Treatment strategies are provided in accordance with the level of global cardiovascular risk, from lifestyle modification in the lower risk group to more comprehensive treatment in the higher risk group. Considering the common trend of combination drug regimen, the choice of the first drug is suggested more liberally according to the physician’s discretion. The purpose of hypertension (HTN) treatment is to prevent cardiovascular disease (CVD) caused by increased blood pressure (BP) and decrease mortality by controlling high BP. In patients who already have established CVD, treatment aims to control BP to prevent progression or recurrence of disease in order to decrease mortality and improve quality of life. HTN treatment provides greater benefit in patients who are at higher risk for CVD. Most clinical studies of HTN have found that lowering systolic blood pressure (SBP) by approximately 10 to 20 mm Hg or diastolic blood pressure (DBP) by approximately 5 to 10 mm Hg can reduce the occurrence of stroke by 30% to 40% and that of ischemic heart disease by 15% to 20%  × 2.5). Salt reduction has many benefits, including lowering of BP and reducing the need for diuretics, which cause detrimental urinary loss of potassium and calcium. The avoidance of urinary calcium loss prevents the development of osteoporosis and renal calculi.Sensitivity to salt tends to be higher in patients who are elderly, obese, or have diabetes or family members with HTN. Greater salt sensitivity means a greater reduction in BP in response to salt restriction. The dietary habits must be modified. Some recommendations are not to put additional salt on the table during the meal and to avoid high-salt processed foodstuffs. Some frequently eaten foods, such as kimchi, stew, soup, salted fermented seafood, instant ramen, and dry bar snacks containing meat and fish, are very salty. When cooking foods, natural ingredients should be used instead of synthetic flavoring agents. The patient should not only reduce absolute salt intake but also try to consume more low-salt foods.HTN is closely related to obesity, and weight reduction decreases BP. Central obesity in particular is closely associated with HTN, dyslipidemia, diabetes, and CV death. In a patient heavier than 110% of ideal body weight, weight reduction of only 5 kg can decrease BP. The beneficial effects of weight reduction are higher in patients with diabetes, dyslipidemia, and left ventricular hypertrophy (LVH). The combination of weight reduction with exercise, moderation of alcohol consumption, and reduction of salt intake has synergistic effects on BP. The recommended initial goal of weight reduction is 4 to 5 kg, with an additional 5 kg reduction after the initial goal has been achieved.2) varies among reports and according to nationality. A collaborative analysis reported that BMI either above or below the apparent optimum of approximately 22.5 to 25 kg/m2 is itself a strong predictor of overall mortality [2 and recommended a BMI of less than 25 kg/m2 [The ideal body mass index (BMI) , one glass of wine , one glass of sake (200 mL), two shots of whisky (60 mL), or two to three glasses of soju corresponds to 30 g of alcohol.The benefits of regular exercise are lowering of BP, improvement of cardiopulmonary function, reduction of body weight, improvement of the lipid profile (including elevation of HDL cholesterol), and reduction of emotional stress. Aerobic exercises such as brisk walking, jogging, bicycling, swimming, jumping rope, playing tennis, and aerobic dancing are recommended for patients with HTN. The appropriate intensity of exercise is 60% to 80% of the maximal heart rate (220—age in years). Such exercise should be performed five to seven times per week. Aerobic exercise should begin at low intensity for 10 to 20 min and then increase to appropriate intensity for another 30 to 60 min. Every exercise session should start with 5 min of warm-up exercise and end with 5 min of cool-down exercise. In addition to aerobic exercise, isometric exercise such as weight lifting can reduce BP, produce metabolic benefits, and increase muscle power. Isometric exercise is recommended two to three times per week . IsotoniDuring smoking, the BP increases temporarily in response to nicotine. Among patients with white coat HTN, smokers maintain a higher daytime ambulatory SBP than do nonsmokers with a similar office BP . SmokingBP is lower in vegetarians than in people who mainly eat meat, and maintaining a vegetarian diet can reduce BP. The BP-lowering effect results not from decreasing the intake of animal protein but from increasing the intake of vegetables and fruits in combination with decreasing the intake of saturated fatty acids. In a study in elderly people, BP decreased by 3/1 mm Hg when intake of vegetables and fruits was increased alone but by 6/3 mmHg when it was combined with a decrease in fat intake -61. In pCaffeine from various foods rapidly increases BP, but the effect does not progress to HTN because tolerance to caffeine develops. Emotional stress increases both BP and the risk for CVD, making the control of emotional stress important for the management and patient compliance of HTN. Further studies are required to examine the long-term effects of stress control on HTN and CVD. The effectiveness of various methods of stress management, such as relaxation and biofeedback, for the management of HTN remains uncertain. There is still no clear evidence for the effects of micronutrients, calcium, magnesium, and supplementary fiber on BP.The occurrence of CV events in patients with HTN can be decreased by reducing the BP. Currently available antihypertensive drugs are more effective than placebo for prevention of CVD. This preventive effect is relatively larger for stroke than for coronary artery disease. The extent to which CV events are reduced depends on the degree of BP reduction. All major classes of antihypertensive drugs, including beta-blockers and diuretics, are suitable for first-line treatment. However, the individual drug should be prescribed with consideration of the patient’s individual situation, including age, comorbidities, and possible adverse effects. Simplifying the medication schedule, careful monitoring of the adverse effects, and checking the BP at home are useful for improving patient compliance and making the patient an active participant in the treatment.For reduction of long-term CV morbidity and mortality, it is essential to control most of the modifiable risk factors and to reduce the BP to less than 140/90 mm Hg . Drugs wIt is reasonable to choose drugs according to the patient’s comorbidities and clinical characteristics rather than his or her BP level. There are five available classes of first-line drugs with proven BP-lowering effects, safety, and acceptable adverse effects according to multiple studies. They are: 1) ACE inhibitors or ARBs, 2) beta-blockers, 3) calcium antagonists, 4) diuretics such as hydrochlorothiazide, chlorthalidone, or indapamide, and 5) other drugs . All reduce BP to a similar extent when the dose has been adjusted. However, there might be individual differences in BP lowering, adverse effects, and long-term CV events, making it very important to choose the appropriate drugs according to the patient’s combined risk factors and comorbidities  despite treatment with more than three different classes of antihypertensive drugs, including diuretics. The prevalence of resistant HTN is reported to be 5% to 30% in other countries. However, considering the frequency of pseudo-resistant HTN, the prevalence of true resistant HTN is assumed to be less than 10% /90 mm Hg.Among the wide range of causes of resistant HTN Table , noncompBilateral destruction of the renal sympathetic nerves that course along the renal artery by the use of radiofrequency ablation catheters is an increasingly popular nondrug therapeutic approach to HTN. Reduction of BP lasts for more than a year after the procedure, and the BP-reducing effect was reported to be maintained for another 3 years of follow-up .The treatment itself has no significant complications and can therefore be used in patients with resistant HTN. However, there is insufficient short-term and long-term evidence for the efficacy of renal denervation . CarotidIn patients whose BP has been well controlled for years, the dose of antihypertensive drug can be reduced. Afterwards, the BP should be checked regularly, and the continued practice of lifestyle modifications monitored .The goal of antihypertensive therapy is to reduce the overall CV risk in patients who have other risk factors such as diabetes, dyslipidemia, coronary artery disease, stroke, and CKD. Accordingly, these other risk factors should be treated at the same time.Aspirin administration was shown to produce an absolute benefit for the secondary prevention of CVD in patients with HTN . HoweverLow-dose aspirin (100 mg) can be prescribed to patients in high-risk groups in order to reduce the risk of CVD ,93. AntiLipid-lowering agents have a protective effect on high-risk patients with HTN. Although there is very little Korean data, a 50% reduction in low-density lipoprotein (LDL) cholesterol in patients who had an LDL cholesterol level ≥130 mg/dL significantly lowered the risk for CVD . LowerinRecent clinical studies have shown that aggressive blood glucose control (a hemoglobin A1C level less than 6.0% or 6.5%) reduces the incidence of ischemic heart disease in patients with type 2 diabetes; however, there was no significant change or even increase in stroke or total mortality. Therefore, in patients with diabetes, the blood glucose level should be controlled so that the hemoglobin A1C is less than 7.0% in most patients and less aggressively (target hemoglobin A1C of 7.5% to 8.0%) in older patients or patients with diabetes of long duration, who have increased risk for hypoglycemia .Patients should generally be followed up once monthly, at least until the target BP is achieved. Patients with severe HTN (stage two or more) need more frequent follow-up. The serum potassium and creatinine levels should be measured at least one to two times yearly. If the BP is controlled and stable, then the patient should be followed up every 3 to 6 months. A longer follow-up interval may be associated with low compliance. Therefore, patient compliance also must be monitored, and the need for blood tests should be emphasized to encourage attendance at follow-up visits. A longer follow-up interval to monitor the status of BP control can be achieved by encouraging home BP measurement.Trust between doctor and patient is the most important issue in the treatment of HTN, and the patient should therefore be encouraged to participate in the development of the treatment plan. Many patients may have obtained information about various antihypertensive agents through various routes, so discussion may be necessary. First, identify the patient’s point of view to determine the relative importance of efficacy, cost-effectiveness, and side effects. It is necessary to reduce overall CV risk as much as possible while maintaining the patient’s compliance. Self-measurement of BP by using home BP monitoring can improve compliance.


