P = 0.001 and P = 0.025, respectively). There were no significant differences in maximal arterial blood flow and maximal LDF between 0 and −10 mmHg (both P = 1.0), or between −40 and −60 mmHg (both P = 1.0). INP of −40 mmHg was the lowest negative pressure level that increased blood flow.Intermittent negative pressure (INP) applied to the lower leg induces acute increase in arterial and skin blood flow. The aim of this study was to identify the optimal level of INP to increase blood flow in patients with lower extremity peripheral artery disease (PAD). We investigated the acute effects of different levels of INP in 16 subjects  age 71(8) years) diagnosed with PAD. During application of INP in a pressure chamber sealed below the knee, arterial blood flow was continuously recorded in the dorsalis pedis artery or tibialis posterior artery (ultrasound Doppler), and skin blood flow was continuously recorded at the pulp of the first toe (laser Doppler). Different pressure levels  were tested in randomized order. Maximal arterial blood flow relative to baseline  was: 0 mmHg; 1.08 , −10 mmHg; 1.11 , −20 mmHg; 1.18 , −40 mmHg; 1.39  and −60 mmHg; 1.48 . Maximal laser Doppler flux (LDF) relative to baseline was: 0 mmHg; 1.06 , −10 mmHg; 1.08  −20 mmHg; 1.12 , −40 mmHg; 1.24  and −60 mmHg; 1.35 . There were significantly higher maximal arterial blood flow and maximal LDF at −40 mmHg compared with −10 mmHg ( Peripheral artery disease (PAD) comprise all conditions resulting in obstruction of blood flow in arteries, exclusive of the coronary, and intracranial vessels Ouriel . AtherosStandard treatment for PAD includes smoking cessation, pharmacological therapy with antiplatelet agents and statins, and supervised physical exercise  to improve blood flow in patients with PAD have been investigated since the early 20th century  <0.9 and symptomatic claudication or radiological detected PAD were included. Subjects undergoing recent (less than three months) endovascular or open surgical revascularization were considered not eligible for the study.We registered age, sex, weight, height, comorbidities, smoking status, medications, main localization of the disease, previous revascularization, and patient reported maximal walking distance for all subjects based on a questionnaire and the subjects’ medical record at Oslo University Hospital.All subjects were encouraged not to eat, and to refrain from tobacco and caffeine two hours before the experiments. Measurements were conducted in a temperature stable environment of 22–24°C. The subjects´ most symptomatic leg was chosen as the test leg.ABI was measured after 5 min of rest, with the subject in supine position using a continuous wave 8 MHz Doppler probe , in accordance with the guidelines from the American Heart Association  amplitude was measured with an air‐plethysmography cuff  placed at the lower leg above the malleoli. Normal arterial inflow to the extremity is pulsatile, leading to measurable changes in lower limb volume within each cardiac cycle . A pulsed 10 MHz Doppler probe  was used to measure the arterial blood velocity during application of INP. The probe was fixed to the foot with surgical tape above the ATP or ADP, at the place where the best Doppler signal was achieved. Based on the peak systolic velocity measured with the ultrasound triplex scan, the Doppler ultrasound was calibrated to record the exact arterial blood velocity in the ATP or ADP.A laser Doppler flow meter was used to monitor microvascular blood perfusion in acral skin using a laser Doppler probe attached to the pulp of the first toe . The same probe recorded skin temperature.Pressure inside the pressure chamber was recorded by a digital manometer .Systemic blood pressure was measured non‐invasively beat‐by‐beat, by a Finometer  attached to the third finger of the right arm.www.randomizer.org).With the subject sitting in a chair, all probes were connected, and the foot was carefully introduced into the pressure chamber. The foot arch was placed on a positioner to avoid the front foot and the heel to touch the pressure chamber. The pressure chamber was sealed just below the knee using a customized thermoplastic elastomer seal and coupled by air hoses to a control unit  that generated INP by actively removing air from and passively venting the pressure chamber Fig. . The conData recorded during the tests were sampled at 300 Hz, and averaged beat‐by‐beat, gated by the R‐waves of a three lead ECG, using custom‐made software . The software calculated beat‐by‐beat blood flow in the ADP or ATP during the tests by adding information on the angle of insonation and the vessel diameter measured with the ultrasound triplex scan before application of INP. The beat‐by‐beat data were resampled to 2 Hz for further analyses. Obviously erroneous data due to for example motion artefacts were removed from the dataset, giving 15 complete INP cycles, each lasting 17 sec, for each subject at each pressure level.P < 0.001 for all tests. Therefore, these data were not assumed to have a normal distribution.Descriptive statistics are presented as