Although resistant hypertension (RH) is known to be associated with higher rates of cardiovascular events than is non-RH, there are no reported data on the prevalence of RH in Korean patients. We evaluated the prevalence and characteristics of RH among hypertensive patients treated at primary clinics in Korea.Between August 2010 and January 2011, 247 primary care physicians enrolled 3088 patients with essential hypertension. We acquired demographic and anthropometric data using a questionnaire, evaluated blood pressure, and conducted a variety of laboratory tests using serum and urine. RH was defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg with the use of three antihypertensive agents of different classes, including a diuretic, or controlled hypertension with the use of four or more medications.P < 0.05). In the multivariate analysis, RH was shown to be significantly associated with the following conditions: presence of electrocardiographic LVH , current smoker , renal impairment , abdominal obesity , and cardiovascular diseases .We analyzed 3088 patients with hypertension, 48.3 % of whom were men. The mean age of patients was 64.3 ± 11.3 years and the prevalence of RH was 7.9 %. Patients with RH were more likely to be men, and to have higher waist circumference, increased blood levels of HbA1c, triglycerides, and serum creatinine, lower blood levels of high-density lipoprotein (HDL), and higher rates of current smoker, history of heart failure or coronary artery disease, and electrocardiographic left ventricular hypertrophy (LVH), than were patients with non-RH (all comparisons, The prevalence of RH was relatively low at primary clinics in Korea compared with the prevalence reported in other countries. RH was associated with electrocardiographically confirmed LVH, renal impairment, current smoker, abdominal obesity, and cardiovascular diseases. These are the first reported data of RH in Korea. Our findings may be helpful in the early detection and thorough clinical management of patients with RH at primary clinics. Resistant hypertension (RH) was defined by the seventh Joint National Committee as the failure to achieve a target blood pressure despite maintaining full doses of three antihypertensive agents of different classes, one of which should be a diuretic . FollowiP < 0.001), over the mean follow-up period of 3.8 years than did those with non-RH [Although the specific prognostic implications of RH have not been well evaluated, RH is frequently associated with cardiovascular risk factors, such as older age, diabetes mellitus, obesity, obstructive sleep apnea, left ventricular hypertrophy (LVH), and chronic kidney disease , 3. Amonh non-RH . TherefoHowever, to our knowledge, the exact prevalence of RH in Korea has yet to be reported. Patients who have difficulty controlling their blood pressure or who are suspected to have RH are usually referred from primary clinics to the hospital, where cardiologists who specialize in hypertension manage their care. Therefore, the investigation of the clinical management of RH in primary clinics may be insufficient to capture the prevalence of this disease, even though the prevalence of RH is reportedly 11 ~ 21 % at tertiary facilities and 10 % at primary clinics in the United States , 6.Hypertension is often present as part of the metabolic syndrome and is associated with insulin resistance. Higher rates of diabetes mellitus or obesity may be present in patients with RH compared with those who have non-RH. Accurate information regarding the prevalence and outcome of RH is important for managing and improving the prognosis of this condition. Identifying and targeting high-risk patients with hypertension can increase the cost effectiveness of primary clinics. Therefore, we investigated the prevalence of RH and evaluated the characteristics of patients with RH in primary clinics in Korea.Patients who were older than 18 years with essential hypertension and who visited primary clinics in 2010 were eligible to participate in this cross-sectional study. Patients were excluded if they had the following conditions: secondary hypertension, white-coat hypertension, acute myocardial infarction, unstable angina, acute phase of stroke, peripheral artery disease, or uncontrolled diabetes mellitus (HbA1c > 9.0 %). Two hundred and forty-seven physicians in 230 primary clinics participated in this study through the network that was organized in a previous investigation . The priPhysicians measured blood pressure using an electronic sphygmomanometer . After the patient had been seated quietly for 5 min, blood pressure was measured with the right arm of the patient supported at the level of the heart. We obtained two or three blood pressure measurements, 30 s apart. If blood pressure was measured twice, the average value was assigned to the blood pressure of the patient. If it was measured three times, the second and the third values were used to calculate the average of systolic and diastolic blood pressure.Each patient enrolled in the study was given a self-administered questionnaire in order to collect data on demography, lifestyle, and a family history of hypertension and cardiovascular disease. The physicians also recorded anthropometrical parameters, such as comorbidities and antihypertensive medications.An 8-h fasting blood sample was collected for the measurement of hemoglobin A1c, fasting plasma glucose, and blood lipids. Urinary analysis was also performed to measure albumin concentration in the spot urine and the albumin/creatinine ratio was estimated to compensate for variations in urinary concentration.The body mass index (BMI) was calculated from the patient’s height and weight. The waist circumference was measured at the narrowest part of the waist between the lowest rib and the iliac crest.The Eighth Joint National Committee defined hypertension as either office systolic blood pressure level of more than 140 mmHg or diastolic blood pressure of less than 90 mmHg . RH was Abdominal obesity was defined as waist circumference of more than 90 cm for men and more than 85 cm for women. Smoking was categorized as current, ex-smoker of less than 1 year, or non-smoker, according to smoking status. The presence of dyslipidemia was defined by low-density lipoprotein (LDL) ≥ 130 mg/dL in patients with hypertension, and also included cases already receiving lipid-lowering agents [2, and/or by an albumin to creatinine ratio of ≥30 μg/mg. Renal impairment was defined as having an estimated GFR < 60 mL/min, as calculated by the Modification of Diet in Renal Disease equation. Microalbuminuria was defined as an albumin to creatinine ratio of 30 to 300 μg/mg [Target organ damage was evaluated by electrocardiographic LVH for the heart, by estimated glomerular filtration rate (GFR) of <60 mL/min/1.73 m00 μg/mg . Electro00 μg/mg , or if S00 μg/mg .Cardiovascular disease included coronary artery disease, congestive heart failure, and stroke. The presence of coronary artery disease was defined as acute myocardial infarction or hospitalization with angina pectoris. The presence of congestive heart failure was defined as the need for hospitalization. Diagnosis of stroke was necessary to confirm infarction demonstrated by computed tomography or magnetic resonance imaging.t-test or one way-ANOVA were used for continuous variables and chi-square test or Fisher exact test were used for the categorical variables. Multivariate logistic regression analysis was performed to determine independent clinical predictors for RH in the stepwise forward selection procedure. All analyses were performed with 95 % confidence intervals, and p-values of less than 0.05 were considered statistically significant.All statistical analyses were performed using SPSS version 18.0 . Interval variables were described as mean ± standard deviation. Nominal or ordinal variables were described as proportions. Student’s Among 3122 recruited patients, 34 patients were excluded: 5 did not sign an informed consent form, 8 had inadequate blood samples, and 21 provided no information about antihypertensive medication . The mean age of the patients was 64.3 ± 11.3 years . Systolic and diastolic blood pressure were well controlled in 2119 patients (68.6 %). Among patients who were prescribed any medication, 71.3 % (N = 801) had controlled blood pressure. The percentage of patients with controlled blood pressure varied according to the number of medications prescribed: one medication, 69.6 % (N = 916); two medications, 63.6 % (N = 334); three medications; and four or more medications, 51.8 % . Renal impairment, defined as an estimated glomerular filtration rate (GFR) of <60 mL/min/1.73 m2, was more prevalent among RH patients as it was among non-RH patients . However, the prevalence of dyslipidemia did not significantly differ between patients with RH and those with non-RH.Compared with patients with non-RH, those with RH had more cardiovascular risk factors at baseline, such as abdominal obesity, smoking, diabetes mellitus, and renal impairment. Significantly more RH patients were current smokers, than were non-RH patients . Among total participants, 131 patients (4.2 %) had cardiac involvement, which was defined by LVH on electrocardiography, and 1217 patients (39.6 %) had renal involvement, which was defined by an estimated GFR < 60 mL/min/1.73 m2 or an albumin to creatinine ratio of ≥30 μg/mg (Table P < 0.001). Although the prevalence of microalbuminuria and/or overt proteinuria were not statistically significant between two groups, these conditions tended to be higher among patients with RH than among those with non-RH.Target organ damage to the heart and/or the kidney was observed in 1284 patients , abdominal obesity (waist circumference ≥90 in men and ≥85 in women), and the presence of cardiovascular disease. Electrocardiographic LVH predicted the greatest odds of RH . Gender, microalbuminuria or macroalbuminuria, and diabetes mellitus did not significantly differ between the groups.Table This observational and cross-sectional study surveyed demographic findings, clinical characteristics, and antihypertensive medication classes in hypertensive patients at 230 primary care clinics in Korea. The purpose of our study was to evaluate the prevalence of the patients who corresponded to the criteria of RH, and to determine the demographic and clinical features that distinguish high-risk individuals who develop RH from all hypertensive patients.N = 244), which is lower than the prevalence reported in some studies. This phenomenon may be explained by the different conditions of our study, as compared with other studies. In the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) trial and the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the prevalence of RH was 18 and 15 %, respectively. Those data were examined from patients who were 55 years or older who had one or more additional cardiovascular risk factors [In this study, the prevalence of RH was 7.9 %  . Forced We showed several predictors to be associated with RH: electrocardiographic LVH, renal impairment, current smoker, abdominal obesity, and cardiovascular disease. In particular, hypertensive patients with electrocardiographic LVH were 2.3 odds  more likely to have RH compared to those without electrocardiographic LVH. LVH is not only one of the most important subclinical cardiac alterations that result from continuous high blood pressure but also represents a target organ damage . In addiN = 698) was 11.0 %, in our study. Previous studies have reported the prevalence of RH to be 50 % or more [The prevalence of RH in the subgroup with renal impairment ( or more . Chronic or more , 20. ThuLifestyle modifications, such as weight reduction and smoking cessation, may also help improve hypertension management. Although the exact mechanism by which obesity increases blood pressure is not well understood, excess weight gain has been reported as the best predictor for the development of hypertension . ObesityIdentifying individuals at high risk of developing RH, who have electrocardiographic LVH, renal impairment, abdominal obesity, current smoking, or cardiovascular disease, is important for the selection of appropriate antihypertensive medications. Difficulty in controlling blood pressure in patients with the aforementioned predictors should prompt earlier consideration of forced titration of medications and evaluation for secondary hypertension.This study has some limitations. First, drug adherence was not measured accurately. Poor adherence to antihypertensive medications is a well-known, major cause of failure to reach target blood pressure . HoweverThe prevalence of RH at primary clinics in Korea was 7.9 %, which is relatively low when compared with the findings of studies conducted in other countries. Predictors for increased risk of RH were electrocardiographic LVH, renal impairment, current smoking, abdominal obesity, and the presence of cardiovascular disease. Therefore, these predictors may be helpful for detecting risk of RH and for improving the efficiency of clinical management for hypertension by forced titration or selection of drugs.