Although it has been demonstrated previously that patients with aneurysmal subarachnoid hemorrhage (aSAH) who also experience neurocardiac injury have lower short term (0-3 days after aneurysm rupture) systemic and cerebral perfusion parameters compared to those without neurocardiac injury, it remains unknown if these changes persist over a longer time.We aimed to determine if systemic and cerebral perfusion parameters across days 0-14 after SAH were persistently lower when cardiac troponin I (CTnI) was elevated  compared to when cTnI was nondetectable (less than 0.01 ng/ml [cTnI-ND]).Longitudinal prospective analysis of 38 patients with aSAH. Inclusion: age 21-75 years, spontaneous aneurysm rupture, Fisher grade >1 and/or Hunt and Hess grade (HH) >2. Exclusion: traumatic SAH, recent myocardial dysfunction. Daily averages of systemic  and cerebral  perfusion parameters were used. Blood pressure was measured with arterial line, or if no arterial line then sphygmomanometer. Intracranial pressure (ICP) was measured using external ventricular drain and was used to calculate CPP (MAP-ICP). Mixed model linear regression was performed to test the difference in perfusion over time. Modeling was performed using the daily average for each perfusion parameter for each of days 0 to 14, and both without and with covariates . The independent variable was daily average cTnI-High.Patients were predominantly female (76%) with HH grade 1-2 (61%) and mean age 53 ± 11 years. The mixed model linear regression revealed that cTnI-High was significantly associated with lower SBP, DBP, MAP and CPP compared to cTnI-ND (Figure Elevated levels of cTnI are associated with lower systemic and cerebral perfusion parameters across fourteen days following aSAH. The driving force for the CPP direction was lower blood pressure and not higher ICP. Therefore, neurocardiac injury is associated with persistently lowered perfusion over time, not just within the first few days after aneurysm rupture. Further research is needed to determine if these persistently lower perfusion pressures translate into worse physical and neurocognitive function in the long term, and if more targeted perfusion support is needed for aSAH patients with neurocardiac injury during hospitalization.NIH NINR R01NR014221


P = 0.008). Cold weather markedly influenced changes in diastolic blood pressure before (P = 0.017) and after lunch (P = 0.013). Fasting salivary amylase activity increased significantly in cold weather but fell significantly after lunch (significantly greater in cold weather) (P = 0.007). Salivary amylase was significantly associated with cold weather, low atmospheric pressure, and low relative humidity 30 min after lunch (P < 0.05). Cold weather significantly influenced heart rate variability (P = 0.001). The decreased low frequency (LF)/high frequency (HF) ratio, increased Δ LF/HF ratio, and increased Δ salivary amylase activity imply that cold outdoor temperature is associated with dominant parasympathetic activity after lunch. Our results clarify the relationship between environmental factors, food intake, and autonomic system and physiological variables, which helps our understanding of homeostasis and metabolism.Previous studies of autonomic nervous system responses before and after eating when controlling patient conditions and room temperature have provided inconsistent results. We hypothesized that several physiological parameters reflecting autonomic activity are affected by outdoor temperature before and after a meal. We measured the following physiological variables before and after a fixed meal in 53 healthy Japanese women: skin temperature, systolic and diastolic blood pressure, salivary amylase, blood glucose, heart rate, and heart rate variability. We assessed satiety before and after lunch using a visual analog scale (100 mm). We recorded outdoor temperature, atmospheric pressure, and relative humidity. Skin temperature rose significantly 1 h after eating (greater in cold weather) (The online version of this article (doi:10.1007/s00484-014-0800-1) contains supplementary material, which is available to authorized users. Behavior and the environment influence human physiology, with the autonomic nervous system and endocrine axes playing a central role in maintaining homeostasis. There has been significant interest in the role played by the autonomic nervous and endocrine systems in the relationships between outdoor temperature and skin temperature, blood pressure, blood glucose concentration, salivary amylase activity, and heart rate variability. Life requires adaptation to changing outdoor temperatures LeBlanc , and theExposure to cold provokes a range of physiological responses, predominantly as a consequence of activation of the sympathetic nervous system, including skin temperature, heart rate, diastolic blood pressure, and blood glucose. Skin temperature falls on exposure to cold because of peripheral vasoconstriction . We limited the amount of exercise before lunch to avoid the effects of strenuous exercise on body fat measurement. We did not limit water intake prior to the measurements but did adjust for body fat percentage in the multiple regression analysis. Satiety was assessed using a visual analog scale (100 mm) before and after lunch.Fifty-three healthy female university students aged 18–29 years volunteered to participate in this study, which was approved by the Human Studies Committee of Hiroshima Bunka Gakuen Two-Year College. Informed consent was obtained from all participants. We studied females because previous studies on physiological responses to eating or temperature were conducted using female participants , allowing 10 min for equilibrium to be reached. Axillary temperature was chosen rather than measuring skin temperature over the region of the liver because the axillary method is the most commonly used method in Japan and because we felt that we would obtain greater participant consent using this method, given that we took four readings. Noninvasive systolic and diastolic blood pressures were measured in the upper arm using a cuff and an Omron HEM-1000 fully automatic monitor . Blood glucose concentration was determined by the glucose oxidase method  from finger prick samples. Salivary amylase activity (fasting and after lunch) was measured using a hand-held noninvasive monitor  based on the 2-chloro-4-nitrophenyl-4-galactopyranosylmaltoside hydrolysis method . Power spectral analysis of heart rate variability was used to determine the R-R interval, and spectrum estimation was analyzed by fast Fourier transformation. Heart rate variability analysis was carried out based on the guidelines of the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology  in spontt tests were used to compare fasting salivary amylase activity or LF/HF ratio 1 h after lunch in three groups of participants stratified by outdoor temperature . Values of P < 0.05 were considered statistically significant. Changes in satiety before and after lunch were analyzed using the Friedman test and the Wilcoxon-signed rank test. Satiety before and after lunch was assessed by stratifying by outdoor temperature as for LF/HF ratio.All statistical analyses were performed using SPSS software . Data for all participants and outdoor environmental conditions are expressed as means ± SD or standard error (SE). The distribution of data was initially examined using the Shapiro–Wilk test then analyzed using parametric or nonparametric tests, accordingly. The Friedman test was performed to assess temporal changes in physiological variables before and after lunch. The Wilcoxon-signed rank test was performed to compare physiological variables recorded before lunch (baseline) with each time point after lunch. Multiple linear regression analyses were undertaken to determine associations between changes in physiological variables from the baseline levels recorded before lunch and outdoor environmental conditions. These analyses were performed after adjusting for room temperature, age, body mass index, and proportion of body fat. To further examine the relationships between salivary amylase activity, LF/HF ratio, and outdoor temperature, unpaired Participant characteristics are shown in Table Diastolic blood pressure and salivary amylase activity both fell significantly after lunch compared with baseline. Systolic blood pressure did not change significantly. Blood glucose concentration and heart rate rose significantly at all time points after eating compared with baseline. Skin temperature also rose after eating, but this was significantly higher than baseline only at 1 h. LF/HF ratio also fell after eating, indicating the predominance of parasympathetic activity; however, this was statistically significant only at 1 h after lunch , salivary amylase activity , and LF/HF ratio (Δ LF/HF ratio) Table , but notSatiety peaked immediately after lunch and fell gradually thereafter : heart rate variability, salivary amylase activity, skin temperature, diastolic blood pressure, plasma glucose concentration, systolic blood pressure, and heart rate.Our study had several limitations. First, we chose to study young healthy women living in Hiroshima, as women’s sensitivity to climate stress appears to differ from that of men Below is the link to the electronic supplementary material.


