The objective of this study was to test the effectiveness of an educational intervention with use of educational technology (flipchart) to promote quality of life (QOL) and treatment adherence in people with hypertension. It was an intervention study of before-and-after type conducted with 116 hypertensive people registered in Primary Health Care Units. The educational interventions were conducted using the flipchart educational technology. Quality of life was assessed through the MINICHAL (lowest score = better QOL) and the QATSH (higher score = better adherence) was used to assess the adherence to hypertension treatment. Both were measured before and after applying the intervention. In the analysis, we used the Student’s t-test for paired data. The average baseline quality of life was 11.66 ± 7.55, and 7.71 ± 5.72 two months after the intervention, showing a statistically significant reduction (p <0.001) and mean of differences of 3.95. The average baseline adherence to treatment was 98.03 ± 7.08 and 100.71 ± 6.88 two months after the intervention, which is statistically significant (p < 0.001), and mean of differences of 2.68. The conclusion was that the educational intervention using the flipchart improved the total score of quality of life in the scores of physical and mental domains, and increased adherence to hypertension treatment in people with the disease. Hypertension is a multifactorial clinical condition characterized by high and sustained levels of blood pressure, when systolic pressure is ≥ 140mmHg and diastolic pressure is ≥ 90mmHg. The blood pressure can be classified as optimal, normal, high-normal, stage 1 hypertension, stage 2 hypertension, stage 3 hypertension and isolated systolic hypertension [High blood pressure (hypertension) is a serious public health problem that affects a significant portion of the population. The disease prevalence among adults is 25% worldwide and the estimate for 2025 is 29% .The control of blood pressure levels and consequently of the disease, can be effective with non-pharmacological antihypertensive treatment (in association with drugs or not), and improve the lives of hypertensive people. Despite the evidence that antihypertensive treatment significantly reduces cardiovascular morbidity and mortality, the inadequate disease control has been observed in several countries –7.The treatment adherence is one of its most important and challenging aspects that stands out in the prevention and control of the disease. Worldwide, governments, health professionals, and researchers have studied and worked the aspects involving treatment adherence in hypertension .An important issue related to hypertension control and treatment adherence has been the quality of life (QOL) of people with the disease, because the antihypertensive treatment impacts on their quality of life –11. The The negative impact of hypertension on people’s lives and the difficulties found with the implementation of actions or health behaviors have provided important reflections for those involved ,14  to promote quality of life and adherence to treatment in people with hypertension.This is a quasi-experimental study of before-and-after design conducted with hypertensive people registered in health centers. The data collection period was between November 2014 and March 2015 in all Primary Health Care Units (UAPS) of a capital city located in the Northeast of Brazil. Educational interventions using the flipchart technology were applied for groups of six to eight people diagnosed with hypertension.The following data collection instruments were used: Questionnaire on Adherence to Systemic Hypertension Treatment (QATSH)-, and theThe QATSH is a questionnaire developed by Rodrigues  in his dThe educational technology used was a flipchart, which is a visual resource with pages in a logical sequence, enabling the development of a single message in a progressive and logical manner. It is used to assist in classes, lectures, demonstrations, workshops, among others .The flipchart contains 11 pictures (front) and 11 script sheets (back) . The picTo apply the educational technology was used the educational intervention of workshops, which allow the interaction and exchange of knowledge between the health professional and patients with hypertension. This intervention was performed in three stages with application of the educational technology for the same group of hypertensive people. Each intervention lasted 60–90 minutes. On average, there was an interval of twenty-five days between every stage of the educational technology application.The educational interventions were conducted by health care professionals  and undergraduate students of nursing and physical education courses.In the first stage, were conducted the following activities: team presentation, reading and signature of the informed consent form, explanations about the educational intervention, completion of the MINICHAL and QATSH questionnaires, verification of anthropometric and blood pressure measurements and application of the educational intervention with use of the flipchart. The first five pictures were presented according to the back of the script sheet and discussed, including an overview of hypertension.In the second stage, the anthropometric and blood pressure measurements were recorded, and the educational intervention was performed. The pharmacological and nonpharmacological treatment was addressed with emphasis on adherence to treatment, and use of three pictures in sequel.In the third and last stage, the MINICHAL and QATSH questionnaires were filled out again, the measurements of weight, waist circumference and blood pressure were taken, and the educational intervention with the flipchart was applied. At this time, was addressed the issue of quality of life in hypertension.The patients with hypertension were invited for the educational interventions (first stage) by nurses and community health agents of the Primary Care Units (PCU) where they were registered. For the subsequent activities (second and third stages), patients were invited by telephone contact made by the researchers.The sociodemographic data collected were gender, age, educational level, income and marital status. The clinical variables were hypertension time, type of treatment, systolic blood pressure, diastolic blood pressure, weight, body mass index (BMI) and waist circumference (WC).2 = weight excess) [The study participants were adults, mostly elderly. The BMI cutoffs of the nutritional status of the elderly were adopted to calculate the body mass index of participants (>27kg/m excess) .The sample has been designed in order to provide a power of 90% to demonstrate the benefit of the flipchart, at a significance level of 5%, based on the changing in the total score of MINICHAL questionnaire. Thus, it was established that a difference of at least 2.5 points in the value of this parameter measured at baseline and 60 days after the intervention should be detected, the clinically significant difference, considering a standard deviation of 5.7 points, according to previous study [The inclusion criteria were people diagnosed with hypertension, aged over 18 years and registered in Primary Health Care Units (UAPS–Unidade de Atenção Primária à Saúde), and the exclusion criterion was blindness.The IBM SPSS Statistics for Windows version 20.0  was used for data processing. The mean and standard deviation statistical measures were calculated. The Kolmogorov-Smirnov (KS) normality test indicated the use of the Student’s t-test for parametric data. To compare the average quality of life and adherence to treatment before and after the flipchart application, was used the Student’s t-test for paired data.The participants signed an informed consent form to give their permission to take part in the study. The Research Ethics Committee of the Universidade Estadual do Ceará approved the study under number 723.860 .The study included 116 participants diagnosed with hypertension. The majority (78.44%) was female; 67.24% were elderly, with average age of 64.58±10.87 years; 71.55% had low educational level, and over half of the sample (56.89%) lived with a partner.The time since hypertension diagnosis varied from six months to 60 years, with a mean of 12.49 ±10 years. Regarding the types of treatment, less than half of participants (40.52%) used only the pharmacological treatment, two people (1.72%) used only the nonpharmacological treatment, and more than half (57.76%) adopted both treatments .2, demonstrating weight excess, and the average waist circumference (WC) was 103.74 ± 12.48 cm.In the first phase, the average systolic blood pressure (SBP) was 135.19 ± 19.90 mmHg, and the average diastolic blood pressure (DBP) was 75.50 ± 11.46 mmHg. Another variable evaluated in the study was weight, with average of 70.24 ± 14.58 Kg among participants. The average body mass index (BMI) was 30.22 ± 5.66 kg/mIn the third phase, the average systolic blood pressure (SBP) was 128.55 ± 20.13 mmHg, showing a statistically significant reduction (p<0.001). The average diastolic blood pressure (DBP) was 73.56 ± 10.88 mmHg, showing a reduction, though not statistically significant (p = 0.054). Two months after the flipchart intervention, the average weight was 70.41 ± 14.82 Kg (p = 0.289) and the BMI was 30.29 ± 5.78 (p = 0.294), showing that both these measures remained unmodified. The average WC was 104.88 ± 12.47 cm two months after the application of the flipchart (p = 0.009) .The two outcome variables of the study (QOL and treatment adherence) changed significantly with use of the flipchart intervention. The average baseline quality of life was 11.66 ± 7.55 the application of the flipchart, and 7.71 ± 5.72 two months after the application of the flipchart, with a statistically significant decrease (p <0.001) and mean of differences of 3.95. The average baseline adherence to treatment was 98.03 ± 7.08 and 100.71 ± 6.88 after using the flipchart intervention, showing statistically significant increase (p < 0.001) and with mean of differences of 2.68 .Regarding the score of the Mental Status domain of the MINICHAL, the average baseline value was of 5.66 ± 4.06 and 3.72 ± 2.91 after two months application of the flipchart, with statistically significant improvement (p <0.001). For the Somatic Manifestations domain, the average score before the intervention was 6.01 ± 4.50 and 3.98± 3.58 after application of the flipchart, also with statistically significant improvement (p <0.001). The mean of differences was 1.94 in the Mental Status domain and 2.03 in the Somatic Manifestations domain .In this study, the educational intervention using the flipchart for the group of hypertensive people was associated with the reduction of systolic blood pressure (average decrease of 6.6 mmHg in SBP among research participants). There was also a reduction of diastolic pressure, although not statistically significant. A study conducted in Canada showed similar findings  on the eRegarding diastolic pressure, a study of educational intervention carried out in the United States  showed iOther measures  evaluated in the study did not show significant changes, probably given the short time of the educational intervention for hypertensive people and because those variables are more difficult to change. A study in Brazil  showed tTwo months after the educational intervention with flipchart, there was an increase of 3.9 points in the total score of quality of life, with improvements in the domains of Mental Status and Somatic Manifestations. The scores of the present study were higher than those found in a study conducted in Germany ,11, 24.Although there are few studies related to the role of interventions, educational activities or health education on the quality of life of hypertensive people, some have demonstrated that these actions can improve the quality of life of people with the disease, making the educational action a promoter of quality of life , 24.The educational intervention also promoted statistically significant increase in treatment adherence. Within two months, patients showed greater adherence to the drug treatment. They were also more likely to adopt a diet almost without fat, sweets and sugary drinks.The adherence to hypertension treatment is a complex issue of great importance for the public health and people with the disease. In addition, it is of hard reach because of the many aspects and factors involved, which are of economic, physical, psychological, social and cultural nature.Thus, several studies sought to understand how treatment adherence can be improved and demonstrated that monitoring the quality of life is one of the ways to improve it with hypertensive people. Moreover, that knowledge of Health-Related Quality of Life (HRQOL) in hypertensive people and of the relationship between these two issues is a reliable determinant of cardiovascular events that can help with preventing or reducing the incidence of cardiovascular disease , 25.Finally, the limitations of this study relate to the lack of a control group to observe the differences in quality of life scores and coefficient of treatment adherence between the groups. However, the educational material used in educational interventions is of low cost and easy application, and can be used by all health professionals caring for people with hypertension in the various scenarios where these people are assisted. The material also demonstrated positive impact on two important and complex constructs within the context of hypertension, which are QOL and treatment adherence.Hypertension: promoting quality of life and adherence to treatment improved the total score of quality of life and the scores of Somatic Manifestations and Mental Status domains. It also increased the adherence to hypertension treatment in people with the disease.The educational intervention with the flipchart titled In this sense, the health-related quality of life can be affected by strategies or actions that provide important reflections in the life context of hypertensive people. Improvements in the quality of life and adherence to treatment in people with hypertension are related to the care and attention provided by health professionals. The association of educational interventions, attentive listening and the dialogue established within health facilities and in community spaces can facilitate the decision-making about the use of strategies or actions by patients in order to promote improvements in their living and health conditions.S1 Fig(PDF)Click here for additional data file.S1 File(PDF)Click here for additional data file.


