Adopting the 45° semirecumbent position in mechanically ventilated critically ill patients is recommended, as it has been shown to reduce the incidence of ventilator-associated pneumonia. Although the benefits to the respiratory system are clear, it is not known whether elevating the head of the bed results in hemodynamic instability. We examined the effect of head of bed elevation (HBE) on hemodynamic status and investigated the factors that influence mean arterial pressure (MAP) and central venous oxygen saturation (ScvO2) when patients were positioned at 0°, 30°, and 45°.Two hundred hemodynamically stable adults on invasive mechanical ventilation admitted to a multidisciplinary surgical intensive care unit were recruited. Patients' characteristics included catecholamine and sedative doses, the original angle of head of bed elevation (HBE), the level of positive end expiratory pressure (PEEP), duration and mode of mechanical ventilation. A sequence of HBE positions  was adopted in random order, and MAP and ScvO2 were measured at each position. Patients acted as their own controls. The influence of degree of HBE and of the covariables on MAP and ScvO2 was analyzed by using liner mixed models. Additionally, uni- and multivariable logistic regression models were used to indentify risk factors for hypotension during HBE, defined as MAP <65 mmHg.P < 0.001) and ScvO2 . Multivariable modeling revealed that mode and duration of mechanical ventilation, the norepinephrine dose, and HBE had statistically significant influences. Pressure-controlled ventilation was the most influential risk factor for hypotension when HBE was 45° (odds ratio (OR) 2.33, 95% confidence interval (CI), 1.23 to 4.76, P = 0.017).Changing HBE from supine to 45° caused significant reductions in MAP  score, sedation, high catecholamine, and PEEP requirements were identified as independent risk factors for hypotension after backrest elevation. Patients at risk may need positioning at 20° to 30° to overcome the negative effects of HBE, especially in the early phase of intensive care unit admission. The semirecumbent position is an upright positioning of the head and torso at an angle of 45°. The effects of adopting the semirecumbent position in critically ill patients have been extensively investigated as a potential means of preventing ventilator-associated pneumonia (VAP). VAP develops in 5% to 25% of ventilated patients and it is associated with prolonged duration of mechanical ventilation, hospital stay, and increased morbidity and mortality -3.Reflux of gastric contents and subsequent microaspiration of bacterial contaminated oropharyngeal fluids play crucial role in development of VAP . Use of Despite being widely adopted, there is still some uncertainty about the routine use of the upright position. Control groups in trials investigating head of bed elevation (HBE) were nursed supine at 0°, which does not reflect current practice. It is also not known whether elevating the head of the bed to 45° may cause hemodynamic instability .We examined the influence of HBE on hemodynamic status in patients on invasive mechanical ventilation. After randomization to one of six possible sequences of positioning we assessed hemodynamic parameters and central venous oxygen saturation in each position and also examined the variables that might be independent predictors of hemodynamic changes.Two hundred patients were recruited in the multidisciplinary surgical intensive care unit (ICU) of a tertiary care university hospital. The study was approved by the local Institutional Review Board . The written consent of unresponsive patients was obtained either from them after they regained responsiveness or from their next of kin. All hemodynamically stable, mechanically ventilated patients over the age of 18 years with a central venous catheter situated in the superior vena cava on the ICU were eligible for inclusion in the study. Hemodynamic stability was defined as a stable mean arterial pressure by constant inotropic support without additional fluid administration. Patients with acute cardiovascular instability, or those with pump-driven circulatory or respiratory support, were excluded from the study. Also excluded were all patients in whom the supine position is contraindicated , or those who were immobilized due to spinal injuries or unstable pelvic fractures.The amount of positive inotropic support, length of mechanical ventilation, ventilation mode, or length of ICU stay did not influence inclusion or exclusion from the study. We chose 15 disease categories to describe the admission diagnoses. Severity of the illness was recorded using the Simplified Acute Physiology Score (SAPS II), which expresses the probability of mortality based on 12 variables including a combination of physiological, laboratory, and clinical data . HemodynSequences of six possible combinations of three positions  were determined: 0°, 30°, then 45°; 0°, 45°, then 30°; 30°, 0°, then 45°; 30°, 45°, then 0°; 45°, 0°, then 30°; 45°, 30°, then 0°. Each combination was randomly assigned a number from 1 to 200. An independent institution created the random order (randomlist) and randomization was made in blocks, to guarantee uniform distribution of positioning sequences. Patients included in the study received a number in order (from 1 to 200) that determined the sequence of positioning from the list.To measure the degree of positioning we used the mini digital protractor BevelBox . The angle sensor was calibrated prior to each measurement.max) (cmH2O); level of inotropic support; dose of propofol and sufentanil for sedation; fluid balance in the last 24 h (mL/24 h); and serum albumin (g/L), hemoglobin (g/dL), and C-reactive protein (CRP) (mg/dL) concentrations. Only patients who mantained the hemodynamic stability during the assessment period were eligible for the protocol administration. The first backrest position was then adopted according to the randomization sequence. After 3 min to allow for hemodynamic adaptation, heart rate, systolic and diastolic blood pressure, and mean arterial pressure were recorded. The blood pressure was measured in all patients via arterial catheter placed either in the radial or femoral artery. The correct position of an arterial pressure transducer was evaluated after each positioning maneuvre. Simultaneously, 2 mL of blood were taken via jugular or subclavian central line for assessment of central venous oxygen saturation. The central venous oxygen saturation (ScvO2) values were automatically transferred from the blood gas analyzer  via network cable to the digital patient record system . Then, these parameters were recorded in exactly the same way for the second and third positions. After the study was complete, the patient was returned to their original position. While the study protocol was being enacted, no changes were made to the doses of vasopressor or sedative drugs or the ventilator settings, nor were additional fluids administered.In the assessment period before intervention, we recorded the following parameters in all patients: positioning degree (°); age (years); gender; weight (kg); height (m); admission diagnosis; SAPS II; duration of mechanical ventilation (h) for the time between admission to ICU and intervention; tidal volume (mL); positive end-expiratory pressure (PEEP) (cmH2O); ventilation mode (either pressure-controlled ventilation (PCV) or pressure support ventilation (PSV)); peak airway pressure  and a central venous oxygen saturation <70% (ScvO2 <70%), respectively, in the 45° position, according to the measured variables. The multivariable models were built using backward selection according to the likelihood ratio. For all significant covariables, we calculated odds ratios (OR) and corresponding 95% confidence intervals (95% CI). All reported P values are two-sided, and a P value of 0.05 is considered the threshold of statistical significance. Since the assessment of the covariables was of purely explorative nature, no adjustment for multiple testing was done. Data entry and calculations were made with the software package SPSS 19.0 , and the linear mixed model analyses were undertaken using the SAS 9.2 procedure PROC MIXED .Continuous variables are presented as means and standard deviations (SD) or as median values and interquartile ranges IQR: q3-q1); categorical variables are presented as absolute numbers and proportions. Normality was verified according to statistical parameters  and visually by Q-Q Plots. To analyze the impact of HBE  and of the covariables  as well as for ScvO2 . In the univariable comparison between both groups we found significant differences in: mean PEEP level, mean PP = 0.023), of 1.13 by raising the level of PEEP  and of 2.33 if they were ventilated in pressure-controlled compared with pressure support mode . Moreover, patients with higher backrest elevation before the intervention were at a significantly lower risk of MAP <65 mmHg in the 45° position   and upright (45°) positions may not be feasible in some mechanically ventilated patients.Increasing the elevation of the head of the bed induces a gravitational transfer of blood from the upper body and central circulatory compartment towards the abdomen and lower limbs. This pooling of blood in the extremities reduces systemic venous return to the right heart and reduces cardiac output. Upright positioning may be responsible for lower mean circulatory pressure in ventilated patients, even if current evidence is lacking. Giving additional fluid boluses to increase circulating volume or increasing vasopressor support can reverse all these hemodynamic changes -14.In our study upright body positioning at 45° was associated with sustained drop of MAP <65 mmHg in 72 (36%) patients. In addition, ScvO2 fell to below 70% in 62 (31%) patients. A MAP >65 mmHg and ScvO2 >70% are widely accepted and recommended hemodynamic parameters for adequate tissue perfusion and oxygenation in critically ill patients, targets that were not achieved by approximately one-third of our patients in the 45° position .Our results showed significantly higher values for MAP and ScvO2 in the supine position. This may reflect the short-term effect of an improved circulation profile with higher systemic venous return, higher cardiac output, and, as a consequence, improved oxygen delivery. However, the supine position is clearly associated with increased incidence of ventilator-associated pneumonia, lung de-recruitment, and hypoxemia ,17. Any Our results suggest that critically ill patients in early phase after admission who require PCV and inotropic support are at high risk of a significant decrease in ScvO2 by increasing backrest position. Patients who required long-term ventilation showed significantly higher ScvO2 levels at the time of the study. They may have been in the recovery phase, with