VO2) and VO2 at the anaerobic threshold. In univariate linear regression analysis, the % change in heart rate recovery, plasma B-type natriuretic peptide levels, resting heart rate, and the minute ventilation /carbon dioxide output slope were significantly related to that of peak VO2 . Stepwise multivariate linear regression analysis showed that the % change in heart rate recovery was independently related to that of peak VO2 (p < 0.05). Our results suggest that heart rate recovery is closely associated with recovery of exercise tolerance in patients with HF and AF after CR.This study aimed to examine the factors that contribute to improvement of exercise tolerance in patients with heart failure (HF) and atrial fibrillation (AF) following cardiac rehabilitation. Our hypothesis is that parasympathetic values are important for recovering exercise tolerance in those patients. We included 84 consecutive patients with HF and AF . All of the patients underwent a cardiopulmonary exercise test and had pre and post 5 month cardiac rehabilitation assessed. After 155 ± 11 days and 44 ± 8 sessions, 73 patients (86%) showed an increase in peak oxygen uptake ( Atrial fibrillation (AF) is a major cardiac rhythm disturbance that is frequently encountered in clinical practice. Even though AF is common in patients with underlying cardiac disease, it also occurs in those without cardiac disease and its incidence is increasing yearly. Risk factors for developing AF include age, sex, obesity, and a low fitness level. Current management of AF mainly focuses on rate and rhythm control and reducing the risk of stroke, and its associated morbidity and mortality , 2. RateThe benefit of cardiac rehabilitation (CR) programs has been shown in many cardiac diseases, including patients with AF –7. The mIn patients with heart failure (HF), worsening of myocardial function is accompanied by the appearance of neurohormonal derangement, with sympathetic activation. Autonomic responsiveness is important in HF and AF. HF and AF have been mechanistically linked to changes, especially in cardiac vagal control. CR can affect sympathovagal balance and reactivity in patients with HF . We hypon = 84). Persistent AF was defined as continuous AF lasting longer than 7 days. Long-standing persistent AF was defined as continuous AF lasting for longer than 1 year. Informed consent regarding CPX was obtained from all patients. All patients were followed during a 5 month CR program with education on medication and lifestyle. The exclusion criteria were as follows: paroxysmal AF; symptomatic HF; acute coronary syndrome; and an implanted pacemaker, inability to achieve an adequate pedal rotation speed, or a maximal respiratory exchange ratio of < 1.05 during CPX. The institutional ethical review board at Kitakyushu Municipal Yahata Hospital approved the study protocol. All patients provided written informed consent.A retrospective analysis of data collected from 245 in to outpatients with HF was performed. The recruitment continued from October 2014 to 2017. HF was diagnosed by a cardiovascular specialist according to the European Cardiology Society HF guidelines . PatientVO2), carbon dioxide output (VCO2), minute ventilation (VE), the fraction of end-tidal O2, and the fraction of end-tidal CO2 were measured on a breath-by-breath basis by computerized metabolic monitoring . Peak VO2 was recorded as the mean value during the last 20 s of the test and is expressed in ml kg−1 min−1. The peak respiratory exchange ratio (RER: ratio of VCO2/VO2 at peak exercise) was used as a measure of the patient’s effort during testing and a value > 1.05 was considered to be sufficient as an objective index [Before training, we determined the exercise capacity of each patient by symptom-limited CPX on a bicycle ergometer. To stabilize respiratory exchange, patients were asked to remain still on the ergometer for at least 4 min before starting exercise. After a 4 min warm-up with a fixed workload, a ramp protocol of 10 W/min was started and continued until exhaustion, which was defined as shortness of breath and leg fatigue, or signs of myocardial ischemia. The protocol included a 1 min cool-down period with no added workload at the end. Then they sat down for 4 min with continued monitoring of blood pressure and heart rate. We used 12-lead continuous electrocardiographic monitoring during the test and cuff blood pressure/ was recorded manually every 2 min. Oxygen uptake  was defined as a reduction in heart rate from the rate at peak exercise to the rate at 1 min after cessation of exercise. Heart rate was calculated as a mean of the last ten beats at each point.R. More precisely, EZR is a modified version of R commander designed to add statistical functions that are frequently used in biostatistics. Continuous variables that followed a normal distribution are shown as mean ± standard deviation and the paired t test was used for comparison. Variables that did not follow a normal distribution are shown as the median and were compared using the Wilcoxon rank-sum test. We estimated unadjusted univariate linear regression coefficients between various variables with the % change in peak VO2 as the dependent variable. Laboratory variables, echocardiographic variables, and CPX parameters were the independent variables. Multiple linear regression analysis was carried out to assess the independent factors affecting the % change in peak VO2. A two-sided p value < 0.05 was considered significant.All statistical analyses were performed with EZR, which is a graphical user interface for Table p = 0.03, p < 0.01, respectively). With regard to echocardiographic values, only left atrial dimension was significantly improved after CR compared with baseline (p < 0.01), but the left ventricular ejection fraction did not improve.Table VO2, and HRR, and were significantly elevated after CR compared with baseline . Resting heart rate and the VE/VCO2 slope were significantly reduced after CR compared with baseline . Parameters of blood pressure were not significantly changed 5 months after CR.Table VO2 between baseline and 5 months after CR. The % change is where designated values were compared between baseline and after CR. The % change in peak VO2 was significantly correlated with that of plasma BNP levels, resting heart rate, the VE/VCO2 slope, and HRR in univariate linear regression analysis .We investigated the contributions to peak sis Fig. . We applIn this retrospective study, we found that HRR is significantly associated with recovery of exercise tolerance in patients with HF and AF. To the best of our knowledge, it has not previously been shown to be associated with AF.In patients with HF and AF, abnormal neurohormonal control may explain the mechanism of advancement of disease. The amount of circulating catecholamines in patients is related to the prognosis . StudiesVO2 under CPX, as performed in our study.Recently, Sydo et al. showed that impaired HRR was associated with a number of well-established cardiovascular risk factors, including diabetes mellitus, hypertension, current smoking, and chronic kidney disease . IncreasThe report from Myers et al.  showed bIn the end of the discussion, we have to mention the sympathetic modulation to HRR. Previous studies have shown that early HRR after exercise is mainly a function of parasympathetic reactivation, with the sympathetic withdrawal becoming important later in recovery. A delayed HRR is, therefore, considered a measure of autonomic imbalance and may be an indicator of a reduction in parasympathetic tone or an exaggerated sympathetic activation –32. AccoVO2. Third, we cannot comment on the value of HRR as measured over different time points, such as 2, 3 or 5 min after cessation of exercise, although we identified HRR as the change during the first minute of the active recovery period. Forth, we did not have data of HRV which is one of parameters of autonomic function, although we discussed the relations between HRR and HRV in the discussion section. Fifth, we did not design our study to compare patients between heart failure with reduced ejection fraction and with preserved ejection fraction. We did not have any results of differences between two groups.This study has several important limitations. First, this was a retrospective observational study although we enrolled consecutive patients meeting the inclusion and exclusion criteria. Second, we did not have enough peripheral parameters other than those of autonomic nerve system, such as skeletal muscle function, vascular endothelial function. We cannot exclude that those factors might influence the changes of peak This study provides new evidence of the association between improved HRR and improved exercise tolerance in patients with HF and AF. Our findings have interest from a clinical point of view because HRR is easily measurable and was found useful. Future research to validate these findings in other populations will reveal the mechanistic links between HRR and exercise tolerance.