mean (standard deviation [SD]) or median . Shapiro–Wilks tests were performed to assess if the flow and LDF data were normally distributed at every 0.5 sec of the INP cycles, giving For each subject and INP level, median arterial blood flow, laser Doppler flux (LDF), and mean arterial pressure (MAP) every 0.5 sec of the 17 sec cycle of INP were divided by the median value at time 0 (baseline) for the pressure level being tested, giving an intra‐subject relative median value for each 0.5 sec of the 17 sec INP cycle. The aggregated medians of flow and LDF for all subjects were plotted to illustrate the differences between the pressure levels. From the intra‐subject median values, the maximal values were found for each INP level, giving the maximal blood flow and LDF relative to baseline for that subject and INP level. We used Friedman test for non‐normally distributed data to examine the overall null hypothesis of no significant differences in any of the rank sums of maximal blood flow, LDF and mean arterial pressure (MAP) between the INP levels  blood velocity in ADP of 6.7 (3.3) cm/sec  and registered at ClinicalTrials.gov (ref: SD0321063). Written informed consent was obtained from all subjects before the start of the experiments.Sixteen subjects with PAD Fontaine stage I 1 subject) and Fontaine stage II (15 subjects) were included in the study , −10 mmHg; 1.11 , −20 mmHg; 1.18 , −40 mmHg; 1.39  and −60 mmHg; 1.48 . Maximal LDF for each pressure level relative to baseline was: 0 mmHg; 1.06 , −10 mmHg; 1.08 , −20 mmHg; 1.12 , −40 mmHg; 1.24  and −60 mmHg; 1.35  . For pairwise comparisons of maximal arterial blood flow, there were significant differences between: 0 and −40 mmHg (P < 0.001), 0 and −60 mmHg (P < 0.001), −10 and −40 mmHg (P = 0.001), −10 and −60 mmHg (P < 0.001) and −20 and −60 mmHg (P = 0.005). For pairwise comparisons of maximal LDF, there were significant differences between: 0 and −40 mmHg (P = 0.001), 0 and −60 mmHg (P < 0.001), −10 and −40 mmHg (P = 0.025) and ‐10 mmHg and ‐60 mmHg (P = 0.012). There were no significant differences in maximal arterial blood flow or maximal LDF between 0 and −10 mmHg (both P = 1.0) or between −40 and −60 mmHg (both P = 1.0). There was no significant difference in the maximal change of MAP between the pressure levels (P = 0.434).Overall, there were significant differences in maximal arterial blood flow and maximal LDF between the pressure levels . IM is the CSO, co‐founder and a shareholder in Otivio AS. Otivio AS has the commercial rights to the INP technology (FlowOx) used in the study. None of the other authors have any conflicts of interest, financial, or otherwise. The authors alone are responsible for the content and writing of the paper.Table S1. Pairwise comparisons of the different levels of intermittent negative pressure.Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.


Introduction: Despite decreasing mortality in pediatric oncology as a result of standardized treatment protocols, the high number of functional and cardiovascular late sequelae due to anticarcinogenic therapy remains unchanged. The aim of this study was to further assess functional limitations in Health-related Physical Fitness (HRPF) and cardiovascular risk by means of markers of arterial stiffness in Childhood Cancer Survivors (CCS).Materials and Methods: Between March 2016 and August 2017 a total of 92 CCS  were recruited from their routine follow-up outpatient visit. HRPF was assessed using five Fitnessgram® tasks. Pulse Wave Velocity (PWV) along with peripheral and central blood pressure were assessed using oscillometric measurements performed by Mobil-O-Graph. Z-scores were used to compare the test results either to German reference values or to a recent healthy reference cohort.Results: In CCS, the HRPF was significantly reduced  as compared to healthy peers. The peripheral Systolic Blood Pressure (pSBP) was significantly increased  and the peripheral Diastolic Blood Pressure (pDBP) was decreased , resulting in an increased pulse pressure. The PWV (p = 0.649) and cSBP (p = 0.408), were neither increased nor showed any association to HRPF.Discussion: CCS showed functional limitations in HRPF and an increased pulse pressure, which acts as an early onset parameter of arterial stiffness. Both a low HRPF and impaired hemodynamics are independent cardiovascular risk factors and needs to be taken into consideration in tertiary prevention of CCS. Due to improved anticarcinogenic treatment regimens (chemotherapy and radiation) more children and adolescents are surviving a cancer diagnosis . As a reHealth related physical fitness (HRPF) is an indicator for the development, growths, and lifestyle of children and adolescents, and it is significantly reduced after acute treatment phase in CCS . PhysicaNevertheless, especially cardiovascular issues are also of particular concern in CCS as even low-dose anthracyclines, a group of chemotherapy drugs, can damage cardiomyocytes in the heart and impair endothelial functioning of the vessels , 7. The Previous studies outlined the beneficial association of HRPF and