positive cumulative fluid balance and more cardiovascular reserve, lower oxygen demand, and less invasive mechanical ventilation than patients in the acute phase.2O creates a relative risk of hypotension (MAP <65 mmHg) of 1.13 in the 45° position, but also that increasing norepinephrine dose by 0.01 μg/kg/min is associated with a relative hypotension risk of 1.03. Increasing dose of norepinephrine reduces unstressed volume and vascular responsiveness. The greatest risk was PCV, which was associated with a relative risk of 2.33 for MAP <65 mmHg in the semirecumbent position. There are several reasons why the spontaneous (PSV) ventilator mode may be less deleterious on MAP during backrest elevation. Spontaneous inspiration with diaphragmatic contraction decreases intrathoracic pressure and hence systemic venous return to the heart is increased [The dose of norepinephrine, level of PEEP, the PCV mode, and the angle of backrest elevation before the head of the bed was elevated can help identify patients at risk of hypotension (MAP <65 mmHg) when they are moved into the 45° position. The hemodynamic effect of PEEP on MAP is well known. Increased PEEP levels raise intrathoracic pressure, decrease right and left ventricular afterload and contractility leading to lower systemic blood pressure, especially in hypovolemic patients -20. We fncreased . Furtherncreased ,23.versus 26.6°). This suggests that patients at high risk of hypotension in the semirecumbent position are those who are routinely nursed below the recommended 30° to 45° of backrest elevation.Van Nieuwenhoven and colleagues have evaluated the feasibility of adopting the semirecumbent position in the daily routine for ventilated critically ill patients. They found that the targeted upright position of 45° was not attained for 85% of the study time in the semirecumbent group. Average elevations in the study group were 28.1° and 22.6° at days 1 and 7, respectively . We measAccording to current published data, raising the head of the bed to 30° and 45° significantly increases the peak interface pressure between the skin at the sacral area and support surfaces in healthy volunteers, and in this context decubitus ulcers still remain a concern . PositioBased on current evidence, the semirecumbent position clearly prevents VAP when compared to full horizontal position. Nevertheless, it is still unclear whether the 45° degree backrest elevation as originally reported by the Drakulovic's study is feasible, and whether lower inclination of head of bed could still be beneficial. The future studies may systematically address safety of the HBE and identify the safest, most effective head of bed orientation for patients on invasive mechanical ventilation.Adopting the 45° semirecumbent position is strongly associated with decreases in MAP and ScvO2 in mechanically ventilated patients. Patients who are sedated, undergoing pressure-controlled ventilation, with higher SAPS II scores, receiving elevated levels of PEEP or higher dose of norepinephrine are at greatest risk of hypotension. They may need positioning at 20° to 30° to overcome the negative influences of backrest elevation on hemodynamic stability, especially in the early phase of critical illness.• Elevating the head of the bed to 45° is associated with significant decreases in MAP and ScvO2 in mechanically ventilated patients.• Pressure-controlled ventilation, increasing SAPS II score, sedation, high catecholamine, and PEEP requirements are independent risk factors for hypotension after backrest elevation.• Patients at risk may need positioning at 20° to 30° to overcome the negative effects of HBE, especially in the early phase of ICU admission.ARDS: acute respiratory distress syndrome; BMI: body mass index; CI: confidence interval; CPR: cardiopulmonary resuscitation; CRP: C-reactive protein; HBE: head of bed elevation; ICU: intensive care unit; MAP: mean arterial pressure; OR: odds ratio; PCV: pressure controlled ventilation; PEEP: positive end expiratory pressure; PSV: pressure support ventilation, SAPS II: simplified acute physiology score; ScvO2: central venous oxygen saturation; VAP: ventilator-associated pneumonia.The authors declare that they have no competing interests.TB was responsible for the study design. FS and IG were responsible for administering the protocol. FZ, FS, IG, and TB performed the data analysis and were responsible for interpretation of data. IG, FZ, and TB drafted the manuscript. MC, BMG, and HJS critically reviewed the manuscript. All authors have given final approval of this version of the manuscript.


There was a strongly positive, and apparently linear, relationship of BMI and WC with blood pressure, with 1 s.d. higher BMI associated with 4.3/2.3 mm Hg higher SBP/DBP and 1 s.d. WC associated with 3.8/2.1 mm Hg (P<0.0001). Additional adjustment for WC only slightly attenuated the association of BMI with blood pressure, whereas additional adjustment for BMI almost completely eliminated the association of WC with blood pressure. Our findings suggest that in relatively lean Chinese adults, general adiposity is more strongly assciated with blood pressure than central adiposity.Obesity is a strong determinant of blood pressure. Uncertainty remains, however, about which indices of adiposity most strongly predict blood pressure, particularly among those who were relatively lean, such as those from rural China. We analyzed cross-sectional data on 55 687 (38.3% men) participants aged 30–79 years who were enrolled into the China Kadoorie Biobank from a rural county in southwest of China during 2004–2008. Measured body mass index (BMI) and waist circumference (WC) were related to blood pressure in multivariable linear regression analyses. The overall mean values of BMI, WC, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 23.3 kg m A good understanding of these questions can inform the assessment of potential impacts of the recent obesity epidemic on blood pressure and related vascular burden in different populations.High blood pressure is a major cause of cardiovascular disease morbidity and mortality in both developed and developing countries. One of the major determinants of blood pressure is adiposity,8 But a few others did not support this, showing that BMI was a better predictor of blood pressure than WC.10 A large majority of these previous studies were conducted among Western populations where most adults are overweight or obese and individuals with hypertension are generally well managed. In China, however, hypertension is highly prevalent and is still poorly detected and managed.11 Moreover, despite the recent increase, prevalence of overweight or obesity remains low, especially in rural China.13 Reliable assessment of the associations between different adiposity measures and blood pressure in relatively lean Chinese population would not only help to improve our understanding about possible mechanisms linking adiposity with blood pressure, but also inform the development of effective public health policies for control of hypertension and related cardiovascular diseases.Several studies have investigated the associations of different measures of adiposity with blood pressure, but findings have been inconsistent. Most of them tended to suggest that WC is either similarly or more strongly associated with blood pressure as compared to BMI.14 The main objectives of the present study are (1) to determine, both qualitatively and quantitatively, the associations of general and central adiposity with blood pressure as well as the prevalence of hypertension; and (2) to assess whether the associations differ by age, gender and lifestyle factors.To help fill this knowledge gap, we report a cross-sectional analysis of data from over 55 000 men and women from rural China who were enrolled into the nationwide China Kadoorie Biobank study.15 Briefly, it involved 10 geographically defined localities  across China chosen to cover wide spectra of risk exposures and disease patterns. All adults who were permanent residents, aged 35–74 years, in defined regions with no major disability were invited to participate in the study. A total of 55 687  participants were enrolled from Pengzhou, Sichuan.Participants were all from Pengzhou, a rural county in the south of Sichuan Province, China, who were enrolled during 2004–2008 as a part of the China Kadoorie Biobank. Details about the design, conduct and data collection of the China Kadoorie Biobank have been described previously.The study was approved by the ethics committees of the University of Oxford, the Chinese Center for Disease Control and Prevention, and the Sichuan Center for Disease Control and Prevention. Written informed consent was obtained from all participants.15 An interviewer-administered computerized questionnaire was used to collect information on sociodemographic characteristics, lifestyle factors , medical history and so on.The baseline survey took place in temporary study clinics, specially set up near participants’ residential areas. All the data collection was undertaken by trained research staff according to standard protocols and procedures.−2). WC was determined to the nearest 0.1 cm using a soft non-stretchable tape at midway between the lowest rib and the iliac crest. Blood pressure was measured twice using a UA-779 digital monitor recommended by the British Hypertension Society . If the systolic blood pressure (SBP) difference between the first two measurements was more than 10 mm Hg, a third measurement was obtained and the last two measurements were recorded in the database. For the current analysis, we used mean of the two blood pressure measurements. Hypertension was defined as either prior physician-diagnosed hypertension, having measured mean SBP⩾140 mm Hg, or diastolic blood pressure (DBP) ⩾90 mm Hg.A range of physical measurements were also undertaken. Height was measured to the nearest 0.1 cm using a portable stadiometer when participants wearing no hat and shoes. Weight was measured using bioelectrical impedance  while participants wearing no shoes and only light clothes. BMI was calculated as weight in kilograms divided by the square of height in meters (kg m−2) and central obesity (WC⩾90 cm for men or ⩾80 cm for women)16 in each of these subgroups were calculated with standardization for the same covariates as mentioned above using logistic regression.All analyses were performed first separately for men and women and then in overall population. Multiple linear regression models (with a statement of LSMEANS) were used to estimate the mean values of BMI and WC by sociodemographic and lifestyle factors and season of survey, with adjustment, where appropriate, for age , education (three groups) and annual household income (three groups). Prevalence rates of overweight  of hypertension prevalence was estimated using the ‘floating absolute risk’ method.18 For the analyses on blood pressure, 2109 participants who were using antihypertensive treatment at the time of survey were excluded, leaving 53 578 in those analyses.Multiple linear regression models were also used to estimate the least square means of blood pressure, and logistic regression models were used to calculate the adjusted prevalence of hypertension by BMI and WC, adjusting for age, education, income, smoking status, alcohol and fresh fruit consumption, sedentary leisure time and season of survey. For BMI, participants were categorized into seven categories, with cut points 18.5, 21, 24, 25, 28 and 30 kg m−2 BMI were calculated both overall and in subgroups by sex, age, education, income, smoking status, alcohol and fresh fruit consumption, sedentary leisure time and seasons of survey, using multiple linear regression models with adjustment for above mentioned covariates.Finally, differences (and their 95% CIs) in blood pressure per 5 kg mIn addition, analyses were also carried out to examine the associations of other general  and central  and waist-to-height ratio) adiposity indices with blood pressure.All these analyses were performed using SAS 9.2  and R version 2.10.1  was used to graph results.Of the study participants, the overall mean (s.d.) age was 51.0 (10.5) years, and means (s.d.) of SBP and DBP were 129.2 mm Hg (19.0) and 77.2 mm Hg (10.2), respectively. About a quarter of our participants were hypertensive, slightly more in men than in women. On average, men were 2 years older, had 3.8/2.6 mm Hg higher SBP/DBP, and were more likely to smoke (67.1 vs 9.5%) and drink regularly (50.4 vs 6.2%) compared with women .−2 in men and 23.6 kg m−2 in women, and the mean WC was 78.9 and 77.4 cm, respectively. In men, more than three quarters (77.4%) had BMI<25 kg m−2, with only 1.5% being obese (BMI⩾30 kg m−2). In women, the corresponding rates were 68.5 and 3.8%, respectively  associated with 4.3 mm Hg (95% CI: 4.2–4.4) and 1 s.d. WC (8.9 cm) associated with 3.8 mm Hg (3.6–3.9). After the additional adjustment for WC, the associations of BMI with SBP were only slightly attenuated to 3.8 mm Hg (3.5–4.0). However, the additional adjustment for BMI almost completely eliminated the associations between WC and blood pressure, down to 0.6 mm Hg . Similar was observed for DBP: additional adjustment for WC only slightly attenuated the associations of BMI with DBP from 2.3 to 1.8 mm Hg for per s.d. BMI, while additional adjustment for BMI dramatically reduced the association of WC with DBP from 2.1 to 0.6 mm Hg per s.d. WC  higher SBP (7.2 mm Hg in men and 6.3 mm Hg in women), with the association being stronger in older than in younger people  mm Hg DBP, with the association being stronger in men and in ex-regular drinkers. But no age trend was seen.After adjusting for potential confounders, each 5 kg m−2), 57.6% of men and 41.1% of women were hypertensive, more than three times as high as those in the lowest BMI group. For WC, additional adjustment for BMI largely reduced its positive association with hypertension . In addition, use of carefully measured anthropometrics and blood pressure is another major strength of our study. Self-reported adiposity measures, as used in many previous studies, are subject to reporting bias that may distort the associations differently depending on the levels of adiposity.26 Our study findings contrast with a number of cross-sectional studies previously conducted in either Asian or Western populations, in which WC was shown either more closely or similarly related to blood pressure or risk of hypertension as compared to BMI.28 In a study of 14 924 people from the third US National Health and Nutrition Examination Survey (NHANES III) during 1988–1994 in which the mean BMI was 25.4 kg m−2, WC was found as an independent predictor of hypertension after adjusting for BMI, with each 1 cm larger WC associated with 3 and 5% higher prevalence of hypertension in men and women, respectively. However, BMI was no longer a predictor of hypertension after adjusting for WC.27 In another two studies of Asian28 and non-smoking Greek adults participating in the EPIC (European Prospective Investigation into Cancer and Nutrition) study,10 however, BMI and WC were found both significantly associated with blood pressure after mutually adjusted for each other.Despite previous research, it is still under debate as to which measurement of adiposity could better predict the risk of cardio-metabolic diseases, such as hypertension, diabetes and heart disease and mortality.29 In a study of 202 young US adults with 6-month follow-up, baseline and change of BMI were both significantly associated with change in blood pressure even after the adjustment for baseline and change in WHR. However, association of baseline or change in WHR with blood pressure did not persist after additional adjustment for BMI.29 In another study of 3312 Japanese adults with 2-year follow-up, change in BMI was shown to be significantly associated with blood pressure difference after controlling for baseline and change in WC, whereas converse was not true.2Several small prospective studies have reported similar adiposity—blood pressure associations as we observed in the present study.32 These dysfunctions may in turn activate the renin-angiotensin-aldosterone system and sympathetic nervous system, which lead to endothelial dysfunction, impaired pressure natriuresis and vascular hypertrophy, and eventually raise blood pressure. As compared to WC, BMI has been found more strongly associated with total body fat mass and body volume.34 Therefore, it might be more closely related to peripheral resistance and aforementioned dysfunctions.The exact cause of the non-significant association between WC and blood pressure after adjusting for BMI is unknown, as are the mechanisms linking adiposity and blood pressure. It has been speculated that increased body volume caused by excessive body fat could lead to a higher peripheral vascular resistance and a series of dysfunction, such as adiponectin deficiency, hyperleptinemia, elevated renin-angiotensin-aldosterone system hormones and mineralocorticoid-stimulating factors.35 Moreover, the stronger association in older people may also reflect the vascular damage of adiposity cumulated during a longer time period. This finding may also implicate a necessity of body weight control among older people for the sake of preventing severe cardiovascular events. The seemingly unexpected positive association between fruit consumption and adiposity might be due to confounding by other dietary factors and/or socioeconomic status. Further investigation in this aspect is outside of the scope of the current paper.The stronger association of BMI with blood pressure per five units higher BMI in men than in women could be explained by the larger s.d. of BMI in women: five BMI units represented 1.7 s.d. in men but only 1.5 s.d. in women. When calculated using per 1 s.d. BMI for SBP, there was no difference in the strength of the association between men and women (4.2 mm Hg in both). The causes for the extremely stronger BMI—blood pressure association in those ex-regular drinkers have yet to be fully understood. It might be true that ex-drinkers might have stopped drinking due to diseases or pre-disease conditions, such as arthrosclerosis, which could modify the association of adiposity with blood pressure. Also, they might have distinct characteristics in lifestyle factors other than the ones we have considered and adjusted for. Elevated arterial wall thickening and stiffening with age may be the potential element leading to a stronger association of BMI with SBP in older people.To conclude, our results provide strong evidence that general adiposity, indicated by BMI, was more strongly associated with blood pressure than WC in Chinese adults. A greater emphasis should be placed on BMI for the purpose of monitoring hypertension risk in Chinese adults.


To evaluate the effects of inspiratory loading on blood flow of resting and exercising limbs in patients with diabetic autonomic neuropathy. Ten diabetic patients without cardiovascular autonomic neuropathy (DM), 10 patients with cardiovascular autonomic neuropathy (DM-CAN) and 10 healthy controls (C) were randomly assigned to inspiratory muscle load of 60% or 2% of maximal inspiratory pressure (PImax) for approximately 5 min, while resting calf blood flow (CBF) and exercising forearm blood flow (FBF) were measured. Reactive hyperemia was also evaluated. From the 20 diabetic patients initially allocated, 6 wore a continuous glucose monitoring system to evaluate the glucose levels during these two sessions . Mean age was 58 ± 8 years, and mean HbA1c, 7.8% (62 mmol/mol) (DM and DM-CAN). A PImax of 60% caused reduction of CBF in DM-CAN and DM (P<0.001), but not in C, whereas calf vascular resistance (CVR) increased in DM-CAN and DM (P<0.001), but not in C. The increase in FBF during forearm exercise was blunted during 60% of PImax in DM-CAN and DM, and augmented in C (P<0.001). Glucose levels decreased by 40 ± 18.8% (P<0.001) at 60%, but not at 2%, of PImax. A negative correlation was observed between reactive hyperemia and changes in CVR . Inspiratory muscle loading caused an exacerbation of the inspiratory muscle metaboreflex in patients with diabetes, regardless of the presence of neuropathy, but influenced by endothelial dysfunction. High-intensity exercise that recruits the diaphragm can abruptly reduce glucose levels. Cardiovascular autonomic neuropathy causes increased morbidity and mortality to diabetic patients . ExercisRespiratory muscle weakness in diabetic patients may be associated with peripheral  and autoAs muscle metaboreflex activity and brachial artery flow-mediated dilatation are both impaired in hypertensive and diabetic patients , endotheThe present study was conducted to evaluate the effects of inspiratory loading on blood flow of resting and exercising limbs in patients with diabetic autonomic neuropathy, comparing their responses to those elicited by the same protocol in controls and diabetic patients without autonomic neuropathy.2, exercise-induced asthma, infectious, osteoarticular, cardiac or pulmonary diseases, as well as regular alcohol or tobacco consumption in the preceding 6 months. A group of 10 healthy controls (C) were selected to match the DM and DM-CAN groups in age, gender, and BMI.The protocol was approved by the Hospital de Clínicas de Porto Alegre (HCPA) Research Ethics Committee. All subjects provided written informed consent for participation. Ten patients with type 2 diabetes without autonomic neuropathy (DM) were matched to 10 patients with type 2 diabetes with moderate and severe cardiovascular autonomic neuropathy (DM-CAN). The presence or absence of autonomic neuropathy was assured using