose tissue accumulation by many etiological factors including age, gender and ethnicity and differences in body fat distribution and composition , but genVisceral adipose index is a good predictor of visceral adiposity which is related to type 2 diabetes , 7 and hIn 2011, the Body Adiposity Index (BAI) was proposed to provide a direct estimate of percentage of body adiposity .Diet with high fiber prevents visceral adiposity reflected by reduction in waist circumference and BMI .Gum Arabic (GA) with its high fiber content has been reported to improve lipid metabolism in experimental animal studies with antioxidant effect and improving capillary function. Consequently we postulated that consumption of GA would lead to improvement of anthropometric indices and blood pressure as indicators of CVD. Therefore, this study was designed to determine effects of daily intake of 30 g Gum Arabic on anthropometric variables associated with cardiometabolic risk among type 2 diabetes.This was a single center, randomized, double blind, placebo-controlled trial comparing pre and post effects of GA versus placebo in diabetic patients who have agreed to participate in this trial.The trial was conducted at Academy Charity Teaching Hospital (ACTH) in Sudan; it took place from August 2014 to February 2015. All patients had been diagnosed with type 2 diabetes mellitus according to the criteria of WHO  X TG (mmol/l) and female LAP = [waist (cm) -58] X TG (mmol/l)  + [6.04 x WC- (cm)] + (− 2.29 x BMI) for men and − 278 + [− 0.86 x weight - (kg)] + [5.19 x WC- (cm)] for women .Blood pressure (BP) was measured using mercury sphygmomanometer.Visceral adipose index (VAI) and blood pressure (BP) were measured as primary outcome measures, HC, WC, WHR, BMI, BAI, LAP, DAAT, HDL-c and triglyceride were evaluated and measured as secondary outcomes. These measurements were performed before and after intervention.P < 0.05 was regarded as statistically significant.Statistical analyses were performed using SPSS  values were expressed as mean ± standard deviation and Paired sample T-Test was used to compare continuous variables or Pearson’s chi-square test within the groups. A total of 120 patients were invited with 100 patients identified as eligible to participate in this study, nine patients were excluded for not meeting the project criteria. Ultimately, a total of 97 patients were randomly assigned to Gum Arabic or placebo group as shown in study flowchart in Fig. P > 0.05), however, the majority of patients were females (80.2%).Demographic characteristics of participants and baseline parameters are reported in Table n = 54) of patients were on combined therapy (sulfonylureas e.g. (glimepiride and glipizide) and metformin) and 40.6% (n = 37) on metformin only [In Table min only .High density lipoprotein had significantly increased by 20% from baseline in GA group with no significant change in placebo group. Triglycerides had not statistically changed in both groups (Table P = 0.121).Gum Arabic consumption significantly decreased weight and hip circumferences by 2% and 2.5% respectively from baseline level, although no significant change in waist circumference was observed among this group (P = 0.007).BMI had significantly decreased by 2% in GA treated group from baseline level ((LAP) significantly reduced in GA group by 14.4% from baseline level but no significant change was observed for deep abdominal adipose tissue (DAAT).Visceral adiposity index and BAI were reduced by 23.7% and 3.9% respectively among GA group from baseline level. Lipid accumulation product Twenty nine point nine percent of total patients were hypertensive on hypertensive medications mainly  beside antidiabetic medication. Systolic blood pressure was significantly reduced in both groups with no significant effect on diastolic blood pressure in both groups as seen in Table Cardiovascular diseases incidence is increased in people with type 2 diabetes . Prevent(LAP) is associated with diabetes, predicting CVD and metabolic diseases better than WC and BMI [Gum Arabic showed anti-obesity effect among healthy adults , and blu and BMI . Our dat and BMI . The obt and BMI . Gum Ara and BMI .The dyslipidaemia in patients with type 2 diabetes (high triglyceride and low HDL-C levels) presents a major risk of cardiovascular disease. Since this was decreased by GA intake in addition to the improvement in body mass composition we can claim that GA can be a beneficial supplementation in diabetic type 2 patients .The findings of this study demonstrated that GA consumption in a dose of 30 g /day was effective in weight reduction and modulating adipose tissue dysfunction in type 2 diabetic patients. This was reflected by the increase in HDL and decrease of triglyceride which were major component in assessing the CV risk factors in diabetic patients.


