The NIRS probe emits light with several wavelengths in the 700- to 850-nm interval and measures the reflected light mainly from a predefined depth. Complex physical models then allow the measurement of the relative concentrations of oxy and deoxyhemoglobin, and thus tissue saturation (StO2), as well as an approximation of the tissue hemoglobin, given as tissue hemoglobin index.Near infrared spectroscopy of the thenar eminence  with a pressure cuff can be used to provide a dynamic assessment of the tissue oxygenation response to ischemia. StO2 changes during such induced ischemia-reperfusion yield information on oxygen consumption and microvasculatory reactivity. Some evidence suggests that StO2 during VOT can detect fluid responsiveness during surgery. In hypovolemic shock, StO2 can help to predict outcome, but not in septic shock. In contrast, NIRS parameters during VOT increase the diagnostic and prognostic accuracy in both hypovolemic and septic shock. Minimal data are available on static or dynamic StO2 used to guide therapy.We found that NIRSth can become part of routine clinical practice.Although the available data are promising, further studies are necessary before NIRS Invasive monitoring of systemic DO2 and VO2 has been used in intensive care medicine for decades [Oxygen delivery .Although the concept of NIRS has already been available during the second half of the 20analysis ,6. Sinceanalysis , numerouanalysis ,9. NIRS culation . Some NIculation . More reth remains a relatively new method in a field where no “gold standards” exist. Thus, clinicians considering the use of NIRSth need to understand the principles and evidence behind it and appreciate the many areas of uncertainty that surround its application. In this review, we assess several of these aspects and suggest studies to address areas of controversy.Clinical application of NIRSThe principle of clinical NIRS is to noninvasively measure the attenuation of light by hemoglobin, where the emitted light is in a wavelength range longer than visible light ,13. NIRSThe near infrared (NIR) light spectrum ranges from 700 nm to 1000 nm. For clinical applications of NIRS, wavelengths approximately 700 to 850 nm are used. The interval stretches on either side of the isobestic point of hemoglobin, i.e., a given wavelength where absorption of light for oxy and deoxyhemoglobin is identical. This wavelength interval maximizes the difference between oxy and deoxyhemoglobin and minimizes the influence of other chromophores, such as myoglobin, cytochrome oxidase, melanin, and bilirubin, on the measurements . FortunaNIRS technology is based on sophisticated physical models, which are greatly simplified in the description below. The attenuation of light in a sample or tissue is proportional to the pathlength of the light and the absorption coefficient of the chromophore according to the physical principles referred to in the Lambert-Beer law . The absBecause the absorption coefficient is direct proportional to concentrations of a chromophore in a tissue studied and extinction coefficient of the compound is constant, estimating the absorption coefficient yields approximations of the absolute chromophore concentration. This is possible through advanced modeling of the behavior of NIR light in tissues and the technical possibility of measuring at several NIR wavelengths . Yet, giThe NIRS probes in current use measure reflected light. Thus, the NIR light source is placed beside the light sensor. The distance between the light source and sensor determine the distance from where the main part of the reflected light is measured. The technical limit of the monitored depth is the energy of light that does not damage tissues . The mai2) measurement even in obese and critically ill patients [The brain , kidney patients . Due to 2. Because absolute hemoglobin content also can be estimated, total tissue hemoglobin and its absolute changes are expressed as tissue hemoglobin index (THI), which can be obtained with this method. THI is, however, not total tissue hemoglobin but its approximation, based on the signal strength of hemoglobin in the monitored area. Low StO2 and THI are common findings in hypovolemic shock states.Assessing the ratio of oxy and deoxyhemoglobin in the monitored tissue gives continuous StO2 and postischemic reperfusion and hyperemia. This, vascular occlusion test (VOT), is of special interest in septic shock [By occluding the arterial  or the vic shock ,31 or duic shock  where th2  after vascular obstruction can be used to estimate VO2 in the thenar muscles. The product of the absolute value of Rdes and mean THI value quantifies the amount of desaturated hemoglobin [2 using the hemoglobin-oxygen binding constant [The rate of desaturation in the thenar muscles . During this reactive hyperemia, the StO2 increases over baseline levels, indicating postischemic vasodilatation and capillary recruitment. The integral of the post reoxygenation StO2 curve over baseline quantifies reactive hyperemia.In addition, after cuff deflation there is a swift restoration of blood flow that can be described in terms of the derivate of the StOdes, Rres, and reactive hyperemia were all lower in septic shock patients than in healthy controls [res had an inverse relationship to sequential organ failure assessment (SOFA) and predicted mortality. Finally, a coefficient of variation of less than 10% has been reported for Rres[The VOT derived variables add to the robustness of NIRS measurements. In a small study, Rcontrols . Moreove for Rres.2. The venous occlusion method also can be used to estimate local VO2. Some have reported varying reproducibility of VO2 measurements with venous occlusion [Venous occlusion is performed by inflating a pneumatic cuff above venous pressure on the arm . In thiscclusion .th during the perioperative period. However, in a recent publication Rres, measured in patients undergoing major abdominal surgery patients, was decreased in fluid responsive patients [Although there is an extensive literature on NIRS used before , during patients . In the th to detect blood loss, an area of central interest in anesthesia. In awake volunteers, a 500-ml blood loss at blood donation did not lead to changes in NIRS variables [2 and THI [Data are conflicting on the ability of NIRSariables . On the  and THI . A possi2 and THI did not correlate with global circulatory parameters, but changes in body-finger temperature correlated with changes in StO2[2 during the perioperative period in cardiac surgery is lower in patients who develop certain postoperative complications [2 at the thenar eminence does not predict mortality in cardiac surgery [In patients after cardiac surgery, StOs in StO2. Howeverications  than thoications . StO2 at surgery  or surgi surgery .2 and Rres appear related to capillary refill time and central to peripheral temperature gradient, but not to the etiology of shock [2 (<70%) on admission. There was no difference in systemic circulatory variables between patients with low or normal StO2, but SOFA scores and acute physiology and chronic health evaluation II scores were higher in patients with decreased StO2. However, blood transfusion substantially increasing blood hemoglobin did not increase StO2 in a mixed group of stable patients [In a general intensive care population with most patients in resuscitated shock, StOof shock . In a miof shock , half hapatients  and the patients ,55. In pth may thus act as a sensor of the vascular response to hypovolemia. In trauma patients with severe shock, StO2 is lower in than in milder grades of shock or in normal individuals [2 values as in controls [The rationale for monitoring peripheral tissue as the thenar eminence in hypovolemic shock is centralization of circulation to vital organs leading to decreased blood flow in muscles . In acutividuals , althougcontrols .2 range overlapped during and after hemorrhage, but StO2 increased after control of bleeding [2 in the trauma bay has been shown to be as good as the lowest systolic blood pressure at identifying severe shock as defined by experienced clinicians [2 within 1 hour of admission is lower in trauma patients who develop multiorgan dysfunction (MODS) or die, and a strongest predictor of MODS or death than other diagnostic modalities [2 within 1 hour of admission was as sensitive as a high base deficit in identifying patients who developed MODS or died, although specificity for both was low [2 within 1 hour of admission identifies trauma patients who will require blood transfusion within the next 24 hours [In a study of severe postpartum hemorrhage, the StObleeding . The lowinicians . Furtherdalities ,61. Low  was low . Finally24 hours .dynamic NIRS parameters, however, is of greater interest. Rres was lower in trauma patients compared with controls with little overlap [res predicted increased troponin I levels in postpartum bleeding [2 predict adverse outcome but dynamic NIRS parameters seem to be more promising.The discriminatory power of  overlap . Moreovebleeding . Thus, i2, but rather by low Rres and impaired postischemic hyperemic response.In septic shock, although hypovolemia can be a finding , there i2 between healthy subjects and patients with severe sepsis or septic shock [2 values overlap between septic shock patients and healthy volunteers. This is not surprising because, in sepsis, StO2 in sepsis can be at the higher end of the normal spectrum or markedly low [des of the thenar muscles is slower in septic shock patients, indicating a lower rate of tissue VO2[des varies with the severity of systemic infections [res appears lower in septic patients compared with healthy controls [res ranges overlap minimally [res improves as septic shock resolves [th could be a method for bedside assessment of the microcirculation [Several studies report a difference in StOic shock ,34,66,67ic shock ,68,69. Aedly low . Dynamicissue VO2,31,68,69controls ,31,34,70controls ,31. Rresinimally ,68,70 orresolves ,31. Thusculation .th also has attracted interest. In sepsis, treatment based