the five noninvasive cardiovascular reflex tests proposed by Ewing, as previously described , 21. TheSubjects came to the laboratory on three separate days for completion of the study protocols. On the first day, pulmonary function, inspiratory muscle function and cardiovascular autonomic function were evaluated. On the second day, individuals underwent endothelial function assessment and cardiopulmonary exercise testing. On the third day, at least two days after the above-described evaluations, subjects underwent a protocol designed to elicit the inspiratory muscle metaboreflex, so as to evaluate its impact on resting hemodynamic parameters, maximal inspiratory muscle pressure, calf blood flow (CBF) and forearm blood flow (FBF). All experiments were performed in a temperature-controlled room and all subjects were in the fasting state (at least for 3 hours), had refrained from consuming caffeinated beverages and alcohol for at least 12 hours, and had not exercised for at least 48 hours prior to the evaluation.Measurements of forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and maximal voluntary ventilation (MVV) were obtained with a computerized spirometer , as recommended by the American Thoracic Society , and resInspiratory muscle function testing was performed using a pressure transducer , connected to a system with two unidirectional valves  as previously described . In shor1) deep breathing, 2) lying-to-standing heart rate ratio, and 3) the Valsalva maneuver. Two tests of blood pressure control were also calculated during 1) orthostatic hypotension and 2) sustained handgrip. All tests were performed three times, and the mean value was used for analysis. Two or more abnormal tests were deemed diagnostic of cardiovascular autonomic neuropathy [th beat after standing up, to the shortest R-R interval, measured around the 15th beat after standing up. The Valsalva test consisted of forced exhalation into a mouthpiece with a pressure of 40 mmHg for 15 s, and the ratio of the maximum R-R after the maneuver to the minimum R-R during the maneuver was calculated. Orthostatic hypotension was defined as a decrease in systolic blood pressure of 30 mmHg when the individual voluntarily changed from the supine to the standing position. Measurements were obtained every minute for at least 3 min. Sustained muscle contraction as measured by handgrip dynamometer. The dynamometer was first squeezed to isometric maximum; then, patients were asked to hold at 30% maximum for 5 min. A rise in diastolic blood pressure of < 10mmHg is considered an abnormal response.The presence of cardiovascular autonomic neuropathy was verified using the five noninvasive cardiovascular reflex tests proposed by Ewing, as previously described  and stanuropathy , 21. HeaReactive hyperemia were measured using cuffs placed at the upper and lower arm. In the lower arm, a rapid cuff inflator was used to occlude venous outflow (50–60 mmHg), and three blood flow recordings were obtained each minute for 3 min. Thereafter, the upper-arm cuff, which induces hyperemia, was occluded at 250 mmHg for 5 min, with pressure released in 10 s intervals over 1 min. Reactive hyperemia was calculated using the percentage of dilatation after the post-occlusion flow 5 min in relation to baseline .The maximal incremental exercise test was performed on an electrically braked cycle ergometer  with minute increments of 10 W for DM-CAN, 15 W for DM, and 20 W for C. During testing, gas exchange variables were measured by a previously validated system .fb) of 15 breaths per min and a duty cycle (TI/TTot) of 0.7 by listening to an audio signal with distinct inspiratory and expiratory tones in both protocols. Inspiratory pressure was continuously recorded and displayed on a computer screen and a 10-point Borg scale [Induction of the inspiratory muscle metaboreflex was performed according to apreviously described protocol . In shorrg scale  was usedImmediately after induction of the inspiratory muscle metaboreflex and the placebo experiment, subjects began the forearm exercise, which consisted of repetitive maximal voluntary contractions of the dominant forearm on a hand dynamometer  that was measured at baseline, maintained for 10 s and released for 30 s until task failure. The session took as long as patients would support until forearm fatigue (approximately 7 min). During the relaxation phase, FBF was measured by venous occlusion plethysmography  and all patients were encouraged verbally throughout the isometric contraction in order to maintain handgrip force at target.fb, arterial oxygen saturation by pulse oximetry (SpO2), and end-tidal carbon dioxide (ETCO2) were measured by oxycapnography . Mean arterial blood pressure (MAP) was measured on the non-dominant arm with an automated sphygmomanometer at each minute of the test . Calf blood flow and FBF were measured by venous occlusion plethysmography . Calf vascular resistance (CVR) and forearm vascular resistance (FVR) ware calculated as CBF/MAP and FBF/MAP, respectively [2 into the inspiratory circuit.During induction of the inspiratory muscle metaboreflex and the placebo experiment, ventilatory and hemodynamic variables were measured as previously described . In shorectively . End-tidOne subgroup of 6 patients with diabetes was randomly assigned to two sessions of inspiratory muscle exercise either with 2% of PImax (placebo condition) or 60% of PImax (metaboreflex activation), in different days with one week apart. Subjects were admitted to the laboratory in the morning, when the CGMS device was placed . The sensor was inserted through a needle into the subcutaneous tissue of the abdominal wall using a spring-loaded device  24h before the beginning of the protocols and maintained through the exercise sessions until a 30 min of recovery after the sessions was reached, when it was removed. Glucose measurements were obtained every 10 s and averaged every 5 min, for a total of 288 readings per day. Sensor readings were calibrated with a glucose monitor  using 4 finger stick blood samples obtained over the 24-h period. Patients were previously instructed about the operation of the monitor. Subjects were asked to closely match their daily nutritional intake.post-hoc test for multiple comparisons. Pearson’s correlation coefficient and multiple linear regression analyses were performed to determine the relationship between VO2 peak, delta of CVR and baseline HbA1c and PImax variables after the protocols. Categorical variables were compared by means of Fisher’s exact test. Findings were considered significant at p < 0.05.A sample size of 10 individuals per group was estimated to detect a 10% difference in CBF response, with for a statistical power of 0.8 and an alpha of 0.05. Values are reported as mean ± SD. All analyses were performed using the Statistical Package for the Social Sciences 18.0 for Windows software . Generalized estimating equations (GEE) were used to compare differences in patients’ characteristics and baseline values among groups. The GEE model for repeated measures was used to compare respiratory and hemodynamic measurements during the inspiratory muscle metaboreflex protocol, followed by Bonferroni’s peak and V̇O2peak were observed in DM and DM-CAN as compared to C. Lower Pthmax/PImax, and HRpeak were observed in DM-CAN as compared to C. The FEV1 was lower in DM-CAN as compared with the C and DM groups. The FVC was lower in DM and DM-CAN as compared to C, and even lower in the DM-CAN as compared with the DM group.The baseline characteristics, resting hemodynamics, pulmonary/ inspiratory muscle function and cardiopulmonary exercise testing results of the subjects are shown in I/TTot of ~0.7 for fatiguing and control protocols. The HR was lower at the end point of the 60% protocol in DM-CAN when compared with C and DM. The ETCO2 remained at eupneic levels during both protocols. These data are shown in P< 0.001. The intermittent static handgrip exercise after inspiratory muscle loading at 60% of PImax resulted in similar SpO2 and HR responses among the groups studied. These data are shown in Calf vascular resistance was negatively associated with baseline values of Pimax , reactive hyperemia  and VO2peak  on pooled analysis of all groups. On multiple linear regression, only reactive hyperemia remained significantly correlated with changes in delta CVR .per se, not by autonomic neuropathy, as no differences were observed between patients with or without this complication. In addition, changes in the peripheral vasoconstrictor response to inspiratory metaboreflex activation were inversely related to reactive hyperemia. This study also shows that glucose levels decreased significantly during the inspiratory muscle metaboreflex activity, and remained low for at least 30 minutes after cessation of exertion.This study shows that voluntary efforts against an inspiratory resistive load of 60% of PImax cause exaggerated vasoconstriction of the resting calf in patients with type 2 diabetes, suggesting an exacerbation of the inspiratory muscle metaboreflex. These fatiguing levels of inspiratory muscle force translated into reduced circulatory responses to forearm exercise. These derangements were determined by the diabetic state Several studies have shown that the inspiratory metaboreflex generated by fatiguing inspiratory muscle work elicits a sympathetically mediated vasoconstrictor response in the resting limbs of healthy subjects , 26. TheIt is known that autonomic neuropathy can impair hemodynamic responses to cardiovascular stress, and also cause decreased heart rate variability  and damaIn healthy subjects metaboreflex activation results in greater increases of sympathetic outflow during heavy exercise, resulting in attenuated reactive hyperemia, an indicator of endothelial function. In type 2 diabetes it is possible that the increased sympathetically-mediated vasoconstriction (metaboreflex activation) resulted in augmented vasoconstriction to a point that the already dysfunctional endothelium  was unabLeg blood flow is reduced in type 2 diabetic subjects during exercise, a response that is correlated with endothelial function . This imThe abrupt decrease in glucose levels observed during inspiratory loading (~40% reduction at 60% of PImax) was of similar magnitude to the acute reduction in glucose levels observed after acute aerobic exercise in a similar population . It is wIn conclusion, inspiratory muscle loading of 60% of PImax caused an exacerbation of the inspiratory muscle metaboreflex in subjects with diabetes. This phenomenon occurred regardless of the presence of neuropathy, but was influenced by endothelial dysfunction. High-intensity exercise that recruits the diaphragm can reduce glucose levels abruptly, and this is an avenue that should be explored for its potential relevance to future clinical practice.