Adipokines are a set of cytokines secreted by white adipose tissue that have been suggested to be involved in the development of cardiovascular diseases. We aimed to evaluate the cross-sectional associations of a panel of representative adipokines with cardiovascular measures in a cohort of hemodialysis patients.We measured plasma adiponectin, resistin, plasminogen activator inhibitor-1 (PAI-1), leptin, monocyte chemotactic protein 1 (MCP-1) and adipsin levels in 366 dialysis patients and 60 healthy controls. The associations of these adipokines with systolic blood pressure (assessed by ambulatory blood pressure monitoring), pulse wave velocity (PWV) and cardiac markers  in these patients were determined by general linear models with stepwise adjustment for covariates.p <0.001) and similar leptin levels (p = 0.82). On adjustment for body mass index and diabetes, however, the PAI-1 level was comparable between group (p = 0.06), whereas leptin levels became significantly higher in the patients(p <0.001). Higher adiponectin, lower PAI-1 and leptin levels were associated with higher systolic blood pressure, even after extensive adjustment . Adiponectin was also consistently and inversely associated with PWV in fully adjusted models (p = 0.003). Resistin, PAI-1, leptin and adipsin showed negative associations with one or more circulating cardiac markers .In unadjusted comparison with controls, dialysis patients showed increased adiponectin, resistin, MCP-1 and adipsin levels, decreased PAI-1 concentrations  contains supplementary material, which is available to authorized users. Adipokines are a group of substances released from white adipose tissue and act as cytokines or hormones in vivo. With proteomic profiling approaches, to date there are over 600 secreted proteins classified as adipokines . PreviouPatients on hemodialysis constitute a disease population with strikingly high risk for cardiovascular morbidity and mortality . DespiteGiven that prior studies evaluating the associations between adipokines and cardiovascular injury were restricted to non-kidney disease populations, we here explore their associations with cardiovascular measures in a group of dialysis patients. In this exploration analysis, we related a panel of adipokines to: (1) blood pressure (BP), as evaluated by interdialytic ambulatory blood pressure monitoring (ABPM); (2) arterial elasticity, as measured by carotid-femoral pulse wave velocity (PWV); and (3) circulating cardiac markers, including BNP, NT-proBNP, Troponin I and Troponin T. The aim of this study was to obtain cross-sectional evidence suggesting: (1) the contributions of adipokines to blood pressure regulation; (2) the effect of adipokines on vascular function and (3) the possible roles of adipokines in cardiac injury.This is a cross-sectional analysis of baseline data from an ongoing prospective cohort study that aims to study vascular dysfunction in dialysis patients. The study included patients who met the following criteria: (1) aged 18-80 years old, (2) on maintenance hemodialysis (4 h/thrice weekly) over 3 months, and (3) who have reached their dry weight by clinical judgment. Exclusion criteria were as follows: (1) Malignant hypertension with systolic blood pressure (SBP) ≥ 180 mmHg or diastolic blood pressure (DBP) ≥ 110 mmHg; (2) Acute infection , acute heart failure or the acute phase of stroke (ischemic or hemorrhagic); (3) Decompensated liver cirrhosis or malignant tumor; (4) Amyloidosis or dilated cardiomyopathy; and (5) Internal jugular vein catheterization, previous fistula creation on the non-access arm or any other conditions that will affect the accuracy of peripheral arterial tonometry. Participants were recruited from six tertiary hospitals: The Second Affiliated Hospital of Nanjing Medical University , The Third Affiliated Hospital of Soochow University , Luan People’s Hospital , Affiliated Yixing People's Hospital of Jiangsu University , Affiliated Wuxi People's Hospital of Nanjing Medical University , and Yijishan Hospital of Wannan Medical College ; To compare adipokine levels between dialysis patients and normal subjects for the current study, we further recruited sixty apparently healthy subjects, frequency-matched to patients by age and sex, without any known history of cardiovascular or kidney disease as healthy controls. All participants provided written informed consent. The study was approved by the Institutional Ethical Committee of The Second Affiliated Hospital of Nanjing Medical University.Carotid-femoral PWV was measured on a midweek nondialysis day using the Complior Analyzer device . Since the centers are in different cities and asking the patients to travel from city to city to get PWV measurement would be infeasible, all PWV measurement were performed by an experienced nurse from the Second Affiliated Hospital of Nanjing Medical University in each coordinating center. By this way the quality of PWV measurement was assured with inter-operator bias avoided. Patients were instructed to restrain from caffeine, meals and nitrates within 2 h before measurement (long-acting nitrates for 12 h). Patients rested for 10 min and then an experienced nurse from the Second Affiliated Hospital of Nanjing Medical University performed the test. Three probes were placed in a location with palpable pulse of the carotid, femoral and radial arteries. Ten consecutive recordings were averaged to calculate the transit time using the intersecting tangent algorithm as recommended . CarotidBP was evaluated using interdialytic ABPM, the current gold standard for blood pressure determination in dialysis patients. Evaluation began after PWV measurement and ended before the next dialysis session. The SpaceLabs 90217  monitor was used and programmed to measure BP every 20 min between 6:00 am and 10:00 pm and every 30 min between 10:00 pm and 6:00 am. Patients were instructed to follow their daily activities and to keep their arm still during measurements. Recordings were downloaded using the manufacturer’s software (SpaceLabs Report Manager System) and were further extracted and analyzed using SPSS 19.0 . For patients who had <6 ambulatory BP readings, predialysis blood pressures from dialysis records were collected and averaged over 2-weeks (6 times) before the ABPM and were used instead. For the purpose of exploring the