In the Systolic Hypertension in Europe trial (NCT02088450), we investigated whether systolic blood pressure variability determines prognosis over and beyond level.n = 286) or cardiovascular (n = 150) mortality or cardiovascular (n = 347), cerebrovascular (n = 133) or cardiac (n = 217) endpoints.Using a computerised random function and a double-blind design, we randomly allocated 4695 patients (≥60 years) with isolated systolic hypertension (160–219/<95 mm Hg) to active treatment or matching placebo. Active treatment consisted of nitrendipine (10–40 mg/day) with possible addition of enalapril (5–20 mg/day) and/or hydrochlorothiazide (12.5–25.0 mg/day). We assessed whether on-treatment systolic blood pressure level (SBP), visit-to-visit variability independent of the mean (VIM) or within-visit variability (WVV) predicted total (vs. high VIM had similar event rates (p≥0.14). Low vs. high WVV was not associated with event rates (p≥0.095), except for total and cardiovascular mortality on active treatment, which were higher with low WVV (p≤0.0003). In multivariable-adjusted Cox models, SBP predicted all endpoints (p≤0.0043), whereas VIM did not predict any (p≥0.058). Except for an inverse association with total mortality (p = 0.042), WVV was not predictive (p≥0.15). Sensitivity analyses, from which we excluded blood pressure readings within 6 months after randomisation, 6 months prior to an event or both were confirmatory.At 2 years, mean between-group differences were 10.5 mm Hg (p<0.0001) for SBP, 0.29 units (p = 0.20) for VIM, and 0.07 mm Hg (p = 0.47) for WVV. Active treatment reduced (p≤0.048) cardiovascular (−28%), cerebrovascular (−40%) and cardiac (−24%) endpoints. In analyses dichotomised by the median, patients with low The double-blind placebo-controlled Syst-Eur trial demonstrated that blood-pressure lowering treatment reduces cardiovascular complications by decreasing level but not variability of SBP. Higher blood pressure level, but not higher variability, predicted risk.NCT02088450ClinicalTrials.gov  Whether blood pressure variability determines prognosis over and beyond level needs further clarification. Recent publications vs. active treatment starting with a dihydropyridine calcium-channel blocker differentially affected visit-to-visit and within-visit blood pressure variability and whether visit-to-visit or within-visit variability had an additive role to blood pressure level in predicting outcome.The double-blind Systolic Hypertension in the Elderly Trial (Syst-Eur) demonstrated that among older patients with isolated systolic hypertension, antihypertensive drug treatment starting with the calcium-channel blocker nitrendipine reduced the rate of stroke and cardiovascular complications The protocol for this trial and supporting CONSORT checklist are available as supporting information; see The protocol of this trial Bayer AG funded investigator-initiated Syst-Eur trial (1988-1997). The corresponding author owns the data and funding by Bayer does therefore in no way alter our adherence to PLOS ONE policies on sharing data and materials.Previous publications describe the Syst-Eur protocol, inclusion and exclusion criteria, and procedures for recruitment and randomisation After stratification by centre, sex, and previous cardiovascular complications, eligible patients were randomly assigned to treatment with active medication or placebo. A computerised random function generated at the study coordinating centre in Leuven without block size restriction ensured random allocation of patients at the 198 participating centres. The study medications were stepwise titrated and combined to reduce sitting systolic blood pressure by 20 mm Hg or more to levels below 150 mm Hg. Active treatment was initiated with nitrendipine (10–40 mg/day). If necessary, the dihydropyridine calcium-channel blocker was combined with or replaced by enalapril maleate (5–20 mg/day), hydrochlorothiazide (12.5–25 mg/day), or both drugs. Placebo tablets were identical to the study drugs with a similar schedule. Patients who withdrew from double-blind treatment proceeded to supervised open follow-up. During double-blind and supervised open follow-up, patients had their sitting blood pressure measured twice at 3-monthly intervals. The two measurements were averaged for analysis of blood pressure level. Terminal digit and number preference were monitored during the trial The main endpoints included death, stroke, myocardial infarction, and congestive heart failure. Stroke, the primary endpoint, was a neurological deficit with symptoms continuing for more than 24 h or leading to death with no apparent cause other than vascular. Acute myocardial infarction required two of the following three disorders: typical chest pain, electrocardiographic changes, or increased cardiac enzymes, and did not include silent myocardial infarction. Congestive heart failure required the presence of three disorders: symptoms, such as dyspnoea, clinical signs, such as ankle oedema or crackles, and the necessity of treatment with diuretics, vasodilators, or antihypertensive drugs. Sudden death encompassed any death of unknown origin occurring immediately or within 24 h of the onset of acute symptoms, as well as unattended death for which no likely cause could be established by necropsy or medical history. Cardiac events included fatal and non-fatal heart failure, fatal and non-fatal myocardial infarction, and sudden death. The endpoint committee, which was unaware of the patients' treatment status, identified all major endpoints by reviewing the patients' files and other source documents, or by requesting detailed written information from the investigators, or by both approaches. The number of endpoints in the present analysis rests on the update published in 1999 Our original sample-size calculations assumed a rate of stroke in the placebo group of 17.0 events per 1000 patient-years. 15 000 patient-years  were required to detect a 40% change in the overall stroke rate with a two-tailed significance of 1% and 90% power For database management and statistical analysis, we used the SAS system, version 9.3 . Significance was a two-tailed α-level of 0.05 or less. Means and proportions were compared using the large-sample z-test or ANOVA and Fisher's exact test, respectively.We limited our analyses to systolic blood pressure, because in middle-aged and older subjects it is a stronger risk factor than diastolic blood pressure is x and multiplied by the population mean to the power x x, where x was derived by non-linear regression analysis as implemented in the PROC NLIN procedure of the SAS package. ARV is the average of the absolute differences between blood pressure measurements obtained at consecutive visits. ARV averages the absolute blood pressure differences between consecutive visits and thereby accounts for the order according to which blood pressure was measured We determined blood pressure level (SBP) and variability separately for the run-in period in 4695 patients and after randomisation in 2297 and 2398 patients randomised to placebo or active treatment, respectively. We assessed visit-to-visit blood pressure variability from the variability independent of the mean (VIM) Within-visit variability (WVV) is the absolute difference between the two blood pressure measurements at each visit averaged over the whole follow-up of each patient We compared the incidence of the pre-defined endpoints between groups, using the log-rank test for rates and Kaplan-Meier survival function estimates. We used Cox regression to compute hazard ratios, while stratifying for centre and adjusting for randomisation group (if applicable), sex, age, body mass index, heart rate, serum total cholesterol, smoking and drinking, and history of cardiovascular disease or diabetes. Hazard ratios express the risk associated with a 1-SD increment in the level or variability of blood pressure. In our main analyses, we used all available blood pressure measurements during follow-up up to an event to compute blood pressure level and variability. In sensitivity analyses of VIM and WVV, we excluded the blood pressure readings obtained during the first 6 months or 1 year after randomisation n = 2297) and active-treatment (n = 2398) groups were similar (p≥0.079) for distribution of sex, age, blood pressure, pulse rate, body mass index, serum cholesterol, use of tobacco and alcohol, previous cardiovascular complications, and antihypertensive treatment. Of 4695 participants, 3138 (66.8%) were women. Age averaged 70.2  years. Sitting blood pressure was 173.8 (10.0) mmHg systolic and 85.5 (5.9) mmHg diastolic.At randomisation, patients in the placebo (x to compute VIM was 0.847 in patients randomised to placebo and 0.981 in the active-treatment group. The correlation coefficients of SBP with VIM were −0.015 (p = 0.49) and −0.015 (p = 0.48) during follow-up on placebo or active treatment; the corresponding correlation coefficients with WVV were 0.12 and 0.071 (p≤0.0006), respectively.The value of Among patients continuing double-blind medication, nitrendipine or matching placebo were the only treatments given at 2 years (median follow-up) in 597 (58.9%) of 1014 randomised to active treatment and in 343 (39.6%) of 866 placebo patients. Among the patients in open follow-up at 2 years, 65 (36.5%) of 178 randomly assigned to active treatment and 157 (58.1%) of 270 in the placebo group were on antihypertensive drugs. Antihypertensive treatment status was undocumented in 88 (49.4%) and 81 (30.0%) patients, respectively.At 2 years , SBP hadThe number of patient-years on monotherapy with first-line treatment was 1754.0 (31.0%) on nitrendipine placebo and 3107.4 (51.4%) on active nitrendipine. In patients remaining on monotherapy, the value of x to compute VIM was 3.354 in the run-in period and 0.058 and 0.659 in patients during follow-up on placebo (n = 885) or active nitrendipine (n = 1351), respectively. At 2 years, the mean between-group differences were 3.9 mm Hg  for SBP, 0.29 units  for VIM, and 0.12 mm Hg  for WVV .x to compute VIM was 3.192 in the run-in period and 0.791 and 0.975 in patients during follow-up on placebo (n = 1412) or active nitrendipine (n = 1047), respectively. At 2 years, the mean between-group differences were 10.9 mm Hg  for SBP, −0.52 units  for VIM, and −0.069 mm Hg  for WVV  of total or cardiovascular mortality  and consistent predictor of all endpoints under study and retained its significance when Cox models also included VIM  or WVV . SBP remAnalyses with a time-dependent adjustment for proceeding to combination therapy, produced results for VIM  and WVV The novelty of our current study lies in the randomised double-blind placebo-controlled assessment of the risk associated with blood pressure variability and in accounting for blood pressure level while assessing blood pressure variability as cardiovascular risk factor. The key finding was that antihypertensive treatment lowered blood pressure and the incidence of cardiovascular, cerebrovascular and cardiac complications, but compared to placebo it did not affect visit-to-visit or within-visit blood pressure variability. In our current analysis, only blood pressure level, not variability, can therefore explain the benefit conferred by antihypertensive treatment. Kaplan-Meier survival estimates and fully adjusted Cox models confirmed that blood pressure level, but not visit-to-visit or within-visit variability predicted outcome. The findings were consistent in the placebo and active-treatment groups analysed separately.Our manuscript differs substantially from previous publications on the role of blood pressure variability as cardiovascular prognosticator. First, our analyses followed the lines of randomisation in a double-blind placebo-controlled trial Factors explaining the difference with previous studies The current study must be interpreted within the context of some potential limitations. First, Syst-Eur involved older patients with isolated systolic hypertension, of whom only one third had a history of previous cardiovascular complications. Our current observations might not be generalizable to younger individuals, patients with more serious cardiovascular disease, in whom blood pressure regulation is often compromised, or patients with predominant diastolic hypertension. Second, the Syst-Eur trial was terminated early at the second interim analysis because of a significant reduction of stroke, while recruitment was still on-going In conclusion, in Syst-Eur, higher blood pressure level, but not higher variability, predicted risk. Blood pressure level is a reversible risk factor, overriding all other modifiable risk factors. The suggestion to consider blood pressure variability as an additional risk indicator and to reduce it by drugs Protocol S1Ethics approval, original protocol, and trial registration.(PDF)Click here for additional data file.Checklist S1CONSORT checklist.(DOC)Click here for additional data file.