aerobic capacity to arterial vessel properties –13, but The study was conducted over two examination periods (March to June 2016 and February to August 2017) at the Department of Pediatric Hematology and Oncology in the Dr. von Hauner University Children‘s Hospital in Munich. Eligibility criteria were oncologic disease, current age of 6–20 years, absence of fever and acute infections, no mental retardation and the ability to write and communicate in German or English language without assistance. All participants could walk and do physical exercises without assistance. Physicians had to confirm the patients study participation. The study protocol (project number 724-16) was approved by the local Ludwig Maximilian University ethical board. Participation was voluntary and informed consent was obtained from the patients and parents after provision of oral and written information about the study procedures.In total, 92 CCS  were examined for their HRPF and arterial stiffness.2 body surface area. Ten children received radiotherapy where the mean radiation dosage was 28.4 ± 19.9 Gray (gy). Four Children were exposed to both chemotherapy including anthracyclines (248.0 ± 89.9 mg/m2), and radiation (18.4 ± 8.5 gy). Finally, three Children received neither chemotherapy nor radiotherapy (treated with surgery only or watch-and-wait).The mean age at diagnosis was 8.8 ± 4.8 years and 54 of the patients were initially diagnosed with Leukemia, 28 with solid tumors and 10 with Lymphomas. This roughly correspond to the general prevalence of cancer diagnosis in children  and weight  were assessed by the study investigator. BMI was calculated by dividing weight in kilograms (kg) by the height squared in meters. Reference values for BMI in children were drawn from the German reference values from Kromeyer-Hauschild et al. .2 body surface) and mediastinal irradiation .Anamnestic data were obtained from the patients file . A physician retrospectively computed the amount of administered anthracyclines (mg/mmaximum repetitions in Push-Ups (upper body strength and muscular endurance)maximum repetitions in Curl-Ups Sit-and-Reach (hamstring flexibility) recorded separately on both sidesShoulder Stretch (upper arm and shoulder girdle flexibility) recorded separately on both sidestrunk extensor strength and flexibility was assessed with the trunk lift  which was performed twice, but just the better value was recorded.The Fitnessgram® is a valid and reliable method to assess HRPF . The tesOne valid Push-Up counted when the body was lifted and lowered in a prone position with an elbow flexion ≤90°. Curl-Ups are complete upper body elevations out of a supine position, without the use of the arms . Sit-and-reach was assessed in a sitting position, one leg straight and the other one flexed, as distance from fingertips to toes at maximal stretch. For Shoulder Stretch, the participants had to stretch one hand up the back and the other hand from above down the back. The distance between both hands was measured. For statistical analysis the mean value of both sides was calculated. A detailed description of these tasks is available in the online supplement of our recent article .For all of the five tasks, individual z-scores (standard deviation-scores) were calculated using data from the “Sternstunden” cohort of 983 children (498 girls), with a mean age of 11.8 ± 2.3 years. This project was designed to estimate several health outcomes in healthy children in multiple Bavarian schools.Blood pressure and arterial stiffness were assessed after 5 min rest in the supine position with a single measurement on the left upper arm using the oscillometric Mobil-O-Graph . Cuff size was adjusted to the upper arm circumference. Based on the recorded brachial pulse, central Systolic Blood Pressure (cSBP) and Pulse Wave Velocity (PWV) were indirectly calculated with the ARCSolver Algorithm.All raw values were also transformed into z-scores according to established German References. For peripheral systolic and diastolic blood pressure the national German cohort (Kiggs Study)  values wAll descriptive data was expressed as mean values and standard deviation (mean ± SD) or as absolute numbers and percentages if appropriate.BMI, SBP, DBP, cSBP, PWV were expressed in terms of standard deviation scores (z-scores) according to the references mentioned above. The LMS values and z-scores for the five HRPF motor tasks were smoothed out with a Box-Cox-transformation using R-Studio  and the module extensions gamlss (version 3.4-8) and AGD (version 0.34). The total HRPF-score represents the mean of the five motor tasks. Normal distribution of the primary outcome parameter (HRPF z-score) was proven with a Kolmogorov–Smirnov test.t-test with test value “0” was conducted to asses significant differences in z-scores from the appropriate reference. Pearson correlation was used to calculate possible associations between HRPF and arterial stiffness. Unpaired Student's t-test were performed to assess differences in the 73 CCS that received anthracycline-containing chemotherapy to those who did not.For statistical analysis, a one sample P < 0.05 were considered to be significant.Data analysis was performed using IBM SPSS 23.0 . p = 0.011) in comparison to healthy peers (p = 0.032), shoulder stretch , and trunk lift . 