Chronic kidney disease (CKD) accelerates vascular stiffening related to age. Arterial stiffness may be evaluated measuring the carotid-femoral pulse wave velocity (PWV) or more simply, as recommended by KDOQI, monitoring pulse pressure (PP). Both correlate to survival and incidence of cardiovascular disease. PWV can also be estimated on the brachial artery using a Mobil-O-Graph; a non-operator dependent automatic device. The aim was to analyse whether, in a dialysis population, PWV obtained by Mobil-O-Graph (MogPWV) is more sensitive for vascular aging than PP.A cohort of 143 patients from 4 dialysis units has been followed measuring MogPWV and PP every 3 to 6 months and compared to a control group with the same risk factors but an eGFR > 30 ml/min.MogPWV contrarily to PP did discriminate the dialysis population from the control group. The mean difference translated in age between the two populations was 8.4 years. The increase in MogPWV, as a function of age, was more rapid in the dialysis group. 13.3% of the dialysis patients but only 3.0% of the control group were outliers for MogPWV. The mortality rate (16 out of 143) was similar in outliers and inliers (7.4 and 8.0%/year). Stratifying patients according to MogPWV, a significant difference in survival was seen. A high parathormone (PTH) and to be dialysed for a hypertensive nephropathy were associated to a higher baseline MogPWV.Assessing PWV on the brachial artery using a Mobil-O-Graph is a valid and simple alternative, which, in the dialysis population, is more sensitive for vascular aging than PP. As demonstrated in previous studies PWV correlates to mortality. Among specific CKD risk factors only PTH is associated with a higher baseline PWV.NCT02327962.ClinicalTrials.gov Identifier:  Chronic hemodialysis patients should have arterial stiffness evaluated monthly using Pulse Pressure as suggested by KDOQI guidelines . This reComing back to arterial stiffness it is also important to mention that the increase in PWV related to the above-mentioned risk factors accelerates with age  and thatRisk factors such as age, hypertension, previous history of heart diseases and diabetes influence the evolution of Pulse Wave Velocity before dialysis initiation whereas their impact during the course of dialysis has not yet been demonstrated . In thisIn the above-mentioned study, the rate of PWV progression (+0.84 m/s per year) was surprisingly high, especially when projected over time as a function of the average life span of ESRD patients on dialysis. Another critical data point outlined in the study was the discrepancy in the annual rate of change in carotid-femoral compared to carotid-radial Pulse Wave Velocity, which was +0.84 m/s per year and −0.66 m/s per year, respectively. The authors of the study postulate that this discrepancy may be due to anatomical differences between central (elastic) and peripheral (muscular) arteries and that the latter could deploy an adaptive response to central aortic stiffening. Although interesting, these data raise some concerns about the promising possibility of using the brachial artery as a site for PWV estimation, even if based on a non-operator dependent method.Furthermore, another limitation identified in the literature currently available on prospective longitudinal studies analysing the PWV behaviour on dialysis patients, is the lack of a control group made up of patients with similar characteristics and co-morbidities but without, or with a less severe, kidney disease ,15,17.In the light of this, we decided to test a Mobil-O-Graph, a simple device estimating PWV (MogPWV) through a modified sphygmomanometer on the brachial artery and to analyse the baseline and follow-up MogPWV values in a cohort of dialysis patients and in a control group with the same risk factors but an eGFR > 30 ml/min.The aim of the study was answering the following 4 questions, which also reflect both the primary and the secondary endpoints of the trial: 1. Is PWV estimated by Mobil-O-Graph on the brachial artery more sensitive for vascular aging and discriminates better the dialysis population from the control group than pulse pressure? (primary endpoint); 2. Is MogPWV progression during dialysis faster compared to the rate calculated as a function of age on the basis of the data obtained at the inclusion day? (secondary endpoint); 3. Are there specific risk factors that correlate to baseline MogPWV? (secondary endpoint); 4. Does mortality correlate to MogPWV? (secondary endpoint).According to the above cited aims, a multi-centre cohort study was designed.Hemodialysis patients were recruited from 4 dialysis units located in the Italian-speaking part of Switzerland , starting from January 2011. The study was designed to last 30 months. Subjects of the control group were recruited from patients hospitalized at Ospedale la Carità, Locarno, for elective minor surgery and waiting for transfer or discharge.Inclusion criteria for the hemodialysis group: age 18 and older; ability to understand the information presented and to sign the informed consent; chronic hemodialysis for at least 8 weeks. Exclusion criteria for the hemodialysis group: mental illness; inability to understand the information presented and to sign the informed consent; acute disease requiring hospitalization at the time of patient enrolment; evidence of stenosis of the subclavian artery of the arm without shunt or of the non-shunt arm chosen to be used for the Mobil-O-Graph measurements; atrial fibrillation.Inclusion criteria for the control group: age 18 and older; ability to understand the information presented and to sign the informed consent. Exclusion criteria for the control group: mental illness; inability to understand the information presented and to sign the informed consent; evidence of stenosis of both subclavian arteries; atrial fibrillation; eGFR(EPI) < 30 ml/min (CKD stage 4 and 5).Non-invasive hemodynamic and MogPWV measurements were performed the day of inclusion in the study and repeated every 3 months the first year and then every 6 months (the non-shunt arm or the right arm being chosen for the haemodynamic measurements), together with a comprehensive screening of general  and specific cardiovascular risk factors for CKD patients . At the inclusion, anamnestic data about the cause of kidney disease , data of dialysis initiation, dialysis modality and prescriptions (including ultrafiltration volume), dialysis quality , medications including phosphate binders, vitamin D and analogues, calcium agonists and antihypertensive and routine laboratory tests  were also collected. At the follow-up visits file information was upgraded and changes protocolled.The Mobil-O-Graph , an electronic blood pressure monitoring system equipped with an arm cuff and a software tool for Pulse Wave Analysis  was chosen for non-invasive hemodynamic and PWV monitoring. The reliability of the Mobil-O-Graph in estimating the PWV by PWA (MogPWV) was demonstrated in previous studies -12,18-22E[MogPWV] = α + β1 * age + β2 * PAsyst. The MogPWV values were then normalized by eliminating the effect of systolic blood pressure, on the basis of the above cited equation, independently obtained from the results of the two groups. Aware of the fact that systolic blood pressure is a parameter already used in the algorithm to calculate the MogPWV by PWA, normalisation was applied considering the strong intra-individual influence of systolic blood pressure on MogPWV and the extreme variability of blood pressure during dialysis. MogPWV outliers were defined as individuals with, Bonferroni corrected studentized residuals P values (of the measured PWV) of less than 0.05.Statistical analysis was performed using the R software tool . StartinTo test the normality of the residuals the Shapiro’s test and the QQ-plot were used while the homoscedasticity was proven thanks to the Levene (for the homogeneity of the variances) and the Breusch-Pagan  tests . To veriP value ≤ 0.05 was considered statistically significant.In all cases, a The protocol of the study was approved by the local ethics committee . Informed consent was obtained from all patients prior to enrolment.143 patients were included in the dialysis group and 100 in the control group .P < 0.01).Systolic blood pressure significantly influenced MogPWV in both groups: in the control group a systolic increase of 10 mmHg generates a MogPWV increase of 0.319 ± 0.014 m/s. The dialysis group featured a lower increase, i.e. 0.237 ± 0.025 m/s (P between groups n.s. on a PP against age distribution), MogPWV significantly discriminates the dialysis population from the control group (P <0.001) ; signifying that 13.3% of the dialysis patients, compared to the rest of the group, had a statistically significant unexpected elevated MogPWV value.Unlike Pulse Pressure ; while the slope increases with age in both groups.The mean horizontal difference between the two MogPWV against age distributions  was 8.4 years (95% CI: 3.8-12.9) meaning that the arteries of our dialysis population were, on average, 8.4 years older than controls. These findings suggest that the difference is exclusively related to the extent of renal function impairment, since other risk factors were comparable across the two groups. The regression line for the dialysis group, divided into 4 quartiles of age, was slightly but significantly steeper than in the control group  was similar in outliers and inliers (7.4 and 8.0 % per year). Patient stratification according to the MogPWV showed a significant difference in survival , lower serum calcium , lower serum phosphate  correlate with higher baseline MogPWV. See Table Hypertensive nephropathy as a presumed cause for ESRD , higher PTH levels  . The results furthermore confirm that PWV estimated by Mobil-O-Graph (MogPWV) is able to intercept a discriminating vascular aging parameter between dialysis patients and control group, which is otherwise undetectable via PP measurement. The 8.4 years difference between the two MogPWV distributions (95% CI 3.8-12.9 years) suggests that the arteries of our dialysis patients were, on average, 8.4 years older compared to a control group with a similar co-morbidity profile but a less compromised renal function.Even if the difference in the antihypertensive medication profile between the two groups , could have increased the magnitude of the difference in vascular aging ,27, the Extrapolating the results of the two curves obtained by the exponential model and expressing the distribution of the MogPWV as a function of age in the two groups, the theoretical convergence point was found to be located many decades before the start of dialysis. Taking into account the limits of such an analysis approach and the potential sources of bias, the result suggests that the acceleration of PWV worsening begins long before the onset of ESRD.The results obtained, substantiate the efficacy of using such a simple non-operator dependent device to measure vascular stiffness in haemodialysis patients in clinical wards.However, the evidence gathered from this trial, as well as previous ones, does not make it possible to ascertain the extent to which MogPWV estimated on the brachial artery, is representative of the actual carotid-femoral PWV for this particular patient setting.Even if a correlation between MogPWV and ultrafiltration rate during dialysis, in the present study, was not demonstrated; we must also bear in mind that PWV is subject to fluctuations during dialysis due to changes in blood pressure, solute concentrations and circulating volume -31. EvenAlthough our results were gathered during dialysis with many potential sources of bias, they provide interesting and intra-patients reproducible