Background. Longitudinal investigations into the origins of adult essential hypertension have found elevated blood pressure in children to accurately track into adulthood, however the direct causes of essential hypertension in adolescence and adulthood remains unclear.Methods. We revisited 152 Peruvian adolescents from a birth cohort tracked from 0 to 30 months of age, and evaluated growth via monthly anthropometric measurements between 1995 and 1998, and obtained anthropometric and blood pressure measurements 11–14 years later. We used multivariable regression models to study the effects of infantile and childhood growth trends on blood pressure and central obesity in early adolescence.Results. In regression models adjusted for interim changes in weight and height, each 0.1 SD increase in weight for length from 0 to 5 months of age, and 1 SD increase from 6 to 30 months of age, was associated with decreased adolescent systolic blood pressure by 1.3 mm Hg (95% CI −2.4 to −0.1) and 2.5 mm Hg (95% CI −4.9 to 0.0), and decreased waist circumference by 0.6 (95% CI −1.1 to 0.0) and 1.2 cm (95% CI −2.3 to −0.1), respectively. Growth in infancy and early childhood was not significantly associated with adolescent waist-to-hip ratio.Conclusions. Rapid compensatory growth in early life has been posited to increase the risk of long-term cardiovascular morbidities such that nutritional interventions may do more harm than good. However, we found increased weight growth during infancy and early childhood to be associated with decreased systolic blood pressure and central adiposity in adolescence. The prevalence of hypertension has increased dramatically in the past two decades among adults in developing nations  and globLongitudinal investigations into the origins of adult essential hypertension have found elevated blood pressure in children to accurately track into adulthood , howeverTo date, the association of these three developmental periods on adolescent and adult blood pressure has varied in both reproducibility and magnitude. Low birth weight has been well established to predict higher adolescent and adult blood pressure . HoweverWe sought to address the following research question: how does growth rate in infancy and early childhood, independently, affect blood pressure and central adiposity in adolescence in a middle-income country? To answer this, we took advantage of a longitudinal cohort of Peruvian infants tracked in infancy via monthly growth measurements and revisited them at adolescence.The study setting was Pampas de San Juan de Miraflores, a peri-urban shanty-town (pueblo joven) located 25 km south of Lima, Peru. Initially settled in the early 1990s, with temporary structures lacking water or sewage lines, the community has undergone many economic and social developments over the last two decades. By 2008, over 75% of homes were constructed from brick or cement with in-home water and sewage. Improved transportation within this community has changed patterns of exercise as “moto-taxis” have decreased the need to walk from main byways to the residential regions. The diet, while maintaining many typical aspects, now is more similar to an urban setting, an energy dense diet. The region continues its transition from a communicable to a chronic disease society, with current rates of hypertension ranging from 12.6% and 14.4 in private urban clinics , to 19.5The enrollment of children into the original birth cohort study was conducted from February 1995 to December 1998 . Beginniz-scores using the 2006 World Health Organization (WHO) child growth standards developed for children from age 0 to 5 years , underweight and overweight as a WLZ < −2 and > 2 SD, respectively. Diarrhea was evaluated by daily home visits. A diarrhea day was defined as a day on which the mother reported the child had diarrhea and the child had passed at least three liquid or semi-liquid stools. A diarrhea episode began on the first diarrhea day and ended on the last diarrhea day followed by two consecutive days without diarrhea. Information on breastfeeding was collected and has been evaluated and published elsewhere  and weight for length (WLZ)  5 years . LAZ is lsewhere . Based o2) and waist-to-hip ratio (WHR).Between April 2008 and July 2009, we conducted a follow-up assessment in those eligible for this study . Particiz-score at follow-up was calculated using the 2007 WHO anthropometric reference for children and adolescents (BMI for age (BAZ) lescents , standarThe outcomes of interest were systolic and diastolic blood pressure, waist circumference and WHR.Data were analyzed in two stages, as described in greater detail elsewhere . In the We then estimated the slopes of change for LAZ and WLZ in infancy as a function of age and sex using a random-effects model  while adIn the second stage, we used a sequence of multiple linear regression models to assess the influence of growth in infancy and early childhood on the outcomes of interest. These analyses were performed independently for LAZ and WLZ in infancy. We used the following regression models: Model 1 adjusted for sex, age at the time of follow-up, and socioeconomic deprivation; and Model 2 adjusted for the variables in Model 1 as well as adolescent BAZ and current height. Adjustment for adolescent BAZ addressed any growth that occurred in between the end of serial measurement in infancy and the follow-up visit. Additionally, we adjusted for current height to minimize overestimating the influence of our exposures of interest, LAZ and WLZ at birth and the rate of change in each during infancy, due to its strong correlation to blood pressure.Additionally, we stratified growth rates in tertiles and compared the mean blood pressure values for each tertile. All analyses were performed using STATA version 9.2 .The original 1995 study was approved by the Institutional Review Boards of A.B. PRISMA  and the Johns Hopkins School of Public Health . Institutional Review Boards of A.B. PRISMA and Universidad Peruana Cayetano Heredia, both in Lima, Peru, approved the follow-up study.p = 0.387) or weight (p = 0.834), maternal height (p = 0.172), the percentage of households without sewage connection (p = 0.077) or in the type of house flooring (p = 0.860) between the 147 participants who completed follow-up and the remaining 49 (25%) participants of the original cohort that met inclusion criteria but did not participate in the follow-up assessments.In the 2008–2009 follow-up visit, we completed measurement on 75% (147 out of 196) of the eligible participants . We founWe first examined the association between growth rates early in development and adolescent blood pressure. We next examined the influence of variable growth rates in infancy on adolescent central adiposity. LAZ at birth and rate of change in LAZ in infancy were strongly associated with adolescent waist circumference in multivariate regression unadjusted for adolescent body parameters (see Model 1 in Similarly, WLZ at birth was positively associated with both waist circumference and WHR prior to adjustment, but these estimates attenuated once adjusted for BAZ and height. The rate of change in WLZ in early and late infancy was also positively associated with waist circumference and WHR prior to adjustment for adolescent body size. However, after adjustment, these relationships with adolescent adiposity became inversed and significant, with more rapid growth in infancy associating with a smaller waist circumference in adolescence.Our longitudinal study aimed to assess the effects of early growth on adolescent blood pressure and central adiposity by taking advantage of serial measurement of anthropometric indicators, with data accruing monthly for a period of up to 30 months, and thus overcoming limitations posed by single ascertainment of birth weight or modelling techniques that approximate growth patterns. We found increased rates of weight gain in infancy were strongly associated with decreased systolic blood pressure and waist circumference but not diastolic blood pressure, 10 years later, at adolescence. Weight gain in early and late infancy, respectively, predicted decreases in systolic blood pressure of 1.3 and 2.5 mm Hg, and decreases in waist circumference of 0.6 and 1.2 cm. This is consistent with findings observed in a population of Filipino adolescent males  where inThe public health implications of these findings are substantial given that blood pressure in teens has been found to track into adulthood. The magnitude of reductions in blood pressure observed in our cohort could be linked to significant gains in terms of cardiovascular disease outcomes. In a meta-analysis of 61 prospective observational studies of blood pressure and vascular disease in adults, for each 2 mm Hg decrease in systolic blood pressure, to a minimum of 115 mm Hg, stroke mortality and cardiovascular mortality decreased by 10% and 7%, respectively .Our findings contrast with recent reports from Belarus  and the Much as growth during development has been correlated with later blood pressure, it has also been found to predict an increased risk of overweight and obesity. We found increased weight at birth and rate of weight gain in early and late infancy to be associated with decreased adolescent waist circumference, a measure of central adiposity and cardiovascular risk . Birth lOur study has a number of strengths. While other studies looking at the developmental origins of disease relied, at most, on yearly anthropometric measurements, frequent serial measurement of our cohort afforded us enough power to find effects of early growth on systolic blood pressure. The use of short interval serial measurements early in life and a relatively novel methodology offered an accurate characterization of growth early in development. This characterization of growth benefited uniquely from the longitudinal diarrheal data, which was incorporated in our modeling to account for growth variations due to infection. Thus, our work provides further advancements on the relationships of early life exposures to adolescent outcomes in countries with a high burden of childhood chronic under nutrition.We also considered various potential limitations to our analysis. First, we did not directly measure birth weight or length, however there was a mean age of entry into the study of 14 days, with many individuals entering in the first days of life. Second, our estimations were adjusted for maternal education and overcrowding as proxies of long-term and current SES respectively. We considered that since the time of the initial study, maternal education was unlikely to have changed and thus a good proxy of SES at baseline . To accoAs has been described by Lucas and colleagues , the incIn low- and middle-income countries undergoing rapid economic development there is an increased risk of concurrent stunting and overweight, due to infectious disease associated growth retardation early in development  followed•Taking advantage of a daily diarrheal surveillance study, this study benefits from monthly anthropometric measurements in infancy.•This study moves beyond single ascertainment of birth weight or the growth curve modeling techniques to address the relationship between growth in infancy and blood pressure in adolescence.•The developmental origins of disease theory posits that characteristic growth patterns during the prenatal period, infancy and childhood predict subsequent risk for elevated adult blood pressure and essential hypertension.•To date, the association of these three developmental periods on adolescent and adult blood pressure has varied in both reproducibility and magnitude.•We found increased weight growth during infancy and early childhood to predict decreases in adolescent systolic blood pressure and central adiposity.