20 (21.7%) of the CCS showed a reduction in HRPF z-scores < 1 standard deviation.CCS showed significant reduced HRPF  and the peripheral DBP decreased , resulting in an increased blood pressure amplitude (pulse pressure). However, the more direct measures of arterial stiffness from the pulse wave analysis; PWV (p = 0.649) and central SBP (p = 0.408), were not increased.The peripheral SBP of CCS was increased  or cSBP , nor beneficially associated with peripheral blood pressure.Moreover, higher HRPF scores were neither associated with lower PWV  hypertension as late complications of cancer treatment regimens , 30.In addition, the significantly decreased pDBP in combination with the increased pSBP results in a high pulse pressure, which is a known risk factor for CVD and is mentioned in the current guidelines for arterial hypertension , 32. In Surprisingly, arterial stiffness (as measured by PWV and cSBP), an early, subtle marker for CVD , was stiFrom the hemodynamic point of view, only the increased pulse pressure possibly reveals early vascular aging in our CCS cohort, whereas the limitations in HRPF were manifest. Regular physical activity has a pivotal role to play in the prevention of both of these factors. Not only does it improve the HRPF, it also improves endothelial function and NO synthesis by the creation of shear stress. Several studies underline this theory and the importance of physical activity as part of successful rehabilitation , 4. HoweIn accordance with previous studies we found the HRPF to be slightly impaired in CCS. We also found the pulse pressure, but not the PWV, to be elevated in CCS. This combination of reduced HRPF and impaired vascular parameters may raises the likelihood of an increased long-term CVD risk in these patients. This should be taken into consideration when planning tertiary prevention measures for CCS.The cohort presented in this study differ widely in number of ways including cancer types, treatment regimens and doses used, age at diagnosis, and time since diagnosis. However, the approach used to assess the questions asked seems reasonable when taking into account recent studies/reviews, which also report similar findings in similarly heterogeneous CCS cohorts . PatientThe datasets for this study will not be made publicly available because Data safety and protection act.The study protocol (project number 724-16) was approved by the local Ludwig Maximilian University ethical board.PvK was responsible for coordination, examination and collecting data, analyzing and processing of the data and drafted the manuscript. JM was responsible for conception and design of the study, analyzing and processing the data and gave important input for drafting and revising the manuscript. CQ and LT coordinated examinations and collected data. RO and TF gave important input for drafting and revising the manuscript. IS performed medical examinations and gave important input for drafting and revising the manuscript. All authors have read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The relationship between dyslipidemia, inflammation and CV organ damage in type 2 diabetes mellitus (T2DM) is complex. Insulin resistance and inflammatory cytokines interleukins (ILs) increase plasma triglycerides (TG). ILs also up-regulate expression of matrix-metalloproteinases (MMPs) that, together with TG, decrease high density lipoprotein cholesterol (HDL) levels. High TG, low HDL, increased ILs and MMPs trigger structural and functional changes in different parts of cardiovascular (CV) system. To understand better the role of lipids and inflammation in CV organ damage, the present study investigated the inter-relationships between lipids, ILs and MMPs, as well as the associations of lipids, ILs and MMPs with various CV measures, both in diabetic and non-diabetic population (nonT2DM).In T2DM patients (N = 191) and nonT2DM subjects (N = 94) were assessed carotid intima-media thickness (cIMT) and inter-adventitial diameter (IADiam), carotid wave speed (ccaWS), carotid-femoral pulse wave velocity (cfPWV), left ventricular (LV) mass, LV systolic (s′) and early diastolic (e′) longitudinal velocities of mitral annulus, together with glycemic control, lipid profile, IL-6, IL-18 and MMP-12.P < 0.05–0.0001). They had also higher cIMT, IADiam, ccaWS, cfPWV and LV mass, and lower e′ velocity (P < 0.005–0.0001). Both in T2DM patients and nonT2DM subjects, MMP-12 increased with IL-6  and IL-18 , and HDL decreased with MMP-12 . In both populations, MMP-12 was directly associated with IADiam, ccaWS, cfPWV and LV mass . In multivariate analysis, MMP-12 remained independently related to IADiam, ccaWS, cfPWV and LV mass in T2DM patients, and to IADiam only in nonT2DM subjects.T2DM patients, as compared to nonT2DM subjects, had significantly higher plasma levels of IL-6, IL-18, MMP-12 and lower HDL  contains supplementary material, which