association between adipokines and blood pressure, we used systolic blood pressure because it is the most potent blood pressure component for predicting adverse events in both the general population and in patients on hemodialysis , 13.Blood samples were drawn through vascular access before dialysis treatment and sent to local laboratory departments at each coordinating centers immediately for routine clinical tests . Analyzers used for routine laboratory tests in each coordinating center were summarized in Additional file Plasma adipokines , leptin, monocyte chemoattractant protein-1 (MCP-1) and adipsin), cardiac markers  and C-reactive protein (CRP) were measured using the Milliplex Map assays   via the Luminex 200 system . Concentrations were calculated using the 5-parameter logistic curve fit. The results outside the range of the standards or the fit were further analyzed using a cubic spline. Intra- and inter-assay coefficients of variation were assessed using quality controls and presented in Additional file U test, Student’s t test or chi-square test as appropriate. For adjusted comparisons, analysis of covariance was used. Gender-pooled associations between adipokines and cardiovascular measures in the patients were determined by general linear models. We built three models for various adjustments for evaluating associations of adipokines with blood pressure and arterial elasticity. The first model served as a basic model where only age and sex were adjusted. The second model was further extensively adjusted for traditional and uremia-specific cardiovascular covariates. In Model-3, BMI was included as a covariate. CRP, as a reflection of inflammation, was entered into Model-3 for blood pressure and Model-2 for PWV since it was conventionally thought to be tightly associated with PWV, rather than blood pressure. For evaluation of associations between adipokines and the four cardiac markers, the same strategy was used to constructed the models, except for the basic model, which was omitted for conciseness. All statistical analyses were performed using SPSS 19.0 . Figures were generated using GraphPad Prism 6.0 . A p value <0.05 was considered to be statistically significant.Kolmogorov–Smirnov test was used to check the normality of data distribution. Numerical variables were expressed as mean ± standard deviation for normally distributed parameters or median (interquartile range) for skewed distributions, while categorical variables were expressed as counts (%) or as ratio if n < 100. Numerical variables with skewed distributions were logarithm transformed for analysis as needed. Comparisons between two groups were performed using the Mann-Whiteny Between July 2015 and July 2016, a total of 368 dialysis patients were recruited for the cohort. Plasma samples were available for 366 subjects. These patients constituted the study sample for the current analysis, except for analysis of associations between adipokines and PWV, from which five patients were further excluded due to invalid PWV measurements.p = 0.29 for age and 0.85 for sex ratio, respectively). Body mass index (BMI) was significantly lower and diabetes mellitus was more prevalent in patients (p <0.01 for both). Dialysis patients were expected to have higher systolic blood pressure level (p <0.001).General characteristics of the study population and healthy controls are summarized in Table p <0.001 for all). There was no difference regarding leptin levels (p = 0.82). To explore the confounding effect of BMI and diabetes status on adipokine levels, we compared log-transformed adipokine concentrations between patients and controls with adjustment for the two variables .Adipokine levels were presented and compared between dialysis patients and healthy controls in Additional file p ≤ 0.005 for all). Adiponectin, resistin and leptin were negatively associated while MCP-1 was positively associated with sex  . Higher BMI was associated with lower adiponectin concentrations (p <0.001) but higher PAI-1, leptin and MCP-1 levels . There were inverse relationships between adiponectin and adipsin and diabetes (coded as 0 = No and 1 = Yes) (p ≤ 0.02 for both). It is worthy noting that most of the significant correlations were weak with correlation coefficient <0.3, except for correlations between BMI and adiponectin, PAI-1 and leptin .Table p ≤ 0.04 for all). In the more extensively adjusted model 2, the associations of adiponectin, PAI-1 and leptin remained essentially unchanged. When BMI and log-CRP were further included in model 3 as covariates, only associations between adiponectin and systolic blood pressure became non-significant. In the basic model (model 1), only leptin was negatively related to PWV. However, after further adjustment, adiponectin emerged as the sole adipokine associated, inversely, with PWV .Table p ≤ 0.02 for all). Negative associations were also found between leptin and NT-proBNP as well as adipsin and BNP . For troponins, we found that PAI-1 was inversely associated with Troponin I while adipsin was negatively associated with both Troponin I and Troponin T .Associations of log-transformed adipokines with log-transformed circulating cardiac markers were also determined, as presented in Table In the current study, we explored the cross-sectional associations of adipokines with blood pressure, arterial elasticity and circulating cardiac markers in a cohort of patients on maintenance hemodialysis. To the best of our knowledge, this is the first report comprehensively relating a panel of representative adipokines to cardiovascular measures in this disease population.Our results demonstrated the following: (1) Compared with healthy controls, circulating adiponectin, resistin, MCP-1 and adipsin concentrations were markedly elevated in dialysis patients while leptin levels remained comparable and PAI-1 levels were even reduced. Adjustment for BMI and diabetes could change the relative levels of the latter two adipokines significantly between groups. (2) Higher adiponectin, lower PAI-1 and leptin levels were associated with higher systolic blood pressures, even after extensive adjustment. (3) Adiponectin was consistently and inversely associated with PWV in fully adjusted models. (4) Resistin, PAI-1, leptin and adipsin were negatively associated with one or more circulating cardiac markers. These findings