The Kidney Failure Risk Equation (KFRE) is a clinical tool widely used to predict progression from chronic kidney disease (CKD) to kidney failure. This study aimed to evaluate the effect of age on KFRE performance in advanced CKD.We conducted a retrospective cohort study among 1701 consecutive patients referred to an advanced CKD clinic in Ottawa, Canada, between 2010 and 2018. Patients were categorized by age as follows: <60, 60 to 69, 70 to 79, and ≥80 years. Calibration plots compared the predicted (through the KFRE) and observed incidence of kidney failure. Concordance statistic (C-statistic) evaluated discrimination. Cumulative incidence of kidney failure was compared between models that accounted for the competing risk of death and those that did not.P = 0.047), and 24.7% and 40.4%, respectively, over 5 years (P < 0.001). The degree of overestimation in the elderly was most pronounced among those with the highest predicted risks for kidney failure. KFRE discrimination was acceptable (C-statistic 0.70–0.79) across all age categories. The cumulative incidence of kidney failure was overestimated in models that did not account for the competing risk of death, and this overestimation was more pronounced with older age.We found that the KFRE overestimated the risk of kidney failure among the oldest subset of patients (≥80 years) with absolute and relative differences of 7.6% and 22.8%, respectively, over 2 years (The KFRE overestimates kidney failure risk among elderly patients with advanced CKD. This overestimation relates to the increasing competing risk of death with older age, particularly over longer time horizons. The global prevalence of CKD is 9.1%, thereby affecting approximately 700 million people, and it continues to rise.,To provide individualized risk estimates for patients with CKD, a number of risk prediction models have been developed and integrated into clinical practice.,Despite widespread external validation, concerns have been raised on the use of risk prediction models, such as the KFRE, in which death before kidney failure is treated as a censoring event rather than a competing event. Not accounting for the competing risk of death has been found to result in an overestimation of the risk of kidney failure particularly over longer periods of follow-up.We performed a retrospective cohort study of adults (≥18 years) with advanced CKD referred to the Ottawa Hospital Multi-Care Kidney Clinic between January 1, 2010, and December 31, 2018. The reporting of this study follows guidelines for prediction model validation .192 or the 2-year KFRE is >20%. Patients are seen in the clinic regularly, from as often as every 2 weeks to a minimum of semiannually, though the exact interval is at the discretion of the nephrologist. At each visit, patients are seen by a nurse, dietician, and nephrologist, with pharmacist and social work support available as needed. Patients are educated on kidney failure treatment options, including hemodialysis, peritoneal dialysis, kidney transplantation, and conservative management.This study was conducted at the Ottawa Hospital Multi-Care Kidney Clinic . The Ottawa Hospital is a 1150-bed academic tertiary care center with a catchment area of approximately 1.3 million people. The Ottawa Hospital Multi-Care Kidney Clinic is a specialty nephrology clinic designed to provide comprehensive, multidisciplinary care for patients with advanced CKD and is the sole such program within the catchment area. Timing of referral is at the discretion of the primary nephrologist, though referrals are suggested when the estimated glomerular filtration rate is <25 ml/min per 1.73 mN = 1834, n = 1176). From this 5-year KFRE cohort, 98 patients (8%) were lost to follow-up owing to the aforementioned reasons listed previously. Ultimately, 1701 patients were included in the data analysis to evaluate the 2-year KFRE whereas 1078 patients were included in the data analysis to evaluate the 5-year KFRE. Patients were subclassified by age categories within the study cohort, such as follows: <60 years, 60 to 69 years, 70 to 79 years, and ≥80 years. All protocols were approved by the Ottawa Health Science Network Research Ethics Board (protocol identification 20200506-01H). Informed consent requirements were waived owing to the retrospective nature of the data.The study cohort was derived from a database of all patients referred to the Multi-Care Kidney Clinic since January 1, 2010, with follow-up data available to December 31, 2020. The database undergoes routine data audits to ensure accuracy. We included patients initially seen in the clinic between the years 2010 and 2018  within 2 and 5 years from initial clinic referral.The predictors used in this study were the 2-year and 5-year 4-variable KFRE scores  at the time of initial clinic referral  if normally distributed and as median (25th–75th percentile interquartile range) if non-normally distributed, whereas categorical variables were expressed as numbers (%). The variables necessary to calculate the KFRE were collected at the initial visit as per clinic protocol; therefore, these data were available for the entire cohort with no missing data. Urine albumin-to-creatinine ratio was obtained from a random spot sample. If a patient died before kidney failure, the patient was included in the analysis as not having developed kidney failure within that time frame. Death was not treated as a competing risk in our primary analyses so as to align with the design of the original KFRE derivationPredicted (based on the KFRE) versus observed risks of kidney failure were compared at the 2-year and 5-year time points across age categories. Fisher exact testing was used to test for statistically significant differences between predicted and observed incidences of kidney failure. We chose this approach to evaluate KFRE performance using actual (rather than modeled) observed kidney failure incidence within 2 distinct time windows  so as to mirror how the KFRE is applied in real-word clinical practice.Discrimination refers to the ability of a model to separate individuals with and without disease. We used time-to-event (Cox) models to measure the C-statistic (95% CI) for the 2-year and 5-year KFRE for the total population and across age categories. We defined the quality of discrimination based on the C-statistic as follows: ≥0.90 = outstanding, 0.80 to 0.89 = excellent, 0.70 to 0.79 = acceptable, 0.51 to 0.69 = poor, and 0.50 = no discrimination.Calibration refers to the agreement between predicted and observed risks. We used loess smoothing curves to compare the observed incidence of kidney failure  to the predicted incidence of kidney failure within both the 2-year and 5-year time points across age categories.In the presence of competing risks (such as death), Kaplan–Meier curves are known to overestimate risk.P values are 2-sided with values < 0.05 considered significant.All statistical analyses were performed using SAS version 9.4. All 2 and similar across age categories. The median (interquartile range) urine albumin-to-creatinine ratio was 1389 (407–2938) mg/g with generally lower levels of albuminuria in the higher age categories. For the 2-year KFRE cohort, the median 2-year KFRE score was 41% (interquartile range 22%–64%)   and decr22%–64%)  and decrP = 0.047) corresponding to a relative difference in risk  of 22.8%. Notably, the rate of death before kidney failure had a direct relationship with age and exceeded the observed rate of kidney failure in the oldest age category.For the 2-year KFRE, there was no statistically significant difference between the predicted and observed risks for the 3 youngest age categories a and b. P = 0.01) and 24.7% (P < 0.001) and relative differences of 14.5% and 40.4%, respectively. Again, the rate of death before kidney failure had a direct relationship with age and exceeded the observed rate of kidney failure in the oldest age category.For the 5-year KFRE, there was no statistically significant difference between the predicted and observed risks for the 2 youngest age categories c and d. For the 5-year KFRE, there was risk overestimation based on the KFRE across the 3 oldest age categories  with a greater degree of overestimation among those of older age and higher predicted risks for kidney failure b. NotablAlthough the KFRE overall performed well in regard to calibration and discrimination in this advanced CKD cohort, we found that the KFRE overestimated the risk of kidney failure among older patients (particularly those ≥80 years of age). This overestimation in the risk of kidney failure by the KFRE relates to the magnified competing risk of death with older age and increases over longer time horizons.et al.et al.Our study expands on previous work evaluating the impact of the competing risk of death on the performance of kidney failure risk prediction models. Ravani Our results now highlight that the overestimation of risk by the KFRE in advanced CKD is predominately driven by the oldest subset of patients. For the oldest patients within our study cohort (age ≥ 80 years), the KFRE overestimated the risk of kidney failure by absolute differences of 7.6% and 24.7% and relative differences of 22.8% and 40.4% at the 2-year and 5-year time frames, respectively. Therefore, the KFRE provides overly pessimistic risk predictions in regard to kidney failure primarily for the elderly population with advanced CKD who are at high risk for both kidney failure and death. This overestimation was most prominent among the elderly population at the highest risk for kidney failure .Is overestimation of kidney failure risk a problem? Certainly, risk overestimation may be preferable to risk underestimation which could lead to lack of preparation for impending kidney failure and subsequent “crash” dialysis starts. Also, if the degree of risk overestimation is small , this may not be enough of a difference to sway clinical decision-making on an individual level. Nevertheless, the more pronounced risk overestimation found with the KFRE in the elderly population with advanced CKD may have important implications surrounding both patient counseling and population-level resource allocation related to kidney failure. In elderly individuals who are wishing to undergo future dialysis, if required, it would allow for planning and investigations to be undertaken with the understanding that predialysis mortality remains a significant risk that may approach or even surpass that of needing kidney replacement therapy. As such, they may choose to delay invasive procedures or interventions until they are more imminently required. In addition, countries such as Canada use the KFRE as a policy-level tool to allocate predialysis resources to patient populations most in need.Our study has several notable strengths. First, it included a large continuous sample of patients with advanced CKD with a high event rate. Second, given the clinic protocol for laboratory data collected at the initial referral visit, we were able to determine the KFRE for all patients seen in our clinic throughout the study period. Third, as the Ottawa Hospital Multi-Care Kidney Clinic is the only such clinic within the catchment area, the vast majority of patients (>90%) continued to be followed in the clinic until the end of the prespecified study period, kidney failure, or death, thereby minimizing loss to follow-up.,We acknowledge several limitations. First, this was a single-center study with a predominantly White population which may limit the generalizability of the findings to other clinical settings and racial demographics. This may be particularly relevant for Black patients given the growing debate on racial disparities surrounding most often used estimated glomerular filtration rate equations which may underestimate the severity of kidney disease in the Black population.In conclusion, although the KFRE overall performs well in the advanced CKD setting, it overestimates the risk of kidney failure among elderly patients with advanced CKD. This overestimation of kidney failure risk by the KFRE is related to the competing risk of death which becomes more prominent with advanced age and longer prediction horizons. Nephrologists should be aware of this limitation of the KFRE as it may affect advanced care planning for the elderly population with advanced CKD.MMS reports receiving speaker fees from AstraZeneca. MJO is a contracted Medical Lead at Ontario Renal Network and Ontario Health, owner of Oliver Medical Management Inc., which licenses Dialysis Management Analysis and Reporting System software, and has received honoraria for speaking from Baxter Healthcare and participating on advisory boards for Janssen and Amgen. All other authors declared no competing interests.