is available to authorized users. Type 2 diabetes mellitus (T2DM) is associated with increased cardiovascular (CV) morbidity and mortality  and a maIt is evident that the relationship between lipids, inflammation and CV organ damage in T2DM patients is complex. Number of studies have shown the associations of TG, HDL, ILs or MMPs with vascular and cardiac alterations , 12–17, To understand better the role of dyslipidemia and inflammation in CV organ damage and CV risk of T2DM patients, the present study evaluated the inter-relationships between TG, HDL, ILs and MMP-12, as well as the associations of lipids, ILs and MMP-12 with different measures of CV structure and function, both in T2DM patients and in subjects free of diabetes (nonT2DM).Study population consists of 191 T2DM patients and 94 nonT2DM subjects of similar age and comparable prevalence of CV disease. All subjects were referred for a complete CV examination to the Clinic for Cardiometabolic Risk Prevention of the Department of Surgical and Medical Pathology, University of Pisa between December 2010 and April 2013. Diagnosis of T2DM was based on plasma glucose criteria  or HbA1c ≥ 6.5% . Two abnTwenty-one T2DM patients were treated by diet, 135 by oral antidiabetic drugs, 22 by a combination of oral antidiabetics and insulin and 13 by insulin only. Antagonists of the renin–angiotensin–aldosterone system (ACE inhibitors and ARBs) were the most frequently used anti-hypertensive agent, followed by beta-blockers, both in T2DM patients and nonT2DM subjects.The protocol of the study followed the principles of the Declaration of Helsinki and was approved by the institutional ethics committee “Comitato Etico di Area Vasta Nord Ovest” (Reference Number: 3146/2010). All subjects gave their informed consent to participate.All study subjects underwent carotid ultrasound and measurement of carotid-femoral pulse wave velocity (cfPWV). Vascular examination was performed in the afternoon, 3 h after a light meal, in a quiet room with a stable temperature of 22°, after resting comfortably for at least 15 min in the supine position. All subjects were asked to abstain from cigarette smoking, caffeine and alcohol consumption and vigorous physical activity for 24 h.CfPWV was measured according to current guidelines using the Complior device . In our laboratory, intra- and inter-individual variability of cfPWV measurement are 4.3 ± 2.8% and 5.1 ± 2.9%, respectively. Increase in cfPWV was defined as cfPWV higher than 90th age- and BP-specific percentiles of cfPWV observed in a reference population of 11.092 subjects .® and QAS®) that allows an automatic and real-time determination of far-wall cIMT, IADiam and carotid distension with a high spatial and temporal resolution (sampling rate of 550 Hz on 32 lines). From the distension curves a local one-point carotid wave speed (ccaWS) was calculated applying the Bramwell–Hill equation that relates the propagation velocity to arterial distensibility as previously described , and were logarithmically transformed for parametric statistical analysis. ANOVA was used to compare continuous variables, and a χCharacteristics of T2DM patients and nonT2DM subjects are reported in Table P < 0.0001). Fasting glucose and HbA1c was not related to ILs in either population.In both T2DM patients Fig.  and nonTP < 0.005–0.0001, and IADiam, ccaWS, cfPWV and LV mass were directly related to MMP-12 . E′ velocity of mitral annulus was inversely related to fasting glucose  and directly to HDL , whereas s′ velocity was not related to any metabolic parameter.In T2DM patients, cIMT, IADiam, ccaWS, cfPWV and LV mass were inversely related to HDL  and e′ and s′ velocities were related directly to HDL . IADiam, ccaWS, cfPWV and LV mass were directly related to MMP-12 .In nonT2DM subjects, LV mass was related inversely , and s′  and e′  velocities were inversely related to LV mass. Only in T2DM patients, cfPWV was directly related to LV mass  and s′ velocity was inversely related to end-systolic wall stress .In both T2DM patients and nonT2DM subjects, cfPWV was directly related to end-systolic LV wall stress  as compared to those without events, after adjustment for sex, age, BP, smoking habit, BP-lowering and lipid-lowering treatment.Within nonT2DM subjects, those with CV events had lower LV systolic longitudinal velocity s′ (8.0 ± 1.2 vs 9.3 ± 1.2 cm/s; The present cross-sectional study investigated the relationships between plasma lipids and inflammatory cytokines as well as the impact of lipids and ILs on CV system in T2DM patients. Plasma ILs were directly related to plasma levels of MMP-12 that were inversely related to HDL. MMP-12 was independently associated with carotid diameter, arterial stiffness and LV mass, whereas HDL was independently associated with carotid wall thickness and LV diastolic longitudinal performance.MMP-12 is a potent elastase highly expressed in macrophages . DiabeteThe role of MMP-12 in arterial wall enlargement and stiffening has been demonstrated in experimental and clinical studies. In MMP-12 knock-out mice, the growth of aortic diameter