information on vascular aging that could be of relevance for individual patients. Therefore, despite the above-mentioned constraints, the results of this trial give the basis for the concrete selection of patients potentially at high-risk , who could benefit from a customized management in the attempt to slow down vascular aging and related factors like vascular calcification; and this even if we were unable to demonstrate, probably because of the relatively small size of the population, a relationship between the outlier status and specific known risk factors (except for elevated PTH levels).In a previous longitudinal study in dialysis, Utescu et al. were in turn unable to demonstrate the impact of classical risk factors on PWV progression; this eventually being also related to the limited caseload or to the fact that the largest amount of pathological changes in the vascular wall could have been accumulated years before the beginning of dialysis.Other risk factors identified during the trial, such as serum ionized calcium under the lower limit of the normal distribution, serum phosphate ≤ 1.78 mmol/L, and physiological vs. supra-physiological dialysate calcium, were unexpected and may have been the result of the treatment strategy deployed during dialysis . Moreover, as suggested above, the risk factors were detected during the trial period and did not account for past or pre-dialysis patient management strategies that might explain the MogPWV outlier status. Emphasizing this hypothesis, evidence of hypertensive nephropathy, although not biopsy proven in most of the cases, as the aetiology of End Stage Renal Disease , correlated to higher MogPWV, as expected.Since this trial shows no evidence of faster MogPWV progression during dialysis vs. pre-dialysis cumulative data (+0.165 vs. +0.169 m/s/year), we can assume, as mentioned above, that the difference vs. controls progressively built up over the years preceding dialysis initiation, most likely due to the severity of kidney dysfunction being a specific risk factor, and, possibly, to patient management strategies.Moreover, the steeper curve depicting MogPWV as a function of Blood Pressure in the control group confirms that the vascular behaviour and the relationship PWV-Blood Pressure between groups is different. A lesser PWV reversibility decreasing systolic blood pressure in the dialysis group could be postulated.Similarly to previous trials ,33-35, mEstimating PWV on the brachial artery using a Mobil-O-Graph is a valid and simple alternative to direct measurement, is more sensitive for vascular aging and discriminates better the dialysis population, identifying at the same time the outliers, than Pulse Pressure. The importance of early prevention of vascular stiffening is once again outlined by the facts that the arteries of our dialysis patients were, on average, 8.4 years older compared to a similar population but with a significant better renal function and that the acceleration of PWV progression has been found to begin well before dialysis initiation. As demonstrated in previous studies, MogPWV correlates to mortality. Among specific CKD risk factors, only PTH correlates to higher baseline MogPWV. Additional studies may contribute to further characterize risk factors, susceptible to being influenced, associated with MogPWV progression during dialysis.


Kangaroo mother care (KMC) has been widely used to improve the care of preterms and low birth weight infants. However, very little is known about cerebral hemodynamics responses in preterm infants during KMC intervention. The aim of this study is to evaluate the changes of cerebral blood flow (CBF) in middle cerebral artery, before and after a 30 minute application of KMC in stable preterm infants.2 were also studied before and after KMC.It is a prospective, pre-post test without a control group study. CBF flow paremeters were measured with Doppler ultrasonography in one middle cerebral artery. Sixty preterm stable infants were assessed before and after 30 min KMC. CBF indices were assessed in different positions before KMC, forty neonates in supine position and 20 in vertical suspension . Other dependent variables heart rate and mean arterial blood pressure and SpoThe mean gestational age of the infants was (32 ± 2 weeks), and mean birth weight was (2080 ± 270 gm). Comparing CBF indices (Pulsatility index and Resistive index) before and after KMC has shown a significant decrease in both Pulsatility index (PI) and Resistive index (RI) after 30 min. KMC, the mean values were (2.0 ± 0.43 vs 1.68 ± 0.33 & 0.81 ± 0.05 vs 0.76 ± 0.06 respectively P < 0.05*) with mean difference (0.32 & 95% CI 0.042-0.41 & 0.05 & 95% CI 0.04 to 0.06 respectively P < 0.05*) and increase in end diastolic velocity & mean velocity 30 min of KMC (10.97 ± 4.63 vs. 15.39 ± 5.66 P < 0.05*& 25.66 ± 10.74 vs. 32.86 ± 11.47 P < 0.05* ) with mean difference (− 4.42 & 95% CI −5.67 to −3.18 and −7.21 & 95% CI - 9.41 to 5.00 respectively). These changes indicate improvement in CBF. No correlation has been found between CBF parameters and studied vital signs or SpO2.Kangaroo mother care improves cerebral blood flow, thus it might influence the structure and promote development of the premature infant's brain. Most of the causes of neonatal death can be prevented or treated through simple, effective and low-cost intervention, at home or in the community  were measured in two different positions , then these data were collected again immediately after 30 mins of KMC.Heart rate was measured by using the signal from the Nonin Pulse Oximeter, blood pressure was measured by Dinamap oscillometric monitor.Middle cerebral artery was visualized by Colored Doppler Ultrasonography (Esaote MyLab apparatus) with a sectorial multi-frequency transducer 7.5 MHz. in the fold of the temporal lobe (as acoustic shadow) from the straight mid portion of the artery while few cases were visualized in frontal lobe. In all cases, the angle between the ultrasound beam and blood flow in the vessel was close to 0 degree, range (0-20°), angle correction and calculation of velocities were made automatically by the instrument's software obtained from five sequential cardiac cycles of optimal quality to obtain reliable flow velocity values .Descriptive data are reported as mean +/− standard deviation, ranges, median and interquartile ranges (IQR). The data collected were statistically analyzed by computer using SPSS release 17 for windows. Tests of statistical significance used were chi-square test, independent t-test, paired t-test  and Pearson correlation coefficients were used to assess the relation between two parameters with quantitative data in the same group. P value of <0.05 was considered as statistically significant.Sixty healthy clinical stable preterm neonates, breathing spontaneously without supplemental oxygenation were included in this study. Their mean gestational age was (32 ± 2 weeks), mean postnatal age was 13 ± 4 days and mean birth weight was (2080 ± 270 gm) ranging from 1600 to 2400 gm. Their median Apgar score after one minute was 7 and after 5 minutes was 8.Comparing data before and after the application of KMC for 30 minutes, there has been a significant decrease in heart rate and an increase in systolic and diastolic blood pressure, MABP and SpO2 Table  .Table 1Regarding CBF parameters, there has been a statistically significant decrease in both PI and RI after 30 min of KMC and increase in the end diastolic velocity and mean velocity (MV) Table  and 2. N2) after 30 min of KMC. Researchers have explained the improvement in oxygenation by the fact that the upright position of KMC increases the efficiency of the diaphragm and pulmonary function [Premature infants have significantly more developmental impairment than their term counterparts. Oxygen is regularly used in preterm infants because of their immature lungs and oxygen is important for metabolism and physiological functions ,13. Thisfunction ,15. On ofunction ,17..In the current study, there has been a statistically significant decrease in heart rate after applying KMC that generally remained within clinically normal range (120–160 bpm). KMC results in significant reduction in B-endorphin as sign of attenuation of stress response. Some researchers have reported an increment in the heart rate during KMC because of changing newborn’s body position from supine to vertical which leads to increased stress for the newborn -21 .Regarding blood pressure, our results have shown a significant increase in mean arterial blood pressure after receiving KMC for 30 mins, may be as an infants response to head up tilt by two mechanisms; the vestibular and baroreceptor reflexes. Head up tilt may cause a fast-acting vestibular-mediated increase in BP. Subsequently, a stimulated baroreflex causes falling in HR and BP returns to resting levels. Other studies haven’t shown any significant changes in blood pressure before and after KMC -26.Very little is known about cerebral hemodynamics during KMC intervention. CBF is an important parameter evaluating brain haemodynamics and oxygenation. Moreover, it has been widely used to monitor cerebral perfusion in infants with birth asphyxia or brain lesion. Our results have shown a statistically significant decrease (P < 0.01) in both Pulsatility index and Resisitive index after 30 min of KMC. On the other hand, there has been a statistically significant increase in the end diastolic velocity (EDV) and the mean velocity. These data suggest that kangaroo mother care leads to improvement of CBF within normal physiological range -29.No difference has been observed in calculated cerebral vascular resistance and velocity between supine and vertical (upright) suspension (holding the baby upright and far away from his mother’s skin). On the other hand, when comparing supine position and KMC, we have found a significant increase in cerebral velocities after KMC, this means that skin to skin itself has provoked a considerable increase in CBF velocity irrespective to the upright position. Improvement in CBF has been probably mediated by stabilized cardio respiratory parameters during sleep. Another explanation; is that human hairy skin has slow conducting unmyelinated (C) afferents that respond to touch and skin to skin contact during KMC. Activation of these fibers stimulates the insular cortex (limbic system) to produce mediators , which in turn enhance postsynaptic Nitric Oxide Synthase. Nitric oxide induces smooth muscle relaxation and plays a pivotal role in regulating blood flow in the microvasculature ,31.In our study, blood pressure did not correlate with CBF velocities. The lack of correlation suggests that preterms can already autoregulate their cerebral blood flow during KMC.Although many aspects regarding the evolutivity of the brain of the preterm infants still need a clarification, the data we reported, if confirmed in further studies, could be extended to lower gestational ages and may be related to the infants’ neurologic outcome to allow a tighter correlation with practice.Kangaroo Mother Care improves cerebral blood flow, within its normal level, thus it might positively influence the structure and the development of the premature infant’s brain. Further study is needed to determine the long-term outcomes of the premature infants.Accessing haemodynamic stability limits the application of KMC to a higher gestational age (32 +/− 2 weeks) and weight (2080 +/− 270 gm) of studied infants. Even though there is a possibility for extended application of KMC for neonates with lower gestational age and lower birth weight.The relatively small sample size.There are other advanced ultrasonography that can calculate more measurements.