clearly suggest the participation of adipokines in modulation of the cardiovascular system of dialysis patients and need to be interpreted together with prior data from other study populations.The six adipokines studied here have been implicated in various roles in different physiological and pathophysiological processes , 14. TheAdiponectin was the only adipokine associated with both blood pressure (positively) and PWV (negatively) in extensively adjusted models in our study. The bidirectional association of adiponectin with blood pressure and PWV is interesting. Previous studies usually suggested adiponectin as a protective adipokine for the cardiovascular system, with effects of lowering blood pressure and preserving arterial elasticity , 19–21. Leptin is the first identified adipokine and is usually considered to elevate blood pressure. It can increase the activity of the sympathetic nervous system and activate the renin–angiotensin–aldosterone system, which will together lead to increased blood pressure , 25. PrePAI-1 is a serine protease inhibitor protein that functions as the principal inhibitor of tissue plasminogen activator. We showed that in dialysis patients, its circulating levels were comparable to those in healthy subjects and were negatively associated with blood pressure and several cardiac markers . Although a previous work demonstrated that increased plasma PAI-1 levels predicted cardiovascular risk in peritoneal dialysis patients , it needIn addition to the adipokines discussed above, we also noticed that there were consistent and negative associations between resistin and adipsin and circulating cardiac markers. Resistin is mainly expressed in macrophages from adipose tissue and is considered to contribute to insulin resistance and inflammation, while adipsin, also known as Factor D, is a key component of the alternative complement pathway. Data regarding roles of the two adipokines in the cardiovascular system of dialysis patients is scarce. Spoto et al. reported that resistin predicted cardiovascular events in a cohort of hemodialysis patients, but this effect was dependent on adiponectin levels . The negSubstantial work has been performed to investigate the physiologic and pathophysiologic mechanisms underlying the effect of different adipokines on the cardiovascular system and had been well summarized , 3, 31. There are certain limitations of our study. First, as mentioned above, the cross-sectional design precludes any inference of causality. The associations of adipokines with cardiovascular measures should be interpreted with this caution and will need support from future evidence. Second, the study was limited to the Chinese population. Whether these associations persist in other races is uncertain, especially given the ethnic difference of adipokines demonstrated in previous studies , 34. ThiIn conclusion, in a cohort of patients on maintenance hemodialysis we studied a panel of adipokines and their associations with several cardiovascular measures, including blood pressure, PWV and circulating cardiac markers. We found significant associations between adipokines and these measures. Our data suggest the possible involvement of adipokines in cardiovascular modulation in dialysis patients.


The pulsatility index on transcranial Doppler was significantly reduced in valsartan (p = 0.002) and fimasartan group (p = 0.008). Plasma NT-proBNP level was also significantly decreased in ARB groups, especially for the fimasartan group . These findings suggest that short-term ARB administration would be favourable for ischaemic stroke patients with hypertension, permitting effective reduction of central pressure and dampening of cerebral pulsatility.Central and cerebral haemodynamic parameters can vary under similar brachial blood pressure (BP). We aimed to investigate the effects of antihypertensive agents on central and cerebral haemodynamic parameters in hypertensive patients with ischaemic stroke. The Fimasartan, Atenolol, and Valsartan On haemodynamic paRameters (FAVOR) study was conducted in a prospective, double-blinded manner. One hundred five patients were randomly administered atenolol, valsartan, or fimasartan during 12 weeks. We measured brachial, central, cerebral haemodynamic parameters and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at baseline and after 12-week. Baseline haemodynamic parameters were balanced among the three groups. Even with similar brachial BP reduction, significantly lower central systolic BP (atenolol; 146.5 ± 18.8 vs. valsartan; 133.5 ± 20.7 vs. fimasartan; 133.6 ± 19.8 mmHg,  Renin-Angiotensin System (RAS) blockades—angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blockers (ARBs) were frequently prescribed antihypertensive agents for stroke patients in anticipation of “beyond blood pressure (BP) lowering” effect that attenuate the vicious cascade such as vascular remodeling, endothelial dysfunction, oxidative stress and inflammation3. In the aspect of other antihypertensive class, some stroke neurologists have concerned about the use of calcium-channel blockers (CCB) due to the potential redistribution of cerebral blood flow by the vasodilatory reaction4. Beta-blockers, despite limited effect on prevention of cardiovascular events compared with ARB5, still have been considered for lowering BP due to their minimal influence on cerebral perfusion especially in acute period7. The optimal class selection of antihypertensives during the acute stage of ischemic stroke patients would still be challengeable in real-world practice8.Hypertension is one of the most important modifiable risk factors in the secondary prevention of stroke9 and target-organ damage10 than brachial pressure. Central pressure could be affected by age, sex, heart rate, or additional systemic diseases. Also, importantly, antihypertensive agents are known to have different effects on central pressure9. RAS blockades consistently showed beneficial effects on central pressure12. Thus, central pressure could be a key mediator as a potential explanation for beyond BP lowering effect. In addition, cerebral haemodynamic parameters including increased pulsatility index on transcranial Doppler is closely associated with white matter hyperintensities13, cerebral micorangiopathy in diabetes14, and elevation of vascular risks after acute ischemic