Speckle tracking echocardiography (STE) is an echocardiography modality that is able to measure left ventricular (LV) characteristics, including rotation, strain and strain rate. Strain measures myocardial fibre contraction and relaxation. This study aims to assess the effect of renal sympathetic denervation (RDN) on functional myocardial parameters, including STE, and to identify potential differences between responders and non-responders.The study population consisted of 31 consecutive patients undergoing RDN in the context of treatment for resistant hypertension. Patients were included between December 2012 and June 2014. Transthoracic echocardiography and speckle tracking analysis was performed at baseline and at 6 months follow-up.n = 19) and non-responders (n = 12) following RDN. RDN reduced office blood pressure by 18.9 ± 26.8/8.5 ± 13.5 mmHg (p < 0.001). A significant decrease was seen in LV posterior wall thickness (LVPWd) , without a significant change in the LV mass index (LVMI). In the total cohort, only peak late diastolic filling velocity (A-wave velocity) decreased significantly by 5.3 ± 13.2 cm/s (p = 0.044) and peak untwisting velocity decreased significantly by 14.5 ± 28.9°/s (p = 0.025).The study population consisted of 31 patients with treatment-resistant hypertension treated with RDN . The total study population could be divided into responders (RDN reduced blood pressure and significantly improved functional myocardial parameters such as A-wave velocity and peak untwisting velocity in patients with treatment-resistant hypertension, suggesting a potential beneficial effect of RDN on myocardial mechanics. Hypertension is associated with a significantly increased risk for adverse cardiac and cerebrovascular events, as well as chronic kidney disease . DespiteCatheter-based renal denervation (RDN) has been introduced as a treatment modality to optimise blood pressure control in patients with treatment-resistant hypertension by reducing sympathetic nerve activity. Unfortunately, the exact blood pressure-lowering effect of renal sympathetic denervation remains disputed, demonstrated by non-responder rates varying between 8 and 37%, depending on study-specific cohorts and definitions used . HoweverThe study population consisted of 31 consecutive patients undergoing RDN in the context of treatment for resistant hypertension according to recent recommendations . PatientOffice blood pressure measurements were recorded three times in a resting situation with intervals of 5 min using an Omron automated blood pressure monitor. Patients were classified as responders in case the drop in 6 months office systolic blood pressure was 10 mmHg or higher. In order to identify subtle changes in LV function, STE was used to obtain apical rotation, basal rotation, LV twist, twist velocity, peak untwisting velocity, time to peak untwisting velocity, global longitudinal strain (GLS), global circumferential strain (GCS), peak early and late longitudinal diastolic strain rate, and peak early and late circumferential diastolic strain rate. LV twist is defined as the maximal value of the apical systolic rotation–basal systolic rotation .Echocardiography measurements were performed before the RDN procedure (baseline) and 6 months after the RDN procedure. Two-dimensional grey-scale images were obtained in the left lateral decubitus position using a commercially available ultrasound system , equipped with a broadband (1–5 MHz) S5-1 transducer . Data were analysed by two experienced echocardiographers according to the recent recommendations . The folFrom the mitral inflow pattern, peak early (E-wave velocity) and late (A-wave velocity) filling velocities, E/A ratio and E-wave velocity deceleration time were measured. Tissue Doppler was applied end-expiratory in the pulsed-wave Doppler mode at the level of the inferoseptal side of the mitral annulus from an apical four-chamber view, to obtain Em septal  and E/Em ratio.To acquire the highest wall tissue velocities, the angle between the Doppler beam and the longitudinal motion of the investigated structure was adjusted to a minimal level. The spectral pulsed-wave Doppler velocity range was adjusted to obtain appropriate scale.To optimise STE, the settings were adjusted to obtain a frame rate of 50–70 frames/s. The echo images were transformed to a QLAB Advanced Quantification Software workstation  for offline analysis.STE is an approved echocardiographic modality that provides information on regional and global ventricular function . In orden = 13), OneShot™  (n = 3), Vessix V2™  (n = 5) and Symplicity™  (n = 10). Procedures were performed according to the device-specific instructions for use [Procedures were performed using four different systems: Paradise™  .All continuous variables are expressed as mean ± standard deviation (SD). Continuous variables were compared using Student’s p = 0.028), no significant differences in patient characteristics were seen between both groups  were male. A total of 19 patients were classified as responders versus 12 non-responders. Besides a significantly lower age of the responders  and 94 ± 16 vs. 85 ± 14 mmHg (p = 0.001), respectively. The same applied for the systolic 24 h ABPM after RDN  and the diastolic 24 h ABPM after RDN  (Table A significant decrease was seen in office-based systolic blood pressure (SBP) and diastolic blood pressure (DBP) after RDN at 6 months follow-up: 182 ± 18 vs. 163 ± 27 mmHg (p = 0.020). LV mass index (MI) reduced by 3.2 ± 11.6 g/m2 at 6 months. A-wave velocity decreased significantly from 69.7 ± 14.2 cm/s at baseline to 64.4 ± 14.0 cm/s at follow-up (p = 0.044). No significant changes were seen in the other conventional echocardiographic parameters. Furthermore, peak untwisting velocity decreased significantly from −70 ± 28.5°/cm at baseline to −56 ± 24.9°/cm at follow-up (p = 0.025) , although it should be noted that LV ejection fraction (EF) showed no difference. Also, no differences were found in the more sensitive systolic parameters GLS, GCS and LV twist.Stratifying the cohort in responders and non-responders did reveal significant changes from baseline to follow-up in A-wave velocity and peak untwisting velocity in the responders Fig. . In the 2)  Table .Table 3BNo association was found between the clinical characteristics, conventional echocardiographic and speckle tracking parameters which could predict response.The aim of this study was to assess if RDN resulted in functional and structural cardiac changes as assessed using both conventional 2D echocardiography and 2D STE. A secondary objective was to assess any differences in these parameters between responders and non-responders. We observed a significant difference in blood pressure and heart rate at 6 months post procedure. Echocardiographically, at 6 months, a significant difference was noted in LVPWd and A-wave velocity. Additionally, STE demonstrated a significant difference in peak untwisting velocity.p < 0.001) and heart rate by 4.5 ± 9.9 beats/min (p = 0.016). In line with these findings, we observed a significant decrease in LVPWd (0.47 ± 1.0 mm), along with a reduction in LVMI of 3.2 ± 11.6 g/m2 in the total cohort. The fact that this reduction did not reach statistical significance could be due to a lack of power.Persistent sympathetic nervous system hyperactivity plays a critical role in hypertension and is associated with significant structural and functional cardiac changes . In thisp = 0.044) in the total population. In the responders, the difference in the A-wave velocity even decreased to 8.5 ± 13.8 cm/s (p = 0.027). The decrease in A-wave velocity after renal denervation could implicate an improvement in the LV relaxation and a subsequent better diastolic function [Looking further into diastolic function, which is strongly related to hypertension and blood pressure control, revealed a pseudonormal diastolic dysfunction, based on normal E/A ratio, but increased left atrial (LA) dimension and E/Em ratio in the overall study population. We observed a significant decrease in the A-wave velocity by 5.3 ± 13.2 cm/s (function . Additiop = 0.025) in patients undergoing RDN. This change was mainly driven by a change in peak untwisting velocity by 24.1 ± 28.7°/s (p = 0.006) in the responders. In non-responders, no difference following RDN was observed. The decrease in untwisting velocity after renal denervation could implicate an improvement in the LV relaxation and a subsequent better diastolic function, similar to A-wave velocity. One may hypothesise that, in hypertension patients, like in hypertrophic cardiomyopathy and aortic stenosis patients, increased peak untwisting velocity serves as a compensatory mechanism for abnormal relaxation and prevents the need to increase LA pressure [R2 = 0.1%).Hypertensive patients have a greater risk of developing cardiac fibrosis, myocyte hypertrophy and diastolic dysfunction . These cpressure , 23. RDNFuture studies, comparing hypertensive patients with a healthy control group, may be warranted in order to investigate myocardial geometry changes in hypertensive subjects in the context of diastolic LV twisting and untwisting, blood pressure or heart rate independently.2. In some patients (n = 6), automatically detected LV contours had be corrected manually, which might have impacted the reliability of the measurements. Four different renal denervation systems were used. Based on individual previous studies, the blood pressure-lowering effect of these individual devices remains in the same range; however, a differential effect on the echocardiographic parameters measured in our study could not be excluded.Data are derived from a small patient population and a lack of power might have impacted our findings. Furthermore, accurate assessment of changes in cardiac systolic and diastolic function and volumes with conventional echocardiography produces limited image quality in patients with a body mass index (BMI) above 25 kg/mRenal sympathetic denervation (RDN) reduced blood pressure and heart rate, and significantly improved functional myocardial parameters such as A-wave velocity and peak untwisting velocity in patients with treatment-resistant hypertension, suggesting potential pleiotropic beneficial effects of renal sympathetic denervation on myocardial mechanics. Further dedicated studies are needed to elucidate the potential role of RDN on echocardiographic parameters.