Fifty consecutive patients were assigned to each of the diabetic nephropathy and nephrosclerosis groups. All data for simultaneously measured eGFR and urinary albumin to creatinine ratio (UACR) were collected from first visit to RRT initiation and were plotted on the KDIGO heat map. Diabetic nephropathy was characterized by higher blood pressure and UACR and lower age, eGFR, and serum albumin levels compared with nephrosclerosis at RRT initiation. The vast majority of patients with diabetic nephropathy and eGFR < 60 mL/min/1.73 m2 had concomitant macroalbuminuria, whereas for patients with nephrosclerosis, even when eGFR was <45 mL/min/1.73 m2, many still had normoalbuminuria or microalbuminuria. The rate of decline of eGFR was significantly faster in the diabetic nephropathy group than that in the nephrosclerosis group. The clinical trajectories of diabetic nephropathy and nephrosclerosis differed markedly on the KDIGO heat map.This study investigated differences between the clinical trajectories of diabetic nephropathy and nephrosclerosis using the Kidney Disease: Improving Global Outcomes (KDIGO) heat map and the clinical characteristics between the two diseases at RRT initiation. This single-center, retrospective study enrolled 100 patients whose estimated glomerular filtration rate (eGFR) was ≥45 mL/min/1.73 m Chronic kidney disease (CKD) progressively increases the risk of end-stage kidney disease (ESKD) and cardiovascular disease in line with its severity . The preType 2 diabetes mellitus is among the leading causes of CKD, including ESKD, in both developed and developing countries; in various countries including the USA and Japan, type 2 diabetes mellitus accounts for nearly 50% of patients on incident dialysis . In the The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Evaluation and Management of CKD was released in January 2013 . KDIGO rAgainst this background, this retrospective study investigated differences between the clinical courses of diabetic nephropathy and nephrosclerosis using the KDIGO heat map and sought to determine how the clinical characteristics differed between the two diseases at the time of the RRT initiation.UMIN000017502).This single-center, retrospective study, conducted between January 2011 and December 2013, was designed to compare the clinical courses of diabetic nephropathy and nephrosclerosis with respect to eGFR and the urinary albumin to creatinine ratio (UACR) in patients with CKD who were already receiving treatment from a nephrologist. Specifically, the study compared the clinical progression of the two diseases as represented by the heat map based on the prognosis of CKD by GFR and albuminuria category stated in the KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease . All dat2 at the first visit to our hospital. Exclusion criteria were (1) age < 20 years at RRT initiation, (2) RRT initiated due to acute kidney injury (AKI), and (3) primary cause of CKD other than diabetic nephropathy and nephrosclerosis . Diabetic nephropathy and nephrosclerosis were diagnosed by renal biopsy or medical history. Specifically, diabetic nephropathy was defined as diagnosis based on kidney biopsy (n = 15), on the presence of type 1 diabetes (n = 2), or on fulfillment of all the following criteria (n = 33): (1) diabetes duration ≥ 10 years; (2) clear presence of diabetic retinopathy; (3) no history of proteinuria or hematuria prior to the first visit; (4) other primary kidney disease, such as secondary, hereditary, cystic, or drug-induced kidney disease or vasculitis completely ruled out by blood work or imaging diagnostics. Nephrosclerosis was diagnosed by kidney biopsy (n = 10) or fulfillment of all of the following criteria (n = 40): (1) no history of comorbid diabetes prior to the first visit or during the observational period; (2) duration of hypertension ≥ 10 years; (3) no history of proteinuria or hematuria prior to the first visit; (4) presence of hypertensive retinopathy by fundus examination; and (5) other primary kidney disease, such as secondary, hereditary, cystic, drug-induced kidney disease, or vasculitis completely ruled out by blood work or imaging diagnostics. Subjects were assigned to either the diabetic nephropathy group or nephrosclerosis group at RRT initiation, with 50 consecutive subjects enrolled per group for a total of 100 subjects.Inclusion criteria were (1) patients who underwent RRT initiation at our hospital during January 2011 and December 2013 and (2) eGFR ≥ 45 mL/min/1.73 mAll data for simultaneously measured eGFR and UACR were used to monitor the clinical course from the first visit to RRT initiation and were collected from the medical records. These data were plotted on the heat map according to the KDIGO guidelines. Serum samples were assayed for creatinine (sCr) at a central laboratory  with the enzymatic Cr assay method using a Japan electron Cr auto-analyzer  and enzyme solution . To assess urinary albumin excretion, we measured urinary concentrations of albumin and Cr  in spot urine samples. Urinary albumin was measured using the immunoturbidimetric assay. Glomerular filtration rate was estimated using the modified, final recommended equation for Japanese patients issued by the Japanese Society of Nephrology-CKD Initiatives, as eGFR values obtained by this method are more accurate for Japanese patients with CKD . The fort-test or the Mann-Whitney U test, and categorical variables were compared by the chi-square or Fisher's exact test as appropriate to the data distribution. To analyze the time course changes in eGFR, we fitted scatterplot smoothing curves to all the eGFR measures for all the patients in each group. Then, we used the Mann-Whitney U test to compare the eGFR decline (mL/min/1.73 m2 per year) between the groups. The eGFR time course data within groups were analyzed by repeated-measures analysis of variance (ANOVA), while changes between the two groups were analyzed by two-way ANOVA followed by Dunnett's test. To analyze the time course changes in albuminuria, we fitted scatterplot smoothing curves to all UACR measures for all the patients in each group. Then, we used the Mann-Whitney U test to compare the regression coefficients between the groups. Statistical significance was set at P < 0.05. All analyses were performed using JMP ver. 11 software .Data were analyzed on the basis of assigned groups and are expressed as the mean ± SD or median [interquartile range], as appropriate. Continuous variables were compared using Student's The clinical characteristics of the patients at the first visit are shown in The patients' clinical characteristics and medications being taken at RRT initiation are shown for each group in P < 0.0001).The final data set collected before RRT initiation is shown in 2 per year, respectively (P < 0.0001). The duration between the observation of eGFR < 45 mL/min/1.73 m2 and RRT initiation was 59 ± 26 months in the diabetic nephropathy group and 94 ± 28 months in the nephrosclerosis group, showing a significant difference between the groups (P < 0.0001). Furthermore, the rates of decline in eGFR in the diabetic nephropathy group and nephrosclerosis group were −9.9 ± 5.3 and −4.8 ± 2.2 mL/min/1.73 m2 per year, respectively (P < 0.0001). P < 0.0001).2. In other words, when eGFR was reduced to <60 mL/min/1.73 m2, albuminuria showed progression from the A2 to A3 stage. Moreover, the eGFR decline resulted in further elevation of albuminuria up to 3000  mg/gCr at RRT initiation. All cases underwent RRT initiation at the G5A3 stage. On the other hand, in the nephrosclerosis group, when eGFR was reduced to <45 mL/min/1.73 m2 and albuminuria had progressed from the A1 to A2 stage, the risk category changed from moderate or high risk to very high risk. Thereafter, eGFR gradually decreased and albuminuria gradually increased. Eight patients (16%) were started on RRT while remaining at the A2 stage, whereas the other 42 patients (84%) had progressed to A3 at RRT initiation.These results reveal that the clinical courses of the two primary causative diseases of CKD—diabetic nephropathy and nephrosclerosis—differ considerably when represented on the KDIGO heat map. As shown in 2; however, the rate was faster in individuals with eGFR < 30 mL/min/1.73 m2 and accelerated in the year before the development of ESKD [Declines in eGFR, such as a 30% reduction over 2 years, were reported to be strongly and consistently associated with the risks for ESKD and mortality and have been considered an alternative endpoint for CKD progression . Althoug of ESKD . Individ of ESKD . Althoug2) in GFR (>3.5 mL/min/1.73 m2 per year) that is over and above what would be expected with aging alone has been highlighted, with this early decline being linked to the development of ESKD in type 1 diabetes [2 per year during 115 months overall. However, when the eGFR declined to less than 45 mL/min/1.73 m2, the decline rate accelerated to −9.9 mL/min/1.73 m2 per year.Recently, the prognostic significance of identifying individuals with diabetes and an early decline  could not be determined. Although some patients with diabetic nephropathy rapidly progress to ESKD, these patients were excluded from the present analysis because they had less data available for simultaneous measurements and most of them already had eGFR < 30 mL/min/1.73 m2 at the first visit. Moreover, we could not clarify the eGFR and UACR trajectories of patients who had no or minimal decline in eGFR over the study period, since our study design allowed for only the investigation of subjects that ultimately progressed to ESKD. Lastly, the sample size was relatively small, and our study was retrospective. However, if this study were to be performed as a prospective study, we would need a relatively long period to complete it, as the endpoint of the study is RRT initiation. Nevertheless, additional studies are necessary to more firmly establish whether the risk categories of the KDIGO classification precisely reflect prognosis; not only the requirements for RRT but also cardiovascular events should be considered as endpoints since the risk categories of the KDIGO classification have three distinct indications, namely, risks for ESKD, cardiovascular events, and all-cause mortality.We recognize that our study is limited by the diagnostic methods used for diabetic nephropathy and nephrosclerosis. Moreover, there were only 17 and 10 biopsy-proven patients in the diabetic nephropathy and nephrosclerosis groups, respectively. Therefore, patients with chronic glomerulonephritis might have been included in the diabetic nephropathy group. However, all patients in the diabetic nephropathy group had diabetic retinopathy and a prolonged duration of diabetes. Therefore, we believe that the diagnosis of diabetic nephropathy was fairly certain in our patients. A second limitation is that the frequency of simultaneous measurement of eGFR and UACR was lower for the duration from the first visit to an eGFR of 45 mL/min/1.73 mThis retrospective analysis showed that the clinical trajectories to RRT initiation on the KDIGO heat map differed between diabetic nephropathy and nephrosclerosis. The rate of decline of eGFR in the diabetic nephropathy group was significantly faster than that in the nephrosclerosis group. Therefore, identification of the primary disease of CKD by kidney biopsy might be important for determining the likelihood of progression to ESKD. Furthermore, compared with nephrosclerosis, diabetic nephropathy was characterized at RRT initiation by higher BMI, higher systolic and diastolic BPs, and higher CRP, NT-proBNP, and albuminuria levels as well as lower age and serum albumin levels. Further studies are needed to clarify the factors that influence the progression to ESKD.