and the expression of MMP-12 in aortic wall were significantly lower as compared to wild-type mice , and an It is worth to note, that in nonT2DM subjects were observed the same direct associations between ILs and MMP-12 and between MMP-12 and CV measures as in T2DM patients. However, since the levels of ILs and MMP-12 were significantly lower, MMP-12 was independently related only to carotid diameter. This observation is in agreement with results of the Strong Heart Study showing that cardiac target organ damage precedes clinical appearance of T2DM and is related to inflammatory status .tpeak [Some members of the MMP family, including MMP-12, can degrade the apolipoprotein A-I and decrease circulating HDL levels , 37. In tpeak . A directpeak  and thattpeak .In T2DM patients, HDL was also independently and inversely related to cIMT. This association has been already described in a large meta-analysis including 21.000 subjects  and is pThe combined role of ILs, MMP-12 and HDL in CV organ damage of T2DM patients was confirmed also by our observation that diabetic patients with established organ damage, i.e. with increased carotid IMT, aortic stiffness and LV hypertrophy, had significantly lower plasma levels of HDL and higher levels of ILs and MMP-12 as compared to those without vascular and cardiac impairment.The only CV measure associated with the presence of CV disease in T2DM patients was cfPWV . Indeed,The present study has some potential limitations. First, plasma insulin levels were not measured, and thus the impact of insulin on ILs, MMP-12 and CV biomarkers cannot be evaluated. Second, measuring HDL levels does not accurately depict their composition and functionality, which can be modified in diabetes. Third, LV diastolic performance was evaluated only by early diastolic longitudinal velocity of mitral annulus and no additional echocardiographic parameters related to LV relaxation and compliance were assessed. Finally, we are aware that cross-sectional design of the study cannot clearly elucidate cause-and-effect relationships.Results of this cross-sectional study indicate that IL-6 and IL-18 trigger an increase in MMP-12 plasma levels, which in turn may reduce HDL levels and directly modify vascular structure and function, both in T2DM patients and nonT2DM subjects. Alterations in vascular structure and function elicit changes in the heart (Additional file Additional file 1: Figure S1. Role of inflammation and dyslipidemia in cardiovascular organ damage of T2DM patients.


There is an alarming rise of chronic kidney disease (CKD) prevalence globally, which is associated with significant morbidity and mortality necessitating special attention as one of the major public health problems. The burden of CKD disproportionately impacts low-income countries like Ethiopia where hypertension and diabetes mellitus, the two most important risk factors for CKD growth rate, are greatest. The aim of this study is to assess patient awareness, prevalence, and risk factors of chronic kidney disease among hypertensive and diabetes mellitus patients. p-value <0.05 considered statistically significant. Hospital based cross-sectional study design was conducted at Jimma University Medical Center among adult (≥18 years) hypertensive and diabetes mellitus patients. Informed written consent was obtained from each participant and data was collected by interview and chart review; blood and urine samples were collected for CKD screening. Glomerular filtration rate (GFR) was estimated from serum creatinine using CKD epidemiology collaboration (CKD-EPI) equation, and CKD was defined using estimated GFR (e-GFR) and albuminuria. Multivariate logistic regression was used to identify independent predictors of CKD and Mean (±SD=standard deviation) age of participants was 54.81 ± 12.45 years and 110 (52.9%) of them were male. Only 59 (28.4%) of the participants had awareness about CKD and its risk factors. The prevalence of CKD was 26% . Factors associated with chronic kidney disease were uncontrolled blood pressure (adjusted odds ratio (AOR)=2.22,95% CI=1.01-4.76), fasting blood sugar ≥ 150 mg/dl, , angiotensin converting enzyme inhibitors (ACEIs) nonusers, , poor knowledge of CKD , and long duration of hypertension . Our study found out low level of patient awareness and high prevalence of CKD. The predictors of CKD were uncontrolled blood pressure, fasting blood sugar> 150 mg/dl, long duration of hypertension, ACEIs nonusers, and poor knowledge about CKD. Chronic kidney disease (CKD), is defined as a progressive loss of kidney function occurring over several months to years; it is characterized by the gradual replacement of normal kidney structure with fibrotic tissues . When thth leading cause of global years loss of life and one of the fastest rising major causes of death because overall mortality due to CKD has increased by 31.7% from 2005 to 015 [There is an alarming rise of CKD prevalence globally associated with significant morbidity and mortality, necessitating special attention as one of the growing public health problems. The prevalence of CKD in