Hypertension trials and epidemiological studies use multiple clinic blood pressure (BP) measurements at each visit. Repeat measurement is also recommended in international guidance; however, little is known about how BP is measured routinely. This is important for individual patient management and because routinely recorded readings form part of research databases. We aimed to determine the current practice of BP measurement during routine general practice appointments.(1) An online cross-sectional survey and (2) a prospective ‘mystery shopper’ study where patients agreed to report how BP was measured during their next appointment.Primary care.Patient charity/involvement group members completing an online survey between July 2015 and January 2016. 334 participants completed the prospective study  of which 279 (83.5%) had diabetes.Proportion of patients having BP measured according to guidelines.217 participants with (183) and without diabetes (34) had their BP measured at their last appointment. BP was measured in line with UK guidance in 63.7% and 60.0% of participants with and without diabetes, respectively. Initial pressures were significantly higher in those who had their BP measured more than once compared with only once .Current practice of routine BP measurement in UK primary care is often concordant with guidelines for repeat measurement. Further studies are required to confirm findings in broader populations, to confirm when a third repeat reading is obtained routinely and to assess adherence to other aspects of BP measurement guidance. This survey has a novel ‘mystery shopper’ design, minimising biases that may be introduced by self-reported practitioner behaviour.We have examined how adherence to guidelines varies according to patient characteristics, whereas previous studies have taken a healthcare professional view.The use of an online survey may have resulted in an under-representation of some groups, such as the very elderly.Larger studies are required to confirm our findings with respect to second and third blood pressure readings.Measurement of blood pressure (BP) is carried out in general practice by healthcare professionals on a daily basis. Such measurement is important for the diagnosis and management of hypertension, a major risk factor for cardiovascular disease (CVD) in both the general population9Many factors can affect the accuracy of BP measurement and the number of measurements used can influence estimates of BP control.5Furthermore, increasing numbers of observational studies in electronic healthcare databases rely on routinely collected BP measurements. In particular, the recommended cardiovascular risk calculator in the UK, QRISK2However, little is known about how BP is measured in routine practice. A 2006 survey of UK general practitioners’ (GPs’) adherence to hypertension guideline recommendations relied on self-reported data and did not ask about the use of repeat measurements.We conducted an online survey of patients, followed by a prospective survey of primary care consultations.An online survey was advertised through charities and patient involvement groups ’) between 23 July 2015 and 24 January 2016. Respondents anonymously reported basic demographic and health information, if and how many times their BP was measured at their last appointment and  their last BP reading online . Respond10.1136/bmjopen-2017-020589.supp1Supplementary file 1Participants completing the online survey were invited to take part in a prospective study. They were told the study would ask similar questions to those already asked about their BP after their next primary care appointment. Those wishing to take part gave explicit consent, provided an email address and were asked when they expected their next appointment to be. After the anticipated time of this appointment, a link to an online questionnaire was emailed to participants. This asked whether BP was measured at the appointment, and if so, how many times, and  for up to three systolic and diastolic BP values online . The queThe prospective study was powered to estimate the proportion of people having their BP measured once or multiple times, in line with guidelines at the 95% confidence level with an accuracy of ±5%. Assuming a proportion of 10%, 139 respondents who had had their BP measured was required.19Demographic and clinical history data were summarised using means and SD or proportions. Mean BP was summarised with 95% CIs and ranges. Respondents were classified as hypertensive if they answered yes to the question ‘Have you got high blood pressure or have you ever been told by your GP that you have high blood pressure?’. Responses were assessed against National Institute for Health and Care Excellence guidance and BP was deemed to have been measured according to guidelines if BP was measured: (1) once and the reading was below 140/90 mm Hg, (2) two times if the initial reading was above 140/90 mm Hg and the first two readings differed by less than 5 mm Hg systolic or (3) three times if the first reading was above 140/90 mm Hg and the first two readings differed by more than 5 mm Hg systolic.Since behaviour among professionals from the same practice may be similar, sensitivity analyses were carried out by randomly selecting one observation from each postal code district (assuming respondents from different districts are registered to distinct practices). We also conducted sensitivity analyses excluding prospective responses that were suspected of being duplicate submissions of the same initial survey data. Analysis was conducted using Stata V.1421In total, 2176 unique users visited the survey site, of whom 756 completed the initial online survey, with complete data available in 743 individuals . Consent for the prospective study was given by 593 participants and was completed by 334 participants  . The chaOf the 743 people completing the first survey, 489 (65.8%) reported having had their BP measured at their last appointment: 156 (31.9% of 489) by a GP, 321 (65.6%) by a nurse and 12 (2.5%) in the waiting room. Most respondents  could recall how many BP readings were taken: 286 (59.6% of 480) one, 144 (30.0%) two and 50 (10.4%) three or more readings. Results stratified by diabetes status are given in the online Baseline characteristics for those with and without diabetes completing the prospective study after a further GP appointment are given in Of the 183 participants with diabetes who had their BP measured, 91 (49.7%) could recall a value for all of the BP readings given. Fifty-eight respondents  had their BP measured according to guidelines. Mean BP values by reading number are presented graphically in The proportion of participants with diabetes who had their BP measured multiple times was similar regardless of hypertensive or treatment status, or measurement personnel  could recall a value for all of the BP readings given. Twelve respondents  had their BP measured according to guidelines. Mean BP values by reading number are presented graphically in The proportion of participants without diabetes who had their BP measured multiple times was similar regardless of hypertensive or treatment status, or measurement personnel  was not obviously reflected in our data, although CIs are wide. Although the majority of this evidence relates to people with diabetes, similar BP measurement practices were observed in those without diabetes.The patient-centred nature of this study has allowed us to see into the consulting room for the first time and to determine how BP is measured in ‘real life’, in those with and without diabetes. Previous studies have taken a healthcare professional view.16Our online survey was limited by the use of convenience mechanisms for recruitment, and like many internet surveys with no known denominator, these results should be interpreted with caution. The use of an online system itself may have resulted in an under-representation of some groups, such as the very elderly.25Although our mechanism of data collection, asking patients to study the behaviour of their healthcare practitioners, has the limitations discussed above, we chose our ‘mystery shopper’ approach over several other study designs. For a full discussion of the study designs considered, see Stevens PhD thesis.Self-reported BP readings may have been subject to rounding error, digit preference or recall error. This introduces uncertainty into some analyses concerning BP values, but the number of measurements taken, is likely to be recalled with greater accuracy, especially in the prospective study. Guidance covers many factors affecting the accuracy of BP measurement, such as the use an appropriately sized cuff, but such factors are less easily assessed by patients and we chose to limit the focus of this study in order to maximise response rates. The type and accuracy of devices used in UK general practice has been studied previously,Fewer than anticipated participants provided all BP readings and therefore we could only estimate the proportion of people with diabetes having their BP measured according to guidelines with an error of ±10% . However, we have demonstrated important differences  despite this. Although we have demonstrated that BP is measured in line with guidance in the majority of cases, this was driven by a large number of participants with low BP who had their BP measured only once. Larger studies would be required to confirm our findings, particularly with respect to second and third readings and in those without diabetes.Many factors, other than the initial BP value, can influence the decision to measure BP multiple times including previous measurement of BP in clinic or at home and the presence of CVD or cardiovascular risk factors. Such factors may explain the considerable variability in BP measurement practices observed in some specific patient examples. Although we have addressed key factors such as diabetes, hypertension and treatment status, future research could explore behaviour in other subgroups. Furthermore, we did not ask respondents about the primary reason for their consultation which may have influenced BP measurement and this also requires further study.A previous review29The finding that patients are more likely to be monitored at home if they have high clinic pressures or hypertension is consistent with results from a recent practitioner survey in Canada,GPs were more likely to recommend home monitoring than nurses in those with diabetes. It is difficult to interpret this finding as it may reflect the primary reason for consultation, with certain tasks (such as diabetes reviews) performed primarily by nurses. Current guidance for BP management in diabetes recommends that high BP is confirmed at subsequent appointments, rather than through home monitoring.34Our findings indicate that routine BP measurement does not reflect the strict measurement protocols in primary research studies. This has implications for patient care if results from primary research studies cannot be appropriately translated into guidance for routine care . Users of electronic healthcare databases should also be aware of the potential for recording biasesThe current practice of BP measurement will, reassuringly, detect white coat hypertension but may not identify those with masked effects (where BP is higher outside of the clinic). This could potentially result in missed diagnoses and suboptimal treatment. One solution which would not increase workload is the use of the Predicting Out-of-Office Blood Pressure (PROOF-BP) tool which was developed by two of the authors with colleagues.Less than one in five participants with hypertension reported having their BP measured in both arms at a single appointment previously. Large differences between arms are associated with vascular disease and mortality.38The results of this study provide a preliminary insight into how BP is measured routinely and indicate that repeat BP measurements are taken in line with guidelines but not with strict study protocols. The impact of these differences on patient care requires further investigation.