Cardiovascular disease, like hypertension, is one of the top killers of human life and early detection of cardiovascular disease is of great importance. However, traditional medical devices are often bulky and expensive, and unsuitable for home healthcare. In this paper, we proposed an easy and inexpensive technique to estimate continuous blood pressure from the heart sound signals acquired by the microphone of a smartphone. A cold-pressor experiment was performed in 32 healthy subjects, with a smartphone to acquire heart sound signals and with a commercial device to measure continuous blood pressure. The Fourier spectrum of the second heart sound and the blood pressure were regressed using a support vector machine, and the accuracy of the regression was evaluated using 10-fold cross-validation. Statistical analysis showed that the mean correlation coefficients between the predicted values from the regression model and the measured values from the commercial device were 0.707, 0.712, and 0.748 for systolic, diastolic, and mean blood pressure, respectively, and that the mean errors were less than 5 mmHg, with standard deviations less than 8 mmHg. These results suggest that this technique is of potential use for cuffless and continuous blood pressure monitoring and it has promising application in home healthcare services. Cardiovascular disease  is one of the top killers of human life. As reported by the World Health Organization (WHO), it took 17.5 million people’s lives globally in 2012 [As the smartphone is becoming ubiquitous, its application in medicine is of increasing interest . The newet al. applied an artificial neural network to evaluate blood pressure from the pulse wave signal acquired by the camera of the smartphone [et al. proposed two other methods to cufflessly estimate blood pressure with smartphones [In this paper, we demonstrate that the smartphone can also be used to estimate blood pressure. Blood pressure is the pressure exerted on the wall of blood vessels by blood when the blood flows through arterial vessels . It is aartphone ,10. Chanrtphones . The firrtphones . If the Heart sounds are mixed audible sounds generated by the contraction and relaxation of the atria and ventricles, the valve movements, and the blood flow . The twoet al., explained this phenomenon as the mechanical oscillation caused by the elasticity of the vessel walls and the inertia of the blood column. When the blood pressure is increasing, the arterial wall will exert an increasing reset force to counteract the tangential tension of the arterial wall, resulting in increasing oscillation frequencies of the blood column [et al., built a mathematical model for the vibration of the closed aortic valve, and the simulation results showed that the increasing aortic pressure lead to an increase both in frequency and amplitude of the produced sound [et al. utilized a force sensor to collect heart sound signals and carefully investigated the relationship between S2 and blood pressure in 146 patients. They found that the S2 recordings quantitatively documented the blood pressure changes and that the correlation coefficients between the amplitude of S2 and systolic, diastolic, and mean blood pressure were 0.544, 0.502, and 0.567, respectively [It is well-recognized in clinical medicine that the S2 has a characteristic “accentuation” in hypertensive patients ,15. Bartd column . Accordied sound . Later, ectively . AccordiThe experiment was approved by the Institutional Review Board of Shenzhen Institutes of Advanced Technology (registration number: SIAT-IRB-120515-H0009). Thirty-two subjects participated in the experiment . They were all healthy without any known diseases and provided their written informed consent. They were asked to refrain from caffeine, alcohol, cigarettes or strenuous exercise for 2 h before the experiment.® MIDI  was used with a finger cuff around the right middle finger to measure continuous blood pressure. The Finometer is a commercial medical device that can measure beat-to-beat blood pressure based on the volume-clamping principle. It provided a report of the systolic, diastolic and mean blood pressure for each heartbeat.In the experiment, all the subjects were instructed to lie in the supine position on a mattress. As shown in As shown in All the data were processed offline in Matlab 7.0  on a personal computer. The heart sound signals were first filtered by a Butterworth low-pass filter with cutoff frequency of 1000 Hz to reduce high-frequency noise, and then were filtered by a Butterworth high-pass filter with cutoff frequency of 5 Hz to remove the baseline wandering. These filters were implemented by filtering the signal in both forward and backward direction to achieve a zero-phase response without group delay. As the heart sound signals were sampled at 44.1 kHz by the smartphone, they were decimated by a factor of 20 to obtain a lower sampling frequency of 2205 Hz.x is the normalized signal. Thirdly, the Shannon energy was averaged in a moving time window of 20 ms with overlap of 10 ms, as expressed by:E is the Shannon energy, AE is the average Shannon energy and N is the length of the window. Since the sampling frequency was 2205 Hz, N was equal to 44 here. Then, AE was normalized by subtracting the mean and dividing by the standard deviation, as expressed by:NE is the normalized average Shannon energy, M(AE) and S(AE) are its mean value and standard deviation, respectively.Then each down-sampled signal was segmented based on its envelope of Shannon energy . FirstlyNE to identify the potential peaks of S1 and S2 [Afterwards, two thresholds were applied to 1 and S2 . A high Once identified, the S2 of each heartbeat in the normalized heart sound signals was truncated by a 64 ms window centered at the maximum of the S2, and its frequency spectrum was obtained by fast Fourier transform (FFT), shown in ix is a feature vector with target value iy, w is weight vector, b is intercept, ix, and ε is a threshold of the deviation. The SVM regression maps the feature vectors ix  into a higher dimensional space by a nonlinear transform, and finds an optimal linear hyperplane with at most ε deviation to fit the target value iy  in this higher dimensional space [Afterwards, the S2 features were separately connected with the systolic, diastolic and mean blood pressure using a support vector machine (SVM). The SVM is a popular machine learning method for classification and regression . The regal space . The nonThe LIBSVM package developed by Chih-Chung Chang and Chih-Jen Lin  was emply is the predicted value, x is the measured value, and n is the number of samples.For each subject, the predicted values using the SVM regression were compared with the ‘true’ values measured by the Finometer device. Pearson correlation coefficient (CC), mean absolute error (MAE), mean error (ME), and standard deviation (SD) were calculated as below:The relationship between the spectrum of the S2 and blood pressure is shown in A typical example of blood pressure estimation was given in The CCs, MAEs, MEs, and SDs for each subject were presented in vs. SBP and PTT vs. DBP were −0.544 and −0.451, respectively. Additionally, as required by the American Association for the Advancement of Medical Instrumentation (AAMI), the ME should be ± 5 mmHg or less, with a SD of 8 mmHg or less [The distributions of CC, MAE, ME, and SD among all the subjects were presented in  or less . These rThe results confirmed that the spectrum of S2 had a strong connection with the blood pressure, and that it was realizable to estimate blood pressure from the heart sound acquired by a smartphone. This new technique can continuously and non-invasively measure beat-to-beat blood pressure using only a smartphone and a stethoscope. It needs neither the sphygmomanometer with an inflatable cuff, nor the bulky and expensive medical instrument used only in the hospital. It is easy-to-use and low in cost, and well-suited for daily use at home. As we have tested, when the environment is quiet, even the stethoscope is not required and the heart sound can be clearly detected by just pressing the microphone tightly on the chest of the subject , or usinAlthough the results are encouraging, there are some technical issues which need to be taken into account to use this technique in practical situations. The first is to reduce the training phase. In the presented experiment, to collect the training data, we elevated the blood pressure by the cold stimulus, which cannot be applied to cardiovascular patients due to its potential risk of strokes or heart attacks. Therefore, the wide blood pressure variation needs to be simplified to a safe and convenient procedure, for example, collecting the training data before and after physical exercise , or chanThe second is to implement a real-time SVM algorithm on the smartphone. At the current stage, the SVM algorithm runs on a personal computer and all the signals are processed offline. In order to monitor blood pressure in real-time, it is important to port the SVM algorithm to a smartphone platform where the CPU power and memories are limited. However, as the smartphone technology is rapidly developing, we think this is not a huge problem.The third is to reduce the interference of environmental noise. The heart sound is so weak that it may be corrupted by the environmental noise. We suggest strengthening the heart sound signals in two aspects. In the hardware aspect, the microphone can be designed as a small piece pasted on the chest of the subject, with a small funnel embedded inside to collect acoustic wave, and with sponges covered outside to prevent environmental noise. However, this design can be only applied to home-made wearable devices, and is not applicable to off-the-shelf smartphones. In the software aspect, adaptive filters  can be uIn this paper, with a smartphone to collect heart sound signals, we demonstrate a new technique to estimate blood pressure from the spectra of the second heart sound, continuously, non-invasively and without a cuff. This technique provides an easy, low-cost and comfortable solution for daily monitoring of blood pressure, which is especially useful for cardiovascular patients.