Blood pressure is directly related to body mass index, and individuals withincreased waist circumference have higher risk of developing hypertension,insulin resistance, and other metabolic changes, since adolescence.to evaluate the correlation of blood pressure with insulin resistance, waistcircumference and body mass index in adolescents.th percentile) and one group of normotensive adolescentswere studied. Body mass index, waist circumference were measured, andfasting glucose and plasma insulin levels were determined, using the HOMA-IRindex to identify insulin resistance.Cross-section study on a representative sample of adolescent students. Onegroup of adolescents with altered blood pressure detected by casual bloodpressure and/or home blood pressure monitoring  were studied; 61% (n = 99) of them were boys and themean age was 14.9 ± 1.62 years. Thirty-eight (23.5%) adolescents hadaltered HOMA-IR. The group with altered blood pressure had higher values ofwaist circumference, body mass index and HOMA-IR (p<0.05). Waistcircumference was higher among boys in both groups (p<0.05) and girlswith altered blood pressure had higher HOMA-IR than boys (p<0.05). Therewas a significant moderate correlation between body mass index and HOMA-IRin the group with altered blood pressure ,and such correlation was stronger than in the normotensive group. There wasalso a significant moderate correlation between waist circumference andHOMA-IR in both groups . Logistic regressionshowed that HOMA-IR was as predictor of altered blood pressure .There was a significant association of insulin resistance with blood pressureand the impact of insulin resistance on blood pressure since childhood. Thecorrelation and association between markers of cardiovascular diseases wasmore pronounced in adolescents with altered blood pressure, suggesting thatprimary prevention strategies for cardiovascular risk factors should beearly implemented in childhood and adolescence. Itis also indicated as a potential causal link between hypertension and insulinresistance (IR), among other metabolic changes.10 It is estimatedthat 20%-30% of overweight / obese children and adolescents havehypertension.12Obesity is highlighted as one of the important risk factors for hypertension, and itreaches epidemic proportions in many parts of the world.13Body composition is one of the main determinants of high blood pressure in childhoodand adolescence. There is a direct relationship between weight, body mass index(BMI) and hypertension, particularly in the second decade of life.8 Waist circumference (WC) has a goodpredictive value for abdominal obesity-related diseases in adolescents, andincreased WC values have been considered as a significant risk factor for IR andcardiovascular diseases.14The strong association between high blood pressure and excessive weight has led to anincrease in the prevalence of hypertension among children and adolescents.16 For decades, abdominal fat hasbeen associated with hyperinsulinemia, which is a predictor of hypertension anddyslipidemias.17IR is also considered a risk marker for cardiovascular disease, and is associatedwith several metabolic changes related to, but not exclusively associated withobesity or type 2 diabetes.19The homeostasis model assessment as an index of IR (HOMA-IR) is a rapid, easy,low-cost method, which has been used as an alternative approach for IRdiagnosis.There are no studies in Brazil correlating IR and blood pressure in adolescents agedover 12 years, and few studies have evaluated the correlation between IR andanthropometric variables in this population. The aim of this study was to evaluatethe correlation between IR, WC, BMI and blood pressure in adolescents, and thebehavior of these variables by sex.Coração de Adolescente, Adolescent's heart). Thestudy was approved by the local Ethics Committee (protocol: 017/2010), and conductedin a capital city of Brazil in 2012. The sample was representative of adolescentstudents, enrolled in the city's (public or private) schools.This was a cross-sectional study, part of the original project CorAdo.20WC was measured using a non-elastic measurement tape (200 cm). The cut-off pointswere adjusted by sex and age, and the 90th percentile was set as indicator ofmetabolic changes.®, 150 kg capacity), calibrated by the NationalInstitute of Metrology, Quality and Technology (Inmetro). Height was measured to thenearest 0.1 cm using a wall-mounted stadiometer (Secca®). Allmeasurements were performed following the World Health Organization guidelines(WHO). 21Body weight was measured to the nearest 0.1 kg using an electronic, portable scale(Kratos22 Theadolescents were classified into obese or overweight based on WHO BMI cut-off pointsfor age and sex (WHO).23BMI was calculated by dividing body weight (kilograms) by the square of the height(meters).th Task Force's4 recommendations.24Casual blood pressure and HBPM were measured using Omron HEM-705CP semi-automaticblood pressure monitors and different sizes of cuffs, in accordance to theth TaskForce, using the MeDCal 3000 software.Four measures of casual blood pressure were taken, the first two measures when theblood pressure monitor was handed to patients, and the other two when patientsreturned the monitors one week later. There was a 3-min interval betweenmeasurements. The mean of the second readings was used for analysis. Blood pressurepercentile was calculated using the formulas proposed by the 4Adolescents and caregivers were instructed in the use of HBPM, to take four bloodpressure measures, two in the morning (between 7h and 9h) and two in the afternoon(between 18h and 19h), with a 3-5 min-interval between them. One week later,participants returned the monitors, totaling 6 days of measurements.The diagnosis of altered blood pressure  was determined according tointernational guidelines. Normal blood pressure was defined as having systolicpressure below the 90th percentile and blood pressure readings below 120/80 mmHg,and altered blood pressure was defined as systolic pressure greater than the 90thpercentile.th Task Force in the study by Stergiou et al.,25 which suggests that both casualand HBPM measures should be similar in adolescents aged greater than 12 years.Since there are no validated criteria for HBPM, we used the criteria proposed by the4Of the initial sample , 198 (19.3%) adolescents had altered systolicand/or diastolic blood pressure in the casual measurement and/or HBPM, and composedthe potential group for phase 2.For sample size calculation, an error of 5% and power of 80% were fixed, consideringthe number of subjects with altered blood pressure (n= 198) identified from theinitial sample during phase 1 of the CorAdo study. A minimum of 127 adolescents wererequired, and we also included 35 adolescents with normal blood pressure (controls),who were invited to the phase 2 of the study. A total of 162 adolescents completedthe study .Participants' parents or caregivers signed the informed consent form beforeparticipating in the phase 2 of the study. Adolescents who met the inclusioncriteria answered a questionnaire and had their blood collected.26Children classified as prepubertal (Tanner stage I) were withdrawn from thestudy.Sexual maturation was assessed by self-assessment, using Tanner's photographs of fivesexual maturation stages.Inclusion criteria were adolescents aged from 12 to 18 years (to be completed),enrolled in public and private schools, with altered blood pressure , and Tanner stage ≥ 2 .Exclusion criteria included patients with physical disabilities that hinder bloodpressure measurement, self-reported chronic disease, diabetes mellitus, kidneydisease or heart disease, pregnancy, and chronic use of medications that may affectblood pressure, such as antihypertensive drugs, corticosteroids, antidepressants,anxiolytics, anti-inflammatories, and oral contraceptives.µu/mL x glycemia mmol/L/22.5) was used to quantify IR,whose threshold set for adolescents is ≥ 3.16;27 values of glycemia (mg/dL) were multiplied by0.05551.29Serum glucose and plasma insulin levels were determined. The HOMA-IR index  software version 20 and Epi-Info™. The Kolmogorov-Smirnov test was used to test thenormality of the continuous variables and the Mann-Whitney U test to compare themeans of the variables. Values were expressed as mean, median, standarddeviation and confidence interval. A descriptive analysis of data was performed;associations between categorical variables were tested by the chi-square test,and the Spearman correlation was used to assess the association between bloodpressure and BMI, WC, and HOMA-IR.Statistical analysis was performed using the Stepwise regression was conducted, considering changes in blood pressure asdependent variable. In the bivariate analysis, variables with a p-value <0.20 were considered predictors. The level of significance was set at p<0.05.A total of 162 adolescents participated in the phase 2 of the study, 127 with alteredblood pressure and 35 controls. Mean age of participants was 14.9 ± 1.62years, and 61.1% were male.Thirty-eight adolescents (23.5%) had altered HOMA-IR, 74 (45.7%) wereoverweight/obese, and 17 (10.5%) had increased WC .Mean values of HOMA-IR, BMI and WC were significantly higher in the group withaltered blood pressure than in controls .When variables were categorized considering the normality criteria, a significantassociation was found only between blood pressure and BMI (p < 0.022), with 50.4%of participants with altered blood pressure and excessive weight, and no differencein sex distribution.HOMA-IR index and BMI were similar between sexes. Mean WC was higher among maleadolescents in both groups  (p<0.05) and 4. IThere was a direct, moderate correlation between blood pressure and HOMA-IR , and a statistically significant but weak correlation betweenblood pressure and BMI, and between blood pressure and WC .In the group analysis, stronger correlations between variables were detected,especially between BMI and HOMA-IR in the group of altered blood pressure . Similar correlations between WC and HOMA-IR were found inboth groups  .odds ratio - OR = 2.0; p = 0.001).In the logistic regression analysis, blood pressure was affected only by HOMA-IR. In the Bogalusa HeartStudy, also conducted on adolescents, the HOMA-IR values were higher than thoseobserved in our study. In another study carried out in Rio de Janeiro, the authorsalso reported higher HOMA-IR indexes, although the study group was composed ofadults rather than adolescents.27 In Cochabamba, Bolivia, a study on 61 children andadolescents adopted33 a differentHOMA-IR cut-off (3.5), and reported a 39.4% prevalence of IR. A higher prevalence ofIR was found in children and adolescents with high systolic pressure (p <0.05).The prevalence of IR in our study group was 23.5%, considering a HOMA-IR cut-offpoint of 3.16, proposed by Keskin et al.34In this study, HOMA-IR was not correlated with changes in blood pressure by using theabsolute cut-off points. However, a significant direct correlation was found betweenmean HOMA-IR values and changes in blood pressure percentiles . This is in accordance with a study carried out in India, involving2,640 adolescents.34 have reported a high prevalence of altered HOMA-IRamong female adolescents, which may be in part explained by differences in body fatdistribution or pubertal stages as compared with boys. With respect to sexualmaturation, girls may enter puberty two years earlier than boys. In the absence ofother known variables, these findings suggest that girls tend to be more resistanceto insulin than boys due to sex-linked genes.35Female adolescents with altered blood pressure had higher mean HOMA-IR values(p<0.05), which was not observed in the normotensive group. Previousstudies36 and one study hasfound a higher IR among boys than girls17. Further studies are needed to elucidate these conflictingresults.It is worth mentioning that previous studies have not reported differences in themean values of HOMA-IR between sexes,By logistic regression, our study identified, for the first time, that adolescentswith altered HOMA-IR are twice as likely to have altered blood pressure 38Other variables, such as BMI and WC did not affect the chance of having altered bloodpressure. This result differed from that found in a study carried out in the southof Brazil on 1,950 children and adolescents, describing a positive relationship ofsystolic pressure to BMI and WC.36Some studies have reported an association between BMI and HOMA-IR, which may beexplained by the increased anabolic effect of insulin and growth hormone related tothe rapid somatic growth of children during puberty. This change in insulinsensitivity results from changes in body fat distribution in this period oflife.40In the present study, a significant, moderate correlation was observed between BMIand HOMA-IR . Singh and colleagues also found a strong correlationbetween HOMA-IR and WC,Our study differs from previous studies in the analysis of correlations betweenvariables (particularly HOMA-IR and BMI) by group, i.e. between adolescents withaltered blood pressure and normotensive subjects.The study has some limitations that need to be considered. First, the lack of acomprehensive assessment of body composition including other methods such asskinfold thickness or electrical bioimpedance analysis, and second, the possibleinaccuracy of the method used for assessing sexual maturation.There was a significant association of IR with blood pressure, and the impact of IRon blood pressure. The correlation and association between markers of cardiovasculardiseases was more pronounced in adolescents with altered blood pressure, suggestingthe need for primary prevention strategies for cardiovascular risk factors inchildhood and adolescence.