After decades of improvement, asthma outcomes have stalled. Mortality, hospitalisations, exacerbations and symptom control remain sub-optimal. In controlled trials, most patients gain high levels of control, but in ‘real-life’ routine clinical practice most patients do not. Avoidable factors are found in most asthma deaths and hospital admissions. This perspective paper considers and contextualises the factors underlying poor asthma outcomes, and it suggests approaches that could improve the situation. Factors discussed include severe, therapy-resistant disease and the role of new and upcoming pharmacological therapies in improving outcomes. These are likely to be beneficial when targeted on patients with severe disease and discrete phenotypic characteristics, identified through biomarkers. However, for the majority of patients treated in the community, they are unlikely to be used widely, and better use of current therapy classes will be more important. Non-adherence with regular inhaled corticosteroid treatment and over-use of rescue bronchodilators are common, and many patients have poor inhaler technique. Self-management is frequently poor, particularly in those with psychosocial disadvantages and co-morbidities. Communication between clinicians and patients is sometimes poor, with failure to detect avoidable poor control and non-adherence, and failure to provide the necessary information and education to support efficient self-management. Strategies for improving monitoring and clinician–patient interactions to allow personalised treatment are considered. These strategies have the potential to allow individual patient needs to be recognised and efficient targeting of the variety of effective pharmacological and non-pharmacological interventions that we possess, which has the potential to improve both individual and population outcomes. Despite effective therapies and an ongoing major investment on the part of commissioners of services and of research, asthma outcomes remain much worse in ‘real life’ than they could be, and much worse than those achieved in controlled trials. This perspectives paper aims to explore the complex web of factors relating to pathology, patients, clinicians and health systems to understand why we have stopped making progress and what we can do to improve outcomes.1 progressive improvements occurred in hospitalisation, mortality, symptom control and quality of life, through safe, effective medication and structured, proactive care.2 Primary care generalists took on diagnosis and management for most patients, with hospital-based specialist care reserved for those with severe, therapy-resistant disease and poor control. In hindsight, a misplaced sense of complacency arose.The remarkable improvements in asthma outcomes at the end of the last century are among the great achievements of medicine. Despite increasing prevalence,3 The disease burden remains huge, resulting in similar levels of global health impairment as chronic liver disease and schizophrenia.4 People continue to die and experience severe, life-threatening attacks, which are frequently avoidable.5 Most of them experience regular symptoms6 and impaired ability to lead a full, productive life, resulting in large direct and even larger indirect costs.7 The aims of management are to reduce the impact on daily life  and the risk of adverse events .8 Surveys have shown little or no recent improvements in these outcomes in most developed countries. For instance, mortality and hospitalisation rates in the UK have not improved,10 with marked regional variations.11 The majority of European patients continue to report significant symptoms,6 except countries prioritising asthma as a public health problem.12 This has occurred despite a continual stream of new licensed asthma products, and evidence that in tightly structured clinical trial settings most patients can achieve good control.13Unfortunately, the new millennium has shown that such an optimism was premature; asthma remains common, incurable and outcomes have stalled.9 For instance, guidelines recommend that quality-assured spirometry should be performed on all patients with suspected asthma to demonstrate obstruction and reversibility; yet, objective lung function is often not measured at all, and there are ongoing issues about the consistency of the quality of primary care spirometry.14 In cases of diagnostic uncertainty, guidelines recommend the use of objective tests such as measurement of bronchial hyper-reactivity or airways inflammation, but in practice these are usually not currently available to primary care clinicians in most health systems. Audits of prescribing patterns in primary care clinicians often show prescribing not in accord with guideline recommendations,15 including overprescribing of rescue bronchodilators, underuse of inhaled corticosteroids (ICS), use of long-acting β2-agonists (LABAs) as monotherapy and over-use of high doses of inhaled ICS, particularly in children.16 These observations point to an ongoing problem of dissemination of best practice and a likely unawareness of guidelines and of spirometry performance or interpretation in some practitioners, with a need for better education and implementation strategies. It is also clear that many patients find it hard to engage with the systems of health care that have been developed for asthma and other long-term conditions that we are unable to cure. Although best care for chronic diseases is proactive and involves self-management education, many patients only attend for care when in a crisis. Increasing numbers of patients have one or more long-term conditions (multimorbidity), yet systems of care are usually directed towards single conditions.17Although a huge effort has gone into producing and updating asthma guidelines aimed largely at primary care practitioners, clinician adherence with, and implementation of, guidelines is frequently poor. Both diagnostic and prescribing patterns often do not accord with actual care.18 The complexity and heterogeneity of asthma is increasingly understood, particularly in difficult asthma, and the phenotypes19 and endotypes20 constituting the asthma syndrome are better described, allowing specific groups to be identified and targeted. However, severe asthma only affects 5–10%,9 and even here behavioural factors are common.21 Greater understanding of biological abnormities with the use of biomarkers to define ‘responder’ groups allows targeting of expensive treatments involving monoclonal antibodies. Anti-IgE is now a part of care, and other mediator modulators are in late-phase clinical trials.3 We can be optimistic that new treatments will soon be available and, if used appropriately in dedicated ‘difficult asthma’ clinics with the necessary expertise, will be clinically effective, as well as cost effective. Indiscriminate use in everyone doing badly will not work. Psychosocial problems and non-adherence are particularly common in this group, and the involvement of primary care in coordinated, integrated multi-disciplinary care is vital.22The ‘stepped’ pharmacotherapy approach of asthma guidelines perhaps encourages the belief that ‘stronger’ medication is needed when the control is poor. Undoubtedly, some patients have intrinsically severe, therapy-resistant disease, requiring more effective treatments. However, even in this group, good quality management (including effective education in self-management) can often improve outcomes.5 Few advances have occured in pharmacotherapy since the leukotriene receptor antagonists, which have a role as an add-on therapy. The mainstay of treatment remains ICS, with LABA as first choice add-on therapy. Newer ICS and LABA molecules show some advantages in pharmacological properties, which may result in limited incremental clinical improvements for some; however, benefits largely relate to medication classes. Once-daily dosing may improve adherence and is preferred by patients, although the benefits over twice-daily regimes are not clear. The variety of inhaler delivery devices grows, with some being easier to use and to teach. However, despite the profusion of devices and molecules, control remains far from optimal.Yet majority of patients rarely see a hospital pulmonologist, and the control remains poor in those with ‘milder’ disease. Although some may have severe disease, the likelihood is that for most of them the reasons lie elsewhere. The UK National Review of Asthma Deaths has shown that most deaths occurred in those considered ‘mild’.23 hospitalisation,24 exacerbations25 and improve symptom control and quality of life. It is a source of bewilderment to clinicians that many patients use ICS sporadically or not at all. Adherence rates in asthma range from 30 to 70%, with under 50% of children adhering to prescribed regimens.26 Non-adherence with ICS is associated with progressively worse outcomes as use decreases,20 and it is common in asthma deaths.5 It is estimated that each 25% increase in time without ICS medication results in a doubling of the rate of asthma-related hospitalisations.27 The reasons for non-adherence are complex, and they include ‘non-intentional’ non-adherence—for example, forgetting medication—and ‘intentional’ non-adherence—a conscious decision not to use medication as prescribed. From their perspective, patients make a rational decision, based on their assessment of health needs and risks. Many overestimate the ICS-related risks and underappreciate the benefits of regular treatment. Some worry that the ICS ‘wear off’ with regular use despite the lack of objective evidence of tachyphylaxis. The relatively slow time course of ICS leads some to conclude that they do not work for them, particularly in comparison with the rapidly perceptible effects of bronchodilators. As many patients experience asthma as being intermittent, some only recommence ICS when symptomatic. LABAs are an effective add-on therapy, but they are unlicensed and associated with the risk of adverse events and even death when used without ICS.28 Unfortunately, this pattern of use continues to occur in real life, sometimes with tragic results.5Possibly the most common reasons for poor control are that many patients either do not take treatment regularly or have poor inhaler technique. Asthma is characterised by persistent airways inflammation, although manifestations are at times subclinical. The evidence for ICS is for regular use, and non-adherent patients do not get into trials or are excluded as protocol violators. However, in ‘real life’, adherence problems are ubiquitous. Regular ICS protect against death,29 yet, it is likely that adherence would increase if the rationale was explained in a way they understood and assimilated. Self-management education,30 involving patients in decisions,31 simplified treatment regimes32 and discussion of non-adherence when detected 33 all improve adherence and outcomes. There is a growing interest in using IT to support self-management and education.34 To progress, we have to work in partnership with patients, respecting their autonomy and recognising that they will self-manage most of the time whatever we do. Our responsibility is to ensure that their decisions are based on good information.We encourage self-management, which is clearly necessary in a variable long-term condition. However, we fail to appreciate that non-adherence is also a form of self-management, although based on misunderstandings and inadequate information, and thus it is fundamentally a problem of inadequate patient–clinician communication. Some clinicians ‘blame’ patients for non-adherence, considering it irresponsible, a breach of the doctor–patient relationship and beyond their remit to remedy;35 Some inhalers are easier than others, and often the least expensive devices are hardest to use and teach.36 Ideally, all would be educated in inhaler technique by suitably qualified professionals when first prescribed, and checked at least annually and after loss of control. However, once again in ‘real life’ this does not happen frequently—some are never instructed, other than from printed packaging inserts, and many are not periodically reassessed and corrected.37 Indeed, some clinicians cannot demonstrate the correct technique themselves. It is incumbent on the prescriber to ensure correct technique, either personally or delegating to colleagues—for example, nurses or pharmacists.Correct inhaler technique is necessary for medication delivery and again the guideline evidence comes from fully trained patients demonstrating good technique. Unfortunately, in ‘real life’, many patients use their inhaler badly—most will make some errors and many make ‘critical errors’ that result in little or no medication delivery. It is unsurprising that there is a relationship between the number of errors and asthma control.39 although they are strongly correlated with psychosocial measures.40 Socioeconomic factors, multimorbidities and psychological state41 have a strong relationship with asthma outcomes of every type, and anxiety is the strongest independent predictor of the unpleasantness of breathlessness for a given degree of brochoconstriction.42 Symptoms, quality of life, health resource use, exacerbation frequency and even mortality are independently related to psychological state, with one study reporting psychiatric co-morbidity accounting for 29% of symptom variance.43As an incurable, life-long condition, asthma heavily affects well-being. Friends, colleagues and sometimes health professionals can fail to appreciate fully the impact asthma has on people’s lives. The recurrent and unpredictable experience of having to struggle to breathe is frightening and disturbing, and it can undermine well-being and stability. Those with other life stressors, such as co-morbidity, psychosocial disadvantage or with genetically or environmentally programmed lack of resilience, may experience symptoms as more distressing. All clinicians know that some patients cope better with illness than others. Some do well despite objectively severe asthma, whereas others have high symptom levels and multiple subjective problems despite apparently mild disease. Patient-reported outcomes, such as symptoms and quality of life, correlate poorly with ‘objective’ physiological and pathological parameters of disease control,37 and asthma-related quality of life correlates more closely with psychological and social status than lung function or treatment step.44 The underlying mechanisms probably relate to a variety of overlapping biological and behavioural factors. Functional neuroimaging has shown that brain structures mediating breathlessness are closely related anatomically and functionally to those processing emotions,45 and emotional state may influence immunological responses.46 Anxiety is associated with impaired self-management.47 Hyperventilation and dysfunctional breathing are associated with anxiety, occur in asthma and may trigger bronchoconstriction and asthma-like symptoms,48 with simple breathing control exercises improving symptoms and quality of life.49 A certain amount of anxiety is natural and inevitable with distressing symptoms, such as dyspnoea, and it can promote appropriate responses such as seeking help or using necessary medication, but excessive anxiety or inappropriate responses can result in a ‘negative feedback’ situation of worsening symptoms leading to further emotional and cognitive distress.Psychological dysfunction is six times as common in people with asthma,50 Assessing rescue bronchodilator use  is often revealing. Having uncovered poor control and risk, the next step is to understand why. Stepping up pharmacotherapy may be right for some patients, but addressing adherence, technique, rectifying self-management deficiencies and identifying co-morbidities  may be helpful in others. Simple behavioural techniques such as breathing exercises or anxiety management may help appropriately identified patients. For those needing increased treatment, better characterisation may lead to more rational and targeted treatment—for example, biomarker evidence of ongoing inflammation may point to the need for more effective anti-inflammatory treatment rather than increased bronchodilatation.51 Current guidelines provide a stepped approach for all patients as if they were similar, based on group mean data from clinical trials. However, responder analyses reveal remarkable heterogeneity of response to different treatments.52 The future lies in a stratified, individualised approach to asthma care;53 this is starting to occur at the severe end of the spectrum, but may be equally feasible and cost effective in wider asthma populations. We have a range of assessment options, including monitoring medication use, validated patient-reported outcome measures and simple, near-patient objective tests and a variety of treatment options  that we need to target appropriately. Having spent years dissecting asthma and unravelling its complexity, we now need to put this information together into coherent, patient-orientated personalised care.We need to get smarter in asthma. We do need new treatments, but we can do much better with what we already have. We require appropriately trained primary care professionals who are adequately resourced to provide quality asthma care. The first requirement is to detect poor control and risk. Unfortunately, patients may not volunteer how symptomatic they are, having grown accustomed to this over the years, and clinicians may not ask probing-enough questions. Structured reviews incorporating objective symptom assessment  will often uncover unmet need. Risk stratification to identify those at higher risk of attacks is feasible and can lead to better outcomes.Although asthma outcomes have stalled, we should use this as a spur to changing models of care rather than as a source of gloom. Our ever-increasing knowledge of the complexity and heterogeneity of asthma, together with a better understanding of how patient and clinician behaviour can be modified to make better use of the resources we do possess, allows us potential new avenues in care. It is unlikely in the foreseeable future that we can ‘cure’ asthma, but we should be able to characterise our patients better, in particular those who, for one reason or another, are not doing well, and for most there will be effective strategies for improving outcomes. However, the most effective intervention(s) will vary greatly between patients, and a ‘one size fits all’ approach will no longer suffice. As with other long-term conditions, we need to help our patients cope with the diverse consequences of having an illness that we can control but not take away.