stroke15. In this study, we aimed to assess the impact of 12-week antihypertensive treatment with ARBs compared to β-blockers on central pressure and cerebral haemodynamics in hypertensive patients with ischaemic stroke under similar brachial BP control.Recently, sufficient evidence from various reports suggests that central pressure is more strongly related to future cardiovascular events16 or transient ischaemic attack17; over 30 years of age; no deterioration of NIH stroke scale (NIHSS) score for at least 48 hours after admission; diagnosed with hypertension (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg)18 or who were already taking antihypertensive agents before hospitalization. Exclusion criteria were haemorrhagic stroke; high stroke severity (NIHSS score ≥ 16); systolic BP over 200 mmHg requiring multiple antihypertensive agents; suspicion of secondary hypertension19; history of allergic reaction to any ARB or β-blocker; renal insufficiency (serum creatinine > 2.0 mg/dl); during pregnancy or lactation, and participating in another pharmacological study.Patients were eligible for this trial if they satisfied all of the following inclusion criteria: presenting with neurological deficits within 48 hours of onset; ischaemic stroke confirmed by diffusion weighted imaging®; Boryung Pharm. Co. Ltd, Seoul, Korea) is a recently developed selective AT1 receptor blocker approved by Korean Food and Drug Administration for the treatment of essential hypertension in 201020. Figure The Fimasartan, Atenolol, and Valsartan On haemodynamic paRameters in ischaemic stroke (FAVOR) study was a 12-week, prospective, randomised, double-blinded, parallel-group design trial with 3 treatment arms . Fimasartan , cerebral haemodynamic parameters , and other systemic parameters . Primary and secondary outcomes were evaluated at baseline and 12 weeks. All adverse events were reported by the investigators and adjudicated by an independent adjudication committee, being classified as serious or non-serious. Serious adverse events were defined as cardiovascular events or events requiring hospitalization.21. For each patient, the measurements described above were repeated twice. The averaged radial artery waveforms were processed with dedicated software and corresponding central aortic pressure waveforms were derived. Peripheral AIx and AIx75, an index normalized for a 75-bpm heart rate, were used because of a close agreement between central and peripheral Aix22. Arterial wave contours were digitalized by a GetData graph digitizer  consequently analysed using statistical software R developed by R Core Team, 2015 . Area under the curve (AUC) was calculated in the area of rectangle (100 × 600).The brachial and central BP measured in the morning after 5-min of rest. The right brachial BP was oscillometrically measured and the left radial arterial pulse waves were recorded simultaneously by the tonometry 23. Mean velocities and PI of the stenotic MCA on brain computed tomography (CT) angiography were excluded in the analysis. Total cerebral blood flow (CBF) volume was measured through previously published duplex method 24. All parameters were measured by well-trained ultrasonographers and expert physicians who were blinded to the clinical findings.All patients underwent TCD ultrasonography using a Doppler machine . The mean cerebral blood flow velocity and the PI from bilateral middle cerebral arteries (MCAs) were automatically calculated25. BaPWV was measured by VP-2000® apparatus  using a volume-rendering method26. We used the FMD method as an evaluation of endothelial function following previously described method 27. FMD (%) was defined as the maximum percent change in brachial artery diameter after reactive hyperemia relative to baseline.Plasma NT-proBNP level was assessed as a marker for ventricular remodeling using a Human NT-proBNP ELISA kit  with the Triage assay at baseline and 12 weeks11. To allow for a 10% drop-out rate, 35 patients were randomly assigned per each group. All parameters were presented as mean value with standard deviation. For the analysis of the baseline differences among the groups, categorical variables were analysed using a χ2 test and numerical variables using a one-way ANOVA test. In case of non-normality variables, Kruskal-Wallis and Mann-Whitney test were used. In the analyses of haemodynamic parameters, repeated-measures analysis of variance was used for adjusting baseline values in comparison among the three groups. All statistical analyses were performed with SPSS version 18 for Windows .A sample of 32 patients per group was calculated based on Dunnett’s procedure of comparing several treatments with a control. The statistical power of the study was set at 80%, given a mean change of central systolic BP 5 and a standard deviation of 3, with a type-I error of 0.05The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.During the study period, a total of 105 were enroled. Table Table Central BP parameters were significantly reduced after the 12-weeks of treatment in all three groups Fig. . ARB groFigure Plasma NT-proBNP level was significantly reduced in the ARB groups after 12-week treatment  BP and cerebral pulsatility, even though similar reductions were seen on brachial  BP in patients with ischaemic stroke. The ARB groups were also associated with a significant decrease in plasma NT-proBNP level, especially for patients on fimasartan, representing a decrease of AIx and a dampened contour of arterial wave reflection.2. In this context, there is the possibility that RAS blockades might induce structural and functional alteration in the central aorta independently from BP changes measured from the brachial artery28. Various lines of evidence suggest that antihypertensive agents have different capacity in affecting the central haemodynamic parameters. The superiority of RAS blockades on central BP and PP, as representative markers of central pressure, has been revealed through numerous studies12. Additionally, RAS blockade administration seems to improve surrogate markers of arterial stiffness including augmentation index (AIx) and pulse wave velocity (PWV)29. A possible mechanism for these effects could be promotion of vasodilation and vascular remodeling by inhibition of angiotensin II and increase in bradykinin level. To the best of our knowledge, this