the general population is 13.4% globally  while po5 to 015 .Chronic Kidney disease is also associated with huge economic burden. In high-income countries treatment of end-stage kidney disease (ESRD) shares more than 2–3% of their annual healthcare budget, while patients with ESRD represent only 0.03% of total population, and lower socioeconomic status is associated with greater risk of end-stage kidney disease . In deveOver half of all people requiring renal replacement therapy died due to a lack of access to dialysis or transplantation worldwide. Lack of access to renal replacement treatment in Africa, particularly middle and east Africa is the largest, where less than 3% of people requiring renal replacement therapy receive it . As a reEarly detection and treatment of chronic kidney disease can prevent or minimize complications associated with CKD ; howeverThus, assessment of knowledge, attitudes, and practices could be an early step forward to determine the extent to which an individual can follow healthy behaviors . ScreeniThe study was conducted at Jimma university medical center, which is the only referral hospital for the south west region. Adult (age ≥ 18 years) diabetes mellitus and hypertensive patients on regular follow-up and those who signed informed written consent were recruited to the study. Confirmed chronic kidney disease, short follow-up period (< 3 months), incomplete patient chart, pregnant women, and critically ill patients were excluded from the study.Hospital based cross-section study design was used at JUMC to assess awareness, prevalence, and risk factors for chronic kidney disease among hypertensive and diabetic patients on regular follow-up. The sample size was calculated by using simple proportion formula with estimated prevalence of CKD among diabetes mellitus patients, p=18.1% , 95 confData collection tool was developed after reviewing different literatures; the tool has three parts: the first part is sociodemographic and disease condition, second part has 7 yes or no questions assessing patients knowledge, and third part has 6 questions assessing attitude; the tool was translated to Afan Oromo and Amharic languages. Using these tools patients were interviewed to obtain respective information when they come for monthly check-up and medication refill. Patient's chart was also reviewed for information like medications, blood pressure, and serum glucose level. The last three months' FBS (fasting blood sugar) and BP (blood pressure) average were used assess glycemic and blood pressure control, respectively.Average knowledge is when at least 4 questions were answered correctly out of 7 knowledge questions, and positive attitude is when patients agreed with at least three of the attitude statements. Patient awareness was assessed using knowledge and attitude; it is considered as patients have awareness about CKD if they have both average knowledge and positive attitude.Laboratory technologists drained 3cc of vein blood according to standard vein puncture, and the serum creatinine level and blood urea nitrogen were determined using ARCHITECT c8000 by kinetic alkaline picrate, and 10cc of middle stream urine was collected and urine dipstick was used to determine urine albumin level which was reported as negative, or +1, to +4). Glomerular filtration rate (GFR) was estimated using CKD –EPI question ; chronicThe study protocol was approved by the institutional review board (IRB) of Jimma University, Institute of Health Sciences, and ethical clearance was obtained. Permission of data collection was granted with formal letter from chief executive director of JUMC. The purpose and protocol of this study was explained to participants and written informed consent was obtained from each patient. The privacy of personal information was protected and kept confidential. Codes were used for patient identification instead of names. Patients with abnormal findings were informed and referred to physicians for further investigation and appropriate management. p-value ≤ 0.25 were considered for multivariate logistic regression. Finally backward conditional logistic regression was used to identify independent predictors of CKD and p-value < 0.05 was considered statistically significant.Data was checked for completeness, grouped, then entered to EPI data, and exported to SPSS version 20 for analysis. Descriptive statistics like percentage and mean and standard deviation were used to present sociodemography and clinical characteristics of participants. Bivariate logistic regression was used to assess the crude association between independent variables and CKD and variables withA total of 208 hypertensive and diabetes mellitus patients were included in the study, of which 110 (52.9%) of the participants were male with mean (± SD) age of 54.81 ± 12.45 years. Majority of the study participants 145 (69.7%) were married, 142(68.7%) were rural dwellers, and 136 (65.4%) were educated at least up to elementary level see .The mean (±SD) systolic blood pressure and diastolic blood pressure of study participants were 136.6 ± 15.7 mmHg and 