A person with a drop of more than 10% in nocturnal arterial blood pressure during the circadian rhythm is referred to as a dipper and one with a smaller decrease is referred to as a non-dipper. In our study, we aimed to compare the thrombolysis in myocardial infarction (TIMI) frame count in non-dipper and dipper hypertensive patient groups who had normal coronary artery angiographyPatients with normal coronary arteries and with ambulatory blood pressure monitoring follow ups were retrospectively investigated and 60 patients  were included in our study. The patients were grouped as dipper (n = 30) and non-dipper (n = 30) hypertensives.2 in the dipper patient group, while it was 25.47 ± 2.92 in the non-dippers. BMI was found to be significantly higher in the non-dipper group than in the dipper group (p = 0.027).The TIMI frame counts in all three coronary arteries and the mean TIMI frame count in the dipper hypertensive patient group were significantly lower than those of the non-dipper hypertensives . The body mass index (BMI) was 23.79 ± 2.81 kg/mIn this study, TIMI frame count, which is a simple, productive, objective and reproducible method for determination of microvascular changes, was found to be higher in non-dipper hypertensive patients than in the dipper patients. Hypertension is a significant risk factor for stroke, myocardial infarction, renal diseases and other vascular disorders. Treatment of high blood pressure may lower the incidence of complications and enable a longer life. Cardiovacular parameters such as blood pressure, heart rate and coronary tonus change with the daily circadian rhythm.1Development of ambulatory blood pressure-monitoring (ABPM) has provided an understanding of diurnal blood pressure variations.4The mechanism of diurnal blood pressure variation disorders is not clear. At night, the balance in the autonomous nervous system probably shifts towards the sympathetic nervous system.7The thrombolysis in myocardial infarction (TIMI) frame count is the sum of the ciné-angiographic squares obtained, after infusing opaque substance into the coronaries, from the time when the dye is seen at the level of the coronary artery ostium to when it reaches the distal part. The TIMI frame count, which is a simple, objective and reproducible method, is a quantitative predictor of coronary flow rate. A high TIMI frame count is a predictor of slow coronary flow and endothelial dysfunction.8The aim of this study was to compare the TIMI frame count in dipper and non-dipper hypertensive patients with normal coronary artery angiography (CAG).This retrospective, single-centre study was performed in a tertiary healthcare centre. The study data were obtained between 15 February 2010 and 15 February 2012 from hypertensive patients aged between 18 and 80 years who had normal CAG and who had arterial blood pressure follow up with ABPM. Patients who were below 18 and above 80 years, with coronary artery disease, haemodynamic changes, congenital heart disease, left ventricular ejection fraction below 55%, and those who had severe valve disease were excluded. The study was approved by the Trakya University Ethics Board .Age, gender, height, weight, hypertension and diabetes mellitus status, smoking and alcohol consumption, medications, electrocardiogram (ECG), lipid profile and creatinine levels were obtained from the patient files. Body mass index (BMI) was calculated by dividing the body weight (kg) by the square of the height (m). Echocardiogram (echo) reports were obtained from the echo laboratory, coronary artery images from the CAG laboratory, and 24-hour blood pressure levels were obtained from the effort-Holter laboratory.The echo evaluations of the patients were performed using the Vivid 7 Pro . Left ventricular ejection fraction (EF) was calculated with the M-mode imaging method.Ambulatory blood pressure follow up was done with the tension artery Holter device (DMS 300-3A Holter Recorder) register system using the ambulatory blood pressure Spacelab 90207 device . ABPM was performed before hospitalisation, irrespective of the type and duration of antihypertensive drug therapy. The patients were recommended to maintain daily activities and to hold the arms straight during measurement. Blood measurements were made every 15 minutes between 07:00 and 23:00, and every 20 minutes between 23:00 and 07:00. Using short time intervals, the 10:00–22:00 interval was accepted as the day-time, and the 24:00–06:00 interval as the night-time period. The recorded data were evaluated at the end of 24 hours.Systolic and diastolic blood pressure levels and heart rate measurements were evaluated for the day and night-time periods. If the mean systolic and diastolic blood pressure levels decreased by less than 10% or did not fall, the patient was considered a non-dipper, and if it decreased by more than 10%, it was considered dipper hypertension.10All of the patients had undergone CAG due to a positive myocardial perfusion ischaemia test. The coronary angiography procedures had been performed up to one month after the ABPM. Coronary artery evaluation of the patients was made using the Philips Integris H 3000  angiogram device. The presence or absence of coronary artery disorders was recorded. Patients who had any degree of coronary artery stenosis or plaques and those who had haemodynamic changes that may have affected the square counts during the angiogram were excluded. The TIMI frame count of patients whose coronary arteries were normal was separately calculated for all three coronary arteries. Nitrate was not administered to any patients during the CAG, as it could have affected the results of the measurements.Gibson et al. were the first to present the TIMI frame count, or the TIMI square-count method as a simple, productive, objective and quantitative technique to provide a standard index for coronary blood flow measurement. They investigated the angiographic images of the TIMI-4 study.8The TIMI frame count was calculated by an independent operator , who did not know the AMBP results. To determine the TIMI frame count following administration of the opaque material, the ciné-angiographic square counts seen between the level of the stained coronary artery ostium and its distal part were added up. The first square was taken at the moment when an opacification was seen filling the whole of the coronary artery orifice and moving forward.The last square was caught at the moment when the dye reached the standard marker point determined separately for the three arteries by Gibson et al. at the distal part of the vessel.8 The prediction points were the distal bifurcation branching point for the left anterior descending artery (LAD) , the branchlet separating from the distal bifurcation at the furtherest point where the artery opacified after the lesion for the circumflex artery (Cx), and the filling moment of the posterolateral branchlet after the posterior descending artery for the right coronary artery (RCA). The best projection angle was the right anterior oblique or the left anterior oblique-caudal angle for the LAD and Cx, and the left anterior oblique-cranial angle for the RCA.In Gibson and co-workers’ study, the TIMI frame count for the RCA was 20.4 ± 3.0, the square count for the Cx artery was 22.2 ± 4.1, and for the LAD, it was 36.2 ± 2.6 (p < 0.001).For the LAD, the correction for this difference was made by dividing the square count by 1.7. Therefore, the TIMI square count corrected for the LAD (cLAD) was determined as 21.1 ± 1.5 squares. The mean TIMI frame count was calculated by adding three coronary artery TIMI frame counts and dividing by three.For the descriptive statistics of the data, the mean, standard deviation and ratios were used. The Kolmogorov–Smirnov test was used for distribution of the data. Comparison of the means between the two groups was done using the independent samples t-test. The Chi-squared test was used for analysis of the ratios. The SPSS 20.0 program was used for the analysis. Statistical significance was set at p < 0.05 for all analyses.Sixty patients , whose mean age was 52.85 ± 10.42 years, were included in the study. The demographic and clinical data of the patients are presented in 2) was significantly higher than that of the dippers (23.79 ± 2.81 kg/m2) (p = 0.027). There was no significant difference between symptoms, hyperlipidaemia and diabetes mellitus between the dipper and non-dipper groups. Similarly, the use of angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), beta-blocker (BB) and calcium channel blockers (CCB) did not demonstrate any significant dfferences between the groups. Of the laboratory parameters, no statistically significant difference was found between high-density lipoprotein (HDL-C) cholesterol, low-density lipoprotein (LDL-C) cholesterol, fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), creatinine, haemoglobin and ejection fraction (EF) levels (The BMI in the