Fibroblast growth factor 21 (FGF-21) is a hormone that regulates glucose and lipid metabolism. High serum FGF-21 levels are associated with carotid atherosclerosis and coronary artery disease. This cross-sectional study aimed to assess the relationship between serum FGF-21 levels and carotid-femoral pulse wave velocity (cfPWV) in patients on maintenance hemodialysis (HD).  Blood samples and baseline characteristics were collected from 130 HD patients. Serum FGF-21 concentrations were measured with an enzyme-linked immunosorbent assay kit. Aortic stiffness was defined as a carotid-femoral pulse wave velocity (cfPWV) of more than 10 m/s. P < 0.001). The FGF-21 level was independently associated with aortic stiffness (odds ratio (OR): 1.008; 95% CI: 1.003–1.012; P=0.001) after adjusting for diabetes mellitus, age, hypertension, C-reactive protein, and body weight in multivariable logistic regression analysis. Multivariable forward stepwise linear regression analysis also confirmed that the logarithmically transformed FGF-21 level  was an independent predictor of cfPWV values. The area under the receiver operating characteristic (ROC) curve predicting aortic stiffness by the serum FGF-21 level was 0.693 .  Of the 130 HD patients, aortic stiffness was diagnosed in 54 (41.5%). Serum FGF-21 levels were significantly higher in those with aortic stiffness than those without ( Serum FGF-21 level positively correlates with cfPWV and is also an independent predictor of aortic stiffness in maintenance HD patients. Cardiovascular disease contributes to nearly half of deaths in patients with end-stage renal disease (ESRD) . Patientα and PPARγ. It exerts versatile metabolic actions by binding to the FGF receptor and β-klotho, an extensively expressed transmembrane protein [Fibroblast growth factor 21 (FGF-21) is a predominantly liver-derived hormone involved in regulating glucose and lipid metabolism, acting as a downstream target of peroxisome proliferator-activated receptor (PPAR)  protein . FGF-21  protein , 7. It h protein , 9; in h protein –12. As a protein , 13. Its protein , 15, sugβ-blockers, statins, or fibrates. The research was carried out in accordance with the World Medical Association Declaration of Helsinki. The study protocol was approved by the Research Ethics Committee, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation (IRB103-136-B), and informed consent was obtained from each subject.We recruited 130 HD patients from Hualien Tzu Chi Hospital Dialysis Center between March and July 2016. All subjects were over 20 years old and had undergone regular HD for at least 3 months. High-flux polysulfone disposable artificial kidneys  were used in the dialysis unit. Patients with malignancy, stroke, acute infection, amputated limbs, or who were bed-ridden were excluded from the study. Blood pressure was taken before HD sessions. A diagnosis of diabetes mellitus (DM) or hypertension was made if a patient was documented or taking insulin, hypoglycemic, or antihypertensive medications. Medical records were reviewed for the etiology of ESRD, prescription of angiotensin II receptor blockers, calcium channel blockers, Height and post-HD body weight were measured, and body mass index (BMI) was calculated , 17. AcccfPWV values were obtained by transcutaneous recording of the pressure pulse waveform in the target artery using applanation tonometry . These measurements were performed with the patient in the supine position after a 10-min rest in a quiet, temperature-controlled room with simultaneous electrocardiographic (ECG) recordings. Pulse wave recordings were obtained consecutively at two superficial artery sites . Each set of pulse waves was processed with the Integral software . ECG data were used to calculate the mean time difference between successive R-waves and pulse waves for each beat over an average of 10 consecutive cardiac cycles. The carotid-femoral distance was determined by subtracting the distance from the carotid location to the suprasternal notch, from the distance between the suprasternal notch and the femoral site. The cfPWV was calculated by dividing the distance by the mean time difference between the two recorded points. Quality indices were set to ensure data uniformity. Increased central arterial stiffness was defined as a cfPWV value > 10 m/s, according to the 2018 European Society of Cardiology guidelines, as a conservative cutoff for an increased cardiovascular risk [t-test. Non-normally-distributed data are expressed as medians and interquartile ranges. The differences between groups were evaluated by Mann–Whitney U test. Categorical data were tested by the chi-square test and are expressed as frequencies (%). Skewed distributions were transformed using base-10 logarithms (log) for analysis. The correlation between clinical variables and cfPWV values was evaluated using simple linear regression analysis, and variables that were significantly correlated with cfPWV values were tested for independence using a multivariable forward stepwise regression analysis. Variables significantly associated with aortic stiffness were tested for independence by multivariate logistic regression analysis. A receiver operating characteristic (ROC) curve was used to calculate the area under the curve (AUC) to identify the FGF-21 level that predicts aortic stiffness in HD patients. P < 0.05 was considered statistically significant.All statistical analyses were done with SPSS . The Kolmogorov–Smirnov test was performed to determine the normal distribution. Normally distributed data are expressed as the mean ± standard deviation, and differences between groups were evaluated by the independent samples P=0.036), had a higher body weight (P=0.027), BMI (P=0.048), systolic blood pressure (P=0.044), pulse pressure (P=0.001), CRP (P=0.040), FGF-21 (P < 0.001) (P < 0.001) and hypertension (P=0.026). Subjects with underlying diabetic nephropathy were more likely to have increased PWV (P < 0.001), while subjects with underlying glomerulonephritis were more likely to have normal PWV (P=0.030).The demographic and biochemical characteristics of the participants are summarized in < 0.001) , and a hP=0.001) after adjusting for other factors associated with increased cfPWV identified from P=0.001). ROC analysis was performed to identify the cutoff values of FGF-21 for aortic stiffness, and the AUC was 0.693 (P < 0.001)  , and at r = 0.194, P=0.027), systolic blood pressure , pulse pressure , logarithmically transformed CRP , log-FGF-21 , and the presence of DM . Furthermore, the stepwise multivariable regression analysis showed the log-FGF-21 level to be an independent predictor for cfPWV  and log-CRP levels . All other tested variables were not significant and were excluded.We analyzed the correlations between the cfPWV values and clinical parameters . The cfPThe most important finding of this study was the association of FGF-21 levels and cfPWV values, shown for the first time in regular HD patients.Patients suffering from ESRD have increased arterial stiffness and cardiovascular mortality –23, resuFactors related to diseases such as DM, hypertension, and chronic kidney disease and lifestyle habits such as smoking contribute to arterial stiffness beyond normal aging . AdvanceBlood pressure is one of the most significant contributing factors to cfPWV . In thisStudies have shown that exogenous FGF-21 analog administration can significantly improve cardiometabolic profiles in obese or overweight diabetic patients –32. ThisStudies showed that FGF-21 exerts protective effects against the development of atherosclerosis through the modulation of interactions between the adipose tissue, liver, and blood vessels , reducinOur study results should be interpreted considering several limitations. First, we cannot assume any causal associations due to the cross-sectional study design. Second, the sample size was small, and larger longitudinal studies will be needed for confirmation. Third, we only investigated the relationship between cfPWV and FGF-21. Other factors of note, such as intima-media thickness or left ventricular mass index, may provide additional invaluable information. Fourth, we did not measure residual renal function, which may influence the development of atherosclerosis. Fifth, a dietary survey may be needed since FGF-21 is maximally elevated under low protein and high carbohydrate intakes . Sixth, Higher serum FGF-21 levels were associated with higher cfPWV values in a group of regular HD patients. This study suggests that serum FGF-21 levels may be a predictive marker of aortic stiffness in HD patients. Defining this new parameter might help stratify the cardiovascular disease risk and offer potential therapeutic strategies for atherosclerosis. Future studies such as interventional trials are warranted to determine the clinical significance of FGF-21.