on venous saturation in the superior vena cava (ScvO2) [2) [2 and VO2 balance [2 or SvO2 would be valuable. In this regard, StO2 correlates to ScvO2[2[2 could be substantially improved by calculating the “NIRS-derived SvO2” [2, however, did not estimate SvO2[2 also have low ScvO2, suggesting hypodynamic circulation [Monitoring global hemodynamics with NIRS (ScvO2)  or the pvO2) [2)  is used, balance . Noninva to ScvO2 and SvO2o ScvO2[2 in patieed SvO2” . In sevemate SvO2. Still, culation .2 may correlate with NIRS parameters. Rres correlates with cardiac output and to a lesser extent with blood lactate levels in septic patients [2 does not correlate with lactate or base deficit [2 predicts a very low DO2 in early sepsis with high sensitivity and specificity [2 does not correlate with StO2. Neither was change in Rres correlated to change in cardiac output in septic patients. Finally, StO2 did not correlate with the severity of illness [2 <78% in resuscitated patients predicted mortality [res correlates with organ failure [res is lower in nonsurvivors than survivors [Variables related to DOpatients , whereas deficit . A low Scificity ; however illness , but a Sortality . Low Rre failure  and Rresurvivors .res[Recently, it has been reported that increasing blood pressure with noradrenalin infusion from 65 mmHg to 85 mmHg in resuscitated sepsis patients normalized Rres. These pres. These dres. Thus, i2, Rdes, and Rres are low [th parameters in these patients improved after 6 hours of dobutamine or levosimendan infusion [In patients with chronic heart failure, thenar StO are low . NIRSth infusion , or 3 moinfusion . Patientinfusion , which iinfusion .th in estimating global circulatory parameters is highly dependent on the coupling between the circulation of the hand and the central circulation. Static NIRS parameters, such as StO2, should, in theory, be related to centrally measured circulatory parameters. However, this relationship has not been demonstrated in general in critically ill patients [2 in sepsis, this relationship is weak [2 and SvO2 can be improved with correction equations [2 levels are detected reliably by StO2 in sepsis [res correlates with cardiac index and blood lactate levels [The performance of NIRSpatients  or afterpatients . Althoug is weak ,74,83. Iquations . Only sun sepsis . In these levels .2 also predicts MODS in a mixed population of critically ill patients [des[res[Low StOpatients , in traupatients -62, and patients . In sepsents [des and Rres [des[res,34, haveth monitors peripheral muscle as a marker of perfusion elsewhere. The theoretical concern is whether the small volume of distal muscle can be a good indicator of the state of the tissue oxygenation in the rest of the body and the vital organs. For example, local factors, such as obstruction to flow by atherosclerosis, an arterial catheter, or thrombosis after previous arterial catheterization, could affect measurement. Although a brief report suggests that catheterization of the radial artery in adult, elective, surgical patients does not affect StO2[NIRSfect StO2, this ma2 is not the same as tissue blood flow in the tissue or even oxygen supply. StO2 is affected by local VO2, which could be affected by states that alter muscle metabolism, such as muscle relaxants. The balance between the metabolic state of the muscle and other vital organs may vary between individuals and intraindividually during the course of disease, affecting the global relevance of some of the NIRS variables. Also tissues overlaying the thenar muscles can influence measurements [StOurements . Very daurements .2 curves at vascular occlusion are used in calculations. Furthermore, studies are conducted on patients in different phases of disease, which may represent different pathophysiologic situations. Hence, comparing results can be difficult (Table There are many studies on NIRS in the perioperative period and critical illness where many different sites are monitored. Moreover, the methodology of NIRS is not standardized ,88. Sevelt Table .2 would be expected to be less affected by peripheral vascular tone.Static NIRS variables are influenced by the temperature of the hands compared with core temperature  and coul2[2, Rdes, could imply mitochondrial dysfunction. However, decreased tissue VO2 also could depend on shunting of delivered oxygen [th is a noninvasive method that, given that supporting data will be available, could become part of anesthetic and intensive care monitoring in a manner similar to pulse oximetry.The question of whether organ failure in sepsis is mostly dependent on disturbed mitochondrial oxygen metabolism -92, or o2,94, is ad oxygen . This phth eminence estimates StO2 in peripheral muscles. In hypovolemia, such StO2 is decreased and relates to severity of disease and outcome. Hence, StO2 measurements could aid with the clinical management of these patients. In unresuscitated or inadequately resuscitated septic shock, Rdes and Rres are decreased, indicating disturbed tissue oxygen metabolism and microvascular reserve. The pathologic findings in these dynamic NIRS parameters could be of value in resuscitated sepsis where macrocirculatory failure has been corrected and during anesthesia to monitor adequacy of peripheral perfusion and fluid status. Despite its limitations, NIRSth takes monitoring from global to local level. The existing literature on NIRSth is mainly focused on validation of this technique. Future studies that implement NIRSth into treatment algorithms in anesthesia and intensive care would be valuable to define the place for this monitoring modality in daily management of critically ill patients.Conclusions NIRSThe authors declare that they have no competing interests.All authors conceived the manuscript. Both ML and NCZW reviewed the literature. ML wrote the first draft. RB reviewed and refined the first draft. Further drafts were completed by ML, RB and NCZW. All authors read and approved the final manuscript.


The relation between primary hypertension (PH), target organ damage (TOD) and oxidative stress (SOX) is not known.We assessed SOX in 86 children with PH before and after 12 months of standard non-pharmacological and pharmacological therapy based on renin-angiotensin system blockade.Patients with left ventricular hypertrophy (LVH) and with carotid intima-media thickness (cIMT) >2SDS had higher thiobarbituric acid reactive substances (TBARS) concentrations in comparison to patients without LVH or with normal cIMT. Patients with metabolic syndrome (MS) had lower activity of gluthatione peroxidase, higher asymmetric dimethyloarginine (ADMA) and oxidized LDL cholesterol (oxyLDL) in comparison to patients without MS. TBARS correlated with left ventricular concentric hypertrophy, cIMT, albuminuria and SBP/24 h. ADMA and oxyLDL correlated with CRP and TG/HDL ratio. After 1 year of antihypertensive treatment blood pressure, TOD and prevalence of MS decreased. TBARS decreased and glutathione concentrations increased. The decrease of TBARS concentration correlated with the decrease of body mass index (BMI). Decrease of oxyLDL and ADMA correlated with increased insulin sensitivity, however markers of SOX did not correlate with BP decrease.SOX in children with PH correlates with TOD, metabolic abnormalities, changes in fat amount and improvement of insulin sensitivity, but not with BP decrease. Primary hypertension (PH) is considered as a state of oxidative stress (SOX) that contributes to the development of arterio- and atherosclerosis and target organ damage (TOD) –4. AbnorOn the other hand, increased physical activity as a standard non-pharmacological intervention in hypertensive patients led to decreased reactive oxygen species generation, improved nitric oxide bioavailability and vascular function , 15. SomWe hypothesized that SOX correlates with severity of PH, metabolic abnormalities and TOD in children with PH. Secondly, standard antihypertensive treatment based on non-pharmacological intervention and blockade of RAAS causes a decrease of SOX, which in turn correlates with normalization of metabolic abnormalities and regression of TOD. To test this hypothesis we assessed changes of SOX markers in relation to TOD in children with PH before and after 12 months of standard non-pharmacological and pharmacological therapy based on ACEi or ARB.The study adhered to the principles of the Declaration of Helsinki and was approved by the local Ethical Committee. All parents and children aged above 12 years of age provided written informed consent.Detailed characteristics of the study group have been described previously , 21. Speth percentile and SBP load between 25 and 50 %, and severe ambulatory hypertension was defined as mean ambulatory SBP above 95th percentile and SBP load above 50 %. Normotension was defined as mean ambulatory SBP below 95th percentile and SBP load below 25 %. Prehypertension was defined as mean SBP below 95th percentile and SBP load in the range 25 – 50 % [In all patients the diagnosis was confirmed by 24 hour ambulatory blood pressure monitoring (ABPM). ABPM was performed at the initial visit and after 12 months. Recordings lasting at least 20 hours with at least 80 % of records were considered as valid. We used the referential ABPM normative values published recently to classify patients as having normal blood pressure, prehypertension, ambulatory hypertension or severe ambulatory hypertension . PatientIn all patients anthropometrical parameters, including body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHTR) were measured. Obesity and being overweight were diagnosed according to International Obesity Task Force (IOTF) recommendations .Blood samples were taken after 12 hours of fasting and were immediately sent to the laboratory. Plasma lipid peroxides were determined with the spectrofluorometric method of Yagi, and results expressed as concentration of thiobarbiturate reactive substance (TBARS). Glutathione and glutathione peroxidase activity were used as indicators of antioxidant status and were measured