non-dipper group (25.47 ± 2.92 kg/m) levels . None ofThe 24-hour Holter data of the patients were evaluated and inter-group comparisons were performed. In the dipper group, the pulse rate (66.57 ± 4.92 bpm) was significantly lower than that of the non-dipper group (72.70 ± 4.86 bpm) (p = 0.001). No statistically significant differences were determined between the groups with regard to the mean systolic and mean diastolic blood pressures . Similarly, there was no significant difference between the groups regarding the day-time mean systolic and diastolic blood pressures . The night-time mean systolic and diastolic blood pressure levels were, however, significantly lower in the dipper group . The percentage change in systolic and diastolic blood pressures was significantly higher in the dipper than the non-dipper group . The inter-group comparisons of ABPM are presented in The mean TIMI frame counts of all three coronary arteries were calculated in the dipper and non-dipper patient groups. In the dipper group, the RCA TIMI frame count (16.83 ± 3.70) was significantly lower than that in the non-dipper group (21.63 ± 3.44) (p < 0.001). In the dipper group, the Cx TIMI frame count (21.28 ± 3.52) was significantly lower than in the non-dipper group (25.65 ± 3.61) (p < 0.001). The LAD TIMI frame count in the dipper group (34.20 ± 2.80) was significantly lower than in the non-dipper group (37.05 ± 3.30) (p = 0.001). The LAD corrected TIMI frame count in the dipper group (20.05 ± 1.63) was significantly lower than in the non-dipper group (21.74 ± 1.95) (p = 0.001). In the dipper group, the mean TIMI frame count (19.31 ± 2.31) was significantly lower than in the non-dipper group (22.94 ± 2.61) (p < 0.001) .Arterial blood pressure has a daily circadian rhythm. Physiologically, nocturnal blood pressure decreases by more than 10% compared to day-time levels, and this is called dipper hypertension. If the nocturnal blood pressure has a less than 10% fall from day-time blood pressure values, it is considered as non-dipper hypertension.12In order to develop a standard index for coronary blood flow measurement, Gibson et al. presented the TIMI frame count as a simple, productive, objective and quantitative technique by investigating the angiographic images of the TIMI-4 study.According to a study by Yazici et al., the number of non-dipper patients was significantly higher than dipper patients in a patient group with slow coronary flow rates. In that study, the non-dipper patients with slow coronary flow rates had a higher percentage of unstable angina-like features, recurrent chest pain, frequency of malignant ventricular arrhythmia and sudden cardiac death rates than dipper patients.14Evola et al. compared the TIMI frame counts of 80 hypertensive patients with normal CAG with 15 normotensive subjects, and found higher TIMI scores in the hypertensive group. In the same study, when the hypertensive patients with negative and positive myocardial perfusion scintigraphy were compared, the TIMI frame counts were significantly higher in patients with positive scintigraphy.In our study, we found a higher TIMI frame count in all three coronary arteries in the non-dipper hypertensive patient group compared to the dipper group. In their study showing the significance of small-vessel disorder, Pekdemir et al. investigated the coronary anatomy using intravascular ultrasonography (IVUS) and epicardial resistance with fractional flow reserve (FFR).In a patient group with slow coronary flow, Xia et al. discovered higher serum uric acid, platelet count, high-sensitivity C-reactive protein (CRP) and two-hour fasting glucose levels compared to the control group.19Using the TIMI frame count, Turhan et al. compared coronary blood flow in 42 metabolic syndrome patients and a control group of 42 subjects without the metabolic syndrome. The TIMI frame count was statistically significantly higher in patients with higher values of waist circumference, body mass index and triglyceride levels.According to numerous robust evidence, deterioration of endothelial-dependent vasodilatation as a result of a decrease in nitric oxide release in brachial, coronary, renal and small arteries is a risk factor in cardiovascular and cerebrovascular patients.27The most important limitations of our study were its retrospective design and the small sample size, as well as the lack of testing for other biochemical and echocardiographic markers that have shown a relationship with coronary slow flow. Studies with a prospective design integrating a larger number of patients and coronary slow-flow markers would provide more valuable data. In our study, the proximal coronary artery diameters were not compared. Due to the fact that vasoconstriction, which may develop secondarily due to an increase in sympathetic tone, may have had an effect on the TIMI frame count. Measurement of proximal artery diameters and comparing them between the two groups would produce more valuable information.In our study, we found higher TIMI frame counts in all three coronary arteries and a higher mean TIMI frame count in the non-dipper hypertensive patients than in the dipper group. Microvascular bed changes and endothelial dysfunction in non-dipper hypertensive patients can be confirmed with TIMI frame count, which is a predictor of coronary slow flow rate.In this study, the TIMI frame count, which is a simple, productive, objective and reproducible method for indirect determination of microvascular changes, was found to be higher in non-dipper hypertensive patients than in dipper hypertensives.


The prevalence of HHcy in Chinese patients with CKD was high, and serum homocysteine levels were associated with impaired renal function in these patients.Hyperhomocysteinemia (HHcy) is recognized as a risk factor for cardiovascular disease. However, the prevalence of HHcy and its role in association with target organ damage in patients with chronickidney disease (CKD) are not well understood. This cross-sectional study included 1042 CKD patients who were admitted to our hospital. Patients were divided into two groups: hyperhomocysteinemia and normohomocysteinemia. Multivariable linear regression analyses were used to evaluate the association between plasma homocysteine and renal/cardiovascular parameters. The prevalence of HHcy in patients with CKD was 52.78%, and the prevalence in CKD stage 1, stage 2, stage 3, stage 4 and stage 5 patients was 10.73%, 29.22%, 58.71%, 75.23% and 83.75%, respectively. Patients with HHcy had higher incidences of renal damage, left ventricular hypertrophy, left ventricular diastolic dysfunction and abnormal carotid intima-media thickness compared with patients with normohomocysteinemia ( The rising prevalence of chronic kidney disease (CKD) has become a large public health challenge in China. One national survey showed that China had the largest number of CKD patients in the world, around 119.5 million (112.9–125.0 million) ,4,5. RecHomocysteine (Hcy) is a sulfur-containing synthesized amino acid emerging on the pathway of the metabolic conversion of methionine to cysteine . Total pApart from playing an important role in cardiovascular and cerebrovascular diseases, HHcy is also associated with microalbuminuria and glomerular injury in general and diabetic populations ,19. AnotInclusion criteria: (1) patients had to be aged 14–75 years; (2) patients who were diagnosed with CKD.Exclusion criteria were: Undergoing treatment with corticosteroids or hormones; acute changes in the eGFR >30% intheprevious 3 months; pregnancy; history of abuse of drugs or alcohol; night work or shift-work employment; acquired immunodeficiency syndrome; cardiovascular disorders ; inability to communicate and comply with all of the study requirements; on maintenance dialysis; and being in receipt of any antihypertensive drug in the previous month.A total of 1042 CKD patients were enrolled in this cross-sectional study. In terms of causes of renal diseases: 610 patients had chronic glomerulonephritis; 136 cases had diabetic nephropathy; 296 patients had other causes of renal disease. This patient cohort was divided in two groups according to levels of plasma homocysteine: (1) normohomocysteinemia group: Patients with normal plasma homocysteine; (2) hyperhomocysteinemia group: Patients with elevated plasma homocysteine.The study protocol was approved by the ethics committee of the Third Affiliated Hospital of Sun Yat-Sen University . All study participants provided written informed consent to be included in the study.Demographic characteristics and the primary cause of CKD were collected. Laboratory values for serum albumin, creatinine, cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), uric acid, intact parathyroid hormone (iPTH) and 24 h proteinuria were collected at the first visit of the study. Plasma homocysteine was determined by ahomocysteine measurement kit (direct chemiluminescence method) using the ADVIA Centaur