Sixty-two healthy volunteers were recruited. There were no significant changes in heart rate, augmentation index (AIx), left ventricular ejection time, Diastolic time (DT) among all of the different steps. A significant increase of time to the inflection point (Ti) was observed during all steps of the study. Diastolic area under the curve (AUC) divided by systolic-AUC (SEVR) increased from baseline to PEEP = 5 cmH2O, and from baseline to PEEP = 10 cmH2O. AIx and Ti were significantly correlated (directly) at the baseline and during PEEP = 10 cmH2O. Ti and DT were significantly correlated at the baseline and during PEEP = 5 cmH2O. In our preliminary results, low levels of PEEP played a role in the interaction between the heart and the vascular system, apparently mediated by a prolongation of the diastolic phase and a reduction in the systolic work of the heart.Positive end-expiratory pressure (PEEP) may affect arterial wave propagation and reflection, thus influencing ventricular loading conditions. The aim of the study was to investigate the hemodynamic variations in arterial wave reflection  associated with the application of increasing levels of PEEP in healthy subjects. We conducted a prospective observational study. Study population was selected from students and staff. Pulse contour wave analysis was performed from the right carotid artery during stepwise increase in PEEP levels (from 0 cmHClinical trials registration number: NCT03294928, 19/09/2017. Furthermore, PEEP may help the respiratory muscles to decrease the work of breathing in some conditions.A Positive End-Expiratory Pressure (PEEP) during mechanical ventilation is commonly applied to prevent alveolar collapse, recruit and stabilize lung units, improve oxygenation, increase functional residual capacity and lung compliance3 and acute respiratory distress syndrome 4. Low levels of PEEP increase intra-alveolar volume in pervious alveoli while higher levels of PEEP are useful for alveolar recruitment: both of them improve functional residual capacity (FRC)2. Finally, PEEP is applied during intraoperative ventilation and after surgery in order to prevent and treat atelectasis5.In light of these positive effects, PEEP is used in various clinical scenarios including pulmonary oedema (where it promotes redistribution of extravascular lung water and improves oxygenation and lung compliance)6. Apart from pulmonary effects of PEEP, hemodynamic consequences are controversial and not completely understood8. Many studies have demonstrated that alveolar recruitment manoeuvres (using high levels of PEEP) increase right ventricular afterload and decrease right ventricular preload, similarly to a Valsalva effect9. Moreover, augmented intrathoracic pressure induced by high level of PEEP, decreases right ventricle and increases left ventricle end—diastolic volume (EDV) as described also by transmitral pulsed-wave Doppler (PW-D)10. At the same time, PEEP decrease left ventricle afterload11. Consequently, to foresee the hemodynamic consequences of PEEP application is challenging in critically ill patients.However, the application of high PEEP level may also lead to adverse consequences such as incomplete expiration, air-trapping (intrinsic PEEP) and increased risk of barotrauma12. Hemodynamic effects of PEEP strongly depend also on arterial function and arterial properties 13, consequently, it will be useful to examine the haemodynamic impact of PEEP using an arterial waveform analysis. CWA can be evaluated with different non-invasive and reproducible techniques16. Among them, applanation tonometry is a non-invasive measurement capable to perform CWA on central arteries (carotid artery)17 that can be practically used in the intensive care unit (ICU). This technique enables the estimation of wave reflection through the analysis of blood pressure waveform.Arterial contour waveform analysis (CWA) is increasingly proposed as tool to estimate the hemodynamic status of a critical care patient as well as essential information about the arterial wall integrity and stiffnessHowever, in critically ill patients, several confounding factors may hinder the interpretation of the hemodynamic effects of PEEP application. Thus, the goal of our study was to investigate in young healthy subjects, with normal cardiovascular compliance and arterial tone, the direct effects of stepwise increase in PEEP. "We aimed to evaluate, in young healthy subjects, the feasibility of carotid pressure waveform analysis in order to detect changes in arterial and LV function associated with various levels of PEEP. Secondary end-point was to assess the best level of PEEP from the hemodynamic point of view, at least in young healthy subjects, in order to have a reference for evaluation of patients in a clinical setting.After approval of the Local Research Ethics Committee of Pisa University Hospital, a prospective observational study was conducted in a single university center in a 2 months period. Written informed consent was obtained from all the participants in the study. Procedure was carried out in accordance with the Declaration of Helsinki (2000).Population in study was selected from students and staff of the University of Pisa. The inclusion criteria were as follows: age between 18 and 40, absence of any chronic diseases, no active smoker, no story of drug abuse, no use of caffeine the day of the exam. We excluded patients with pregnancy, and intake of caffeine the day of the exam.The design of the study consisted in four-step measurements of central artery blood pressure evaluating contour wave analysis during a progressive increase of PEEP level. Subjects rested supine for 10 min before starting; recordings were performed in the morning, 2–4 h after light breakfast, abstaining from smoking and caffeinated beverages. Each step takes two minutes to be performed.Spontaneously breath in air at atmospheric pressure during applanation tonometry.2O.Applanation tonometry performed during the application of PEEP = 5 cmH2O.Applanation tonometry performed during the application of PEEP = 10 cmHSpontaneously rebreating air at atmospheric pressure during applanation tonometry.®; DiaTecne Srl, Milano, Italy18). The applanation tonometry technique consists of locating the sensor over the skin where the artery is found and apply a moderate pressure in order to slightly compress the artery. Thus, the sensor records the pressure in the middle of the compressed artery. A PEEP valve was connected to the “face mask-Ambu bag” system in order to set each increasing level of PEEP19. Subjects were breathing spontaneously.Contour wave analysis was performed with applanation tonometry technique using a hand-held tonometer probe  was measured with a standard adult cuff on the left brachial artery, in order to calibrate waveforms using the oscillometric method18. Tonometry has a high sensitivity to sensor position and angle.Right carotid arterial pulse waves were recorded with an arterial tonometer sensor array integrated with an electrocardiogram unit for a total of four times per patient (one time for each step). In the study the tonometer was applied to the right carotid artery without head support. The shape of the peripheral pulse wave was captured electronically using a laptop computer linked to a desktop . The PulsePen system generates an average peripheral pulse wave contour from a 12.5 s period22:Augmentation pressure (AP): the amount by which central pressure increases due to reflected wave, expressed in mmHg.Pulse pressure (PP): the pressure difference between the systolic and diastolic pressures, expressed in mmHg.Augmentation index (AIx): defined as reflected wave amplitude divided by pulse pressure, expressed as a percentage (AP/PP).Time to the inflection point (Ti): is measured from the foot of the forward traveling pressure wave to the foot of the reflected wave, expressed in msec.Left Ventricular Ejection Time (LVET): duration of left ventricular systolic ejection in msec.Diastolic time (DT): duration of left ventricular diastole in msec.SEVR: diastolic area under the curve (AUC) divided by systolic-AUC (Buckberg index)Heart rate (HR) in beats per minute (bpm)Mean systolic blood pressure (MSBP): the mean of the systolic blood pressure (mmHg)Mean diastolic blood pressure (MDBP) the mean of the diastolic blood pressure (mmHg)The following parameters were obtained from pulse wave analysisAll measurements taken on single patients were performed by the same operator (JB) and only high-quality pulse wave traces were considered acceptable. We also calculated the intra-observer reproducibility, computed as the percentage of the absolute difference between two sets of measurements, divided by their mean. Consequently, these measurements allow analysing the degree of agreement of measurements by the same observer (intra-observer) on the same patient.After the measurements were performed, a case report form was filled out with participant ID, age, weight, height, Augmentation pressure, Pulse pressure, AIx, Ti, Left Ventricular Ejection Time, Diastolic time, SEVR, Heart rate, Mean systolic blood pressure, Mean diastolic blood pressure.Main goal of this work was to investigate the variations in wave reflection time (Ti) and augmentation index (AIx) induced by the application of different stepwise levels of PEEP in healthy subjects. Secondary aim was to assess the effects of stepwise PEEP on cardiac indices such as left ventricular ejection time (LVET), diastolic time (DT), SEVR induced by the application of different level of PEEP.23. We calculated our sample size assuming that a standard deviation (SD) in population was about 1124 and an effect size (d) was 5.8%25. The precise estimation sample size was 56; therefore, we decided to recruit a total of 62 participants in order to have sufficient statistical power.In order to calculate the sample size, we followed the recommendations of Charan and Biswasp-value < 0.05 was considered to be significant.Data were analyzed using Stata 11.1 software . Data were expressed as mean values ± SD. Student’s t-test was used for assessment of intragroup changes between two different steps . Pearson’s linear regression analysis  was used to investigate relationship between two parameters in the same step. Intraclass parameter modifications among all of the different steps were calculated using one-way analysis of variance (ANOVA). A Approval of the Local Research Ethics Committee of Pisa. Procedure was carried out in accordance with the Declaration of Helsinki (2000). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards”.Informed consent was obtained from all individual participants included in the study.This study was approved by the Local Research Ethics Committee of Pisa .We recruited 62 healthy volunteers, 31 males and 31 females (aged between 20 and 35 years old); all subjects were apparently healthy, with not known cardiovascular disease or major cardiovascular risk factors, and none was receiving any medication. General characteristics of the study population were reported in Table Hemodynamic parameters obtained by applanation tonometry are shown in Table 2O , from baseline to PEEP = 10 cmH2O  and from baseline to spontaneous rebreathing  , significant from baseline to the application of PEEP = 5 cmH2O  and from baseline to the application of PEEP = 10 cmH2O   and during the application of PEEP = 5 cmH2O (p < 0.05), while AP and Ti resulted correlated during the application of PEEP = 10 cm H2O (p < 0.05).AIx and Ti were significantly correlated at the baseline (2O (both p < 0.01).Ti and DT were significantly associated at the baseline and during the application of PEEP = 5 cmH2O. No significant changes were found in heart rate, mean systolic and mean diastolic blood pressure among all stepwise of PEEP.In our observational study, we evaluated the hemodynamic variations in wave reflection induced by the application of increasing levels of PEEP in healthy subjects. In healthy volunteers, cardiovascular compliance and intravascular status can be assumed to be normal. Consequently, the direct effects of progressive higher levels of PEEP on intact cardiac and arterial systems can be assessed without confounding factors due to comorbidities and therapies. We found a progressive prolongation of Ti and SEVR during each PEEP application. In addition, we observed an inverse correlation between Ti and AIx and a direct correlation between Ti and DT from baseline to PEEP = 5 cm H12. These parameters, assessing mechanical arterial properties, are extensively used as an aid to the cardiovascular risk stratification for atherosclerotic-related diseases18. AIx depends on age, gender, weight, arterial pressure, LDL concentration and position; several studies shows that AIx independently predicts adverse cardiac events27. Ti, together with reflected wave magnitude, contributes to systolic pressure and is a supposed indicator of aortic stiffness28. Buckberg index is a ratio between systolic and diastolic portions of AUCs in the central aortic pulse wave. Blood flow within the coronary arteries occurs mainly during diastole, consequently, the diastolic-AUC indicates myocardial perfusion and oxygen supply. In normal coronary arteries, subendocardial ischemia occurs when SEVR% falls below 50%29. Arterial CWA appears to be also a promising non-invasive tool to evaluate arterial properties and ventricular-arterial function in the critical care setting. In our study we observed a transient prolongation of Ti during PEEP ventilation, suggesting a delay of reflected waves and their shift on diastole. This observation can be putatively ascribed to a decrease of arterial peripheral resistance that is directly correlated with diastolic blood pressure and inversely correlated with cardiac output (CO). However, we did not observe significant changes in MDBP during all PEEP steps, and consequently, the arterial peripheral resistance reduction could be the result of an increase of CO. The evaluation of CO is difficult to assess without echocardiographic or invasive measurements but, from a physiological point of view, the possible increase in CO could be in contrast with PEEP effects on preload reduction but in agreement with a decrease in left ventricle afterload 9. In addition there was an increase of SEVR during the application of both levels of PEEP. Hence, this result can account for an increase of diastolic AUC or a decrease on systolic AUC. This trend, in addition to a decrease in AIx, may reflect a positive effect of PEEP ventilation on the systolic phase. Having recruited healthy patients, we did not observe significant changes in HR, mean systolic and mean diastolic blood pressure among all stepwise of PEEP.The cardiovascular response to PEEP depends on several factors; intravascular volume status, cardiac compliance, arterial properties and levels of PEEP. Applanation tonometry provides information on hemodynamic status as well as on arterial wall mechanical properties. The carotid CWA technique allows to obtain surrogate indexes of central hemodynamics and wave reflection, in particular central augmentation index (AIx), timing of the returning reflected waves (Ti) and Buckberg index (SEVR)30. The VM consists in a forced expiratory effort against a closed glottis leading to an increase in intrathoracic pressure, similarly to the PEEP effect. They found that hemodynamic variations induced by the VM predict fluid responsiveness in this group of patients. Contrarily from the above-mentioned study, we did not study the fluid responsiveness to VM and our trial included only healthy subject with normal arterial tone. However, this trial shows the impact of the VM on the haemodynamic system.Garcia et al. evaluated the arterial pressure response  to the Valsalva manoeuvre (VM) in spontaneous breathing patient2O. Thirdly, we recruited only healthy subjects, thus, our findings might not be applicable to the critical care patients or during mechanical ventilation.There are three main limitations in our study. Firstly, the absence of echocardiographic or invasive measurements of CO that is important to assess PEEP effects on pump function. Secondly, for ethical reasons, we did not investigate changes on CWA induced by levels of PEEP higher than 10 cm HDespite these limitations, this preliminary study may contribute to provide a new protocol for assessing the effects of PEEP atrio-ventricular (A-V) coupling in critical patients. It will be important to integrate echocardiographic assessment and lung ultrasonography examination in order to obtain CO measurement and to diagnostic possible lung injuries. In fact, in patients with ARDS or heart failure, there are many cofactors that influence positive effects of PEEP, together with the seriousness of the disease.In conclusion, together with the effects on pulmonary ventilation, we observed an influence of PEEP ventilation on hemodynamic status that is confirmed by morphological changing on contour arterial waveform. It seems that in healthy patients there are not adverse effects induced by PEEP. In healthy subjects, low levels of PEEP seem to have an impact on cardiovascular efficiency thanks to the prolongation of the diastolic phase.