spectrophotometrically in erythrocytes (GSH-420(Oxis) and GPx-340(Oxis)). Concentration of oxyLDL and asymmetric dimethyloarginine (ADMA) were measured by ELISA using a commercially available kit.Methodology of measurement of other biochemical variables, including plasma insulin, blood lipids, L-homocysteine, hsCRP and albuminuria were described previously , 21.th percentile for age and gender, arterial hypertension, serum triglycerides > 110 mg/dl, fasting plasma glucose > 100 mg/dl or > 140 mg/dl at 2 h of oral glucose tolerance test and HDL cholesterol < 40 mg/dl [Because some of our patients were below 10 years of age, metabolic syndrome (MS) was diagnosed when at least 3 criteria were present (BMI ≥ 9540 mg/dl ).Carotid and femoral superficial artery intima-media thickness (cIMT and fIMT), and wall cross-sectional area in carotid artery (WCSA) were evaluated by ultrasound according to the methodology described previously . The medth percentile for age and gender, based on the pediatric LVMi reference data of Khoury et al [th percentile for RWT for normal children and adolescents, and the 95th percentile for LVMi were used as cutoff points in evaluation of LV geometry [All ECHO examinations were performed by one examiner blinded to the severity of PH and effectiveness of treatment. ECHO measurements were performed according to American Society of Echocardiography guidelines . To stanry et al . Relativgeometry .Principles of treatment were already described previously , 21. At rd and the 6th month during ambulatory visits. If after 3 or 6 months office BP was still in the hypertensive range ABPM was done. In patients who still had ambulatory or severe ambulatory hypertension, pharmacotherapy was started. Finally, ABPM was performed after 12 months of treatment.Pharmacological treatment was immediately started in patients who had a significant TOD and/or severe ambulatory hypertension. BP was checked at the 3Drug therapy was based on the ACEi enalapril (0.2 – 0.3 mg/kg/day bid). Patients who had asthma or who did not tolerate ACEi were prescribed angiotensin 2 receptor type 1 blocker (ARB) losartan in a dose of 0.7 – 1 mg/kg/day in one or two daily doses.All patients were evaluated at regular 3 months intervals during routine ambulatory, out-patient visits. Compliance to recommended lifestyle modifications was assessed by interview with patients and parents. When the antihypertensive effect was inadequate, amlodipine as the second drug was introduced and in patients treated only with lifestyle intervention, therapy with ACEi, ARB or amlodipine was started. Patients who were still hypertensive after 6 months and/or fulfilled the criteria of stage 2 hypertension based on home and casual BP measurements were prescribed metoprolol in a dose 0.5 mg/day as the third drug.2.7. The change of measured parameters was expressed as a delta value (Δ), ie the difference between measurement at 12 months and at start of treatment. Homogeneity of variance was checked with the Levene test. Continuous variables with a normal distribution were compared by the Student’s t-test for independent variables. Continuous values with non-normal distribution were compared by the Mann–Whitney U test. Comparison between groups was evaluated with an ANOVA test. Measurements taken at the start and after 12 months of treatment were compared using the Wilcoxon test. Dichotomous variables were compared using the Chi-square test, and change in prevalence during treatment was analyzed with the McNemar test. Correlation analysis was done with the Spearman test. P values less than 0.05 were regarded as statistically significant.Because the analyzed groups included subjects of different age and gender, BMI and WC values were expressed both as absolute values and as SDS for age and gender. LVM values in g were standardized to height in metersAt start of treatment 67.4 % of patients were obese or overweight and their mean (±SD) BMI-SDS was +1.9 ±1.8. Metabolic syndrome was diagnosed in 13 patients (15.1 %) , 21 (Tabp < 0.01). 40 patients with non-dipping status had lower values of GPX than patients with normal nocturnal fall of BP .36 (41.9 %) patients with severe ambulatory HT had significantly lower concentrations of GSH in comparison to 50 (58.1 %) patients with ambulatory HT (748.7 (365.2-862.5) vs 773.6 (361.5 -889.4) μmol/l, p = 0.02)  and not significantly higher ADMA concentration (0.71 (0.25-1.37) vs 0.49 (0.17-1.45) μmol/l, p = 0.1) and GPX activity (32.0 (26.2-39.2) vs 31.4 (25.4-39.9) U/gHb, p = 0.1).40 patients with LVH had higher values of TBARS compared to 46 patients without LVH (0.33 0.14-1.28) vs 0.24 (0.16-1.25) μmol/l, 4-1.28 vsPatients with MS had lower activity of GPX, and higher concentrations of ADMA and oxyLDL when compared to patients without MS Table , 3.TableTBARS concentrations correlated with LVMi, RWT, cIMT, cIMT-SDS, WCSA, urinary albumin excretion and SBP/24 h Table . ADMA anSOX markers did not differ between overweight/obese vs normal weight patients, between patients with visceral obesity and without, and between patients with positive vs negative family history of cardiovascular disease (data not shown).As described previously, after 1 year of antihypertensive treatment, there was a significant decrease of blood pressure, prevalence of TOD and of MS, and improvement of some metabolic abnormalities, such as a decrease of hsCRP, uric acid, total – and LDL cholesterol concentration and a decrease of visceral fat amount . CompareSOX markers did not correlate with blood pressure changes. 64 (73.8 %) patients who had lowered blood pressure, did not have significantly different concentrations of ADMA and oxyLDL.p = 0.01). Patients in whom LVMi decreased had no significant change in oxyLDL (ΔoxyLDL: -26.5 (−626.1-810.1) vs 42.2 (−253.1-804.2) mU/ml) and ADMA (ΔADMA: -0.10 (−0.91-0.91) vs 0.18 (−0.25-0.53) μmol/l, both p = 0.07) compared to patients who did not have decreased LVMi.Patients with regression of TOD in comparison to patients with progression/no change of TOD did not differ significantly regarding changes of SOX parameters, however patients who had decreased fIMT-SDS also had decreased oxyLDL concentrations in comparison with patients in whom fIMT-SDS increased or did not change (ΔoxyLDL: - 56.0 (−242.2-460.3) vs 82.3 (−59.1-809.5) mU/ml, p = 0.05, ∆oxyLDL: -59.1 (−626.6-460.3) vs 100 (−295.6-810.1) mU/ml, p = 0.008, ∆GPX: 0.2 (−7.2-10.3) vs −0.1 (−9.1-5.3) U/gHb, p = 0.1). Patients in whom ADMA concentrations decreased at follow-up, had lower insulin and HbA1C concentrations, HOMA-IR, TG/HDL and LDL/HDL ratios when compared to patients with increase/stabilization of ADMA (Table Changes in SOX markers correlated with changes in insulin resistance and lipids. ADMA and oxyLDL concentrations decreased and GPX activity showed no significant change in patients who lowered TG/HDL ratio in comparison to patients with stabilization/increase of TG/HDL ratio (∆ ADMA: -0.16 (−0.58-0.91) vs 0.12 (−0.91-0.57) μmol/l, 1 −626.6-60.3 vs 1p = 0.04, r = 0.22) but there was no statistically significant correlation with a decrease of WC .The decrease of TBARS concentrations correlated with a decrease of BMI (The step-wise regression analysis did not reveal any significant predictors of decrease of TBARS concentrations and of increase of GSH.The main finding of the study is that in newly-diagnosed hypertensive children, the severity of hypertension, TOD, metabolic abnormalities and immune activity were all associated with the magnitude of oxidative stress. The second finding is that standard antihypertensive treatment based on lifestyle modifications and/or blockade of the renin-angiotensin system caused a decrease of SOX and improved antioxidative defense. Further, the changes of SOX after 1 year of treatment correlated with regression of TOD and increased insulin sensitivity, but not directly with decrease of blood pressure.Several reports have evaluated antioxidative defense and SOX in patients with PH and cardiovascular disease , 16–19. The corresponding finding is a strict relationship between SOX and LVH and arterial injury. Finding that SOX markers were associated with blood pressure status and TOD expressed as LVH and/or cIMT and fIMT thickening does not indicate any causation. The common pathway may be metabolic abnormalities. Baykal et al found that, despite a similar decrease of blood pressure, only ACEi and ARBs caused a significant decrease of SOX accompanied by decrease of total cholesterol, triglycerides and LDL-cholesterol concentrations . It is iIt has been shown that there is relationship between genetic polymorphisms of NADPH oxidase and extent of atherosclerosis . DecreasThe main limitation of our study is the relatively low number of patients. Moreover, due to ethical reasons, we could not separate the effects of antihypertensive drugs and non-pharmacological treatment, because healthy nutrition and regular physical activity were recommended for all patients. The other limitation of our study is its observational design and lack of normotensive and BMI-matched control group. Therefore, although we found significantly increased oxidative stress in hypertensive children, and especially among children with LVH and arterial injury, we did not find a causative mechanism or explain the influence of obesity and hypertension, separately. On the other hand, the link between increased insulin sensitivity and SOX reduction underlines the importance of non-pharmacological treatment, first of all based on an increase of physical activity.We have shown the relation between oxidative stress and the severity of hypertension, TOD and metabolic disorders typical for PH. Decrease of SOX correlated with regression of TOD and normalizations of metabolic abnormalities and immune activity, but not with hypotensive effect of treatment. This finding underlines the importance of immuno-metabolic factors in the pathogenesis of hypertensive TOD and indicates that antihypertensive treatment should be focused both on hypotensive effects and metabolic abnormalities.