systems . Clinic blood pressure was also collected.Serum concentrations of creatinine (Scr) were measured by an enzymatic method, traceable to isotope dilution mass spectrometry. We measured estimated GFR (eGFR) using the equation developed from data based on Chinese patients with CKD . The CKDScr is serum creatinine concentration in mg/dL; age is measured in years.Each patient underwent transthoracic two-dimensional echocardiography assessment by two investigators trained for this purpose before starting the study. Cardiac structure was assessed by two investigators trained for this purpose before starting the study. Left ventricular mass (LVM), systolic function, and diastolic function were assessed using two-dimensional echocardiography. Linear measurements of end-diastolic interventricular septal wall thickness (IVSd), end-diastolic left ventricular internal dimension (LVIDd), and end-diastolic posterior wall thickness (PWTd) were obtained from M-mode tracings. LVM was calculated using the following formula :LVM = {The left ventricular mass index (LVMI) was obtained by calculating the ratio of LVM to body surface area .What is more, echocardiographic evaluation of left ventricle (LV) diastolic function was performed by pulsed-wave Doppler examination of mitral inflow and Doppler tissue imaging of the mitral annulus. Peak velocities of early (E) and late (A) trans-mitral flow and deceleration time (DT) were measured, and the ratio E/A was used to assess LV diastolic function.The assessment of Carotid intima-media thickness (cIMT) was performed as described previously . BrieflyHyperhomocysteinemia was defined as plasma homocysteinemia >15 μmol/L .2 for ≥3 months, irrespective of the presence or absence of kidney damage. We divided these CKD patients into five stages (1–5) according to this guideline [A CKD diagnosis was made when the patient met either of the following criteria set by the Kidney Disease Outcomes Quality Initiative: (1) kidney damage is present for ≥3 months, with or without decreased eGFR, manifested by either pathologic abnormalities or makers of kidney damage ; (2) eGFR <60 mL/min/1.73 muideline .Chinese Guidelines for Diabetes Prevention and Treatment: (i) symptoms of DM and casual blood glucose >11.1 mmol/L; (ii) fasting blood glucose >7.0 mmol/L [Diabetes mellitus (DM) was defined as the need for anti-DM drugs or meeting the diagnostic criteria for DM specified by the 0 mmol/L ,27.2 [2 (man) and >95 g/m2  were diagnosed as having “left ventricular hypertrophy” (LVH), E/A <1 was regarded as left ventricular diastolic dysfunction [Target organ damage (TOD) was defined as having any of the following three conditions: Firstly, impaired renal function was defined as an eGFR <60 mL/min/1.73 m2 . Secondlfunction . Thirdlyfunction .Descriptive statistics are the mean ± standard deviation (SD) for continuous variables and as the median and interquartile range for non-parametric variables. Frequency and percentage were used for categorical variables. Log transformation for proteinuria in regression analyses was undertakendue to the skewed distribution of these data.p value for multiple comparisons was corrected according to the Bonferroni method (six comparisons).Comparisons of continuous variables between groups were evaluated by an analysis of variance (ANOVA) or non-parametric tests. Differences among categorical variables were analyzed using the chi-squared test or the two-tailed Fisher’s exact test, as appropriate. p < 0.05 explored in a univariate regression analysis.Multivariable linear regression models were employed to study the association of indices of renal function (eGFR) and cardiovascular damage  with age, gender and other variables with p < 0.05 explored in univariate regression for this analysis were age, gender and other variables with p < 0.05 explored in univariate regression analysis.Predictors associated with plasma homocysteine were explored by a multivariable linear regression analysis. The variables with p < 0.05 was considered to be statistically significant. Data were analyzed using SPSSv20.0 .All values were two-tailed and p < 0.05). A total of 192 (18.43%) patients had diabetes mellitus, 20.92% were current smokers, and 9.98% consumed alcohol. Patients with HHcywere of older age; had a longer course; a higher prevalence of diabetes mellitus; were current smokers; had lower hemoglobin, proteinuria, cholesterol, LDL-C, HDL-C and urinary sodium excretion; and had higher clinic systolic blood pressure (clinic-SBP), serum albumin, iPTH, calcium×phosphate, uric acid, serum cystatin C, blood urea nitrogen and serum creatinine compared with subjects with normohomocysteinemia (p < 0.05)  .p < 0.05)  overall, and 10.73%, 29.22%, 58.71%, 75.23% and 83.75% in CKD stage 1, stage 2, stage 3, stage 4 and stage 5 patients, respectively. Patients with poorer kidney function had a higher prevalence of HHcy than patients with better renal function ( < 0.05) .p < 0.05). The incidences of renal insufficiency, left ventricularhypertrophy, left ventricular diastolic dysfunction and abnormal cIMT in patients with HHcy were higher than patients with normohomocysteinemia (p < 0.05)  .Multivariate linear regression analysis showed that iPTH, hemoglobin, plasma homocysteine, age, calcium×phosphate, serum uric acid, clinic-SBP, and urinary sodium excretion were associated with eGFR. Hemoglobin, iPTH, gender, clinic-SBP and age were associated with left ventricular mass index. However, age, clinic-SBP, smoking and diabetes mellitus were associated with the E/A ratio. Age, clinic-SBP, smoking and diabetes mellitus were associated with abnormal carotid intima-media thickness .Multivariable linear regression analyses showed that plasma homocysteine was associated with eGFR, uric acid, albumin, gender, hemoglobin and calcium×phosphate .Multivariable linear regression analyses showed that proteinuria was associated with eGFR, uric acid, serum albumin, diabetes mellitus, age, clinic-SBP and triglyceride .In this cross-sectional study, we investigated the prevalence of HHcy in Chinese CKD patients. Furthermore, its correlation with target organ damage and the main factors that determine HHcy were also analyzed. For all 1042 CKD subjects, the prevalence of HHcy in Chinese patients with CKD was 52.78% (550/1042) overall; the prevalence of HHcy in patients with poorer renal function was higher than patients with better renal function. Patients with HHcy had more severe target organ damage compared with normohomocysteinemia subjects, while multivariable the linear regression analyses showed that plasma homocysteine only correlated with eGFR. Age, male sex, diabetes, hypertension and hyperuricemia were associated with the presence of HHcy. All these above data suggested that HHcy is very common, especially in patients with poorer renal function. In these CKD patients, HHcy play a role in kidney damage.HHcy has been associated with an increased risk of many diseases, such as CKD, diabetes, cardiovascular and cerebrovascular diseases ,30,31. ISome studies have shown that HHcy plays a role in target organ damage. A meta-analysis found that a 25% lower homocysteine level (about 3 μmol/L) was associated with an 11% lower ischemic heart disease risk and a 19% lower stroke risk in healthy populations after adjustment for known cardiovascular risk factors . One hisThe present study had strengths and limitations. Firstly, the size of the study is rather larger compared with previous studies in CKD patients, while only one center was enrolled. Secondly, all CKD patients underwent comprehensive assessments. Thirdly, all CKD patients were admitted to our hospital division, which helped to finish the assessment. Fourthly, these patients had severe proteinuria or severe renal damage, thus some CKD patients with non-severe proteinuria or non-severe renal damage might have been excluded, leading to a difference from general CKD patients. Fifthly, CKD patients who received medications, such as any antihypertensive drug in the previous month, were excluded, so drug use would not have affected analyses. However, we could not rule out the effect of Chinese medicines. Finally, we cannot set a cause–effect relationship based on this associative and cross-section study. The underlying etiology or comorbidity  are associated with the decline of kidney function as well. Good quality, long-term, large longitudinal trials to validate the role of plasma homocysteine in clinical practice for Chinese CKD patients are needed.We have provided the first evidence ofthe prevalence of hyperhomocysteinemia and its close association with kidney damage in CKD patients in China, while we cannot set a cause–effect relationship based on this associative and cross-section study. Further prospective randomized clinical trials are needed to clarify whether lowering homocysteine treatment has a beneficial effect on attenuating the progression of renal failure in CKD patients.