Conclusion: Primiparity, induction of labor, episiotomy, instrumental delivery with forceps or spatula, and a birth weight of 3000 g or more are significantly associated with an increased risk of third and fourth degree perineal tears.Objectives: To analyze the main risk factors associated with third and fourth degree postpartum perineal tears in women attended to in our obstetrics service. Methods: An observational, retrospective, hospital cohort study was carried out in women whose deliveries were attended to in the obstetrics service of the Hospital General Universitario Gregorio Marañón de Madrid (HGUGM), during the period from January 2010 to April 2017. Results: During the study period, a total of 33,026 patients were included in the study. For maternal variables, the associated increased risk of severe perineal tearing in nulliparous women is OR = 3.48, for induced labor OR = 1.29, and for instrumental delivery by forceps OR = 4.52 or spatulas OR = 4.35; for the obstetric variable of episiotomy, it is OR = 3.41. For the neonatal variables, the weight of the newborns has a directly proportional relationship with the risk of severe tears, and for birth weights of 3000 g (OR = 2.41), 3500 g (OR = 1.97), and 4000 g (OR = 2.17), statistically significant differences were found in each of the groups ( In recent years, the relationship between vaginal birth and pelvic floor diseases has been studied. These diseases are often due to pelvic floor trauma and can be objectified as perineal tears after childbirth; they are categorized into different levels of injury depending on the involvement of the anatomical structures ,2.Among those with the highest level of involvement are third degree perineal tears  and fourth degree perineal tears . In the literature, we can find a wide range of involvement, depending on the studies, with an incidence between 0.1% and 10.9% among women who have a vaginal delivery ,4. The mThe risk factors associated with the development of third and fourth degree tears include maternal characteristics such as age, weight gain during pregnancy, parity; neonatal variables such as birth weight; and obstetric or intrapartum variables such as induction of labor, gestational age, type of anesthesia, type of delivery, and including instrumental deliveries ,7,8,9,10Within the group of births that end vaginally, there are studies that have published the benefits of performing an episiotomy for reducing the risk of high-grade perineal tears ,12. HoweIt is clear that pelvic floor morbidity associated with vaginal delivery would increase with a decrease in the rate of caesarean sections. However, the increased maternal and perinatal morbidity and mortality associated with this surgical procedure  has led institutions such as the WHO recommend a reduction in the rate of caesarean sections , among oThe aim of this study is to analyze the distribution of maternal−perinatal variables in the group of postpartum patients with third and fourth degree perineal tears in our reference population compared with patients without injury or with a mild degree of injury, as well as to determine the distribution and association of the maternal−perinatal variables most associated with third and fourth degree perineal tear events. The main hypothesis of this study is that the identification of maternal and perinatal risk factors can help to minimize third and fourth degree perineal tears during childbirth.An observational, ambispective study was conducted on a hospital-based cohort of patients whose deliveries  were attended to in the obstetrics service of the HGUGM  during the period from January 2010 to April 2017. Over the years, a prospective record was made in the database, although the analysis of the data was retrospective. The diagnosis of second, third, and fourth degree tears was made by obstetric physicians, even when these patients were initially attended to by midwifery. Records of third and fourth degree tears were made by the obstetrical doctors who were responsible for the repair of the tear, after the surgical process in the delivery room, once it had been completed.We do not have the follow-up data at the moment for severe perineal tears. Exclusion criteria include caesarean delivery, fetal exitus, and multiple gestations.The patients were divided into two groups: group I, those with a third and fourth degree tears, and group II, the rest of the patients, including those with less severe tears (first and second degree tears).In both groups of patients, the maternal , obstetric , and neonatal  variables were studied.p < 0.2 were taken into consideration for inclusion in the multivariate analysis in order to assess the magnitude of association weighted by all of the variables included. A p < 0.05 was defined for statistical significance.The data collection method was carried out by the delivery room staff, recording all of the data of the different patient variables in a digitalized system, which was subsequently transferred to an Excel spreadsheet for dissociation and analysis, using the Microsoft Office Excel database, version 2019 . The statistical analysis was performed with SPSS version 25 . For each group, the descriptive parameters for the mean, standard deviation, and 95% confidence interval were calculated for all quantitative variables, and for the qualitative variables, the relative percentage frequencies were calculated. Hypothesis testing for the comparison of the results of variables in each group was carried out by applying the tests according to the type of variable and its distribution. For the independent calculation of the magnitude of effect of each variable, a predictive/explanatory analysis of the uni- and multi-variate logistic regression was carried out. After the first univariate analysis, those variables clinically relevant and/or with a During the study period 43,025 patients were delivered in our centre. The flow diagram of the patients included in the study can be seen in Of the 33,026 patients, 301 (0.91%) were in group I and 32,725 were in group II (99.09%).p < 0.001). As for the induction of labor, there were 84 patients (27.9% vs. 21.4%); p = 0.046), a slight increase. Epidural or spinal regional anesthesia were significantly more frequent in group I compared with the rest . Episiotomy was performed in 18,025 (59%) of the cases, with a much higher incidence of severe tearing in 248 (82.4%) patients compared with the rest of the patients. The mean birth weight of the newborns in the study was 3237 ±483.94 g. The detailed results for these variables are shown in p < 0.001), instrumental delivery , episiotomy , and newborn weight . In the multivariate analysis, primiparity , instrumental delivery , episiotomy , and fetal weight  were presented as risk factors for severe tearing .p < 0.001) and for delivery after >38 weeks gestation , while in the obstetric variables, induction of labor ; instrumentalization, in particular with forceps ; and the performance of an episiotomy in instrumental procedures  are highlighted as those that most increase the risk of severe tearing. Regarding fetal variables, it should be noted that the weight of newborns increases the risk of developing third and fourth degree tears by approximately two times for every 500 g increase in weight from 3000 g, as shown in A more precise study was carried out in relation to the significant variables in the univariate analysis. In relation to the maternal variables, it is worth highlighting the increase in risk associated with each vaginal birth, both the nulliparity  to the result presented in our study .The induction of labor is also associated with an increased risk of severe tearing. Wilson et al.  in a revIn our study, among the patients with severe tearing, 52.5% had an instrumental delivery vs. 19.8% who had mild tearing. The analysis significantly quadruples the risk for forceps and spatula deliveries, with similar ORs, compared with a minor increase in risk associated with vacuum extraction . Other sIn relation to episiotomy, we found a significantly higher percentage in the severe perineal tear group vs. the rest. We observed that, from the multivariate analysis, the magnitude of the effect decreased compared with the result obtained in the univariate analysis. In routine clinical practice, an episiotomy is performed prophylactically and there is clear controversy in the literature regarding its association with severe tears. For Gebuza et al. , a rate Finally, it should be noted that a birth weight of over 3000 g doubles the risk of suffering a third and fourth degree tear for every additional 500 g, possibly due to the greater increase in biomechanical stress on the vulvar fork, as the newborns are larger, with higher head circumference diameters. Other studies also show that a birth weight greater than 3500 g has been established as a risk factor for severe tearing ,23.The study has limitations that are important to take into consideration when interpreting the data. Firstly, we consider that our reference center has an increased percentage of patients with a maternal pathology. Secondly, as mentioned above, there are other variables that were not the focus of this study, and that could provide additional information. Such is the case for variables such as ethnicity, BMI, weight gain, the existence of shoulder dystocia, and the characteristics of the episiotomy and of the tear itself. In addition, anal ultrasound in the delivery room has been reported in other studies as a useful tool in the more accurate diagnosis of third and fourth degree tears , althougp < 0.05) in the differences found between the maternal-neonatal variables between the groups. Specifically, for the statistical significance found p = 0.03 after comparing the proportion of the different types of anesthesia found between the groups with our sample size, we reached a statistical power of 80%. In relation to the strengths of the study, although our results are not novel and support those obtained previously by the various studies already described in the discussion, one of our strengths is that, to our knowledge, it is the first to be carried out in our country and in a center with a large number of births over so many years. On the other hand, the methodology of being able to perform a multivariate analysis considering both maternal and neonatal variables, such as the type of instrumental delivery and its association, as well as the cut-off points for neonatal weight, stands out and obtained data from a hospital cohort of more than 40,000 deliveries, attended over more than 7 years, in a tertiary hospital in Madrid, one of the reference hospitals for obstetrics in Spain. As a result of the large sample size of our study, we found a statistical power of more than 80%, with which we were able to find significant associations (The frequency of severe third and fourth degree perineal tears is low in the population of women who deliver vaginally—about 1 in 100 patients. The uni- and multi-variate regression analysis showed that primiparity, induction of labor, episiotomy, instrumental delivery with forceps or spatula, and a birth weight of 3000 g or more are significantly associated with an increased risk of third and fourth degree tears. Among these variables, episiotomy, instrumental delivery, and the birth weight of newborns are particularly relevant, all of which are modifiable factors in delivery care.