The ambulatory arterial stiffness index (AASI) can be used to predict cardiovascular morbidity and mortality in hypertensive patients. However, data on AASI in Chinese patients with chronic kidney disease (CKD) is not available.This cross-sectional study enrolled 583 CKD patients. Univariate and multivariate analyses were used to evaluate the relationship between AASI and renal function and parameters of cardiovascular injury.r=0.296, P < 0.001), serum creatinine , and LVMI  and negatively correlated with the eGFR . Multivariate analyses revealed that serum cystatin C, eGFR, serum creatinine and LVMI were independently correlated with AASI.Patients with a higher AASI had a higher systolic blood pressure, a lower estimated glomerular filtration rate (eGFR), a higher serum cystatin C, a higher left ventricular mass index (LVMI) and carotid intima-media thickness (cIMT). Univariate analyses showed that AASI was positively correlated with serum cystatin C (These data suggest that AASI was closely correlated with renal function and parameters of cardiovascular injury in Chinese CKD patients. Good quality, long-term, large longitudinal trials to validate the role of AASI in clinical practice for Chinese CKD patients. The rising prevalence and associated morbidity of chronic kidney disease (CKD) has resulted in a significant disease burden and became a major public health problem for many countries . CardiovIn 1914, MacWilliam and Melvin stated that a loss of elasticity in the arterial system influences diastolic blood pressure (DBP) and its relationship with systolic blood pressure (SBP). According to this basic principle, Li et al. proposed a novel, easy-to-obtain index of arterial stiffness: the ambulatory arterial stiffness index (AASI). AASI is defined as 1 minus the regression slope of DBP plotted against SBP obtained from individual 24-h blood pressure (BP) recordings. They also described the close correlation of AASI with pulse wave velocity (PWV) as well as central and peripheral augmentation indices . Moreoverd Hospital of Sun Yat-sen University. All of the study participants provided written informed consent to be included in the study. Six hundred and fifty consecutive in patients with CKD were included from May 2010 to July 2012. A cross-sectional study was carried out in our division. The exclusion criteria were: treatment with corticosteroids or hormones; acute changes in the estimated glomerular filtration rate (eGFR) >30% in the previous 3 months; pregnancy; history of abuse of drugs or alcohol; night or shift-work employment; acquired immunodeficiency syndrome; cardiovascular disorders ; intolerance to ambulatory blood pressure monitoring (ABPM); inability to communicate and comply with all of the study requirements; or maintenance dialysis. We excluded 67 patients for abnormal ABPM or incomplete measurement of baseline characteristics. Therefore, 583 patients were enrolled into the study. Forty-nine subjects had diabetic nephropathy and 109 patients had immunoglobulin (Ig) A nephropathy in this group.The study protocol was approved by the ethics committee of 31. ABPM: Patients underwent 24-h ABPM using a TM-2430 monitor . Cuff size was chosen based on arm circumference. The cuff was fixed to the non-dominant arm. Three BP readings were obtained in the morning (07:00 to 10:00) concomitant with sphygmomanometric measurements to ensure that the average of the two sets of values differed by ≤5 mmHg. BP was recorded every 15 min from 07:00 to 22:00, and from every 30 min from 22:00 to 07:00. The values for daytime and nighttime periods were derived from diaries recorded by the patients during ABPM. Monitoring was done on a working day. Patients had no access to ABP values. Strenuous physical activity was discouraged in all patients during the monitoring period, and their daily activities were comparable.BP series were eliminated from the analysis if: >30% of the measurements were lacking; they had missing data for >3-h spans; they were collected from subjects who were experiencing an irregular rest–activity schedule or a nighttime sleep span <6 h or >12 h during monitoring. Raw data were examined by scatter plots. The regression slope of DBP on SBP was computed to obtain the AASI (1-slope). The diagnosis of hypertension was based on accepted criteria for ABPM : ambulat2. BP measurement in the physician’s office: BP was measured during a visit to the physician’s office (8 am to 11 am) . Briefly2.7 as well as current therapy were obtained at the initial study visit. The experimental data were measured using a Hitachi 7180 biochemistry auto-analyzer .6. Other data collection: We also collected urine samples from 07:00 to Continuous variables were expressed as the mean ± standard deviation (SD). Frequency distributions were used for qualitative variables. Non-parametric variables are expressed as median and interquartile range. The log transformation for proteinuria was done in view of the skewed distribution of these data, and Ln (proteinuria + 1) was used because some patients had low levels of proteinuria.p < 0.05 was considered significant. Data were analyzed using SPSS ver18.0 .One-way analysis (ANOVA) or non-parametric test was used to analyze differences among the quartiles of AASI distribution. Pearson’s correlation coefficient was employed to estimate the relationship between quantitative variables, and the chi-squared test was used to associate qualitative variables. We employed multivariate linear regression models to study the association of indices of renal function  and cardiovascular damage  with AASI values. All values are two-tailed. 1 Clinical characteristics of patientsr = 0.263, P < 0.001). The AASI in patients with IgA nephropathy was 0.47 ± 0.18, which was lower than non-IgA nephropathy patients (P < 0.05). The AASI in DM patients was 0.57 ± 0.11, which was similar to that seen in non-DM patients.Of 583 CKD patients  only 49 (8.4%) had diabetes mellitus (DM) but 109 (18.7%) had IgA nephropathy. The mean AASI was 0.54 ± 0.17. Univariate analyses showed that AASI was positively related with age ; iPTH  and calcium × phosphate ; serum levels of uric acid , and negatively correlated with levels of hemoglobin  and HDL-C  , over 24 h , while at daytime  and bedtime . It was also positively correlated with mean BP  and heart rate . AASI was negatively correlated with the variability of DBP over 24 h , while at daytime and bedtime . AASI was also negatively correlated with SBP while at daytime  and bedtime  as well as the decline in bedtime SBP  and DBP   and positively correlated with serum levels of cystatin C  and serum creatinine Multiple linear regression analyses were done to evaluate the relationship between eGFR, serum levels of cystatin C and creatinine with AASI. The eGFR was independently correlated with age (β = -1.477), 24-h mean BP (β = -1.538), the decline ratio of bedtime SBP (β =0.534) and the AASI (β = –20.033). Serum levels of cystatin C were independently correlated with age (β = 0.022), 24-h mean BP (β =0.045), the decline in the ratio of bedtime SBP (β = -0.038), and AASI (β = 1.795). Serum creatinine were independently correlated with sex (β = -91.657), 24-h mean BP (β = 9.259), the decline in the ratio of bedtime SBP (β = -8.568) and AASI (β = 262.347). A significant relationship between AASI and proteinuria was not found when univariate and multiple linear regression analyses were undertaken  and cIMT , and was negatively related to the E/A ratio . However, we found that the LVMI (but not the cIMT and E/A ratio) was independently correlated with AASI (β = 1.712) after multiple linear regression analyses were carried out (Table Univariate analyses showed that AASI was positively correlated with the LVMI (In this clinical trial, we initially explored the relationship between AASI and target-organ damage in CKD patients in China. The mean AASI in our patients was 0.54, which was higher than hypertensive patients in China . PatientAASI is derived from BP parameters and thus the multiple reports on the correlation between AASI and pulse pressure or systolic BP do not necessarily reflect a true biological relationship. In a recent study using a computer model of the arterial circulation, arterial stiffness along with vascular resistance and heart rate were identified as the main determinants of AASI . MoreoveIgA nephropathy is the most common cause of primary glomerulonephritis in “developing” countries such as China , whereasCVD is a leading cause of morbidity and mortality, accounting for 30-40% of deaths in patients with renal failure. Left ventricular hypertrophy, left ventricular dilatation, systolic dysfunction and diastolic dysfunction are very common and independently associated with mortality in CKD patients . The cIMProteinuria is a strong, independent predictor of ESRD in a mass-screening setting. Even a slight increase in proteinuria is an independent risk factor for ESRD . ProteinOur study had several strengths. We are the first to report the close relationship between AASI and cardiovascular/renal damage in CKD patients. Also, the sample size was large. Finally, we reported the relationship between AASI and renal cardiovascular damage in Chinese CKD patients. However, we need larger perspective studies to confirm the role of AASI in Chinese CKD patients.The present study provided evidence that AASI is associated with renal function and cardiovascular risk factors in Chinese CKD patients. AASI might be a potential index for assessment in CKD patients. More clinical studies with larger cohorts of patients are needed to confirm the role of AASI in Chinese CKD patients.AASI: Ambulatory arterial stiffness index; ARB: Angiotensin receptor blocker; ACEI: Angiotensin-converting enzyme inhibitors; BMI: Body mass index; CCB: Calcium channel blocker; cIMI: Carotid intima-media thickness; eGFR: Estimated glomerular filtration rate; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; iPTH: Intact parathyroid hormone; LVEF: Left ventricular ejection fraction; LVMI: Left ventricular mass index; E: Early mitral inflow filling velocity; A: Peak mitral filling velocity at atrial contraction.The authors declare that they have no competing interests.Conceived and designed the experiments: CW, JZ and TL. Performed the experiments: XL, CL, WG and ZY. Analyzed the data: JZ and CW. Contributed reagents/materials/analysis tools: HP and ZY. Wrote the paper: CW. Review the manuscript for intellectual content: Dr CW, JZ and TL. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/14/257/prepub