The Los Angeles County Department of Public Health teamed with a culturally tailored, community-based organization to augment their hepatitis B screening program with blood pressure assessments. During 6 months, 2,298 people were served by the program; descriptive statistics and models were generated to describe demographics and screening and assessment results. Despite the program having good reach, sustainability was challenging. This experience draws attention to the need for invested desire to change at both the organizational and patient levels to sustain interdisciplinary provision of clinical preventive services. The Centers for Disease Control and Prevention’s 2012 Community Transformation Grants (CTG) program sought to improve health by addressing 3 strategic directions, including the ABCs of prevention   and hepatitis B surface antibodies (anti-HBs) at 26 community health events; at 18 events, 1,499 people were also offered blood pressure assessments. Blood pressure assessments were not offered at 8 events because other organizations were providing this service. Hepatitis testing was administered by certified and licensed staff, and blood pressure measurements were taken by trained volunteers using an automated sphygmomanometer. Events were held in primarily Asian communities, but services were available to any person regardless of race/ethnicity. People interested in screening or assessment were given educational information and asked to complete a self-administered intake questionnaire, which included questions about date of birth, sex, race/ethnicity, and marital status, in the appropriate language.Hepatitis B results were mailed directly to participants and/or their referring physician within 2 or 3 weeks of screening. Blood pressure results were available immediately. Those who screened positive for hepatitis B or possible hypertension were referred to local clinics for follow-up, using standardized clinical protocols. Protocols for the case study were reviewed and approved by the Los Angeles County Department of Public Health institutional review board.Descriptive statistics were generated to describe demographics and screening and assessment results. Contingency tables of HBsAg and anti-HBs results were created to stratify disease staging . A multiMost program participants  were women. More than half  were aged 45 to 64 years, and most were married  .Of those screened , 159 participants tested positive for HBsAg; 1,458 tested positive for anti-HBs ; 1,445 pOf the 1,499 participants who were offered blood pressure assessments, 1,318 had their measurements taken. Of these, 34.6% had readings in the prehypertension range; 28.8% had readings in the hypertension range . Forty-tP < .05). Those aged 65 or older also were less likely than those aged 44 or younger to test positive . Men were more likely than women to test positive .In the regression analysis of HBsAg results , race/ethnicity was associated with a positive test . When stP ≤ .001)  were more likely to have blood pressure readings in the prehypertension and hypertension ranges ( ≤ .001) .The integration of blood pressure assessments to an existing hepatitis B screening program reached a good number of high-risk people during the 6-month study period. About 7% of those screened for hepatitis B were thought to have active chronic infection; however, disease severity, including the degree of portal hypertension and liver cirrhosis, was not assessed in this study. Another 28% had no immunity and could benefit from vaccination. Almost two-thirds of those assessed for blood pressure had readings in the prehypertension or hypertension ranges. A subgroup analysis suggested that treatment was not uniform. For example, of 42 Chinese adults with readings in the hypertension range, only 22 reported taking blood pressure medications. These and other results from the models were consistent with the literature, further highlighting the risks associated with these conditions  to leverage resources and develop community–clinical linkages. For this model of practice to be sustainable, coordination of investments, services, and innovation in the community should be strengthened. Furthermore, a shift in the collective attitude toward supporting these and other prevention efforts is needed.


Use of renin-angiotensin system (RAS) blockade has become increasingly widespread driven by evidence-based guidance. There is concern about the role of these agents in the genesis of avoidable acute kidney injury (AKI).To investigate the association between AKI and use of RAS blockade.Multilevel hierarchical analysis of a large cohort of patients registered with UK general practitioners.Primary care practices in East and West Kent, United Kingdom.244,715 patients from 27 practices.Demographic, clinical, biochemical and prescription data.Analyses of data acquired between 02/3/2004 and 17/04/2012 using multilevel logistic regression to determine the relationship between AKI and use of RAS blockade; further analysed by indication for treatment with RAS blockade.Sufficient serum creatinine data were available to define AKI in 63,735 patients with 208,275 blood test instances. In 95,569 instances the patient was prescribed a RAS antagonist of which 5.4% fulfilled criteria for AKI. The unadjusted odds ratio (OR) for AKI in those prescribed RAS blockade was 1.93  falling to 1.11  when adjusted for age, gender, co-morbidity, GFR category, proteinuria, systolic blood pressure and diuretic therapy. In patients with an evidence-based indication there was no difference in absolute risk of AKI. However, prescription of RAS blockade in the absence of indication appeared to be associated with greater risk of AKI.When analysis was repeated with AKIN2/AKIN3 as the outcome, although risk of AKI remained significant when unadjusted , after full adjustment there was no increased risk  in those taking RAS antagonists. However, when analysed by indication AKIN2/AKIN3 was significantly more likely in those prescribed RAS antagonists without indication .Observational database study. No information concerning hospitalisation. Prescribing assumptions and potential inaccurate coding. Potential survival bias; patients surviving longer will contribute more data.Use of RAS antagonists increased the risk of AKI, independent of common confounding variables. After correction for confounders the risk fell away and became non-significant for moderate and severe AKI. However, where there was no evidence-based indication for RAS antagonists the risk of AKI, whether mild, moderate or severe, remained greater. These agents are effective in lowering of blood pressure, reducing proteinuria and amelioration of chronic kidney disease (CKD) progression -3. EvideIn addition hypertension guidance recommends use of RAS antagonists in those with hypertension and age <55 years or resistant hypertension at any age  and in tOutside these indications there is no evidence to support the choice of RAS antagonists over other classes of anti-hypertensive agent in the management of hypertension, with or without CKD. The majority of patients with CKD will not progress to ESRD and these patients are predominantly managed by primary care in the community. In England during 2012 prescriptions for ACEIs, ARBs and DRIs accounted for 6.0 percent of all prescription items . Not allDespite these concerns over the safety of RAS antagonism, in particular in relation to AKI we do not know the level of risk of AKI associated with the routine prescription of these agents in primary care.The aim of this study was to examine the relationship between prescription of RAS antagonists and development of AKI in the community.We performed a multilevel hierarchical analysis of a large cohort of patients registered with UK general practitioners.2 or on renal replacement therapy were excluded.Data were extracted from the System for Early Identification of Kidney Disease (SEIK) database. SEIK is a computerized decision support system developed to assist in the management of CKD. The system extracts anonymised demographic, clinical, biochemical and prescription data from primary care systems. Reports aiding and advising on the management of CKD generated using an automated decision tree matrix and several computer algorithms based on NICE guidance -6,8 are In initial analyses it was evident that a large proportion of patients may switch between treatment with and without RAS antagonists over time, and therefore comparing outcomes in terms of episodes of AKI between these as 2 distinct groups was not viable. We therefore chose to analyse the data at the serum creatinine blood test level. For each patient we extracted all recorded serum creatinine estimations between 02/3/2004 and 17/04/2012. Each serum creatinine then became a data point “blood test instance” at which we extracted and defined the independent and outcome variables.In performing the analysis at the blood test level there was then the inherent risk that several blood tests for an individual patient could represent the same episode of AKI. Therefore for a given episode of AKI the analysis algorithm excluded all blood results 30 days either side of the peak AKI result, unless a result within the 30 days no longer defined AKI. In this instance subsequent results were not thought to be part of that AKI episode, either prior to the AKI in the 30 days preceding the peak AKI result or demonstrating recovery in the 30 days post the peak AKI.At each data point, “blood test instance”, we extracted or determined: age, gender, co-morbidity , GFR category, proteinuria, blood pressure readings and prescription data including all anti-hypertensive agents and RAS antagonists. For the purposes of determining proteinuria indications for RAAS antagonists the highest proteinuria result for each patient was used. Proteinuria was categorised as per the KDIGO CKD Clinical Practice Guideline 2012 into three categories: “normal to mildly elevated”, ACR  <3 mg/mmol; “moderately elevated”, ACR  3–30 mg/mmol; and “severely elevated”, ACR  >30 mg/mmol . There iIn this study the outcome variable of interest was AKI in primary care. AKI was defined by the acute kidney injury network (AKIN) creatinine criteria  but usinThis work was supported by the East Kent Hospitals Charity and approved by East Kent Hospitals University NHS Foundation Trust R&D Department, R&D ref: 2010/RENAL/09.The primary aim of this analysis was to examine the association between patients taking RAS