It is not well-known which components of central blood pressure (CBP) are more influential to target organ damage (TOD). This study aimed to determine the relationship between CBP measurements and various types of TOD in high-risk patients.A total of 148 patients who had documented atherosclerotic cardiovascular disease or its multiple risk factors were prospectively enrolled. CBP was measured by using applanation tonometry of the radial artery. The following nine TOD parameters were evaluated: left ventricular mass index, relative wall thickness, septal e′ velocity, septal E/e′, brachial-ankle pulse wave velocity, ankle-brachial index, estimated glomerular filtration rate, urine protein and obstructive coronary artery disease.P = 0.010), but this association was not observed in other CBP measurements (P > 0.05 for each).The mean age of the study population was 67.1 ± 9.0 years and 108 (73 %) were male. Among four CBP measurements , central pulse pressure (CPP) was associated with the largest number of TOD parameters. As CPP increased, the number of TOD increased (CPP had a stronger correlation with TOD than other CBP measurements. Non-invasive CPP could be a useful indicator for predicting TOD in patients at high coronary risk. Hypertension is one of the major risk factors for cardiovascular disease (CVD) and is a leading global burden , 2. BecaTOD is earlier structural and functional changes in vital organs in response to long-standing high BP, such as left ventricular hypertrophy (LVH), arterial stiffening, renal impairment, and retinopathy . The preWe prospectively enrolled the study patients aged between 20 and 85 years who had documented atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease and ischemic stroke, or at least two of the traditional risk factors for ASCVD  from March 2017 to July 2018. In order standardize the effects of other factors influencing the CBP as much as possible and to perform a more accurate analysis, patients with following conditions were excluded: (1) recently deteriorated chest pain, dyspnea or palpitation; (2) unstable or uncontrolled BP;; (3) left ventricular ejection fraction < 50 %;; (4) valvular regurgitation or stenosis of moderate degree or greater; (5) the presence of pericardial effusion; and (6) atrial fibrillation or other uncontrolled arrhythmia. The study protocol was approved by the Institutional Review Board (IRB) of Boramae Medical Center  (IRB No: 26-2017-55) and written informed consent was obtained from each study patient.2). Coronary artery disease (CAD) was defined according to (1) a history of myocardial infarction or coronary revascularization, including percutaneous coronary intervention or coronary artery bypass surgery; (2) documented luminal narrowing of epicardial coronary artery more than 50 % on invasive coronary angiography or coronary computed tomographic angiography; or (3) documentation of myocardial ischemia on exercise treadmill test or single-photon emission computed tomography. Ischemic stroke was defined as a previous diagnosis: a history of focal neurological deficit that continued for > 24 h, which was confirmed by brain imaging. Hypertension was defined as previous diagnosis, the use of antihypertensive medications or a resting BP of ≥ 140/90 mmHg. Diabetes mellitus was defined as a previous diagnosis, the use of oral hypoglycemic agents or insulin or fasting blood glucose ≥ 126 mg/dL. Patients were classified as smokers if they had smoked regularly during the previous 12 months. All subjects underwent laboratory tests by sampling venous blood in the morning after overnight fasting. Blood levels of following parameters were measured by an automated enzymatic procedure: white blood cell count, hemoglobin, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, triglyceride, glucose, glycated hemoglobin, creatinine, C-reactive protein, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Estimated glomerular filtration rate (eGFR) was calculated using 4-component Modification of Diet in Renal Disease (MDRD) study incorporating age, race, sex, and serum creatinine level [Body mass index was calculated as weight in kilograms divided by the square of height in meters  to calculate late systolic pressure in the radial artery (SBP2) and to estimate central systolic BP (CSBP) . The HEM2 for man and > 95 g/m2 for woman [2; (7) proteinuria defined as albumin-creatinine ratio (ACR) > 30 mg/g in spot urine; (8) increased arterial stiffness defined as brachial-ankle pulse wave velocity (baPWV) > 1,600 cm/Secs. [The following nine parameters of TOD were assessed: (1) obstructive CAD defined as > 50 % stenosis in the major epicardial coronary arteries on computed tomographic angiography or invasive coronary angiography; (2) LVH defined as left ventricular mass index (LVMI) > 115 g/mor woman ; (3) conor woman ; (4) diaor woman ; (5) diaor woman ; (6) chrcm/Secs. , 33; andContinuous variables are presented as means ± standard deviation, and categorical variables are presented as number (%). Pearson correlation analysis was performed to investigate the linear association between the two parameters of CBP measurements and TOD parameters. Scatter plots were used for the demonstration of linear correlations between the two parameters. Mean values of CBP measurements between patients with or without TOD were compared using Student t-tests. Analysis of variance was used to assess the association between mean values of CBP measurements and numbers of TOD parameters. Two-sided P-values < 0.05 were considered statistically significant for all tests. All statistical analyses were performed using IMB SPSS ver. 20.0 .P = 0.010). Other CBP measurements did not show this association (P > 0.05 for each)  Fig. .Our result, using four CBP measurements and nine TOD parameters, showed that each CBP measurement were related to different TOD parameters in patients with ASCVD or its multiple risk factors. Among four CBP measurements , CPP was the best correlate with TOD. It also revealed that the higher CPP was, the more target organs were damaged.Vital organs, such as the heart, kidneys, and brain, are more directly exposed to CBP rather than to BrBP. In this study, CPP was correlated with the most indices of TOD 6/8), although both CBP and BrBP parameters could predict TOD well. There is a theoretical background that central aorta is closer to major organs, so CBP’s influence is greater than BrBP , 35. CBP, althougIt is not well-known which CBP measurements are clinically relevant. A few studies have emphasized the importance of CPP, as it was associated with the risk of TOD and ASCVD. Jankowski et al.  showed tPossible mechanisms explaining the association between CPP and TOD can be suggested. Elevation of PP is both a cause and a result of arterial damage and atherosclerosis. Degenerative changes in the aortic wall and arterial tree by aging increase stiffness of the aorta, and lead to an increase in PP . With reRisk stratification and early aggressive management for high-risk patients is important for preventing future cardiovascular events and for reducing morbidity and mortality. The present study revealed that CBP, especially CPP, is valuable in the prediction of TOD. Measurement of CBP using radial artery tonometry, which is non-invasive and well-validated, could be useful for the risk stratification of high-risk patients. This study could also be a hypothesis-generating trial for further investigations into the development of novel medications lowering CPP or using CPP as a monitoring tool.Some limitations are present in this study. First, because cardiovascular outcomes, such as myocardial infarction or mortality, were not investigated, we could not conclude whether CPP was related to long-term prognoses of patients. However, as TOD is a well-known factor closely related to worse cardiovascular outcomes , 20, CPPCPP had a stronger correlation with TOD than other CBP measurements in patients with ASCVD or multiple risk factors. Non-invasive measurement of CPP may be a useful tool for risk stratification of high-risk patients.