study provides the first data for the class differences of antihypertensives in ischaemic stroke patients on central pressure, and its results are consistent with previous findings in hypertensive patients without a history of stroke12.Experimental and clinical data suggest that the RAS may play a pivotal role in the vascular remodeling process and structural adaptation to increased afterload2. Deleterious vascular remodeling has been observed in the retina30 and kidney31 in hypertensive patients, which is explained by an increase of vascular resistance. Prior experimental33 and clinical studies34 show that treatment with RAS blockades would be beneficial in not only cardiovascular disease but also in cerebrovascular disease. Cerebral ischaemia induces the overexpression of angiotensin II type 2 (AT2) receptor, which can lead to cerebral vasodilatation and other pleotropic effects35. Augmentation of this pathway can improve vasodilatory capacity and vascular reserve in the brain. Pulsatility index (PI) has been used as a noninvasive surrogate of the relevant arterial impedance23. Therefore, the attenuation of cerebral pulsatility in our dataset might be a reflection of reinforcing the AT2 pathway through selective AT1 receptor block by ARBs36. It is consistent with the previous experiments that showed selective RAS alterations in cerebral tissue33.Numerous researchers believe that inhibition of the RAS mitigates target organ damage beyond BP lowering37, and it is an independent predictor of outcome in heart failure38 and coronary artery disease39. In hypertensive patients, the role of BNP was not clear, several studies showed that RAS blockades decreased plasma BNP levels in patients without heart failure41. Our data demonstrated that fimasartan significantly decreased NT-proBNP levels as compared with atenolol and valsartan. There was also a significant association with the levels of NT-proBNP and AIx in this trial, which is consistent with the previous research11. Moreover, there seems to be an associative trend between NT-proBNP level and overall contour change of the arterial reflection wave, both of which can be due to RAS alteration, even in a short-term ARBs administration. Therefore, our results–namely, concurrent decreases of central BP, arterial reflection, cerebral pulsatilities and plasma NT-proBNP–can be a surrogate evidence that ARB can be a more favourable choice for stroke patients with hypertension. Fimasartan, a recently developed selective AT1 receptor blocker, is a pyrimidin-4(3 H)-one derivative of losartan with the imidazole ring replaced20. This molecular change might enable higher binding affinity with longer half-life of 14.0 to 17.9 hours for AT1, and several preclinical studies have shown target organ-protecting effects43. In addition, a recent randomised-controlled trial showed that fimasartan had better 24-hour BP profiles than valsartan due to different pharmacokinetics44. In this context, our data addresses that effective and sustained BP reduction in fimasartan group, which might influence on central vessel and targeted-end organ protections.Plasma NT-proBNP level is attributed to increases in left ventricular stretch and cardiac afterloadThis study has several limitations. Although our study is solidly based on central haemodynamic and biochemical surrogate markers, it has to be cautiously interpreted, as our conclusion may be hypothetical. Second, our investigation was based on non-invasive methods of haemodynamic measurement. Noninvasive measurements can be influenced by various factors including age, gender, height, and heart rate, therefore, its values may be indirect compared to other invasive methods of central and cerebral haemodynamics. However, such non-invasive methods provide easy and practical application to patients with ischaemic stroke and systemic hypertension, and assist in gaining clinical insight into the underlying pathophysiology. Finally, the results should be interpreted cautiously because our study population was relatively small. However, this was the first investigation for evaluating drug class effects under similar brachial BP control in hypertensive patients with ischaemic stroke. In the future, large-scale trial would be required for confirming the observations in this study.In conclusion, administration of ARBs can be more beneficial on central pressure and cerebral haemodynamic parameters under similar brachial BP control compared to atenolol in patients with ischaemic stroke. This trial supports the view that the benefits of ARB in cardiovascular prevention exist beyond BP lowering and that it provides additional therapeutic advantage for ischaemic stroke patients. In the future, these findings need to be confirmed in large-scaled and long-term trials with clinical outcome measures.Supplementary material


During liver transplantation, the thermodilution cardiac output (CO) technique cannot respond to sudden hemodynamic changes associated with postreperfusion syndrome. Photoplethysmography (PPG) can reflect changes in intravascular volume and thus can be used to assess vasomotor tone and arterial stiffness on the pressure–volume relation. We investigated whether a beat-to-beat analysis of the arterial pressure–PPG relationship can estimate dynamic changes in vascular characteristics immediately after liver graft reperfusion.amp/PP, as relative vascular compliance) to total peripheral resistance (TPR) and Windkessel compliance (Cwk) obtained from the Modelflow CO algorithm.In 10 recipients, arterial blood pressure and PPG waveforms recorded simultaneously were analyzed from the beginning of fall to nadir in systolic blood pressure immediately after reperfusion. On a beat-to-beat basis, we compared the ratio of the amplitude of PPG to arterial pulse pressure , whereas TPR decreased . Beat-to-beat PPGamp/PP was negatively correlated with TPR (median r = –0.80 [95% CI –0.85 to –0.76] on linear regression and r2 = 0.84 [95% CI 0.73–0.92] on curvilinear regression), and was positively correlated with Cwk (median r = 0.86 [95% CI 0.81–0.91] on linear regression and r2 = 0.88 [95% CI 0.75–0.96] on curvilinear regression).Following graft reperfusion, PPGOur results suggest that relative compliance, obtained from beat-to-beat analysis of PPG and arterial pressure waveforms, can track abrupt changes in vascular