Muscle passive contraction of lower limb by neuromuscular electrostimulation (NMES) is frequently used in chronic heart failure (CHF) patients but no data are available concerning its action on sympathetic activity. However, Transcutaneous Electrical Nerve Stimulation (TENS) is able to improve baroreflex in CHF. The primary aim of the present study was to investigate the acute effect of TENS and NMES compared to Sham stimulation on sympathetic overactivity as assessed by Muscle Sympathetic Nerve Activity (MSNA).We performed a serie of two parallel, randomized, double blinded and sham controlled protocols in twenty-two CHF patients in New York Heart Association (NYHA) Class III. Half of them performed stimulation by TENS, and the others tested NMES.Compare to Sham stimulation, both TENS and NMES are able to reduce MSNA . No variation of blood pressure, heart rate or respiratory parameters was observed after stimulation.The results suggest that sensory stimulation of lower limbs by electrical device, either TENS or NMES, could inhibit sympathetic outflow directed to legs in CHF patients. These properties could benefits CHF patients and pave the way for a new non-pharmacological approach of CHF. Chronic heart failure (CHF) is characterised by sympathetic overactivity causing direct effect on the initiation and progression of heart failure. Consequently, sympathetic activity (SA) is a strong predictor of morbidity and mortality . Risk –rIt has been shown that exercise can improve symptoms, morbidity and outcomes related to CHF partly due to a diminution of resting SA ,7. ExercWe therefore decided to undertake the following study in order to demonstrate that TENS benefits (i.e. baroreflex sensitivity enhancement) could be related to a direct effect on SA as assessed by Muscle Sympathetic Nerve Activity (MSNA). In addition, since NMES, unlike TENS, is the electrical standard treatment used in the rehabilitation of CHF patients, we sought to test whether NMES would be associated with a decrease in SA (TENS effect during NMES) or another modulation of sympathetic activity.Using a double blind, randomized, sham controlled design, we examined successively the effects of TENS and NMES on sympathetic activity assessed directly by nerve recording (MSNA) in CHF patients.Twenty two patients  Class III) with systolic CHF were prospectively recruited. All patient received pharmacotherapy according to the current guidelines for advanced CHF corresponding to Beta-blockade drugs, Angiotensin-converting enzyme inhibitors or angiotensin II type-1 receptor inhibitors, diuretics and anti-aldosterone drugs. Exclusion criteria were: non sinusal rhythm, severe cardiac arrhythmia, diabetes, sensibility deficiency, neuropathy, chronic pain on leg. Informed written consent was obtained from all participants in accordance with standards established by the latest revision of the Declaration of Helsinki. The study was approved by the local Institutional Human Subjects Review Committee named “CPP Sud-Ouest et Outre Mer II”.Heart rate (HR) was measured continuously by an electrocardiogram . Blood Pressure was measured continuously by the Finometer system . Multiunit postganglionic sympathetic nerve activity was recorded as previously described . BrieflyEach burst was carefully determined, and the sympathetic activity was calculated as bursts per minute and bursts for 100 hearts beats  by a blinded investigator (ML) in both protocols for baseline and post stimulation (TENS and NMES).All patients had a standard cardiac transthoracic echocardiography with assessment of classical parameters among them the left ventricular ejection fraction estimated by Simpson estimation.The both protocols were performed in parallel because of the difficulty in carrying out too long assessment in heart failure patients who are frail and tired and to limit the risk of loss of MSNA signal over time. However, each of the two protocols (A and B) was cross over, randomized and sham controlled. Thus, in consequence with these methodological particularities, the 22 subjects were randomized either to TENS (Protocol A) or NMES (Protocol B) but not to both of them. Subjects were in a supine rest position for thirty minutes before MSNA recording, at the same time of the day. For each patient, the total duration of participation in the protocol was about 3 hours. We tested the effect of two different electrical stimulations. TENS is classically able to induce stimulation of big myelinated afferent fibers, property used for pain treatment . NMES isPatient had solely skin stimulation without muscular contraction, through the use of TENS procedure. Current intensity was defined as the maximum level of current able to induce sensory stimulation without muscular contraction. The electrodes were placed in the left leg in front of the quadriceps and the suralis triceps. The current, delivered by an electrostimulator , was non polarised with a frequency of 80 Hz, a pulse width at 200us. The total duration of stimulation was of five minutes alternating with 3 seconds of stimulation and 3 seconds of rest. The intensity was equal to the maximum to produce sensory stimulation without muscle contraction. The Sham stimulation shared the same characteristics that TENS except for intensity that was increased to reach the minimal threshold able to induce cutaneous sensation without any muscular contraction, as the Sham method described in the reference study . BecausePatient had a muscular and sensory stimulation by NMES. As in protocol A, electrodes were placed in the left leg in front of the quadriceps and the suralis triceps. A non polarised current was administrated by an electrostimulator  during five minutes, with a frequency at 25 Hz, an intensity to obtain maximal tolerated muscular contraction, and a pulse width at 200 µs. The total duration of stimulation was five minutes alternating with 3 seconds of stimulation and 3 seconds of rest. The Sham stimulation shared the same characteristics that NMES except for intensity that was increased to reach the minimal threshold able to induce cutaneous sensation without any muscular contraction. The two sets of stimulation (NMES and Sham) were made in a random order. MSNA was recorded in the right leg immediately after electrical stimulation cessation. Because of electrical interferences, MSNA cannot be recorded simultaneously during electrical stimulation. Blood pressure, heart rate and the respiratory parameters  were recorded during all the procedure.Our primary endpoint was the effect of acute stimulation on MSNA, as measured by bursts per minute. Based on our previous studies realized on similar type of patients (namely CHF patients), we hypothesized that one session of TENS or NMES would be able to modify the MSNA by 25%. This value is approximately what we observed in studies where where comorbidities of heart failure modulate sympathetic reflexes  were compared by the use of an unpaired student’s t test and chi-square tests with Yates correction. Data of protocol A and B were analysed by the use of a repeated measure ANOVA for parameters obtained during and after stimulation with post hoc analysis (Sidak correction). Data are presented as the mean ± SEM. A The clinical characteristics of the patients are noted in -1, p < 0.01, 81.1± 5.3 vs 87.8± 4.1 burst.100 HB-1 delta of -9.1 ± 1.6 %). Blood pressure, heart rate and the respiratory parameters were not changed. Eleven patients were randomized to perform the protocol A. During the electrical stimulation , heart r-1, p < 0, 01; 72,2 ± 3,9 vs 80,9 ± 3,9 burst.100 HB-1, delta of -9.2 ± 2.4 % ) without difference in blood pressure, heart rate and the respiratory parameters (Eleven patients were randomized to perform protocol B. During stimulation (NMES), heart rate, blood pressure and respiratory parameters were unchanged . After Nrameters  and 3. In this double blind, randomized and sham-controlled study, we provide for the first time evidence that TENS is able to directly reduce sympathetic activity in patients with CHF. We also show that this putative beneficial effect linked to a sensory stimulation is preserved while CHF patients are exposed to an electromyostimulation by NMES, the latter combining sensory and muscular stimulation.. To the best of our knowledge, this is the first time that sympathetic activity was measured by MSNA after lower limb electrical stimulation in CHF patients. MSNA is considered as the most accurate and sensitive technique comparatively to more standard techniques such as catecholamine dosage ,22 or heWe first show that TENS is able to reduce SA as assessed by microneurographic recording. This is the first time that effect of cutaneous stimulation on SA, measured directly in CHF patient, is realized. The diminution of MSNA is not due to a local axonal reflex which could be implicated in alteration of the efferent vegetative fibers response directed to lower limbs  because Another mechanism could explain our results in addition of the modulation of baroreflex. Electroacupuncture, a form of cutaneous electrical stimulation apparented to TENS, is known to inhibit sympathetic activity via opioïd excretion in spinal cord ,30. FurtIn our study, NMES (protocol B) is associated with a significant decrease of MSNA (decrease of 9.2 % towards baseline) with no modifications of hemodynamic or respiratory parameters similarly to the results shown in protocol A (TENS effect). These results are surprising, since non electrical muscle stimulation is usually associated with an increase of sympathetic outflow in CHF patients in response to activation of afferents nerve fibers type III and IV. This is related to both, muscular contraction or stretch, known to induce an elevation of MSNA . HoweverIn our study, despite reduction of MSNA we didn’t find significative variation of blood pressure and / or heart rate. These results are in accordance with Gademan’s observation . This isWe were unable to record continuously MSNA due to interferences between electrical stimulation and microneurography recording. The potential consequence of this technical limitation is that during stimulation, the modulation of MSNA has not been evaluated. However hemodynamic and respiratory parameters were not modified during stimulation suggesting that MSNA was not influenced by stimulation during this acute phase. Other parameters like catecholamine level or heart rate variability could have been recorded during stimulation but both are indirect measurements of SA and thus less powerful than MSNA. Finally it is well known that other reflexes could influence SA modulation  but we did not analyse these pathways in our study. We also cannot exclude local release of substance under electrode that could be at the origin of MSNA modification by modulation of endothelial function as suggested by Karavidas in a repetitive NMES stimulation .In this cross over randomized study we show for the first time that electromyostimulation in CHF patients is able to reduce muscle sympathetic nerve activity partly through a somatosensory stimulation. These data suggest that in CHF patient unable to perform physical activity this type of approach could provide both muscular rehabilitation and putatively enhancement of the natural history of CHF since SA has been considered as a risk factor for cardiovascular complications. These acute effects need to be confirmed by a long-term approach. This refers to a clinical trial in which we are currently involved  aiming to demonstrate that NMES could improve CHF patient status through SA decrease.