Compared to adults, coronary artery disease abnormalities, significant enough to warrant viability assessment and adenosine stress perfusion cardiac magnetic resonance (CMR) imaging, are rare in pediatric patients. As a result, the role of adenosine stress perfusion CMR as a routine clinical imaging tool in these patients has not been clearly defined. We aim to evaluate the impact clinically-indicated adenosine stress perfusion CMR on decision-making and follow-up strategy.Medical records and CMR images of all adenosine stress perfusion CMR studies performed on pediatric patients between August 2009 and May 2013 at a single institution were retrospectively reviewed. All examinations were performed on a 1.5T Siemens Avanto MRI scanner. Patients </=10 years old were examined under general anesthesia. Adenosine stress perfusion CMR protocol included adenosine at 140 μg/kg/min for a target heat rate increase of 20% or infusion duration of up to 5 minutes and gadolinium of 0.1 mmol/kg. Institutional review board approved this study and all patients signed informed consent.Twenty-seven patients were enrolled . Twenty-six patients completed the protocol with one study terminated due to extreme chest discomfort and nausea. In all completed studies, a heart rate response of >20% was achieved. List of diagnoses and reasons for referral are reported in Table This retrospective study demonstrates that adenosine stress perfusion CMR performed in pediatric patients can positively direct clinical decision-making, Lack of ionising radiation makes this an attractive investigation with which to monitor response to revascularisation.The authors would like to acknowledge the support received from Commonwealth Scholarships, UK National Institute of Health Research (NIHR), Royal Academy of Engineering and EPSRC. This report is independent research by the National Institute for Health Research Biomedical Research Centre Funding Scheme. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.


Although asthma increases the risk of cardiovascular disease, little is known about the relation of asthma and its severity to coronary vasospastic angina (CVsA). We hypothesized that asthma contributed to the development of CVsA.Patients in this population-based cohort study were retrospectively collected from the Taiwan National Health Insurance database. Using propensity score matching, subjects were stratified at a 1 : 4 ratio into a study group comprising 3087 patients with a diagnosis of CVsA, and a control group consisting of 12,348 patients who underwent coronary intervention for obstructive coronary artery disease (CAD) during the period 2000 to 2011.P < 0.001]. In addition, the risk of new-onset CVsA was significantly higher in previous users of oral or inhaled corticosteroids . In addition, the prevalence of asthma was highest among patients with CVsA alone, followed by patients with CAD and CVsA and patients who underwent coronary intervention for CAD alone (P trend < 0.001).Asthma significantly increased the risk of new-onset CVsA independent of other comorbidities [adjusted odds ratio (OR) = 1.85, 95% confidence interval (95% CI) = 1.47–2.32, Our study suggests that asthma is independently associated with CVsA and prior steroid use increases the risk of CVsA development. In our previous studies, we found that patients with CVsA have abnormally high levels of inflammatory markers, such as high-sensitivity C-reactive protein (hs-CRP), indicating that inflammation is associated with CVsA.5 Other investigators have also shown that inflammation plays an important role in coronary spasm and variant angina.7 Although clinical similarities exist between CVsA and atherosclerotic coronary artery disease (CAD), the risk factors for those cardiac conditions are not same. For example, known risk factors for CAD include hypertension, diabetes mellitus, dyslipidemia, and cigarette smoking, whereas only cigarette smoking has been identified as a major clinical risk factor for CVsA.8 It has also been shown that treatment with calcium antagonist/nitrates and cessation of smoking can achieve favorable outcomes for patients with CVsA who experienced cardiac arrest.9 Interestingly, treatment with calcium antagonist/nitrates has also been shown to be associated with a reduction in levels of the inflammatory marker hs-CRP.10Coronary vasospastic angina (CVsA), a condition characterized by the presence of reversible stenosis of an epicardial coronary artery, is an important cause of ischemic heart disease and sudden cardiac death.11 and studies have shown that systemic inflammation contributes to the high rates of cardiovascular complications in patients with asthma, such as atherothrombosis.13 Although the pathogenesis of atherothrombosis is complex, low-grade systemic inflammation is one of the central promoters of plaque and clot formation. The inflammatory cytokines interleukin-6 and interleukin-17 have been shown to be related to the severity of asthma.14 Interestingly, we also found that interleukin-6 levels are independently associated with CVsA.15 In a recent in vitro study,16 we demonstrated that increased level of interleukin-6 was associated with a decrease in endothelial nitric oxide synthase activation and subsequently a decrease in nitric oxide bioavailability. In a retrospective chart review, Prinzmetal's angina was shown to be associated with obstructive lung disease.17 The reversible airway obstruction of asthma and reversible coronary artery obstruction of coronary vasospasm may share similar pathophysiologies, for example, smooth muscle contraction and inflammation. In this population-based cohort study, we investigated whether asthma contributes to the development of CVsA.Asthma increases the risk of cardiovascular disease,18 This well-defined health insurance database has been described in more detail in previous studies.20 The encryption system used in the NHI Research Database makes identifying individuals impossible. Confidentiality assurances were addressed by abiding by the data regulations of the Bureaus of NHI, and institutional review board approval was waived.Patients in this population-based cohort study were retrospectively collected from the Taiwan National Health Insurance (NHI) Research Database. The International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes for clinical diagnosis were used in the NHI database, which collect information of more than 23 million people, representing more than 98% of Taiwan residents.15 diagnostic criteria of CVsA were angina at rest associated with electrocardiographic ST-segment elevation or depression, which was relieved by sublingual nitroglycerin; without obstructive CAD on coronary angiography after intracoronary nitroglycerin administration; and a positive intracoronary methylergonovine provocation testing result. Patients with CVsA who had received coronary intervention during index hospitalization were excluded. The control group comprised patients ≥18 years of age without CVsA who received coronary intervention for obstructive CAD (ICD-9-CM code 410.xx–414.xx except for 4131) during index hospitalization.The study group comprised patients ≥18 years of age with newly diagnosed CVsA (ICD-9-CM code 4131) at index hospitalization during the period January 1, 2000 to December 31, 2011. Similar to our prior studies,A diagnosis of asthma (ICD-9-CM code 493.xx) before the index hospitalization in all study and control participants was carefully evaluated. The pharmacological treatment for asthma before index hospitalization was evaluated as follows: exposed to corticosteroids: corticosteroid use by either oral, parenteral, or inhaled within 3 years before the index hospitalization; nonexposed: all others; and nonsteriod bronchodilator use. Exposed to corticosteroids was further classified as never; new: first use within 6 months before index hospitalization; and previous: use within 7 to 36 months before index hospitalization.21 The propensity score for each patient was estimated by modeling the probability of having CVsA on the basis of logistic regression. The covariates included age, sex, history of myocardial infarction (ICD-9-CM codes 410.xx and 412.xx), heart failure (ICD-9-CM codes 428.xx), stroke (ICD-9-CM codes 430.xx to 437.xx), peripheral artery disease , history of other comorbidities such as hypertension (ICD-9-CM codes 401.xx to 405.xx), dyslipidemia (ICD-9-CM codes 272.xx), diabetes mellitus (ICD-9-CM codes 250.xx), chronic kidney disease and dialysis , atrial fibrillation (ICD-9-CM codes 427.31), gout (ICD-9-CM codes 274.xx), malignancy (ICD-9-CM codes 140.xx to 208.xx), as well as year of the index admission. After deriving the propensity scores, each patient in the CVsA group was matched with 4 counterparts in the control group. In order to increase the power of the statistical analysis, we randomly selected a ratio of 1 : 4 (CVsA group: comparison group). The PSA algorithm was based on the nearest-neighbor method (Greedy's matching) and used the caliper radius (set as 0.5 sigma), which signifies the tolerance level for the maximum distance in the propensity score. The matching procedure was performed with the software package SAS .To simulate a randomized trial, we used propensity score analysis (PSA) to reduce potential confounding and selection bias.t test. Due to the retrospective nature of case–control studies, conditional logistic regression analyses22 were performed to evaluate the association between asthma, the use of corticosteroids or bronchodilators, and the risk of CVsA. To rule out confounding factors, the regression analyses were adjusted for gender, age, and all of the underlying diseases listed in Table P for linear trend). All data analyses were performed with the statistical package SPSS for Windows .Categorical data are expressed as frequencies and percentages and were compared between the study and control groups using the Chi-square test. Continuous data are presented as the mean and standard deviation and were compared between the study and control groups using the independent sample During the period January 1, 2000 to December 31, 2011, a total of 3697 patients received a diagnosis of CVsA. Of them, we excluded 96 patients because they had received coronary intervention during the index hospitalization, 15 patients because they were less than 18 years old, and 6 patients because the gender was unknown. Therefore, the total number of patients in the study group before PSA matching was 3580. Also during the study period, we identified 219,649 patients who received a diagnosis of obstructive CAD and received coronary intervention. Of them, we excluded 114 patients because of unknown gender and 20 patients because they were less than 18 years old. Therefore, the control group before PSA matching consisted of 219,515 patients .Table Before adjustment, asthma was significantly associated with a higher risk of new onset CVsA . Asthma was still independently associated with an increased risk of new onset CVsA after adjustment for age and gender  and in the fully adjusted model   or inhaled corticosteroids  was higher than that for never users in the fully adjusted model. However, use of oral or inhaled corticosteroids within 6 months of the index date was not associated with risk of CVsA. Interestingly, new users of nonsteroid bronchodilators were less likely than