The correlation with sixth-generation bronchi was significantly greater than with the third-generation bronchi (p = 0.047). Partial rank correlation analysis indicated FeNO was significantly correlated with WA/BSA of the sixth-generation bronchi, independent from confounding factors of Ai/BSA, age, duration of asthma, dose of inhaled corticosteroid, blood eosinophil percentage, and blood IgE . In contrast, there was no correlation between FeNO and Ai/BSA. FeNO correlates with bronchial wall thickening in asthma patients. Measurement of FeNO may be useful to detect airway remodeling in asthma.Fraction of exhaled nitric oxide (FeNO) provides information about chronic inflammation in asthma. However, its relationship with structural changes in the airways is unknown. We aimed to evaluate the correlation between computer-based airway changes and FeNO in patients with asthma. The wall area (WA) and airway inner luminal area (Ai) of the third- to sixth-generation bronchi were measured using three-dimensional computed tomography in asthmatic patients. Each value was corrected by body surface area (BSA). Relationships between FeNO and WA/BSA and Ai/BSA were evaluated. Forty-one clinically stable patients with asthma were evaluated. FeNO was significantly correlated with WA/BSA of the third-, fourth-, fifth- and sixth-generation bronchi (Spearman correlation coefficient ( Spirometry and peak expiratory flow measurements are widely used for the diagnosis and management of asthma1. These physiological function tests evaluate the severity of airflow limitation caused by airway narrowing, but cannot directly evaluate bronchial wall thickening, which is an important pathogenic feature in asthma3.Asthma is an airway inflammatory disease characterized by airway narrowing and wall thickening7. These findings are mainly based on postmortem studies because of the difficulty in sampling bronchial tissues in clinical practice. Some previous studies using transbronchial biopsy reported similar pathologic changes in the airways of asthmatic patients, which correlated with bronchial hyperresponsiveness and disease severity11. In addition to being an invasive procedure, endoscopic biopsy is limited because it can only sample from the surface of bronchial tissue and therefore cannot evaluate all layers of the bronchial wall and the wide range of bronchial trees.Bronchial wall thickening in airway remodeling is attributed to the infiltration of inflammatory cells, thickening of the basement membrane, epithelial hyperplasia, and smooth muscle hypertrophy19. CT analysis can assess the airway inner luminal area and total wall area in a wide range of airway trees in a non-invasive manner that cannot be assessed by endoscopic biopsy. We previously evaluated the airways of third- to sixth-generation bronchi in patients with chronic obstructive pulmonary disease using three-dimensional CT analysis and reported correlations between morphological changes of the airway and physiological function tests20. Regarding asthmatic patients, airway changes by chest CT were correlated with pulmonary function21, hyperresponsiveness22, and disease severity28. Bronchial wall thickening assessed by CT also demonstrated a correlation with pathologic measurements of remodeling in transbronchial biopsy specimens from asthmatic patients30.With recent advances in imaging technology, quantitative computed tomography (CT) analysis can provide detailed information about airway changes in lung diseases33 and its measurement provides supplemental information for the diagnosis and management of asthma in a simple and noninvasive manner. FeNO correlates with symptoms35, physiological function tests37, and disease severity36 and FeNO measurement-based therapy for asthma demonstrated favorable clinical outcomes39. However, how and whether structural changes in the airways in asthma correlate with FeNO is unknown.Chronic airway inflammation is an essential component of asthma, which leads to airway remodeling. The fraction of exhaled nitric oxide (FeNO) is considered a marker of airway inflammationThe current study aimed to evaluate the relationship between FeNO and airway structure assessed by three-dimensional CT in patients with asthma.The characteristics of the patients are shown in Table p = 0.017), but not with duration of asthma, body mass index, blood eosinophil percentage, blood total IgE, percent predicted FEV1, or dose of inhaled corticosteroid (Table The median concentration of FeNO was 27.0 (8.2–329.4) ppb. FeNO was significantly correlated with age (Spearman correlation coefficient (ρ) = 0.370, p = 0.018; ρ = 0.376, p = 0.018; and ρ = 0.384, p = 0.016, respectively), but not in the third-generation . The WA/BSA was significantly correlated with age in the third-, fourth-, fifth- and sixth-generation bronchi  corrected by body surface area  and airway inner luminal area (Ai) corrected by BSA (Ai/BSA) from the third- to sixth-generation bronchi assessed by three-dimensional CT are shown in Table p = 0.041; ρ = 0.356, p = 0.025; ρ = 0.496, p = 0.002; and ρ = 0.529, p < 0.001, respectively, Table p = 0.047, Table FeNO was significantly correlated with WA/BSA of the third-, fourth-, fifth- and sixth-generation bronchi  when adjusted for age, duration of asthma, blood eosinophil percentage, blood total IgE, dose of inhaled corticosteroid, and Ai/BSA . However, they did not evaluate the actual thickness of each bronchial wall, but only counted the total number of visible bronchi with no distinction of bronchial generations in five sections of horizontal CT images29. In the current study using three-dimensional CT analysis of the bronchial trees, the correlation between FeNO and wall area gradually increased toward the sixth-generation bronchi, and was strongest in the sixth-generation bronchi. Although the underlying reason for the difference in the correlation with FeNO among bronchial generations is unknown, different parts of the bronchial tree might unevenly contribute to FeNO. Aikawa et al. reported a postmortem analysis where patients who died of asthma attack had significantly severe goblet hyperplasia in restricted airways compared with asthmatic patients that died of non-asthma related causes. The change was only observed in the peripheral airways (defined by the absence of cartilage), but not in the central airways6. Hamid et al. reported that airways with an inner luminal diameter <2 mm had significantly larger numbers of activated eosinophils than those with a >2 mm in lung specimens obtained from asthmatic patients who underwent surgical resection for lung cancer7. These data suggested that peripheral airways undergo greater inflammatory changes than the central airways in asthma. Although we could not evaluate more than sixth-generation bronchi in the current study, the gradual increase in the magnitude of correlation between FeNO and wall area toward the sixth-generation bronchi suggests that the more distal airways probably have a stronger influence on FeNO.The serial assessment of the bronchial tree revealed differences in the correlation between FeNO and wall thickening among bronchial generations. De Blic et al. evaluated the pathologic changes in the airways of 27 fatal asthmatic patients. The subjects were in their 40 s (n = 13) and had significantly greater bronchial wall areas, compared with younger subjects , which was mainly because of an increase in smooth muscle area9. Gelb et al. evaluated FeNO in 106 non-smoking healthy subjects and reported that elderly subjects ≥60 years had significantly higher FeNO levels (median of 27 ppb) than younger subjects <60 years . They suggested that the potential mechanism for increased FeNO with age was caused by a reduction in the diffusing capacity of NO into surrounding vessels47. The correlation between FeNO and bronchial wall area was independent from age in the current study, although age-related changes should be considered when interpreting the value of FeNO in clinical practice.Age was correlated with both bronchial wall area and FeNO. Bai 20. Actually, two patients had atelectasis and airway collapse in the middle lobe. The left lung was also excluded from analysis to avoid artifacts caused by transmitted cardiac motion. Few study directly compare the morphological changes of right lung and those of left lung in relationship with eosinophilic inflammation or FeNO. The optimal method to assess airway morphology should be further investigated. Second, the limited resolution of CT did not allow a detailed evaluation of distal airways greater than sixth-generation bronchi. There are two compartments of FeNO that represent different parts of the airways. Central airway NO represents airways of the first- to sixteenth-generation bronchi, whereas peripheral airway/alveolar NO represents airways of the seventeenth- to twenty-third-generation bronchi48. The evaluation of small airways is needed to obtain further information regarding alveolar NO. Third, the elevation of FeNO was not fully accountable by bronchial wall thickening alone. Wall thickening is a result of several pathologic changes including epithelial hyperplasia and increased smooth muscle, of which eosinophilic inflammation is but one of the causes9. In the current study, FeNO was not correlated with Ai/BSA, which might be because these factors including eosinophilic inflammation had strong effect on wall area than airway intraluminal area. In addition, several clinical factors affect FeNO including inhaled corticosteroids (administered to most of the study patients), or smoking status (only never- or light former-smokers were included in the study), which affects the level of exhaled NO46. Even though there was no significant correlation between FeNO and these factors in the current study, the potential influence should be considered when interpreting FeNO. In particular, inhaled corticosteroids decrease both FeNO level and bronchial wall thickening in asthma49, which could affect the results. However, our data demonstrated that correlation between FeNO and bronchial wall thickening was independent from the dose of inhaled corticosteroid in partial correlation analysis. Thus, our data might be applicable in clinical practice among asthma patients receiving inhaled corticosteroids.The current study had three main limitations. First, we evaluated the six segmental bronchi  in the right lung. Middle-lobe bronchi as well as B6 and B7 were excluded from analysis because they are readily associated with atelectasis, airway collapse or mucus hypersecretion. It is assumed that the artifact caused by airway collapse can be avoided by using this methodIn conclusion, FeNO was correlated with bronchial wall thickening from the third- to sixth-generation bronchi in asthma patients. The measurement of FeNO may be useful when assessing structural changes in the airways of asthma patients.1. Exclusion criteria were: uncontrolled asthma defined by GINA1; requirement of treatment change, respiratory tract infection, or exacerbation  within 4 weeks before enrollment; current or former smokers with smoking history ≥10 pack-years; use of oral corticosteroid in the previous 6 months; use of long-term oxygen therapy; diffuse lung diseases; neuromuscular diseases; presence of congenital anomalies of the bronchial tree; and a history of thoracic surgery. The study was conducted in accordance with the ethical standards of the Declaration of Helsinki and approved by the Institutional Review Board of Hamamatsu University School of Medicine . Each patient provided written informed consent to be included in the study.Clinically stable asthmatic patients were enrolled in this study. The patients were required to satisfy the definition of asthma set by the Global Initiative for Asthma (GINA)20. We obtained three-dimensional CT images of airway trees reconstructed from the MDCT images using image-analyzing software . All airway candidates were detected using the airway classifiers learned by machine learning. Based on the detected airway candidates, an airway center line was constructed using a minimum spanning tree, and inner and outer airway contours were automatically extracted using the graph cuts method50. A bronchial pathway was reconstructed into multiplanar reconstruction images with a window width of 1600 HU and a window level of −600 HU  who was blinded to patient’s information. For each selected bronchus, four levels of the airways , fourth- , fifth-, and sixth-generation bronchi) were identified by tracing airway trees peripherally on the same trunk of each segmental bronchus. At the midpoint of each level of airway, WA and Ai perpendicular to the long axis of the airway were computed automatically  imaging was performed using a 64-slice MDCT machine  in the supine position at full inspiration breath-hold for research purpose. The details of MDCT scanning were described a previous study51. The measurements were performed in triplicate, and the results were reported as the mean of three measurements. All subjects abstained from food and coffee for 2 h, and alcohol for 12 h before testing.FeNO was measured with an online method at a flow of 50 mL/s using a chemiluminescence NO analyzer, Sievers NOA280i  according to American Thoracic Society/European Respiratory Society recommendations52. Spirometry and measurements of FeNO were performed on the same day as the chest CT scans, and spirometry was performed after measurement of FeNO.An Autospirometer System 7  was used to measure spirometry according to the standards of the Japanese Respiratory society54. Differences between rank correlation coefficients were evaluated by the Meng-Rosenthal-Rubin method55. Data are the median (range) unless indicated otherwise. Statistical tests were two-sided, and p < 0.05 was considered significant. Values were analyzed using JMP v9.0.0 software , except for partial rank correlation analysis and Meng-Rosenthal-Rubin method which used R version 3.2.4  with additional packages 55.Correlation between continuous variables was undertaken using the Spearman rank correlation coefficient. Partial rank correlation analysis between FeNO and WA/BSA and Ai/BSA were performed with adjustments for age, duration of asthma, dose of inhaled corticosteroid, percentage of blood eosinophils, and blood total IgE as the potential confounding factors