characteristics associated with postreperfusion syndrome. This simple index would contribute to differential diagnoses of sudden hypotension. Restoration of blood pressure and systemic vascular resistance with vasoactive drugs ensures adequate perfusion to the liver graft and vital end organs; however, the excessive use of vasoconstrictors may lead to severe ischemic complications such as renal failure.,5 Therefore, accurate and timely assessment of arterial compliance and resistance is of interest to optimize vascular tone for adequate perfusion pressure.When hypotension develops suddenly during an operation, it is helpful to assess the compliance of the arterial system to decide which treatment is appropriate for the patient . Particularly during liver transplantation, hemodynamic deterioration caused by factors such as postreperfusion syndrome is frequently observed in up to 50% of patients.,7 Therefore, despite their invasiveness, thermodilution techniques that use a pulmonary artery catheter continue to be used as routine monitoring devices during liver transplantation. Nevertheless, this technique is limited in not being able to reflect abrupt hemodynamic changes associated with rapid shifts in temperature changes when rushing cold presentative solution into the heart.Although various less invasive hemodynamic monitoring devices that employ arterial pressure waveform analyses have been used to monitor cardiac output and vascular resistance, these devices are expensive and may be unreliable to apply in patients undergoing liver transplantation, because such patients have hyperdynamic and low-resistance circulation.amp) reflects peripheral blood volume varied according to arterial pulsation, which is well known as the “alternating current .” Considering that PPG is influenced mainly by pulsatile changes in blood, it can be used to estimate vascular compliance on the pressure–volume loop. Shelley et al suggested that the ratio of changes in PPG to arterial pressure may reflect the effects of vasoconstrictors on vascular compliance, and can be used as a relative compliance measure, regarding PPGamp and arterial pulse pressure (PP) as Δvolume and Δpressure, respectively. They showed that large PPGamp is associated with narrow PP indicating high vascular compliance, and this relationship is reversed after phenylephrine administration. Therefore, we hypothesized that the ratio of changes in PPG to arterial pressure recorded simultaneously would be able to detect the beat-to-beat dynamic changes in vascular compliance associated with postreperfusion syndrome in liver transplantation.Photoplethysmography (PPG) waveforms appear as the result of changes in arterial and venous blood, affected by the complex interaction of stroke volume, vascular compliance, and condition of local tissue. Particularly, the amplitude of PPG  and pulmonary valve stenosis. None of patients had significant arrhythmia, such as atrial fibrillaion, frequent premature ventricular complex, or complete atrioventricular block. Ultimately, 10 cases were available for analysis after excluding 9 patients with incomplete data on PPG or arterial pressure waveforms, or whose signal quality was poor. We conducted this study after receiving approval from our Institutional Review Board (no. 2016–0571) in accordance with the Helsinki II declaration.We retrospectively evaluated the data of 55 consecutive adult recipients who had undergone living-donor liver transplantation from a prospectively collected registry between January 2015 and May 2015 at our hospital. Among these cases, we selected 26 patients who developed postreperfusion syndrome, defined as a decrease in mean arterial pressure of more than 30% of the value at the end of the anhepatic stage for more than 1 minute within 5 minutes after graft reperfusion.2.2,14 we performed routine monitoring using electrocardiography, noninvasive blood pressure monitoring, pulse oximetry, and end-tidal capnography. Anesthesia was maintained with continuous infusions of fentanyl and vecuronium under 1 to 1.5 vol% sevoflurane in a 50% O2/air mixture. We monitored direct arterial blood pressure by radial artery catheterization. The pulmonary artery catheterization  was performed via central venous access  and connected to a Vigilance device .In accordance with standard protocol at our institution,2.3In the anhepatic phase, all patients underwent partial clamping of the inferior vena cava using a piggyback technique without venovenous bypass. For preservation of the liver graft, histidine-tryptophan-ketoglutarate solutions were used in all cases. Before reperfusion of the hepatic graft, the serum levels of potassium and pH were maintained at < 4.5 mmol/L and >7.35, respectively, and the target serum level of calcium was >0.8 mmol/L. Central venous pressure was adjusted to 6 to 8 mm Hg using fluid and blood products. The donor hepatic graft was not flushed with the patient's own blood or colloid solution to remove the preservation solution. After reperfusion of graft, epinephrine of 10 to 20 mcg was used as the first choice of drug and incrementally administered until blood pressure is restored, if the spontaneous recovery of postreperfusion syndrome is delayed.2.4TM; Covidien, Boulder, CO) was placed over the index finger on the same side as the radial artery catheterization.Electronic medical records of hemodynamic variables of recipients were routinely recorded during the liver transplantation with a computerized data-acquisition system . The waveform variables recorded included continuous electrocardiography, arterial blood pressure, central venous pressure, pulmonary arterial pressure, capnography, and airway pressure, all of which were digitized at a sampling rate of 1000 Hz. In the same way, we also recorded PPG waveforms using a pulse oximetry monitoring device , which serves full-scale waveforms without autogain. A pulse oximeter sensor (Nellcoramp/PP), which served as relative vascular compliance because of uncalibrated PPG signals. To estimate beat-to-beat cardiac output, stroke volume, total peripheral resistance (TPR), and arterial Windkessel compliance (Cwk), we analyzed arterial pressure waveforms with Beatscope software , employing the Modelflow technique. The Modelflow algorithm incorporates age, sex, height, and weight information of the patient to