Guidelines indicate eligibility for lipid lowering drugs, but it is not known to what extent GPs' follow guidelines in routine clinical practice or whether additional clinical factors systematically influence their prescribing decisions.A retrospective cohort analysis was undertaken using electronic primary care records from 421 UK general practices. At baseline (May 2008) patients were aged 30 to 74 years, free from cardiovascular disease and not taking lipid lowering drugs. The outcome was prescription of a lipid lowering drug within the next two years. The proportions of eligible and ineligible patients prescribed lipid lowering drugs were reported and multivariable logistic regression models were used to investigate associations between age, sex, cardiovascular risk factors and prescribing.Of 365,718 patients with complete data, 13.8%  were prescribed lipid lowering drugs: 28.5%  of those eligible and 10.1%  of those ineligible. Only 41.7%  of those prescribed lipid lowering drugs were eligible. In multivariable analysis prescribing was most strongly associated with increasing age ; diabetes ; total cholesterol level ≥7 mmol/L ; and ≥4 blood pressure measurements in the past year . The predictors were similar in eligible and ineligible patients.Most lipid lowering drugs for primary prevention are prescribed to ineligible patients. There is underuse of lipid lowering drugs in eligible patients. Statins are known to be highly effective treatments for primary and secondary prevention of cardiovascular disease The use of calculated CVD risk as a criterion for recommending preventive drugs has a long history. CVD risk algorithms and equations have been available since the 1970s GP decision making may not have kept pace with changes in thinking around CVD prevention. In a secondary analysis of data from a UK CVD prevention project GP prescribing of statins in usual practice was associated with raised total cholesterol levels and with antihypertensive prescribing but not with other cardiovascular risk factors However it is unclear to what extent the findings of this study apply to other settings as it was confined to six general practices in a single urban area in the West Midlands in the context of a specific cardiovascular prevention project.This present study uses a large dataset of electronic primary care records from general practices across the UK. It aims to investigate the prescribing of lipid lowering drugs for patients without existing cardiovascular disease in relation to their eligibility under clinical guidelines. We then investigate the association between patient characteristics and GP prescribing of lipid lowering drugs in patients without existing cardiovascular disease.This is a retrospective cohort study using data from a database of electronic primary care records: The Health Improvement Network (THIN). Data are uploaded from UK general practices that use the VISION computer system and used for research st May 2008 (the index date) who were not currently receiving a prescription for a lipid lowering drug and provided they had at least one year of records prior to the index date. To avoid the problem of inflation of the denominator population during periods when deaths are under-recorded, practice records were excluded if they fell before a period of acceptable mortality recording st May 2010 this meant that patients had up to two years of follow up from the index date.More than 5 million anonymised patients are collected from 421 practices that are broadly representative of UK general practice in terms of patients' age and sex, practice size, and geographical distribution. The database includes coded data on all diagnoses, consultations, prescriptions, measurements and laboratory investigations. The analysis included all patients aged between 30 and 74 in the database on 1Only patients without clinical evidence of CVD  before the date of prescribing a lipid lowering drug or the last date of follow up were included in the analyses . All patPatients' age (years), sex, practice and quintile of area deprivation score (Townsend score) For measurement variables - systolic and diastolic blood pressure (mm Hg), serum total cholesterol , HDL cholesterol  - the most recent records during the period of follow up were used. These could be up to one year prior to the index date or the final value during the two years of follow up. We excluded implausible values of the measurement variables. The most recent smoking status  was also included. If no record existed for smoking in that period, the patient was assumed to be non-smoker. Previous analyses suggest that the prevalence of smoking in the THIN database is similar to that seen in other sources and that those with missing smoking status are likely to be ex-smokers or non-smokers Our dataset did not include all GP contacts but we determined the number of blood pressure recordings carried out in the last year of follow up and used this as proxy for frequency of GP visits.Although we are primarily interested in statin prescribing we used first prescription of a lipid lowering drug at any point during the period of follow up as the outcome. This is because GPs may prescribe another lipid lowering agent instead and are unlikely to prescribe both. In practice this makes little difference as in England 93% of prescriptions for lipid lowering drugs are for statins Calculating ten-year risk requires knowledge of age, sex, diabetic status, smoking status, total cholesterol, HDL cholesterol and systolic blood pressure. Our primary analysis made use of cases for whom these data were complete. We undertook a sensitivity analysis using all patients including those with missing data. Since the absence of lipid levels and blood pressures may be related to the prescription of a lipid lowering drug, for each of the missing continuous variables we created a “missing value” category.Ten-year cardiovascular risk was calculated from each patient's risk factors using the modified Framingham equation advocated in 2005 UK guidelines For each patient, treatment eligibility was determined from their cardiovascular risk, diabetic status, total cholesterol and HDL cholesterol levels.For this analysis, patients were considered to be eligible for lipid lowering drugs they met the relevant criteria in the principal relevant UK guidelines. This includes Scottish and joint British guidelines on cardiovascular prevention, NICE guidelines on diabetes, NICE guidelines on familial hyperlipidaemia and NICE guidelines on lipid lowering We first describe prescribing in relation to eligibility under UK clinical guidelines. For subsequent analyses continuous variables were categorised. Age (years) was categorised into four bands . Total cholesterol was divided into three categories  as these thresholds are used in some local clinical guidelines. Systolic and diastolic blood pressure were divided into three categories  and . As there are no clinically accepted thresholds for HDL cholesterol (mmol/L) this was divided into quartiles . The frequency of blood pressure measurements in the past year was also categorized into 3 levels .In the multivariable logistic model, we included all risk factors. We also carried out stratified analyses for patients eligible and not eligible for lipid lowering drugs under UK guidelines in order to investigate the relationship between predictors in the model and patient eligibility.We used robust standard errors throughout to account for dependency between patients clustered within the same practice. We also undertook secondary analyses to examine the role of variation between practices, because some practices may differ in their overall propensity to prescribe lipid lowering drugs. We performed all analyses using multilevel random intercept logistic regression models with patients nested in practices and with robust standard errors.To determine whether cardiovascular risk factors might have an additional influence on prescribing beyond their contribution to the cardiovascular risk equation, further analysis was undertaken including ten year cardiovascular risk as well as individual risk factors.For the sensitivity analysis using complete cases, an additional “missing” category was created for total cholesterol, HDL cholesterol, systolic and diastolic blood pressure. It is not possible to calculate CVD risk for patients with missing blood pressures or cholesterol measurements, however patients with missing risk factor data may be identified as eligible for treatment if they are diabetic and aged ≥40 years and (if cholesterol levels are available) they have familial hypercholesterolaemia.All analyses were performed using SAS version 9.2 for windows .There were 1,364,383 patients without clinical evidence of cardiovascular disease who were not on lipid lowering drugs at baseline, after exclusion of those without records of blood pressure, total cholesterol or HDL there were 365,718 complete cases for analysis . Table 1In univariable analysis increasing age, diabetic status, prescription of antihypertensive drugs, frequent blood pressure measurements and eligibility for lipid lowering drugs were all strong predictors of treatment. Eligible patients were more likely to be treated than those not eligible. But eligibility because of diabetes in patients age ≥40 years or familial hypercholesterolaemia were much stronger predictors of treatment than eligibility because of a ten-year CVD risk ≥20% or a total cholesterol to HDL cholesterol ratio ≥6.0. In multivariable analysis including individual risk factors the likelihood of a prescription of lipid lowering drugs was most strongly associated with increasing age ; diabetes ; total cholesterol level ; and the frequency of blood pressure measurements in the past year .  