We determined the influence of age on the effects of glucose and blood pressure control on diabetic kidney disease in patients with type 2 diabetes.2], were enrolled in this study between August 2001 and December 2002. All participants were followed up at our clinics until December 31, 2010. Primary outcomes were the development of end-stage renal disease (ESRD) and all-cause mortality. Secondary outcomes were the development of clinical albuminuria and a severe decline in eGFR.A total of 721 patients with type 2 diabetes, aged 41–85 years and with an estimated glomerular filtration rate (eGFR) ≥30 mL/ [min · 1.73 mDuring the follow-up period (median: 8.3 years), 27 (3.7%) patients developed ESRD, 130 (18.0%) patients died without developing ESRD, and 16 (2.2%) patients died after developing ESRD. Mortality rate increased with age, but the incidence rate of ESRD did not. Poor glucose and blood pressure control was associated with the development of clinical albuminuria and with a severe decline in eGFR in younger patients with diabetes, but not in older patients. The development of severe decline in eGFR and ESRD was significantly lower in the middle tertile of blood pressure  in older patients.Adequate glucose and blood pressure control did not reduce the risk of ESRD; however, it may have delayed the onset of clinical albuminuria as well as eGFR decline in younger patients with type 2 diabetes.The online version of this article (doi:10.1186/1758-5996-6-81) contains supplementary material, which is available to authorized users. Diabetic kidney disease is a major cause of morbidity and mortality in people with diabetes, and it is the single leading cause of end-stage renal disease (ESRD) in many countries. Approximately 37.2% of all prevalent ESRD cases and 43.3% of all new ESRD cases in the United States are currently attributed to diabetes. PopulatElderly patients with type 2 diabetes are associated with an increased risk of adverse outcomes, including ESRD and death. A number of factors potentially contribute to these outcomes including poor glycemic control, hypertension, dyslipidemia, and smoking, 10. The2], or with clinical albuminuria were also excluded. The remaining 721 patients were treated at our clinics, and were repeatedly examined until December 31, 2010. The flow diagram for the study is presented in the Figure A total of 777 patients with type 2 diabetes, who were regularly followed up at the Taipei Veterans General Hospital in Taiwan, initially provided informed consent for participating in this study. Baseline data were collected between August 2001 and December 2002. Serum Cr, fasting blood glucose, glycated hemoglobin (HbA1c), serum cholesterol, triglyceride, urine albumin, and urine Cr levels, as well as blood pressure were subsequently measured for all patients. Patients with cardiovascular disease, malignancy, or serum Cr levels >176 μmol/L, and those who were pregnant were excluded. Patients aged <40 years, aged >85 years, with an estimated glomerular filtration rate (eGFR) <30 mL/) and all-cause mortality. Secondary outcomes were the development of clinical albuminuria (UACR >30 mg/mmol creatinine) and a severe decline in eGFR (<30 mL/ [min · 1.73 m2]). If no event was reported, observations were censored to the last surveillance time for each patient and outcome. If an event was reported, the event time was recorded as the midpoint between the time of event discovery and the most recent surveillance time. Outcomes data were determined based on the period from baseline to December 31, 2010.Primary outcomes were the development of ESRD , using HLC-723 GHb IIIs  prior to May 2007 and HLC-723 G7  after May 2007. Both urine albumin and Cr levels were assessed using spot urine specimens collected early in the morning. Urinary albumin concentrations were measured by rate nephelometry . Urinary Cr concentrations were measured using a Hitachi 7600 automatic analyzer .2 test. In order to examine the influence of the interaction, between age on one hand and glycemic and blood pressure control on the other hand, on outcomes, we further divided study participants according to their mean HbA1c and systolic blood pressure (SBP) tertiles. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using multivariable Cox regression models, after adjusting for other baseline risk factors or potential confounders. For example, in order to compare glycemic control between different age groups, the results were not adjusted for age and HbA1c. Unadjusted incidence rates were calculated through dividing the number of participants with a given complication, by the total number of patient-years including the follow-up period; rates were reported as events per 1000 patient-years. Statistical significance was considered at P < 0.05.Statistical analyses were performed using IBM SPSS Statistics version 19.0 for Windows. Data were expressed as mean ± standard deviation, unless otherwise indicated. UACR and serum triglyceride level were expressed as median values with interquartile ranges (IQR), and analyzed using non-parametric tests. Continuous variables were analyzed via one-way analysis of variance (ANOVA). Non-continuous data were presented as percentages, and were analyzed using Pearson’s χ2, mean total cholesterol level was 5.13 ± 0.94 mmol/L, median triglyceride level was 1.91 mmol/L , mean serum Cr level was 99.9 ± 25.6 μmol/L, mean eGFR was 67.1 ± 17.5 mL/[min · 1.73 m2], and median UACR was 2.18 mg/mmol .The mean age of the 721 participants with type 2 diabetes was 67.6 years, and their mean duration of diabetes was 10.1 years. The mean HbA1c level was 7.90% ± 1.66%, mean BMI value was 25.5 ± 3.1 kg/mThese patients were divided into 4 age groups according to their age at recruitment: 41-60, 61-70, 71-75, and 76-85 years old in order to have similar number of patients in each group. The characteristics of the study population are presented in Table 2], 27 (3.7%) patients developed ESRD, and 146 (20.2%) patients died. In order to evaluate the effect of the interaction between age and diabetes control on kidney disease, we classified our subjects into 2 age groups: older patients aged 71–85 years, and younger patients aged 41–70 years.A total of 5002 patient-years were available for examining mortality rates and kidney outcomes during the follow-up period . Accordingly, 144 (20.0%) patients developed clinical albuminuria, 78 (10.8%) patients had an eGFR <30 mL/ ,  ESRD,  all-cause mortality of the 2 groups of subjects. (TIFF 55 KB)Additional file 1: Figure S1: Glycemic control and cumulative incidence of outcomes  clinical albuminuria,  eGFR <30 mL/[min · 1.73 m2],  ESRD,  all-cause mortality of the 2 groups of subjects. (TIFF 62 KB)Additional file 2: Figure S2: Blood pressure control and cumulative incidence of outcomes  clinical albuminuria,  eGFR <30 mL/[min · 1.73 m


P<0.05). A correlation analysis determined that the ratios of A/S, A/(S+D), AVTI/(SVTI+DVTI) were positively correlated with pulmonary artery mean pressure . An ROC curve analysis determined that the diagnostic effect of A/(S+D) was superior to the other two parameters. On the ROC curve, when the ratio of A/(S+D) was 0.30, the sensitivity was 85.37% and specificity was 75.00% for predicting PH. The spectral parameters of MHV, including the ratios of A/S, A/(S+D) and AVTI/(SVTI+DVTI), increased with increasing pulmonary pressure in CHD patients. When the ratio of A/(S+D) was 0.30 in MHV spectra, it had sufficient sensitivity and specificity for diagnosing PH, and this method could be used as a new non-invasive complementary echocardiographic parameter for predicting PH.The aim of this study was to analyze the changes of the middle hepatic vein (MHV) spectra in patients with pulmonary hypertension (PH) caused by congenital heart disease (CHD) and determine the proper parameters of MHV to predict PH. Eighty patients with CHD were included, whose pulmonary artery pressure was measured via right heart catheterization, and the MHV spectra were detected via echocardiography. The peak value of velocity (V) and velocity time integral (VTI) of the waves, including S wave, D wave and A wave, were measured at the end of inspiration. The values of the MHV parameters that were predictive of PH were evaluated and their cut-off points were determined. Compared with the control group, V of S wave (S), VTI of S wave (SVTI), V of D wave (D), VTI of D wave (DVTI) decreased and V of A wave (A), VTI of A wave (AVTI), A/S, AVTI/SVTI, A/(S+D), AVTI/ (SVTI+DVTI) increased in the