Orthostatic challenge produced by upright posture may lead to syncope if the cardiovascular system is unable to maintain adequate brain perfusion. This review outlines orthostatic intolerance related to the aging process, long-term bedrest confinement, drugs, and disease. Aging-associated illness or injury due to falls often leads to hospitalization. Older patients spend up to 83% of hospital admission lying in bed and thus the consequences of bedrest confinement such as physiological deconditioning, functional decline, and orthostatic intolerance represent a central challenge in the care of the vulnerable older population. This review examines current scientific knowledge regarding orthostatic intolerance and how it comes about and provides a framework for understanding of (patho-) physiological concepts of cardiovascular (in-) stability in ambulatory and bedrest confined senior citizens as well as in individuals with disease conditions  or those on multiple medications (polypharmacy). Understanding these aspects, along with cardio-postural interactions, is particularly important as blood pressure destabilization leading to orthostatic intolerance affects 3–4% of the general population, and in 4 out of 10 cases the exact cause remains elusive. Reviewed also are countermeasures to orthostatic intolerance such as exercise, water drinking, mental arithmetic, cognitive training, and respiration training in SCI patients. We speculate that optimally applied countermeasures such as mental challenge maintain sympathetic activity, and improve venous return, stroke volume, and consequently, blood pressure during upright standing. Finally, this paper emphasizes the importance of an active life style in old age and why early re-mobilization following bedrest confinement or bedrest is crucial in preventing orthostatic intolerance, falls and falls-related injuries in older persons. In most persons, the hemodynamic and neurovascular responses to orthostatic challenge produced by standing up are adequate to stabilize arterial blood pressure and to maintain cerebral blood flow after standing. However, numerous patients come to clinics with the complaint of dizziness upon standing  leading to increasing public health costs as well as costs for older people and their families. The negative consequences of aging such as illness or injury often require admission to hospital. However, the bedrest confinement that occurs during hospitalization is considered a major factor in physiological deconditioning and functional decline and can contribute to a downhill spiral of increasing risk of frailty, and orthostatic intolerance, leading to falls  position, the hemodynamic responses may not be enough to sustain the arterial blood pressure, and syncope may ensue. In a healthy person, upon standing up, 10–15% (~700 mL) of blood volume can pool due to gravitational effects in the legs  to naturally optimize body positioning  was observed, a new physiological model—Recently, Rodriguez et al.  reportedOrthostatic hypotension is common in older adults. The prevalence of asymptomatic orthostatic hypotension  in 5,201 randomly selected persons aged 65 and older with natural history of—or with risk factors for—cerebrovascular or cardiovascular diseases was found to be 16.2% , and after taking into account all the confounders, orthostatic hypotension risk was found to be 64% higher in summer  is the arbitrary decrease in systolic BP ≥ 20 mmHg or postprandial reduction in systolic BP to <90 mmHg within 2 h following a meal  show blood pressure reducing effect , who were free from coronary heart disease or heart failure and participating in a general health checkup. A higher prevalence of cerebral lacunar infarctions as evidenced by MRI was shown in subjects with postprandial hypotension compared with controls , concussion and long term bedrest itself. Orthostatic intolerance can also arise in patients with stroke  signaling, resulting in constant sympathetic activity, which over time can increase resistance at adrenergic beta-receptors to stimulation or there may be a greater inhibition of sympathetic catecholamine release. Patients with hypertension, stroke, and chronic heart disease often display this type of reactivity and the Rodriguez et al. . Following exercise it was observed that MAP decreased in patients with cervical SCI (−9.3 ± 2 mmHg) but increased in thoracic SCI . They suggested that these effects might partially arise due to the loss of descending sympathetic nervous control of the heart and vasculature, which accompanies SCI of higher levels. However, these data were obtained from a sample of younger persons. Therefore, interpretations in terms of effects of exercise in older people with SCI must be applied with caution.OH that accompanies SCI can also complicate a patient's participation in rehabilitation, especially when carrying out exercises conditioning, muscle loss, cardiovascular and vestibular effects, is followed. Such an approach will lead to more effective management of bedrest confinement, reduced orthostatic intolerance and falls and falls-related injury, and consequently decrease public health costs, costs for older people and their families as well as decrease secondary care dependency.Outlined below are some of the possible countermeasures that are currently in use or being examined. While not all of these interventions have been tested in older persons, we present here some evidence that these countermeasures can reduce orthostatic intolerance in young and middle aged persons.Physical exercise is therapeutic for many medical disorders  fail to even maintain calf muscle strength and size under bedrest conditions  are still lacking for hospitalized older people. As a result, in many hospitals, the acute care of older persons does not incorporate procedures to promote remobilization early enough. Physical exercise interventions are often delayed and the procedures implemented may be based on individual therapist experience leading to non-standardized interventions which are often only applied after substantial loss of muscle mass and function has occurred. Thus patients may be discharged without recovering sufficient physical function leading to a vicious circle of hospital deconditioning leading to injury and further hospitalization and further dependency (Singh et al., The responses to water consumption in young healthy persons are complex with a simultaneous increase in vagal tone, as evidenced by bradycardia and an increase in the high-frequency component of the HRV, and some vasoconstriction, as evidenced by a rise in peripheral resistance (Brown et al., In older persons, the effects of water drinking has been sparsely studied. However, one study has clearly shown that drinking half a liter of water leads to acute increases in blood pressure also in older subjects (Jordan et al., Mental challenge increases heart rate, cardiac output, force of cardiac contraction, and blood pressure (Lackner et al., In a pilot study, Goswami et al.  have shoMental challenge-induced increases in sympathetic activity also affect the venous system. As 70% of total blood volume is approximately in the venous system, and veins are strongly controlled by the sympathetic system (reviewed in Pang, The responses to mental challenge conducted in upright position are unsurprising, as mental challenge induced central drive modulates physiological responses (e.g., cardiovascular reflexes, Ross and Steptoe, Mental arithmetic, Stroop color-word conflict, and public speaking are commonly used mental stressors (Steptoe and Vogele, exact timing of the application. Lackner et al. (Goswami et al.  propose r et al.  have repr et al. . For insr et al. . As longr et al.  recommenStanding up slowly in older persons with histories of orthostatic hypotension has been shown to antagonize the blood pressure decreases within the first 15 sec of changes in posture/ standing (de Bruïne et al., Some other countermeasures that could potentially prevent orthostatic intolerance include standing up slowly (de Bruïne et al., Recent evidence also suggests that cognitive training (Goswami et al., The concept of using cognitive training as a countermeasure in preventing functional decline originates from the observations that cognitive interventions promote functional outcomes, particularly improvements in mobility in older sedentary persons (Verghese et al., Finally, as mental challenge causes increased blood flow in skeletal muscles (Kuipers et al., −1 · d−1 provided by red lean meat has been shown to improve the effects of progressive resistant training on lean tissue mass and muscle strength in older women (Daly et al., Nutritional therapy, along with resistance training affects muscle mass in healthy older adults (Strandberg et al., Inspiratory-expiratory pressure threshold respiratory training has recently been shown to reduce the incidence of orthostatic hypotension in more than 50% of patients with SCI (Aslan et al., This review outlines orthostatic intolerance connected to age, bedrest confinement, and diseases. Aging-associated illness or injury due to falls often leads to hospitalization. As older patients spend significant amounts of time during hospital admission lying in bed, the consequences of bedrest confinement such as physiological deconditioning, functional decline, and orthostatic intolerance represent a central challenge in the care of the vulnerable older population.timing of the countermeasure application is also considered. Finally, this paper emphasizes the importance of an active life style in old age and why early re-mobilization following bedrest confinement is crucial in preventing orthostatic intolerance, falls and falls-related injuries in older persons.The review also discusses contributing mechanisms of orthostatic intolerance and examines countermeasures such as exercise, water drinking, and mental arithmetic. The There is a need to integrate cerebrovascular and cardiovascular variables into a combined analysis to allow for the development of improved orthostatic intolerance and fall risk-screening monitoring in older persons. Hand held devices for the analysis of global HRV (a key aspect for monitoring autonomic function (Grote et al., Additionally, rehabilitation post-stroke could benefit from combination of mobile monitoring of the autonomic and cardiovascular systems with effective physical therapy interventions to ensure that older persons are protected from muscle wasting and muscle loss after stroke. Future sit-to-stand protocols that include MSNA evaluation, by which the magnitude and timing of sympathetic responses could be measured, could be carried out to clarify the relationship between MSNA and HRV. All these aspects are important in the asssement of orthostatic intolerance risk in patients during hospitalization and upon discharge.Finally, there is a need to implement more integrated screening procedures during hospital admission to personalize countermeasures against orthostatic intolerance, which can arise due to bedrest confinement.NG conceived the idea and wrote the manuscript. AB supported in editing the manuscript and contributed to sections related to cardio-postural interactions. HH-S helped in writing the manuscript. J-PM supported in editing the manuscript and contributed to sections related to water drinking as well as post-prandial hypotension.The section related to mental stress is based on the Doctoral work of NG. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.