antagonists and experiencing episodes of AKI. In the analyses AKI was considered primarily as a binary variable, present or absent (ie AKI or no AKI and AKIN2/AKIN3 or no AKI/AKIN1). A feature of the data was that there were multiple measurements from some patients and as a result of this it was unlikely that the outcome values were all independent of each other. It was likely that outcomes for the same patient at different time periods were more similar than from different patients. Therefore it was necessary to account for this in the data analysis. Due to the binary nature of the outcome, and the lack of independence of the data, the analyses were performed using multilevel logistic regression. Two-level multilevel models were used with individual measurements nested within patients.The relationship between RAS antagonists and AKI could potentially be confounded by various other parameters. Therefore, the relationships between the two key variables were adjusted for several pre-determined factors. Variables considered as potentially confounding were: age, sex, hypertension, diabetes, ischaemic heart disease (IHD), heart failure, GFR, proteinuria, systolic blood pressure and diuretic usage. The status of each of these was updated at the time of every blood test.GFR category was used in preference to the baseline GFR value, as there were several particularly large GFR values, which might have been influential in the analyses. The GFR categories used followed the KDIGO CKD Clinical Practice Guideline 2012 classification of CKD . A serieThe first analysis assumed a constant effect of RAS antagonists for all patients. Subsequently all patients remained in the analysis, but the interaction between RAS antagonists and an evidence-based indication for their use was included in the analysis. This allowed the effects of RAS antagonists to vary for patients with and without an indication.2. This left outcome data for 208,275 “blood test instances” from 63,722 patients. Table There were 345,986 “blood test instances” from 121,933 patients in a practice population of 244,715. In 137,276 (39.7%) of the “blood test instances” no prior creatinine data were available and the presence or absence of AKI could not be assessed. The baseline characteristics of these subjects showed them to be significantly younger, with very little co-morbidity compared to those with baseline GFR data  representing only 2.5% of 7,765 blood test instances.Table The results for all four models suggested that treatment with RAS antagonists was significantly associated with an increased risk of AKI. The size of the effect decreased after adjustments for potential confounders falling from a 93% increased risk in the unadjusted model to 69% after adjustment for age and gender and to 11% in the fully adjusted model. All of the confounding variables examined were significantly associated with AKI. There was an increased risk of AKI for patients with hypertension, diabetes, ischaemic heart disease (IHD), heart failure, worsening severity of CKD, proteinuria and diuretic therapy. Males were at an increased risk relative to females. There was a non-linear relationship between age and AKI, and thus it is easier to view the results graphically Figure , the resTable The analysis was then repeated with at each “blood test instance” an assessment made of whether there was an evidence-based indication for the prescription of a RAS antagonist, other than simple hypertension. The exception was proteinuria where the highest proteinuria result was used. Table This summary suggests a greater effect of RAS antagonists on AKI for patients prescribed RAS antagonists with no evidence-based indication. If there was an indication for RAS antagonist prescription then there was no real difference in the risk of AKI. In the patients prescribed RAS antagonists without an evidence-based indication there appeared to be an increase in the risk of AKI.The multilevel logistic regression was then repeated to examine the effects of RAS antagonists on AKI in the groups with and without an evidence-based indication Table , using oAnalysis of the data in this was way suggested that there was a significant interaction between evidence-based indication and RAS antagonist use. In both models the risk of AKI was significantly higher with RAS antagonist use in both subgroups. However, the effects appeared greater in patients with no evidence-based indication.Where there is an evidence-based indication for RAS antagonists over and above simple hypertension the literature suggests clear benefits in terms of reduction in all cause and cardiovascular mortality, progression of CKD and reduction in proteinuria -3. Our sIn high risk situations such as cardiac surgery the risk of AKI in those prescribed RAS antagonists preoperatively is significantly increased, by 27.6% in one study . There aWhy is it that we find an increased risk of AKI in those prescribed RAS antagonists in the absence of an evidence-based indication, but not in those with an indication for prescription? It is likely that this relates to the relative contribution of confounding variables to risk of AKI. When we examined the risk of all AKI conferred by prescription of RAS antagonists that risk fell when adjusted for confounding variables and there was no increased risk of moderate to severe AKI after adjustment. We conjecture that because significant comorbidities such as systolic hypotension, heart failure and proteinuria are absent in those without an evidence-based indication for RAS antagonists prescription the contribution of RAS antagonism in such patients is that much more significant. There may also be a lower level of awareness and monitoring in those with fewer co-morbidities.Our study has limitations. The study cohort is derived from the primary care population with recorded serum creatinine estimations. Although serum creatinine tests were recorded in 50 percent of the whole primary care population serum creatinine testing in primary care is not random. People with diabetes, hypertension and cardiovascular disease are over represented within our serum creatinine sample. In just under half of the population with serum creatinine estimations there were no baseline data to determine the risk of AKI and these patients could not be considered further. However, in the data analysed the absolute number of serum creatinine tests in those prescribed RAS antagonists was not dissimilar to the number in those not prescribed RAS antagonists. Furthermore those with no baseline data to determine risk of AKI were significantly younger with very little co-morbidity and only 5 percent had CKD. In this analysis we could not determine absolute risk of AKI and it is also important to note that the analysis only included blood tests from primary care, and therefore there is the possibility that we have not accounted for episodes of AKI that were managed in hospital and from which no blood tests were recorded in primary care. This is however a potential strength, as this excludes hospital acquired AKI and possible additional confounders. Another limitation is in the prescribing assumptions. Although primary care databases record the prescription of a drug the quantity given is often not available, and this may range for example from 1 – 3 months. We therefore made the assumption that if the last prescription date was within 70 days of the “blood test instance”, then the patient was still receiving the medication at that time. Although we were able to include diuretics in the analysis we were unable to accurately define the impact of non-steroidal anti-inflammatory combinations with other agents on the risk of AKI and therefore did not include this in the analysis.Whilst there may be inaccuracies in database coding of co-morbidities individual patient level co-morbidity coding in primary care databases has been shown to be accurate, allowing correction for a number of known confounders in our analysis . The intThis data set is also subject to survival bias in that people who live longer may contribute more tests to the analysis. Another potential source of bias was a misdiagnosis of AKIN1 purely as a result of change in serum creatinine following introduction of RAS antagonists. However, only 4% of AKIN1 occurred within 90 days of starting treatment with a RAS antagonist making this an unlikely source of significant bias.This is the first study that identifies the risks associated with the indiscriminate use of RAS antagonists in a large general population cohort. For the first time we present data concerning the potential adverse effects of RAS antagonists in patients without a clear evidence-based indication for their use other than simple hypertension. Inclusion of all adults is a particular strength as older people are largely under-represented in randomised controlled trials of RAS antagonists and the incidence of AKI rises exponentially with age. A further strength of the study is the access to complete prescription data because primary care in England records all prescription data electronically.Use of RAS antagonists independently predicted AKI in the multivariate analysis and it should be noted that in people with no evidence-based indication for treatment with RAS antagonists the risk of AKI was significantly increased. There will always be disease groups where the benefits of treatment with RAS antagonists clearly outweigh the risks, however we submit that treatment with these agents should be restricted to people in whom there is a clear evidence-based indication. Given the increasing incidence of AKI with increased age this is especially important in older people.Strategies to mitigate the risk of AKI in people prescribed RAS antagonists should be encouraged, including regular monitoring of kidney function and the use of tablet holidays during intercurrent illness, especially that likely to involve intravascular volume depletion.In conclusion the use of RAS antagonists increased the risk of mild AKI in the community in this analysis and was independent of common confounding variables including age, baseline kidney function, gender, relevant co morbidities and systolic blood pressure. The risk of moderate to severe AKI was also increased by prescription of RAS antagonists but was no longer significant when fully adjusted for confounders. However, where there was no evidence-based indication for use of RAS antagonists the risk of mild, moderate and severe AKI remained significantly increased.