In acute respiratory distress syndrome (ARDS), response to positive end-expiratory pressure (PEEP) is variable according to different degrees of lung recruitability. The search for a tool to individualize PEEP based on patients’ individual response is warranted.End-expiratory lung volume (EELV) assessment by nitrogen washing-washout aids bedside estimation of PEEP-induced alveolar recruitment and may therefore help titrate PEEP on patient’s individual recruitability.We designed a randomized trial to test whether an individualized PEEP setting protocol driven by EELV measurement may improve a composite clinical outcome in patients with moderate-to-severe ARDS .2/FiO2 ratio ≤ 150 mmHg within 24 h from endotracheal intubation while on mechanical ventilation with PEEP 5 cmH2O.IPERPEEP is an open-label, multicenter, randomized trial that will be conducted in 10 intensive care units in Italy and will enroll 132 ARDS patients showing PaO2O for 30 min (EXPRESS PEEP).To standardize lung volumes at study initiation, all patients will undergo mechanical ventilation with tidal volume of 6 ml/kg of predicted body weight and PEEP set to obtain a plateau pressure within 28 and 30 cmH2O), and EELV will be measured at each step. Recruitment-to-inflation ratio will be calculated for each PEEP range from EELV difference. Patients will be then randomized to receive mechanical ventilation with PEEP set according to the optimal recruitment observed in the PEEP trial (IPERPEEP arm) trial or to achieve a plateau pressure of 28–30 cmH2O . In both groups, tidal volume size, use of prone positioning and neuromuscular blocking agents, and weaning from PEEP and from mechanical ventilation will be standardized.Afterwards, a 5-step decremental PEEP trial will be conducted (EXPRESS PEEP to PEEP 5 cmHThe primary endpoint of the study is a composite clinical outcome incorporating in-ICU mortality, 60-day ventilator-free days, and serum interleukin-6 concentration over the course of the initial 72 h of treatment.The IPERPEEP study is a randomized trial powered to elucidate whether an individualized PEEP setting protocol based on bedside assessment of lung recruitability can improve a composite clinical outcome during moderate-to-severe ARDS.ClinicalTrials.govNCT04012073. Registered 9 July 2019.The online version contains supplementary material available at 10.1186/s13063-021-05993-0. VT); plateau and driving pressure mitigates lung injury and improves clinical outcome [Mechanical ventilation is the cornerstone treatment of the acute respiratory distress syndrome (ARDS). However, mechanical ventilation can itself initiate and worsen lung damage due to the so-called ventilator-induced lung injury (VILI), which is an inflammatory response that worsens lung function and contributes to the development of the organ dysfunction observed in ARDS patients . Differe outcome –6.VT may generate alveolar derecruitment and worsen oxygenation that can be reversed by the application of a positive end-expiratory pressure (PEEP) [Low e (PEEP) , 8. It ie (PEEP) –11, oxyge (PEEP) , 13, ande (PEEP)  have beee (PEEP) , oxygenae (PEEP) , 13 or te (PEEP) , failed e (PEEP) .Despite a meta-analysis highlighted a survival benefit in more severe patients treated with higher PEE P, the mosMeasurement of end-expiratory lung volume (EELV) by the nitrogen washing-washout technique, bedside available from recent ICU ventilators, has been shown to reliably estimate lung aeration and may help mechanistically titrate PEEP on patient’s individual response –25.We designed an open-label, multicenter, randomized trial to test the safety and feasibility of an individualized PEEP setting protocol driven by EELV and to determine whether this may improve a composite clinical outcome in patients with moderate-to-severe ARDS.2/FiO2 ratio equal to or lower than 150 mmHg. The study will be conducted in 10 intensive care units (ICU) in Italy  on July 9, 2019.The study has been registered on The primary objective of the study is to determine whether a PEEP setting protocol driven by EELV measurement may improve a composite clinical outcome in patients with moderate to severe ARDS, as compared to the EXPRESS protocol .2/FiO2 ≤ 150 mmHg while receiving controlled mechanical ventilation with PEEP = 5 cmH2O) will be the studied population.All adult ICU patients requiring invasive mechanical ventilation due to acute hypoxemic respiratory failure will be screened for the enrolment. Patients with ARDS and moderate-to-severe oxygenation impairment , bone marrow transplantation or chemotherapy-induced neutropenia, history of liver or lung transplant, decision to withhold life-sustaining treatment, need for therapy with inhaled nitric oxide due to documented pulmonary arterial hypertension, life-threatening hypoxemia deemed to require extracorporeal membrane oxygenation (ECMO), documented barotrauma, high risk of mortality within 3 months from other than ARDS , and persistent hemodynamic instability/intractable shock .Exclusion criteria will be as follows: pregnancy, pneumothorax, acute brain injury, decompensated heart failure (NYHA 3–4 before the acute phase of the disease or documented ejection fraction< 35% or pulmonary capillary wedge pressure > 18 mmHg) or acute coronary syndrome, intubation as a result of an acute exacerbation of chronic pulmonary disease, body mass index greater than 35 kg/m2O in the semi-recumbent position; afterward, arterial blood gas analysis (ABG) will be performed to compute PaO2/FiO2 ratio. Patients showing PaO2/FiO2 ≤ 150 mmHg will be enrolled. Patients showing PaO2/FiO2 < 200 and > 150 mmHg will be treated according to the standard clinical practice and reassessed for the presence of oxygenation criterion within 24 h from endotracheal intubation. To limit the exposure to low PEEP of possibly recruitable patients with severe oxygenation impairment, the ABG certifying the oxygenation criterion will be permitted at any time during the 30-min monitoring period.Each patient meeting inclusion criteria will be evaluated for the presence of the oxygenation criterion. After neuromuscular paralysis and endotracheal suctioning, eligible patients will be ventilated for 30 min with PEEP = 5 cmH2O/L) will be encouraged in patients that remain hypercapnic (pH < 7.30 and PaCO2 > 50) despite all ventilator settings provided by the study protocol [After inclusion in the study, all patients will receive continuous neuro-muscular blocking agents (NMBA) infusion for 48 h and will be connected to a mechanical ventilator equipped with EELV measurement module . A standard bi-tube low-resistance circuit with a low-dead space, low-resistance, and high-efficiency heat and moisture exchanger or a heated and humidified bi-tube circuit will be used to connect the patient to the ventilator, according to the preference of the attending physician and the practice of each institution. The use of heated and humidified bi-tube circuits , Italy) to monitor esophageal pressure, estimate pleural pressure, and compute transpulmonary pressure will be placed in all enrolled patients after inclusion. The correct placement of the catheter and the adequate filling of the balloon will be confirmed by an occlusion test ; the occlusion test will be repeated before any measurement is done to ensure the recordings of reliable values , 30.A closed endotracheal suctioning system will be preferentially used in all the enrolled patients.VT = 6 mL/kg of predicted body weight; inspiratory flow set at 60 l/min resulting in an end-inspiratory pause of 0.3–0.5 s; respiratory rate 20–35 to maintain pH > 7.30, PEEP set so that the plateau (PPLAT) pressure will be within the following limits: PPLAT = 28–30 cmH2O (EXPRESS PEEP), FiO2 set to achieve a SpO2 > 88–95% and not higher than 90%. In case of hypercapnia with pH < 7.30 despite a respiratory rate = 30–35, an increase in VT up to 8 ml/kg will be allowed over the entire course of the study.After the enrollment, mechanical ventilator will be set according to the following strategy: Predicted body weight (PBW) will be calculated according to the following formulas :\docume2. In case of evident airway closure [TOT = airway opening pressure [After 30 min with these settings to standardize lung volumes at maximum recruitment, a new ABG will be recorded. Afterwards, a 5-step decremental PEEP trial (EXPRESS PEEP to PEEP 5) will be conducted with the dedicated software on the ventilator . Each step will last 8 min, and EELV will be measured with a 0.2 change in the FiO closure , 32, thePEEP-induced lung recruitment across each PEEP step (Rec) will be computed as follows:2O in one breath with respiratory rate ≤ 8 breaths per minute. In particular, the lung volume due to the presence of PEEP 5 (PEEP5volume) will be measured by subtracting the insufflated VT from the expired VT during a 5-s exhalation (respiratory rate < 8) just after PEEP is reduced from 5 to 0.After the PEEP trial, a one-breath derecruitment maneuver from PEEP 5 to PEEP 0 will be conducted to assess baseline functional residual capacity (FRC) that will be measured as the difference between EELV at PEEP 5 and the lung volume increase above FRC, measured as the difference in expired tidal volume as PEEP is decreased from 5 to 0 cmHThis procedure will not be conducted in patients with airway closure.IND/cmH2O will be computed as REC divided by the PEEP difference. For each PEEP range, the recruitment-to-inflation ratio (RI) will be then calculated as previously described [In particular, when interpreting the results of the PEEP trial, Rec across two adjacent PEEP levels will be normalized to the changes in the effective PEEP  applied: RECescribed , 33:\doEach patient will be then randomized to undergo mechanical ventilation according to the two PEEP-setting protocols described in the next paragraph. Randomization will be stratified according to the volume of effective lung recruitment during the PEEP trial, as described in the “Randomization and record keeping” section.Patients for whom the measurement of the EELV is not be feasible due to any technical reason will not be randomized and accurately recorded on the screening log.VT = 6 mL/kg; inspiratory flow set at 60 l/min and end-inspiratory pause of 0.2-0.5 sec, PEEP set so that PPLAT, measured during the end-inspiratory pause of 1–3 s, will be within the following limits: 28 cmH2O ≤ PPLAT ≤ 30 cmH2O;. FiO2 set to achieve a SpO2 > 88–95%.The EXPRESS protocol is as follows : VT = 6 VT up to 8 ml/kg will be allowed.In case of hypercapnia with pH < 7.30 despite a respiratory rate = 30–35, an increase in Full details of the procedures performed in the intervention group are provided in Fig. VT = 6 mL/kg; inspiratory flow set at 60 l/min resulting in an end-inspiratory pause of 0.2–0.5 s. Respiratory rate set between 20 and 35 to maintain pH > 7.30. FiO2 set to achieve a SpO2 > 88–95%.In