never users to develop CVsA in the fully adjusted model     Fig. .25 and indicate that CVsA and obstructive CAD differ in their respective pathogenesis, although they are both manifestations of ischemic heart disease. The most probable mechanisms governing the development of CVsA are vascular smooth muscle cell hypercontraction and endothelial dysfunction.26 Both mechanisms are linked to inflammation,28 which is present not only in cardiovascular disease but also in obstructive lung disease. Asthma and obstructive CAD share some risk factors, such as smoking and hypertension and both have similar pathogenic mechanisms, such as systemic inflammation. Nonetheless, the National Health and Nutrition Examination Survey found that impaired lung function is an independent risk factor for cardiovascular death, predominantly due to atherosclerotic disease.29 It has also been suggested that there is an important interplay between systemic inflammation and airflow obstruction in the development of ischemic heart disease.30To the best of our knowledge, this is the largest observational study to demonstrate that asthma is independently associated with CVsA. We found that CVsA patients were likely to be younger and less likely to have cardiovascular risk factors and diseases than patients with obstructive CAD. In addition, less all-cause mortality was observed in CVsA patients. We also found that the prevalence of asthma was highest among patients with CVsA alone, followed by patients with CAD and CVsA and patients who underwent coronary intervention for CAD alone. Our findings are consistent with those reported by other investigators31 Larsen et al32 studied patients with and without obstructive CAD who had myocardial infarctions. In the majority of patients without CAD, myocardial infarction was presumably due to coronary vasospasm. They found that patients without obstructive CAD were younger than those with CAD and were more likely to have chronic lung disease, which was referred to as asthma because of the young age of the patients. In a chart review, it was found that preexisting chronic obstructive lung disease, usually asthma, was present in 36% of patients with CVsA patients, which was higher than the 5% of Americans who self-reported having asthma in the 1992 Centers for Disease Control survey.17 These observations suggest that there is a connection between CVsA and asthma. The shared pathphysiology might be responsible for the connection. Autonomic dysfunction appears to be a contributing factor in both disorders.31 Histamine provokes bronchospasm and ccoronary vasospasm, and allergic hypersensitivity reactions trigger asthmatic exacerbations and coronary vasospasm. Both disorders have significant inflammatory components.33We found that a stronger association exists between asthma and CVsA than between asthma and obstructive CAD. The coexistence of CVsA with asthma has been previously reported.35 However, Huerta et al36 found no association between inhaled corticosteroids and cardiac arrhythmias. On the contrary, we observed that previous users, but not new users, of corticosteroids were at an increased risk of CVsA development. A possible explanation for that finding is that previous corticosteroid users have more severe inflammation, which might easily induce CVsA than new corticosteroid users. To the best of our knowledge, no studies have specifically addressed this relationship. The current study also observed that new users of noncorticosteroid bronchodilators, but not previous users, had a decreased risk of developing CVsA. Bronchodilators may stimulate and increase sympathetic activity and subsequently induce vasospasm. New users of noncorticosteroid bronchodilators might therefore be less susceptible. Further large-scale prospective studies are needed to confirm these associations.Previous studies of asthma found that current users of corticosteroids, especially high-dose users, were at an increased risk of developing atrial fibrillation, especially when inhaled corticosteroids were used.37 Our previous study showed that diabetes mellitus contributes to CVsA development in men with low C-reactive protein levels, but not in women.5 There are negative effects of diabetes mellitus and hypertension on CVsA development in patients with high C-reactive protein levels, especially in women. Although no studies have specifically addressed the relationship among CVsA, asthma, and diabetes mellitus, it is suggested that there is an interplay between systemic inflammation with asthma and diabetes mellitus in the development of CVsA. In the current study, the association between asthma and CVsA was independent of age, gender, and hypertension.We also observed that patients with asthma and associated diabetes mellitus had a higher risk of CVsA than patients with asthma but without diabetes mellitus. Inflammation is common in both diabetes mellitus and asthma.38 Smoking was independently associated with CVsA as compared with nonobstructive CAD. Compared with obstructive CAD group, smoking was less prevalent in CVsA. Our current study tried to investigate whether asthma contributes to the development of CVsA as compared with obstructive CAD. The effect of smoking may be considered as equal to both groups. Third, the dosage and frequency of using bronchodilators cannot be clearly identified due to the limitation of Taiwan NHI Research Database. The heart rate changed after using this medication was not obtained because heart rate was not recorded in NHI Research Database. The heart rate, which can affect outcomes of CAD,39 is not the major risk factor to affect the prevalence of CAD, however. Fourth, the data resource is from an insurance data, that is, Taiwan NHI Research Database, which might be less confident in data validity. As with all observational studies, nonexperimental results cannot prove causality. The value of large national databases depends on the novel hypothesis, reasonable study design, and careful analysis of the studies by researchers. Using Taiwan NHI Research Database, some researchers discovered many important medical findings.41 Recently, Hsing et al42 commented on Taiwan NHI Research Database and supported its studies, as its extensiveness and its ability to answer a wide variety of questions. Finally, the data of asthma and angina severity were not available in Taiwan NHI Research Database. Therefore, we cannot analyze the severity association between asthma and angina.There are some limitations in this study. First, diagnoses of asthma and CVsA were based on ICD-9-CM codes rather than obtained through biochemical testing. To ensure the validity of the diagnoses, we selected patients who had at least 2 consecutive diagnoses by clinicians. Second, data on some variables such as smoking and body mass index, which might be related to CVsA and asthma, are not available in the NHI database. The prevalence of smoking recorded in Taiwan NHI database should be underestimated and not be reliable. In addition, smoking is also the major risk factor for the obstructive CAD. Our prior study showed that the prevalence rate of smoking is 53%, 41%, 21% in obstructive CAD, CVsA, and nonobstructive CAD, respectively.Asthma is independently associated with CVsA and prior steroid use increases the risk of CVsA development. Large-scale prospective studies or meta-analyses are necessary to confirm our findings.


Combination drugs containing an angiotensin receptor blocker and a calcium channel blocker have been widely commercialized in recent years, and their advantages, such as improvements in adherence, and reductions in medication costs, have been greatly emphasized. However, the actual situations and the impact of switching to combination drugs in clinical practice of nephrology are not fully understood.This study was conducted in outpatients of nephrology who received antihypertensive medicines, and who switched to combination drugs. Changes in the potency of the antihypertensive drugs, and blood pressure were examined retrospectively before and after changing treatments. In addition, the study also involved patients’ questionnaire, which examined changes in blood pressure at home, the presence or absence of missed doses, the impact on medication-related expenses, and the level of patients’ satisfaction with regard to combination drugs.Survey results from 90 participants revealed that changing to combination drugs resulted in a reduction of missed doses, a decrease in blood pressure measured in an outpatient setting, and a reduction in medication-related expenses in total patients, non-chronic kidney disease (CKD) patients, and CKD patients.Our study shows that switching to combination antihypertensive drugs resulted in an improvement in adherence and a reduction in medication-related expenses, and revealed that patient satisfaction was high. Combination drugs for hypertensive patients may be beneficial in both medical and economical viewpoints. Hypertension has the highest incidence among lifestyle-related diseases , 2 and iAntihypertensive therapy extensively inhibits cardiovascular events , and theIn recent years, various types of antihypertensive agents have been used in clinical practice; nonetheless, the number of hypertensive patients whose blood pressure levels <140/90 mmHg only accounts for 50 % in the United States, and 42 % in Japan .To achieve target blood pressure levels, various clinical guidelines recommend using angiotensin receptor blocker (ARB) as the first line because of its organ-protective effect, as well as calcium channel receptor blocker (CCB) because of its potency , 5.Based on this background, combination antihypertensive drugs of ARB and CCB have been commercialized and widely used in clinical practice. However, much remains unknown about the situation of the patients whose drugs were switched to combination drugs. This study was conducted on outpatients with hypertension with or without CKD whose treatment was switched to combination drugs. We retrospectively examined the patients’ characteristics, clinical situations, physicians’ intention, and physicians’ judgments when conventional antihypertensive drugs were switched to combination drugs. Questionnaire survey was also conducted to reveal the patients’ satisfaction and missed doses.The study was conducted on hypertensive patients with or without CKD , who visited the outpatient department of nephrology in Teikyo University Hospital. The study consisted of a retrospective survey in 90 patients whose antihypertensive medications had been switched to combination drugs containing ARB and CCB since December 2010. This study was conducted upon approval from the Ethics Committee of our hospital  as well as oral and written consent from the patients. The study procedures were performed in accordance with the Helsinki Declaration.At the time of this clinical trial, four different types of combination drugs containing ARB and CCB were on market in Japan. These drugs are Unisia LD (candesartan 8 mg + amlodipine 2.5 mg), Unisia HD (candesartan 8 mg + amlodipine 5 mg), Exforge , Micamlo AP (telmisartan 40 mg + amlodipine 5 mg), Rezaltas LD (olmesartan 10 mg + azelnidipine 8 mg) and Rezaltas HD (olmesartan 20 mg + azelnidipine 16 mg). The decision of the switch and the selection of the combination drug were fully entrusted to the judgment of a physician in charge.The