estimate aortic cross-sectional area, and provides beat-to-beat hemodynamic variables.Arterial blood pressure and PPG waveforms were retrieved from the beginning of fall to the nadir in systolic blood pressure immediately after reperfusion, before administration of epinephrine. Beat-to-beat data were extracted using a peak detector . We calculated the beat-to-beat ratio between the amplitude of PPG and arterial pulse pressure . To analyze data points of all patients, we calculated percent changes from baseline value in PPGamp/PP, TPR, and Cwk. Relationships between percent changes in variables were also examined using linear and curvilinear regression. SPSS software version 21.0  and SigmaPlot  were used for statistical analysis.Demographic and hemodynamic data are presented as median with interquartile range (IQR). Appropriate changes in hemodynamic variables between those before and after graft reperfusion were tested using a paired 3amp after reperfusion was not significantly different compared to that before reperfusion (P = .26). Cardiac output increased but to statistically nonsignificant level (P = .05), although stroke volume increased from 60 mL (IQR 44–80 mL) to 77 mL (IQR 63–97 mL) (P = .004). The PPGamp/PP ratio increased by 41.5% (IQR 29.8–88.5%) and Cwk increased by 42.0% (IQR 26.4–60.9%). TPR markedly decreased by 46.4% (IQR –56.0 to –33.6%)  in each patient. Table –62 in eaamp/PP ratio was negatively correlated with TPR  . On curvilinear regression, it also increased exponentially to the maximum curve (median R2 = 0.88 [95% CI 0.75–0.96]) . Percent change in the PPGamp/PP ratio of all data points was also strongly associated with percent change in Cwk (r = 0.822 on linear regression and R2 = 0.811 on curvilinear regression) , whereas the change in PPGamp was relatively small. Consequently, these findings support the fact that PPGamp alone is limited when estimating vascular characteristics in peripheral arteries during sudden hemodynamic changes.The PPGamp/PP ratio and TPR or Cwk fitted better to curvilinear regression than linear regression. We speculated that the reason was that estimation of arterial compliance could be affected by the measurement site. The PPGamp/PP ratio was obtained from peripheral sites of the finger and radial artery, which can be considered peripheral arterial compliance. Meanwhile, TPR and Cwk were determined using the Modelflow algorithm, which estimates aortic flow pulsation by simulating aortic characteristic impedance, arterial compliance, and systemic vascular resistance. Considering the differences between the aorta and peripheral vascular system, a gradual increase in peripheral arterial compliance may be persistent even after fully increased central arterial compliance, resulting in a plateau in a curvilinear curve. Meanwhile, in patient 8, 9 and 10, the relationships between PPGamp/PP ratio and TPR or Cwk may be shown to fit better linear interpolation. It is speculated that TPR or Cwk may persistently increase with the increase of PPGamp/PP ratio until the nadir in systolic blood pressure was reached in these patients.In the present study, we also found that relationships between the PPG,12 Severe hypotension that develops during the postreperfusion period is associated with lower systemic vascular resistance, higher compliance, and/or reduced cardiac output. Therefore, the identification of vascular characteristics helps guide treatment appropriately. Unfortunately, however, arterial pressure contour analysis can be unreliable under circumstances of alterating vasomotor tone, particularly in patients with advance liver cirrhosis.,7 The thermodilution technique using pulmonary artery catheterization also cannot provide continuous cardiac output and systemic vascular resistance under conditions of thermal noise.,20 This method takes about 10 to 15 minutes for stabilization.,21 In fact, we observed that the Vigilance device could not display hemodynamic parameters even in stat mode. Currently, the use of transesophageal echocardiography (TEE) has been increasing for intraoperative monitoring in liver transplantation, because it is helpful for assessing real-time ventricular contractility and preload. Although it has been proposed that vascular stiffness can be calculated using aortic blood flow and diameter, TEE still has shortcomings and cannot provide continuous information about vascular compliance.,23 Therefore, further research is needed to investigate that our simple index together with TEE can be used complementarily to assess hemodynamic status during the reperfusion period.Postreperfusion syndrome can be associated with poorer outcomes after liver transplantation if there is persistent hypotension despite treatment. In addition, as a unit of PPGamp is arbitrarily given, the PPGamp/PP ratio should be regarded as relative compliance. Therefore, we also performed correlation analysis using TPR and Cwk data and the PPGamp/PP ratio either as absolute values or relative changes. Second, we measured PPG at the index finger, which is markedly sensitive to sympathetic activation. During the anhepatic phase in liver transplantation, sympathetic activation and elevation of systemic vascular resistance are caused by decreased cardiac output related to vascular clamping. Therefore, this effect may influence the calculation of the PPGamp/PP ratio even if PPGamp shows insignificant changes during reperfusion.The present study had some limitations of note. First, we used the Modelflow method to generate beat-to-beat reference values. This method computes cardiac stroke volume by analyzing the pulse wave contour of the arterial blood pressure wave and we used it because we could not directly measure vascular characteristics. The Modelflow method allows for estimation of beat-to-beat stroke volume and derivatives, but its variables have not been calibrated.5Our current results suggest that analysis of the relationship between plethysmographic and arterial pressure waveforms can provide information on beat-to-beat vascular compliance and track the abrupt changes in vascular characteristics associated with hypotension during liver graft reperfusion. This simple index could contribute to differential diagnoses of sudden hypotension and thus could help inform decisions as to which treatments are adequate during this critical period.