case of hypercapnia with pH < 7.30 despite a respiratory rate = 30–35, an increase in VT up to 8 ml/kg will be allowed.2O and set to ensure the maximum recruitment observed in the PEEP trial, with a maximum permitted PPLAT of 30 cmH2O.PEEP will be ≥ 5 cmHRI ≥ 1.5 between two PEEP levels will lead to the setting of the higher PEEP.RI < 0.5 will lead to the setting of the lower PEEP value.In case of RI ≥ 0.5 and < 1.5, the choice among two adjacent PEEP levels will be left to the attending physician, who will indicate the set PEEP in order to best balance between the commitment of limiting total, static, and dynamic strain and of optimizing oxygenation and hemodynamics.In particular, when interpreting the results of the PEEP trial, RI across two adjacent PEEP levels will drive PEEP setting.Due to possible interferences with EELV measurement, in patients showing airway closure , 32, 34,A similar 5-step PEEP trial will re-assess lung response to different levels of PEEP every 12–24 h, in case of changes in the body position or any other clinical events requiring modifications of the ventilatory settings.Following PEEP trials will be conducted to investigate RI at the five PEEP levels closest to the set one.PPLAT remains below the safety limit with this setting: no PEEP< 5 cmH2O, generating PPLAT > 30 cmH2O or lower than the airway opening pressure (in case of airway closure) will be tested or used over the entire course of the study in this intervention group. In particular, each following PEEP trial will investigate response to PEEP at values ranging from + 6 and − 6 than the previously set one .Before the procedure, PEEP will be set for 15 min at the maximum PEEP expected to be tested during the PEEP trial, to ensure that The PEEP level will be then modified according to the strategy described above.In both groups, the assigned ventilation protocol will be followed for a minimum of 72 h from randomization and any time fully controlled ventilation is deemed necessary by the attending physician up to 14 days from randomization. After 14 days from randomization, PEEP will be set according to the clinical practice of each institution.All patients intubated due to hypoxemic respiratory failure and not included will be recorded on a dedicated screening log.Demographics will be collected at study entry. Physiological variables will be recorded at the moment of enrolment (PEEP 5), after maximum PEEP is set before the PEEP trial, 1-6-12-24-48 h after randomization, and then on a daily basis up to 60 days or ICU discharge.2, tidal volume, mean airway pressure, PEEP, plateau pressure, minute ventilation, respiratory rate, esophageal end-inspiratory and end-expiratory pressures, static stress, dynamic stress and total stress, proportion of spontaneous ventilation on minute ventilation, VO2, VCO2), physiologic data , and results of the blood gas analyses  will be collected.Data of the ventilation management , at each step of the first PEEP trial, and 1-6-12-24-48 h from randomization and then on a daily basis (72-96-120…) up to 60 days or ICU discharge. End-expiratory airway pressure (PEEPAW) and the end-expiratory esophageal pressure (PEEPES) will be recorded during a 4-s expiratory hold. End-inspiratory airway pressure (PplatAW) and end-inspiratory esophageal pressure (PplatES) will be measured during a 1-s end inspiratory hold. Expired tidal volume (VT) will be measured as the integration of the flow-time curve during expiration.AW) and the end-expiratory esophageal pressure (PEEPES) will be recorded during a 4-s expiratory hold. End-inspiratory airway pressure (PplatAW) and end-inspiratory esophageal pressure (PplatES) will be measured during a 1-s end inspiratory hold. Expired tidal volume (VT) will be measured as the integration of the flow-time curve during expiration.End-expiratory airway pressure  will be assessed from serum probes (enzyme-linked immunosorbent assay (ELISA)) of all included patients at study inclusion and 24, 48, and 72 h after randomization.The levels of scoring systems will be calculated daily: simplified organ failure assessment score (SOFA), modified clinical pulmonary infection score (CPIS), and Richmond agitation and sedation scale (RASS). These systems and organ failure definitions used for the study purposes are reported in Additional file The following Concomitant patients’ management, including medical treatments and procedures, is detailed in Additional file The primary endpoint will be a composite clinical outcome that incorporates in-ICU mortality, 60-day ventilation-free days (VFD60), and the area under the curve of the interleukin-6 serum blood cytokine concentration (IL6AUC) during the first 72 h of observation.2/FiO2 ratio, oxygenation stretch index and oxygenation index during the study treatment; and SOFA, CPIS, the incidence of complications or adverse reactions, the frequency and duration of other adjunctive therapeutic measures, transfusion requirements, the daily cumulative doses of analgesic and sedative agents, cumulative catecholamine requirements/24 h throughout the study period, frequency and duration of renal replacement therapy, the number of failing organs, and the “organ-failure-free days” within 28 days after randomization.Secondary endpoints will be as follows: ICU-, 90-day and in hospital mortality, 28 and 60-day ventilation-free days (VFD60), the area under the curve (AUC) of serum blood cytokines concentrations measured as stated in the study protocol; lung static, dynamic and total stress and strain after randomization; airway and lung driving and plateau pressures, compliance, compliance/PBW, dead space fraction, PaOPatient data, clinical status, laboratory results, and respiratory parameters will be collected on a web-based case report form . Participants will be randomized in a ratio of 1:1. Randomization will be performed by an electronic, web-based centralized, validated system.RI ≥ 1 and < 1 across the range between the lowest and highest PEEP tested during the PEEP trial  . Amis of monitoring will be to evaluate the study progress and to verify the accuracy of data recording.t-test. In particular, analysis of the primary efficacy criterion will be performed with Wilcoxon-Mann-Whitney sum of ranks test.All collected data will be tabulated descriptively by study group and analyzed on an intention-to-treat basis. Comparisons between groups will be performed with the chi-squared test or the Fisher’s exact test, as appropriate. Ordinal qualitative variables or non-normal quantitative variables will be compared with the Wilcoxon sum of ranks test. Quantitative normal variables will be compared with the Student Consistently to other published studies , every pMortality takes precedence over VFD60, which takes precedence over IL6AUC. Two VFD60s will be considered different for the purpose of scoring only if their difference is larger than 5 days. Similarly, two IL6AUC’s measurements will be considered different only if their difference exceeds 10% of the smaller of the two.These individual-comparison scores are added up to obtain the cumulative score primary endpoint for each participant. Scoring system for the primary endpoint is detailed in Additional file For the purpose of the study, mechanical ventilation will be defined as: invasive mechanical ventilation with endotracheal tube or tracheostomy and noninvasive positive pressure ventilation, including continuous positive airway pressure. High flow oxygen therapy through nasal cannula or tracheostomy will not be considered as mechanical ventilation.The assumptions and methodology used for the determination of the sample size are detailed in Additional file ∆EELV5-16/FRC ≥ 73%  during t∆EELV5-16/FRC < 73 % during tRI ≥ 1 and < 1 across the range between the lowest and highest PEEP tested during the PEEP trialP/F ratio < 100 mmHg at study inclusionIL-6 > 400 pg/ml at study inclusionPrimary and secondary endpoints will also be analyzed in subgroups, as defined below:All analyses will be performed at a 0.05 type I error level, two tail. All statistical analyses on secondary endpoints and on subgroups will be deemed to be exploratory in nature; for this reason, no correction of nominal significance levels for multiple inference will be applied.A Safety Monitoring Committee (SMC) will conduct an analysis to assess the safety and feasibility of the IPERPEEP protocol after 30 patients complete the study, and the study will be continued only if both safety and feasibility are established. In this assessment, no other data besides the criteria for safety and feasibility will be unblinded. The study will be considered feasible if at least 80% of the patients randomized to the intervention group will correctly undergo the allocated treatment according to the study protocol. The study will be considered safe if no serious adverse events related to treatment will be detected in the intervention group while the allocated treatment is ongoing.Serious adverse events (SAE) will be defined as any event that is fatal or immediately life threatening, permanently disabling, severely incapacitating, or requires prolonged hospitalization or that may jeopardize the patient and requires medical or surgical intervention to prevent one of the outcomes listed above. SAE will be considered related to the treatment if the attending physician believes that they might be directly related to enrollment in the clinical trial. In particular, SAE’s will be considered to be study-related if the event follows a study procedure and could readily have been produced by the study procedure.This investigator-initiated, pragmatic, multicenter, prospective, interventional, open-label randomized clinical trial will assess the potential benefits for ARDS patients of a PEEP-setting strategy based on individual patients’ response to PEEP in terms of alveolar recruitment and overdistension, as assessed by sequential measurement of EELV by the nitrogen washing-washout technique during a PEEP trial. Indeed, alveolar recruitability as a response to PEEP has wide inter-subject variability, and it is well established that PEEP can increase overdistension and thus static strain, while decreasing dynamic strain only if recruiting new alveolar units for tidal ventilations . This vaProtocol version 2.0, July 2019.At the time of submission, the regulatory authorization has been obtained in the coordinating center. Enrolment has not yet started in the participating centers. First inclusion is planned in November 2022, and completion of recruitment is estimated to be completed in December 2024.Additional file 1: Participating centers.Additional file 2: Organ failure definitions and scoring systems.Additional file 3: Concomitant patient medical management.Additional file 4: Scoring system for the primary endpoint.Additional file 5: Sample size determination: assumptions and methodology.