Background. Limited data exist regarding endothelin-1 (ET-1), a vasoactive contributor in vascular tone, in a population subjected to early vascular deterioration. We compared ET-1 levels and explored its association with markers of arterial stiffness in black and white South Africans. Methodology. This cross-sectional substudy included 195 black  and 197 white  South Africans. Serum ET-1 levels were measured as well as markers of arterial stiffness . ET-1 levels were higher in black men and white women compared to their counterparts after adjusting for C-reactive protein. In both single and partial (adjusting for body mass index and gamma glutamyl transferase) regression analyses ET-1 correlated with age, interleukin-6, high density lipoprotein cholesterol, systolic blood pressure, pulse pressure, and pulse wave velocity in black women. In multivariate regression analyses the independent association of ET-1 with systolic blood pressure  and pulse pressure  was confirmed in black women only. ET-1 additionally associated with interleukin-6 in black women (p < 0.01). Conclusion. Our result suggests that ET-1 and its link with subclinical arteriosclerosis are potentially driven by low-grade inflammation as depicted by the association with interleukin-6 in the black female cohort. The high incidence of hypertension and development of early vascular deterioration among the black population remains to be elucidated –3. VascuET-1 is an important vasoactive biomarker due to its pivotal role in vascular tone and dysfunction , 8. EndoErgul et al. –21 reporn = 99; women: n = 95) and 197 white  South Africans. Detailed information regarding the procedures of the SABPA study has been published previously [n = 10) by residual statistics with participants with missing ET-1 data (n = 6). A standard health survey was used for the collection of demographic information and antihypertension medication usage. The Health Research Ethics Committee of the North-West University, Potchefstroom Campus, granted ethical approval for this substudy (NWU-00036-07-A6). The study protocol conforms to the ethical guidelines of the Declaration of Helsinki (as revised in 2008) for the investigation on human subjects.Cross-sectional data from the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study was used including 194 black , based on the vascular unloading technique of Peñáz, and were processed with the Beatscope 1.1 software to obtain systolic blood pressure, diastolic blood pressure, mean arterial pressure, pulse pressure, stroke volume, and arterial compliance . The ComA fasting blood sample was collected from each participant and serum prepared according to standard procedures. Serum samples were frozen at −80°C until analysed. ET-1 was determined by an ET-1 Quantikine enzyme linked immunosorbent assay (ELISA) . Intra- and interassay variability for ET-1 were 2.7% and 17.15%, respectively. Serum interleukin-6 was determined with a high sensitivity interleukin-6 Quantikine ELISA . Intra- and interassay variation of interleukin-6 were 4.2% and 6.4%, respectively. Serum cotinine was determined with a homogenous immunoassay on a Roche Modular system . Fasting lipids , glycated hemoglobin A1c, C-reactive protein, and gamma glutamyl transferase were determined using two sequential multiple analysers in serum samples . Intra- and interassay variability were less than 10%. Gamma glutamyl transferase was used as an indication of alcohol abuse and cotinine for smoking , 27. Low∗Power version 3.1.9.2 software was used to compute the achieved power in post hoc analysis to determine a fixed model, single regression coefficient for black women in linear regression analysis [α error probability of 0.05, effect size (f2) of 0.15, and one-tailed input method, the achieved power (1-β error probability) was estimated at 98.21%. Statistical analyses were done using IBM SPSS Statistics version 22 . Main effects of race and sex were tested on the associations between ET-1 and cardiovascular components by means of multiple regression. t-tests were used to compare means and Chi-square tests to compare proportions between the groups. Bivariate and partial correlations were used to determine the correlation of ET-1 with cardiovascular and biochemical variables. Forward stepwise multiple regression analyses were performed to determine independent associations between ET-1 and cardiovascular measures. We applied a sensitivity analysis for estradiol and antihypertensive medication as covariates in the same multiple regression models.Ganalysis . At α erThe following covariates were considered for entry into the models: age, waist circumference, gamma glutamyl transferase, glycated hemoglobin A1c, high density lipoprotein cholesterol, albumin : creatinine ratio, and interleukin-6. Each model included a main independent measure of vascular function or arterial stiffness, that is, model 1 with systolic blood pressure, model 2 with pulse pressure, model 3 with arterial compliance, and model 4 with pulse wave velocity, whereas ET-1 was the designated dependent variable. Additionally in model 3 (pulse wave velocity) mean arterial pressure was added to the list of covariates. Graphpad v5.03  was used to plot endothelin-1 against systolic blood pressure, pulse pressure, pulse wave velocity, and arterial compliance in black women only .F(391) = 6.78; p < 0.001) and sex (F(391) = 2.39; p < 0.05).Basic descriptive characteristics of this study population are listed in p < 0.001). Black men and women had higher systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse wave velocity in comparison with their white counterparts . C-reactive protein, interleukin-6, and glycated hemoglobin A1c were higher in the black compared to the white groups . White participants had higher low density lipoprotein cholesterol and total cholesterol levels in comparison with black individuals (p < 0.001). Gamma glutamyl transferase levels were higher in black men and women (p < 0.001), with no significant difference in cotinine levels between the two groups.There was no significant difference in ET-1 levels between the black and white groups before adjusting for C-reactive protein. We additionally adjusted for C-reactive protein to investigate the effect of inflammation on ET-1 levels. After adjusting for C-reactive protein, the ET-1 levels were significantly higher in black men than white men and higher in white women than black women , no correlations were evident between ET-1 and cardiovascular or biochemical variables in men. A positive correlation was observed between ET-1 and systolic blood pressure , pulse pressure , and pulse wave velocity  in black women only . A positive correlation was observed between ET-1 and age , interleukin-6 , high density lipoprotein cholesterol , and a borderline positive correlation with mean arterial pressure  in black women.In bivariate analysis , high density lipoprotein cholesterol , systolic blood pressure , pulse pressure , pulse wave velocity , and a borderline positive correlation with mean arterial pressure  in the black women. An inverse correlation between ET-1 and arterial compliance  also emerged in black women. The correlation between ET-1 and stroke volume persisted in white women .After adjustments for body mass index and gamma glutamyl transferase , the posR2 = 0.025; β = 0.12; p = 0.55). In black women , pulse pressure , and mean arterial pressure  was confirmed, but no association with pulse wave velocity  and arterial stiffness  was confirmed. ET-1 also associated with high density lipoprotein cholesterol  and interleukin-6  in all four models and with age in model 4 .Since no significant correlations existed in men, the forward stepwise multiple regression analyses were only performed in women. The previous association between ET-1 and stroke volume in white women disappeared , pulse pressure , pulse wave velocity , and arterial compliance  in black women.After performing the same multiple regression analyses and additionally correcting for estrogen and hypertension medication, no change was observed in the previous association of ET-1 with systolic blood pressure .In conclusion, ET-1 independently associated with systolic blood pressure, pulse pressure, and interleukin-6 in black women. Our result suggests that ET-1 and its link with subclinical arteriosclerosis are potentially driven by low-grade inflammation as depicted by interleukin-6 in the black female cohort.Our study found an unadjusted correlation between endothelin-1 and age, systolic blood pressure, pulse pressure and pulse wave velocity in black women. ET-1 also correlated positively with interleukin-6, high density lipoprotein in black women and stroke volume in white women. No correlations where observed between endothelin-1 and cardiovascular and metabolic markers in black and white men.