antihypertensive potency of drugs was quantified based on the interview forms; a maximum dose of the standard doses was allocated as 1. The potency of the combination drug was calculated as a sum of the single antihypertensive drugs. Because the potency of diuretics is difficult to calculate, we excluded the patients whose treatments were switched to combination drugs containing diuretics or whose diuretic treatment had changed.Table Each patient visited approximately at the same time (from 9 a.m. to 3 p.m.). Office blood pressure measurement was evaluated with an automated digital brachial artery blood pressure device  with patients in a sitting position. Blood pressures were measured three times and averaged for the evaluation before and at least 1 month after the switch.A patient questionnaire survey was conducted after switch to the combination drugs. The questionnaire consisted of four items: increase or decrease in the frequency of missed doses, increase or decrease in the drug costs, changes in home blood pressure, and satisfaction of the combination drugs.t test or paired t test as appropriate. Comparison among three groups was performed by ANOVA followed by Tukey HSD as post hoc analysis. For correlation analysis, Pearson’s or Spearman’s rho was utilized as appropriate. All statistical analyses were performed with IBM SPSS for Windows version 22 . P values <0.05 were considered as statistically significant.Numerical data are presented as mean ± SD. Comparison between two groups was done by n = 58, 64.4 %), ARB + CCB + diuretic agent , monotherapy using CCB , monotherapy using ARB , ARB + CCB + alpha-blocker + diuretic agent , ACE inhibitor + CCB , and others   were switched to combination of antihypertensive drugs containing ARB and CCB between December 2010 and February 2012. The baseline characteristics of the patients are shown in Table 2 calculated from an equation for the estimation of GFR in Japanese subjects [Forty-two patients (46.7 %) had CKD defined by the presence of proteinuria or an eGFR <60 mL/min/1.73 msubjects .p = 0.65)  , resulting in an average decrease of 18,167 yen per year  showed a decrease in potency after the switch; the group that showed no change in drug potency comprised 55 patients (61.1 %) and the group that showed an increase in drug potency comprised 21 patients (23.3 %). As a whole, the potency varied from 2.31 ± 1.09 to 2.27 ± 0.76 without a statistical significance (5.6 % shop < 0.001) and DBP  , neither SBP nor DBP significantly changed; SBP from 135.4 ± 13.8 to 134.9 ± 13.5 mmHg (p = 0.90), DBP from 79.4 ± 8.9 to 79.1 ± 7.4 mmHg (p = 0.89) , SBP and DBP significantly decreased; SBP from 137.2 ± 15.9 to 131.1 ± 13.8 mmHg (p = 0.013) and DBP from 80.8 ± 12.9 to 76.7 ± 10.6 mmHg (p = 0.008) , SBP significantly decreased from 161.7 ± 18.2 to 143.6 ± 25.3 mmHg (p < 0.001) and DBP significantly decreased from 89.4 ± 11.2 to 82.3 ± 15.0 mmHg (p = 0.018) . The decrease of the drug costs was also associated with the lowering of SBP and DBP .We then examined the factors which correlated with the change in blood pressures. The changes of potency were significantly associated with the changes of SBP and DBP (Spearman’s n = 33). In this group, neither SBP  nor DBP  significantly changed. The potency did not change from 2.38 ± 0.80 to 2.31 ± 0.77 (p = 0.19) but the number of antihypertensive tablet dramatically decreased from 2.49 ± 0.78 to 1.33 ± 0.53 (p < 0.001) as well as the number of total tablets , and costs of antihypertensive drugs appreciably decreased from 7,089 ± 2,114 to 5,697 ± 2,949 yen (p < 0.001). The second highest cases were the patients whose treatment had been switched or added on the basis of the ARB, and accounted for 28.9 % (n = 26). In this group, SBP decreased from 141.8 ± 19.0 to 133.4 ± 19.0 mmHg (p = 0.01) but DBP did not . The potency did not change from 2.73 ± 1.45 to 2.46 ± 0.88 (p = 0.20) but the number of antihypertensive tablet significantly decreased from 3.31 ± 1.79 to 2.08 ± 1.35 (p < 0.001) as well as the number of total tablets changed , and costs of antihypertensive drugs also decreased from 8,569 ± 3,344 to 5,740 ± 1,869 yen (p < 0.001). The third highest cases were the patients whose treatment had been switched or added on the basis of the CCB; they accounted for 14.4 % of the cases (n = 13). In this group, SBP decreased from 152.0 ± 17.3 to 133.2 ± 17.9 mmHg (p = 0.02) as well as DBP . However, the potency did not change from 2.18 ± 0.97 to 2.19 ± 0.61 (p = 0.96). The number of antihypertensive tablet decreased from 2.46 ± 0.93 to 1.15 ± 0.36 (p < 0.001) but neither the number of total tablets  nor the costs of antihypertensive drugs significantly decreased . In 20.0 % of the cases (n = 18), the treatment was switched to combined drugs which were unrelated to previous ARB or CCB. In this group, SBP decreased from 148.7 ± 13.4 to 136.2 ± 13.1 mmHg (p = 0.001) but DBP did not change . The potency increased from 1.67 ± 0.58 to 2.00 ± 0.53 (p = 0.018) and the number of antihypertensive tablet decreased from 2.10 ± 0.71 to 1.38 ± 0.59 (p < 0.001) as well as the number of total tablets  but the costs of antihypertensive drugs did not change .To examine how attending physicians switched the treatments, we compared the recipe before and after the switch. In most cases, combination drugs were chosen based on the ARB and CCB previously used. Patients who had already been using the same agents of ARB and CCB as those present in the combined drugs accounted for 36.7 % , CKD patients showed slightly higher SBP  with the similar DBP   . The costs for the antihypertensive drugs were significantly higher in CKD patients than non-CKD patients   and DBP (from 84.0 ± 10.3 to 80.3 ± 7.8 mmHg) (p = 0.012) significantly decreased after the switch  and DBP significantly decreased after the switch (from 81.3 ± 15.4 to 76.3 ± 14.5 mmHg) (p = 0.019)   . Urine protein in CKD patients tended to decrease but did not reach statistical significance .In both non-CKD and CKD patients, the potency of antihypertensive drugs did not change significantly before and after the switch  Fig. c. The nu2, p = 0.41) or in CKD patients .eGFR did not change either in non-CKD  replied that “missed doses have decreased” while 64.4 % (n = 58) answered that “never missed before” , and DBP significantly decreased from 85.0 ± 12.3 to 80.0 ± 7.7 mmHg (p = 0.039). Even in the group that replied “never missed before,” SBP decreased from 142.6 ± 20.1 to 135.0 ± 20.1 mmHg (p = 0.004). However, the patients that replied “missed doses have decreased” did not necessarily showed the greater decrease in SBP or DBP (p = 0.69 by Spearman’s rho) probably because the patients who replied “missed doses unchanged” received relatively higher potency .All patients responded to the questionnaire and the result is shown in Fig. n = 47) replied that “medication-related expenses decreased”  responded that “home blood pressure decreased”, whereas 47.8 % (n = 43) responded “no change” and 18.9 % (n = 17) responded that they “do not measure home blood pressure”  answered that “they prefer the combination drug” and only 3.3 % (n = 3) answered that they “prefer previous drugs” (Fig. As for question B, 52.2 % of the patients n = 7 repliedHypertension is the most frequently encountered disease in daily medical practice; however, the rate of achievement of target blood pressure levels is not always high , 10. TheThe first finding is that the largest number of patients was the category of “no change in drug potency” after switch to combined formulation. This suggests that in most cases, the contents of the antihypertensive drugs themselves are left unchanged. The group with the second largest number of patients was the category of “increase in drug potency”. Interestingly, this group had higher blood pressure before switching treatment, revealing that switch was also intended to increase in potency in these cases.Secondly, in our study, most of the patients took less than three kinds of oral antihypertensive drugs. According to the ALLHAT study, approximately 30 % of patients with blood pressure controlled at 140/90 mmHg or lower were reported to be taking at least 3 different types of drugs orally . Our finWe also examined how the combination drugs were selected and used by each physician. The findings showed that in many cases, the patients had already been using the same ARB and CCB included in the combined drugs or the combined drugs included the same ARB which patients had already used. This may reflect the fact that antihypertensive therapy had been conducted with a focus on ARB, as recommended by various guidelines pertaining to hypertension.In this study, a significant decrease in blood pressure was found not only in the group that showed an increase in potency but also in the group in which potency remained unchanged. This decrease was probably due to an improvement in adherence. Adherence to medication is known to have an impact on blood pressure control, and patients often hesitate to take their oral medication when the number of tablets is large . Our resFrom the perspective of medical economics, our survey also suggested that switching to combination drugs may lead to a reduction of medical expenses. Based on previous reports, combination therapy using both ARB and CCB has also been shown to be more cost-effective in treating hypertension than monotherapy using CCB or ARB . The priIn our patients, no major adverse effects were observed, including severe hypotension, rapid deterioration of renal functions, and electrolyte disorders. That might be due to the fact that most of the patients’ antihypertensive potency did not change between before and after the switch. In this regard, mixed formulations containing ARB and CCB might be safe when switching treatment.There are several limitations in the present study that need to be taken into consideration. First, the study was not a parallel comparative study between a group that had switched treatment to combination drugs and a group that had not. Thus, the evidence level is not high enough, but our study vividly revealed the actual situations of clinical practice especially in nephrology. Next, switching to combination drugs was entrusted to the attending physician’s judgment and choice, which might create some bias. However, by surveying retrospectively, we could successfully reveal the physician’s attitude in clinical practice. The third limitation was related to the questionnaire survey. Blood pressure, adherences and antihypertensive potency were expressed as numerical values, whereas the level of satisfaction was subjective. There is a method using an analog scale, but in the present study, there was no need to do so. Final limitation was the method used in the calculation of the antihypertensive potency. The issue is whether a comparison of the antihypertensive effects belonging to different classes is possible or not. However, when antihypertensive drugs are released in the market, the doses are determined on the basis of their antihypertensive effects, thus our methods of quantification might not be precise but sufficient for comparison.Despite these limitations of our study, the present results clearly show that switch to combination drugs is of high clinical utility from the perspective of blood pressure control, adherence, health economics, and patient’s satisfaction.