Other chMultivariable analyses were also performed separately on subgroup patients who were eligible and ineligible for lipid lowering drugs . PredictUnivariable analysis showed a linear relationship between cardiovascular risk and prescribing lipid lowering drugs, with no threshold at 20% ten-year CVD risk.  Adding 1The analysis was repeated including all 1,364,383 patients. In this analysis, 27.9% of those eligible and 2.8% of those ineligible were started on treatment and only 38.2% of those prescribed lipid lowering drugs were eligible. In multivariable analysis the same factors predicted prescribing of lipid lowering drugs and odds ratios for predictors were very similar to those found with the complete case analysis. The strongest predictors were: increasing age ; diabetes ; total cholesterol level ≥7 mmol/L  and ≥4 blood pressure measurements in the past year . In the analysis including patients with missing data the predictors of prescribing were similar in eligible and ineligible patients.Patients with missing blood pressure or cholesterol measurements were much less likely to be prescribed lipid lowering drugs.Over half of patients without cardiovascular disease who were started on lipid lowering therapy were ineligible for treatment. Many eligible patients were not started on treatment. Most ineligible patients who were started on treatment were aged ≥55 years but not at high risk of CVD. Eligible patients who were non-diabetic and those with infrequent blood pressure measurements were unlikely to be started on treatment. The frequency of opportunities to prescribe appears to influence prescribing. We found no evidence of inequitable prescribing, as patients in deprived areas were slightly more likely to be prescribed lipid lowering drugs. However this finding should be treated with caution as deprivation was assessed by postcode of residence and allocated to quintiles.We found evidence that GP prescribing is systematically influenced by cardiovascular risk factors – most strongly by older age, diabetic status and a total cholesterol level≥7 mmol/L. There was no evidence of a threshold effect at 20% ten-year CVD risk. Frequent blood pressure measurements (a proxy for cardiovascular related contacts) were also associated with treatment. Although all guidelines recommend treatment above a risk threshold and there is universal access to electronic risk calculators in UK primary care, cardiovascular risk was not the main predictor of prescribing. The patient characteristics associated with prescribing were similar in eligible and ineligible patients.The analysis uses a large dataset of electronic primary care records from across the whole of the UK and is representative of usual clinical care in measurement and recording of risk factors. We determined predictors of physician rather than patient behaviour as we are unable to identify whether prescribed drugs were collected or taken.Absolute contraindications to lipid lowering drugs are uncommon and are unlikely to influence findings. We have no information on patients' treatment preferences, which are not predictable from patients' age, sex or risk factor status and may not accord with guideline recommendations Our findings concur with previous studies reporting underuse of statins in primary care and greater prescribing of statins in patients with more risk factors We found diabetes to be a strong predictor of prescribing. Case vignette studies have demonstrated that both UK and Australian GPs are more likely to prescribe statins to eligible diabetics than eligible non-diabetics LDL cholesterol levels above a threshold have been found to be an important of treatment in eligible patients Our finding of a relationship between prescribing and frequency of consultation is consistent with clinical inertia, a tendency to delay the decision to prescribe until the next visit We found that most statins are prescribed to patients who are not eligible for treatment. Overtreatment with statins has been reported from the USA, with a majority of those on treatment not meeting eligible under guidelines Overall we find more evidence to support the view that prescribing of statins is influenced more by single risk factors treated as categories  and frequency of contact with a clinician than by calculated CVD risk. The result is that there is a poor match between eligibility for lipid lowering treatment and being prescribed it.Previous studies have shown variation in adherence to guidance in routine clinical practice The cost and cost-effectiveness implications of divergence from statins guidelines may be substantial We should investigate whether poor discrimination in prescribing lipid lowering drugs extends to secondary prevention and to antihypertensive prescribing. Our findings are adjusted for the effects of practice, but the role of practice and GP characteristics on guideline adherence requires further analysis. While analysis of this kind can identify the importance of patient characteristics in influencing prescribing behaviour, it does not explain why or how these patient characteristics exert an influence. Divergence between prescribing behaviour and guidelines may reflect GPs' considered views about the effectiveness or adverse effects of treatment in relation to specific patient characteristics (e.g. prescribing to diabetics under the age of 40 years). If so these beliefs should be identified and tested against empirical evidence. If divergence between GP prescribing behaviour and guidelines may reflects lack of awareness of existing evidence (e.g. that lipid lowering drugs are effective in women), this can be addressed through better research dissemination. There is now strong evidence for the effectiveness of statins in primary prevention


Older adults are disproportionately affected by hypertension, which is an established risk factor for cardiovascular disease. Little attention has been focused on hypertension and associated factors among older adults in Africa. Therefore, this study aimed to investigate the prevalence and associated factors of hypertension in a national sample of older South Africans who participated in the Study of Global Ageing and Adults’ Health (SAGE) in 2008.In 2008 we conducted a national, population-based, cross-sectional study of a sample of 3 840 subjects aged 50 years or older in South Africa. The questionnaire included socio-demographic characteristics, health variables, and anthropometric and blood pressure measurements.The prevalence of hypertension in the sample population was 77.3% . The rates of awareness, treatment and control among the hypertensive participants were 38.1, 32.7 and 17.1%, respectively. The results of multivariate logistic regression analysis revealed that the prevalence of hypertension was associated with being in the Coloured population group, having had a stroke, being overweight or obese and having had five or more out-patients care visits in the past 12 months. Hypertension was inversely associated with current alcohol use.This study revealed high rates of hypertension among older adults (50 years and more) in South Africa, which puts them at risk for cardiovascular disease. The percentages of hypertensive subjects who were aware, treated and controlled were very low. These data underscore the urgent need to strengthen the public health education and blood pressure-monitoring systems to better manage hypertension among older adults in South Africa. High blood pressure in South Africa is estimated to have caused 46 888 deaths and 390 860 disability-adjusted life years in 2000.3In other countries, in Dakar, Senegal, 65.4% of subjects had hypertension,13Various factors have been found to be associated with hypertension, including socio-demographics ,27In general, it is estimated that in South Africa only 26% of men and 51% of women are aware of their hypertension.10Few studies exist investigating hypertension among older adults in low- and middle-income countries. Yet, research studies ‘demonstrate a clear evolution in the prevalence, awareness, treatment and control of hypertension during the ageing process’.We conducted a national, population-based, cross-sectional study with a sample of 3 840 subjects aged 50 years or older in South Africa in 2008. The SAGE sample design entailed a two-stage probability sample that yielded national and sub-national estimates to an acceptable precision at provincial level, by locality type  and population group . The overall response rate among those aged 50 years or older was 60%.The Global Study on Ageing (SAGE) survey was carried out in South Africa in partnership with the World Health Organisation (WHO), the National Department of Health, and the Human Sciences Research Council (HSRC). The study was approved by the Human Sciences Research Council Research Ethics Committee and the national Department of Health.Blood pressure (systolic and diastolic) was measured three times on the right arm/wrist of the seated respondent using an automated recording device .Out of three measurements, the average of the last two readings was used. In accordance with the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, individuals with systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg and/or who reported the current use of antihypertensive medication were considered to be suffering from high blood pressure.28Awareness was defined as history of hypertension based on diagnosis by a healthcare provider. Treatment was defined as taking any medication or other treatment for hypertension in the last two weeks prior to the survey, and control was defined as blood pressure < 140 and < 90 mmHg at the time of the survey.Lifetime tobacco users were asked ‘Do you currently use  any tobacco products such as cigarettes, cigars, pipes, chewing tobacco or snuff?’ The response options were ‘Yes, daily’, ‘Yes, but not daily’ and ‘No, not at all’. Daily tobacco use was coded = 1, and not daily and not at all = 0.29Lifetime alcohol users were asked about current (past month) alcohol use. Past month alcohol use was coded = 1 and no past month alcohol use = 0.2), calculated as weight in kg divided by height in metres squared. Overweight and/or obesity were defined as BMI ≥ 25 kg/m2 and underweight as < 18.5 kg/m2.Height and weight were measured. Body mass index (BMI) was used as an indicator of obesity . The instrument gathers information on physical activity in three domains , as well as time spent sitting. The questionnaire also assesses vigorous and moderate activities performed at work and for recreational activities. Information on the number of days a week spent on different activities, and time spent in a typical day for each activity was also recorded.For physical activity, in addition to the total minutes of activity, the activity volume was also computed by weighting each type of activity by its energy requirement in metabolic equivalents (METs). One MET was defined as the energy cost of sitting quietly, and was equivalent to a caloric consumption of 1 kcal/kg/h. A MET-minute showed the total activity volume on a weekly basis, and was calculated by multiplying the time spent on each activity during a week by the MET-values of each level of activity. MET-values for different levels of activities were set as 4 MET for moderate intensity physical activity, 8 MET for vigorous physical activity, and 4 MET for transport-related walking or cycling.The total physical activity for GPAQ2 was calculated as the sum of the total moderate, vigorous, and transport-related activities per week. The number of days and total physical activity MET-minutes per week were used to classify respondents into three categories of low, moderate and high level of physical activities. Less than 600 MET-minutes per week was classified as low physical activity.30Fruit and vegetable consumption was assessed with the questions ‘How many servings of fruit do you eat on a typical day?’ and ‘How many servings of vegetables do you eat on a typical day?’ Insufficient fruit and vegetable consumption was defined as less than five servings of fruits and/or vegetables a day.Overall self-rated health status was based on respondents’ assessment of their current health status on a five-point scale in response to the question: ‘In general, how would you rate your health today?’ Response categories were: very good, good, moderate, bad and very bad. Very good and good were grouped together and coded = 1, moderate = 2 and bad and very bad were grouped together and coded = 3.Activity limitation  was assessed with one item ‘Overall in the last 30 days, how much difficulty did you have with work or household activities?’ Response options ranged from 1 = none to 5 = extreme/cannot do. None were coded = 1, mild = 2, moderate = 3 and severe and extreme were grouped together and coded = 4.Finally, participants were asked about a list of chronic and other conditions they had been diagnosed with, including diabetes, hypertension, stroke, angina and arthritis. Of participants who responded to having been diagnosed with hypertension, the question was asked, ‘Have you been taking any medication or other treatment for it during the last two weeks?’ Other treatment might include a weight-loss programme or change in eating habits.Attendance at out-patient care was assessed with the question, ‘Over the last 12 months, did you receive ant healthcare not including an overnight stay in hospital or long-term care facility?’ Of those who indicated ‘yes’ they had to report the number of times they had received healthcare or consultation in the last 12 months. Frequency of attendance at out-patient care was grouped into none = 0, one to four = 2, five or more = 3.To estimate economic or wealth status, a random-effects probit model was used to identify indicator-specific thresholds that represent the point on the wealth scale above which a household is more likely to own a particular asset than not. This enabled an estimation of an asset ladder. These estimates of thresholds, combined with actual assets observed to be owned for any given household, were used to produce an estimate of household-level wealth status. This was used to create wealth quintiles.http://www.statssa.gov.za/publications/P0302/P03022009.pdf.The data were entered using CSPro and analysed using STATA Version 10. The data were weighted using post-stratified individual probability weights based on the selection probability at each stage of selection. Individual weights were post-stratified by province, gender and age groups according to the 2009 medium mid-year population estimates from Statistics South Africa, available at: Computed estimates and odds ratios were reported with 95% confidence intervals and a two-tailed p-value of 0.05 was used as the cut-off point for statistical significance. Associations between key outcomes of hypertension, and socio-demographic and health variables were evaluated calculating odds ratios (OR).p < 0.05 in bivariate analyses were included in the multivariable models. In the analysis, weighted percentages were reported.Multivariate logistic regression was used for evaluation of the impact of explanatory variables for key outcome of hypertension (binary dependent variable). All variables statistically significant at The total sample included 3 840 South African subjects 50 years or older, 44.1% were men and 55.9% were women. The most prevalent population group was black Africans (74%), and almost half (49.9%) were between 50 and 59 years old. The educational level of most participants (71.6%) was lower than secondary school education and almost two-thirds (64.9%) lived in an urban area.A large group (72.4%) of older adults were overweight or obese, 20.4% were daily tobacco users, 4.0% had had a stroke, and 9.2% had diabetes. More than half (52.2%) engaged in low physical activity, two-thirds (67.7%) ate insufficient fruit and vegetables, and a small proportion (13.7%) were current alcohol users. A sizeable proportion (17.5%) rated their health status as bad or very bad, 10.7% reported severe or extreme activity limitation and 28.1% were out-patients five times or more. The prevalence rates of hypertension were 77.3%  The results of the multivariate logistic regression analysis revealed that the prevalence of hypertension was associated with being in the Coloured population group, having had a stroke, being overweight and having had five or more out-patients care visits in the past 12 months. Prevalence of hypertension was inversely associated with current alcohol use Overall, 30.3% of older hypertensive people were aware of their diagnosis, 24.8% of older hypertensives were taking treatment in the past two weeks to lower their blood pressure, and 48.8% of those who were taking antihypertensive treatment had their blood pressure controlled. Women, older age and more frequent out-patient visits in the past 12 months were associated with awareness of their hypertensive status and were taking treatment to lower their blood pressure in the past two weeks. However, there were no statistical differences in gender, age and out-patient visits among those who were taking antihypertensive treatment and had their blood pressure controlled. Of the total 2 841 hypertensive participants, 1 081 (38.1%) were aware of their hypertension, 985 (32.7%) were being treated, and 486 (17.1%) had their hypertension under controll The study found significant rates of hypertension of 77.3%  among older adults (50 years and older) in South Africa. These rates seemed to be higher than in a previous survey in South Africa (men 44.0–52.0% and women 51.6–60.4%) in 1998,13The study further found that regarding socio-demographics, with multivariate analysis, being in the Coloured population group was associated with higher rates of hypertension. This confirms previous studies in women.In terms of health variables, this study was in agreement with other studies,21The rates of awareness, treatment and control among the hypertensive participants in the present study  were as low as in some studies in rural China ,34As found in some other studies, in this study, women were more frequently aware of their hypertension and more frequently treated.10This study had several limitations. Firstly, the self-report of health variables such as tobacco or alcohol use should be interpreted with caution; it is possible that respondents under-reported, especially females. As in many studies, arterial blood pressure was measured three times during a single session (two hours), which may have led to an overestimation of the prevalence of hypertension. In addition, the awareness and treatment rate of hypertension was solely assessed by individual self-report. Furthermore, this study was based on data collected in a crosssectional survey. We cannot, therefore, ascribe causality to any of the associated factors in the study.This study revealed high rates of hypertension among older adults (50 years and more) in South Africa, which put them at risk for cardiovascular disease. The percentages of hypertensives who were aware of, treated for and controlled were very low. These data underscore the urgent need to strengthen the public health education and blood pressure-monitoring systems to better manage hypertension among older adults in South Africa. Community healthcare workers in their new role in South Africa could screen for hypertension among older adults using a primary care ‘high-risk’ approach once every two years. This screening process would enable the health system to identify and cater for the needs of this vulnerable population group.37