PH group. These differences were statistically significant ( The estimated prevalence of congenital heart disease (CHD) is approximately 6–10 per 1,000 live births . BecauseIn patients with PH, the right atrial (RA) pressure is maintained at a high level during breathing and cardiac cycles because the blood flow to the right ventricle is limited. Then, the blood flows of the large veins that are connected to the RA are affected. An examination of the inferior vena cava (IVC) diameter and its change with respiration is the most commonly used technique to estimate RA pressure . HoweverThis study complied with the Declaration of Helsinki. All participants provided written informed consent and the Ethics Committee of the Fourth Military Medical University and General Hospital of Shenyang Military Area Command approved the conduct of this study.2) with CHD undergoing RHC and echocardiography between January 2012 and June 2013 were included in this study. The subjects included 35 cases of atrium septal defect (ASD), 22 cases of ventricular septal defect (VSD), 18 cases of patent ductus arteriosus (PDA) and 5 cases of VSD combined with PDA. All the included patients had no history or clinical symptoms of liver disease and had normal liver function as determined via serology analysis. Patients with arrhythmias, pericardial effusion (moderate and severe) were excluded from the study.80 consecutive patients  male gender, BMI 21.65±2.85 kg/mRHC was performed in the cardiac catheter laboratory under radiographic guidance  immediately after echocardiography. RHC was performed by placing a triple-lumen, a polygraph recorder  and a right cardiac catheter  through the femoral vein to measure the pressure of the RA, right ventricle and pulmonary artery. Then SPAP, MPAP and diastolic pulmonary artery pressure (DPAP) were recorded.The subjects were studied using a Phillips iE33 ultrasound device equipped with an S5-1 transducer operating at 2.5–3.5 MHz or a GE Vivid E9 ultrasound device equipped with an M5S transducer operating at 2.0–4.5 MHz. An electrocardiogram was recorded simultaneously in all subjects.In all patients who had fasted for 8 hours, a gray-scale B-mode evaluation of the liver was first performed, followed by color and spectral Doppler evaluation, using the intercostal or subcostal approaches. The Doppler gate was placed in non-forced end inspiration so that it would sample the MHV 2–4 cm from the orifice of the IVC . The Dopt-test was used to compare variables between the PH group and control group. Correlations were examined via Pearson bivariate correlations. The comparison of the parameters and the selection of the cut-off point for PH diagnosis were tested using a receiver operator characteristic curve (ROC curve). A value of P<0.05 was regarded as statistically significant and P<0.01 was considered extremely statistically significant.Statistical analysis was performed using SPSS version 16.0 . Continuous data are expressed as the mean ± standard deviation (SD). The independent samples P<0.001, A total of 80 patients were enrolled in the study. 28 cases were in the control group, and the others were in the PH group based on the diagnostic criteria (MPAP ≥ 25 mmHg). Between the patients of the two groups, there were no significant differences in demographics, such as age, sex, heart rate or body mass index (BMI) . The RHCIn the control group, there were 18 patients with four-phasic waves , and 10 patients with tri-phasic waves  . In the P<0.05). The PH group also had a lower value of S, SVTI, D, DVTI compared with the control group (P<0.05)  and AVTI/(SVTI+DVTI) ((P<0.05) , Fig. 2.r = 0.529, P<0.001), A/(S+D)  and AVTI/(SVTI+DVTI)  .There were correlations between MPAP and A/S (P<0.001) , Fig. 5.The ROC curve determined that the ratio of A/(S+D) had the largest area under curve (AUC) (A/(S+D) 0.84 vs. A/S 0.81 vs. AVTI/(SVTI+DVTI) 0.70). A cut-off value of A/(S+D) = 0.30 had a sensitivity and specificity of 85.37% and 75.00%, respectively, for the prediction of elevated MPAP .Our results demonstrated that the hemodynamic changes of the MHV were characteristic in CHD patients with PH and that the observation of MHV spectral indicators could provide a reference for PH diagnosis.The morphology and flow velocity of the MHV is related to RA pressure, IVC pressure, the flexibility of the liver parenchyma and pressure changes in the abdominal and thoracic cavity caused by breathing. When the impact of liver disease and breathing had been excluded, the RA pressure directly affected IVC pressure; therefore, it played a decisive role on changing the MHV spectra.The Doppler flow spectra of MHV is primarily composed of two distinct forward systolic and diastolic waves (S wave and D wave) during ventricular systole and early diastole, and two small reverse flow during late ventricular systole and atrial systole (V wave and A wave). It is described as four-phasic waveform. However, the V wave is transitional, which may be antegrade, retrograde, or neutral . HealthyThe ultrasound showed a bi-phasic waveform in 9 patients with PH. In 11 out of total 52 patients with PH, the D wave was not available. The prolongation of the right heart isovolumic relaxation time (IVRT) in PH patients led to a delay in tricuspid valve opening, which delayed the onset of diastole in the right heart. The Doppler spectra of hepatic veins revealed a blunted or absent diastolic velocity (D wave). The absence of the D wave strongly suggested the presence of significant PH, specifically when other echocardiographic PH findings were absent or uninformative .In the PH group, two patients had mono-phasic Doppler waveform without a retrograde flow phase in the MHV. There were no patients with cirrhosis as determined via serology analysis and ultrasound check in all the subjects. The mono-phasic waveform reflected an increased stiffness of the liver parenchyma around the liver veins , and a dAlong with the increasing of RA pressure, the flow reversed to vena cava in right atrial systole. In the spectra waveform of MHV, it showed as a reverse A wave. In the PH group, the RA pressure had a further elevation, which leading to a trend of increasing of the reverse flow. The velocity (V) and volume (VTI) of A wave increased along with the increasing of RA pressure. The spectral data of tri-phasic waves demonstrated that A and AVTI increased in the PH group and these differences were statistically significant in the severe group. Zhang-An et al  reportedIn ventricular systole and early diastole, the increased PAP and RV pressure hindered the venous returning to RA (S wave and D wave), resulting in the decreases of blood flow in velocity (V) and volume (VTI). Our results also demonstrated the reduction of venous velocity towards the heart. The velocity and VTI of the S wave and D wave decreased in the PH group and these differences were statistically significant in the severe group. In a study by Zhang LZ et al  in 28 CHr = 0.706, 0.651, P<0.01). Zhang-An et al [Due to the changes of the A wave, S wave and D wave, the ratios of A/S, A/(S+D) and AVTI/(SVTI+DVTI) would be even more sensitive indicators to evaluate PH. The spectral data of the tri-phasic waves demonstrated that all three ratios were correlated with MPAP. Zhang LZ  reportedAn et al  also notTR is a common complication in patients with PH. There were 9 patients (11.25%) without TR, and one of them was from the control group. Er F et al  found thHowever, TR can also influence the hemodynamic parameters of the returning venous. During systole the RA pressure suddenly increases, which is caused by TR flowing into the RA. This process could decrease the flow of the S wave, as well as interrupt or even reverse the S wave . There wSonographer and patient factors both affected the appearance of the hepatic vein spectral Doppler waveform. Scheinfeld MH et al  proved tFirst, the Doppler and RHC studies were not simultaneous, although the delay between the two examinations was always less than one day and there was no change in the clinical condition or treatment between the two studies. Second, all subjects included in this research were CHD patients with left to right shunts. It is necessary to examine larger samples and different diseases in future research to verify our results.We concluded that MHV hemodynamic changes could be a useful method for evaluating PH. This method could counteract the weakness of the currently used diagnostic methods and improve the accuracy of assessing PAP when combined with other methods.


Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage renal disease and a common pathologic diagnosis of idiopathic nephrotic syndrome (NS), especially in steroid-resistant cases. FSGS is known to recur after kidney transplantation, frequently followed by graft loss. However, not all patients with FSGS suffer from recurrence after kidney transplantation, and genetic and secondary FSGS have a negligible risk of recurrence. Furthermore, many cases of recurrence achieve remission with the current management of recurrence , and other promising agents are being evaluated. Therefore, a pathologic diagnosis of FSGS itself should not cause postponement of allograft kidney transplantation. For patients with a high risk of recurrence who presented with classical symptoms of NS, that is, severe edema, proteinuria, and hypoalbuminemia, close monitoring of proteinuria is necessary, followed by immediate, intensive treatment for recurrence. Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage renal disease (ESRD). In children, the major causes of ESRD are congenital anomalies of the kidney and urinary tract and hereditary nephropathies, followed by FSGS as the most common form of acquired glomerulopathies causing ESRD , 2. FSGSThe reported rates of recurrence are quite variable, from 6 to 58%, depending on the characteristics of the population studied –14. The  NPHS2 mutation is the dominant cause of genetic FSGS in European countries, but it is rare in Koreans and the Japanese [ COQ6 [ NUP107 [First, there are several genetic defects that cause FSGS –33, and Japanese , 34–36. Japanese  and is tJapanese –40. Somee [ COQ6  ” causing FSGS , these f2 up to 6 doses or a single dose of 100 mg [2 rituximab have been satisfactory in achieving sustained complete remission in our practice  and mecf 100 mg ) of thispractice .α treatment [α mRNA in patients with FSGS [There are several promising therapeutic agents that are awaiting validation. Cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin fusion protein  has been tested on the basis that B7-1 (CD80) induction on podocytes plays an important role in the pathogenesis of proteinuria  and coulreatment  (based oith FSGS ), adrenoith FSGS , and allith FSGS , 79.An important point is that treatment failure on native kidneys does not predict treatment failure for posttransplantation recurrence of FSGS. Why? For recurrent FSGS after transplantation, we start treatment almost immediately, before the formation of sclerosis. This implies that delays in treating the native kidney lead to treatment failure, resulting in progressive renal damage. Therefore, if we are equipped with reliable biomarkers that indicate which medications will be effective in specific patients at the time of NS diagnosis, we will be able to tailor the treatment of pediatric NS, thus applying “precision medicine” to these patients.2) along with immunosuppression of corticosteroid, calcineurin inhibitor, and mycophenolate mofetil for two weeks prior to kidney transplantation was shown to prevent recurrence [While any discussion of preventive treatments efficacy is futile because we do not know whether subjects will experience recurrence after transplantation, patients who had lost their previous allograft to recurrence of FSGS have particularly high risk of recurrence , 18, 22.currence , 84.Recurrence after kidney transplantation is devastating for patients and families. However, the outcomes of recurrent FSGS are quite good with the current management strategy; therefore, the pathologic diagnosis of FSGS itself should not be a cause for postponing allograft kidney transplantation. For patients with a high risk of recurrence, close monitoring of proteinuria as suggested by the Kidney Disease: Improving Global Outcomes guidelines for the management of kidney transplant recipients  is neces


Although a variety of non-invasive methods for measuring cardiovascular (CV) risk , coronary artery and aortic calcification scores (measured either by CT scan or X-ray) and the ankle brachial index (ABI)) have been evaluated separately in chronic kidney disease (CKD) cohorts, few studies have evaluated these methods simultaneously. Here, we looked at whether the addition of non-invasive methods to traditional risk factors (TRFs) improves prediction of the CV risk in patients at different CKD stages.We performed a prospective, observational study of the relationship between the outputs of non-invasive measurement methods on one hand and mortality and CV outcomes in 143 patients at different CKD stages on the other. During the follow-up period, 44 patients died and 30 CV events were recorded. We used Cox models to calculate the relative risk for outcomes. To assess the putative clinical value of each method, we also determined the categorical net reclassification improvement (NRI) and the integrated discrimination improvement.Vascular calcification, PWV and ABI predicted all-cause mortality and CV events in univariate analyses. However, after adjustment for TRFs, only aortic and coronary artery calcification scores were found to be significant, independent variables. Moreover, the addition of coronary artery calcification scores to TRFs improved the specificity of prediction by 20%.The addition of vascular calcification scores  to TRFs appears to improve CV risk assessment in a CKD population. Cardiovascular disease (CVD) has become a major cause of morbidity and a leading contributor to mortality . In the Chronic kidney disease (CKD) is associated with a high incidence of cardiovascular (CV) mortality . Indeed,Comité de Protection des Personnes Nord-Ouest II, approval number 06H3) and written, informed consent was provided from all participants, in line with the tenets of the Declaration of Helsinki.Over an 18-month period (from January 2006 to June 2007), 143 patients at various stages of CKD were recruited by the Nephrology Department at Amiens Hospital . The present study was approved by the local investigational review board  at a 3– to 6–month interval [The inclusion criteria included age over 40, close monitoring by a nephrologist, and CKD, as defined by (i) two estimated glomerular filtration rates < 90 ml/min per 1.73 minterval  or (ii) The main exclusion criteria were the presence of chronic inflammatory disease, atrial fibrillation, complete heart block, abdominal aorta aneurysm, an aortic and/or femoral artery prosthesis, primary hyperparathyroidism, kidney transplantation or any acute CV event in the three months prior to screening.One hundred and forty-three patients were day-hospitalized for research purposes: laboratory blood tests, blood pressure measurements, IMT, PWV, and ABI determinations, a lateral lumbar X-ray and a multislice spiral computed tomography (CT) scan .Hemodialysis patients were examined on a dialysis-free day or, if this was not possible, the morning before a dialysis session. These patients underwent a four-hour, standard hemodialysis session three times a week. A patient interview focused on comorbidities, the disease history , concomitant medications, and TRFs . The patient’s medical files were reviewed in order to gather more exhaustive information. Previous CVD was defined as a history of any of the following events in the patient's medical records: myocardial infarction, stroke, heart failure, angina pectoris or surgical procedures for angina or coronary/peripheral artery disease . Hypertension was defined as treatment with at least one antihypertensive agent. Diabetes mellitus was defined as treatment with insulin or oral antidiabetic medications.Blood samples were collected on the morning of the study day (before any other investigations), prepared and then stored at -80°C. All assays were performed on subsequently thawed plasma or serum samples.2 vitamin D levels were determined in an RIA . Serum cystatin C (Cys C) levels were determined by immunonephelometry  and serum creatinine (Scr) levels were measured using the Jaffe method based on standard isotope-dilution mass spectrometry (IDMS). The Chronic Kidney Disease Epidemiology Collaboration equation was then used to calculate a more accurate estimate of the glomerular filtration rate in all non-dialyzed patients [-0.62 x Cys C-0.57 x age-0.20 x . Next, patients were classified into CKD stages according to the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative [Serum total calcium, phosphate, albumin, LDL cholesterol, hemoglobin, creatinine and C-reactive protein levels were measured in an on-site biochemistry laboratory with standard auto-analyzer techniques . The laboratory's normative range of phosphate concentrations was 0.8–1.45 mmol/l. Serum intact parathyroid hormone and 25 hydroxyvitamin D levels were assayed with a chemiluminometric immunoassay . Serum 1.25 (OH)patients : 177.6 xitiative .The IMT was measured semi-automatically from carotid ultrasound data using dedicated software . All measurements were performed by the same sonographer. Using an automated edge detection algorithm, the IMT was measured along a 10 mm-long segment of the far wall of the common carotid artery  and corresponded to the distance between the lumen-intima interface and the media-adventitia interface. A mean of 50 measurements were automatically performed on each image (two images per body side) and on each body side (left and right). The greatest measured values for the right and left CCA-IMTs were used in the analysis. Data on reproducibility have been previously published by our group; the correlation coefficient for repeated readings of the CCA-IMT was 0.96 .The PWV between the carotid and femoral arteries was determined transcutaneously by trained physicians, using an automatic, dedicated, validated device , as previously described , 24. TheThe ABI was calculated after the participant had rested in the supine position for 5 minutes. A hand-held Doppler probe was used to measure the systolic pressures at the right brachial artery, right posterior tibial artery, left posterior tibial artery and left brachial artery (in that order). According to a previously validated method, the ABI was calculated as the ratio of brachial to ankle artery pressure for each leg. The lower of the two values was subsequently analyzed .A technique similar to that described by Kauppila et al.  was usedIn order to quantify the presence and extent of aortic and coronary artery calcifications, each patient underwent a multislice spiral CT scan. All examinations were performed with a 64-detector CT scanner . Detailed technical information on the procedure has been provided elsewhere. BrieflyPatients were followed up prospectively for the occurrence of non-fatal CV events or all-cause death (whichever occurred first). A total of 64 events (composite endpoints) were analyzed. Cardiovascular-related hospitalizations and deaths were collected prospectively every six months and adjudicated by two nephrologists. In each case, the patient's medical records were reviewed and the cause of death or the CV event was assigned on the basis of all the available clinical information. For out-of-hospital deaths, the patient’s family doctor was interviewed to obtain pertinent information on the cause. The following criteria were used for the adjudication: angina pectoris was defined as symptoms with objective evidence of ischemia (electrocardiogram or coronary artery angiography); adjudication as congestive heart failure had to be supported by a physician's diagnosis or treatment for heart failure, pulmonary congestion or cardiac dysfunction.Cardiovascular mortality was defined as any death directly to CV system dysfunction . Non-fatal CV events were defined as systemic CV dysfunction  or surgical procedures for angina or coronary/peripheral artery disease. When several events occurred in the same patient, only the time to the first event was considered in our analysis.Data were expressed as the mean ± SD, median and range or frequency, as appropriate. In the study population, patients were stratified according to the presence or absence of events. Intergroup comparisons were performed with a chi-squared test for categorical variables and Student’s t test or the Mann-Whitney test for continuous variables. The Kaplan-Meier method was used to estimate percentage survival as a function of the presence or absence of the composite factor (a CV event or death). Survival curves were compared in a log-rank test. Putative associations between clinical factors, biological factors and mortality were assessed in univariate and multivariate Cox models. The proportional hazard assumption was checked with the Kolmogorov-type supremum test. In the multivariate analysis, the initial model included TRFs only: age, gender, diabetes, triglyceride level, hypertension, and smoking status. In the additional models (Models 2 to 7), the TRFs were supplemented with the various non-invasive measurements. The discriminant ability of the seven Cox models was assessed with Harrell’s C-index , which eThe threshold for statistical significance was set to p≤0.05. All statistical analyses were performed using SPSS software  for Windows  and SAS software .2 vitamin D and 25 (OH) vitamin D levels (relative to event-free patients). Moreover, patients with events had higher aortic and coronary artery calcification scores (according to CT and X-ray data) and IMT and PWV values than event-free patients. There was no significance difference between the two groups in terms of the ABI or concomitant treatments. We observed a significant, linear relationship between the aortic calcification score  and the aortic calcification score  (p<0.0001)  are summarized in <0.0001) . All non<0.0001) .During the follow-up period (mean duration: 873 ± 393 days), 44 patients died  and 30 patients had CV events leading to 64 composite endpoints for analysis. In a crude analysis , a high The various Cox regression models  confirmeThe adjusted Cox models' respective abilities to predict outcome with the different non-invasive methods are presented in The NRI was calculated in order to assess the putative clinical utility of the aortic calcification score  and the coronary artery calcification score as markers of CV risk when combined with TRFs . A signiAt present, only TRFs are routinely evaluated as predictors of CV events, CV mortality and all-cause mortality. Some studies have shown that addition of a non-invasive measurement to these TRFs improves the predictive value in the general population and in CKD patients , 32, 33.It is noteworthy that in our study population, the IMT and PWV did not have predictive value for CVD events and mortality–even after adjustment for TRFs . The X-ray-based evaluation of aortic calcification is a relative simple tool and could be easily performed routinely in CKD populations. Matsushita et al. evaluated a number of methods  likely to improve CV risk prediction in 6553 multi-ethnic participants (including subjects with CKD) . In Cox Our study had some limitations, including the relatively small cohort size, the relatively small number of CV events and deaths and the lack of data on proteinuria. However, we used composite criteria to overcome this limitation. In contrast, the study's main strength relates to the simultaneous use of several methods to evaluate atherosclerosis/arteriosclerosis.In conclusion, we have highlighted a simple, non-invasive diagnostic tool that may be capable of improving CV risk assessment  in patients with CKD. Patients with high vascular calcification scores  can be considered as having the highest CV risk. However, the present results should be confirmed in larger cohorts.