85 ± 8.9 mmHg, respectively. Mean ((±SD) fasting blood sugar was 145.6 ± 52 mg/dl and more than half 114 (54.8%) of the study participants had healthy body weight. Seventy-six (36.5%) of participants had average knowledge while 86 (41.3%) had positive attitude towards chronic kidney disease. Majority 143 (68.8%) of the study participants do not use social drugs like tobacco, alcohol, and Khat see .About 59 (28.4%) of the participants had awareness about CKD and 76 (36.5%) of the participants had average knowledge see . Over haThe overall prevalence of chronic kidney disease was 26% with ; of this, majority 41 (75.6) of the CKD were detected at early stage , while 8 (14.8%) were with moderately increased risk for chronic kidney disease and 5 (9.3%) were high risk group see .In crude analysis using bivariate logistic regression, age greater than 55 years, rural residence, ACEIs nonusers, poor CKD knowledge, negative attitude, long duration of hypertension, long duration of diabetes mellitus, social drug use, high level of fasting blood sugar, and uncontrolled blood pressure were associated significantly with chronic kidney disease.Independent predictors for chronic kidney disease were identified using multivariate logistic regression; ACEIs nonusers, poor knowledge of CKD, long duration of hypertension, fasting blood sugar ≥ 150 mg/dl, uncontrolled blood pressure (>140/90mmHG) were found to be independent predictors of chronic kidney disease,According to our finding, patients with uncontrolled blood pressure were 2.22  times at risk for chronic kidney disease than those with controlled blood pressure. Patients who were not using angiotensin converting enzyme inhibitors (ACEIs) were 4.35  times likely to develop chronic kidney disease when compared to users see .In our study we assessed patient awareness , prevalence of CKD, and its predictors among hypertensive and diabetes mellitus patients. Overall knowledge about CKD was low: only 36.5% of the participants have average knowledge which was similar with low knowledge level (mean=3.85) reported from community study in Tanzania , higher Overall attitude favoring early detection and prevention of CKD was low; most 149 (71.6%) of the participants believed kidney function screening is costly, though majority 190 (90.3%) of the respondents agreed to seek modern medical care; this was in agreement with report from Tanzania. All (100%) were willing to seek healthcare from a biomedical clinic and many participants with CKD were concerned about the health and economic impact of a diagnosis of kidney disease .The prevalence of chronic kidney disease was found to be 26% (95% CI:20.07%- 31.93%) which was corresponding to the report from UK which was 27.5%  higher tIn our study, fasting blood sugar>150mg/dl was independently associated with chronic kidney disease ; this was similar with report from USA were high level of Hemoglobin A1c was associated with CKD , and in This study also revealed that long duration of hypertension and uncontrolled blood pressure (BP> 140/90 mmHg) were independent predictors of CKD; this supports previous reports, where uncontrolled blood pressure was associated with high risk of CKD , 28 and Use of ACEIs in the management of hypertension was found to be protective in the current study  which supported previous studies  even thoAge was significantly associated with bivariate logistic regression however not significantly associated with the final analysis which was different from most findings , 24, 26.Our study used cross-sectional study design; temporal relationship between risk factors and the outcome cannot be determined. Single measurement of serum creatinine and urine albumin was used to define CKD; semiquantitative urine albumin was used and so could not grade level of albuminuria, and the assessment of knowledge and attitude was based on self-report with possible risk of bias; we used “yes” or” no” and “agree and disagree” type of questions which limit possible answer of the respondents.Despite these limitations, the finding of this study can be used as input for researchers and healthcare providers because as to our knowledge there was no prior study assessing patient awareness of CKD and risk factors among patients with both hypertension and DM; it will greatly contribute to increasing awareness of chronic kidney disease and its risk factors.Our study found out low level of patient awareness of chronic kidney disease and its risk factors among patients with both hypertension and diabetes mellitus. The prevalence of chronic kidney disease was high and uncontrolled blood pressure, high fasting blood sugar, long duration of hypertension, ACEIs nonusers, and poor knowledge about CKD were found to be independent predictors for chronic kidney disease. Working toward increasing patient awareness and screening for CKD at regular intervals among high risk groups is paramount to recognize chronic kidney disease at early stage before it progresses to kidney failure.


Background and objectives: The purpose of the study is to correlate vascular calcification biomarkers osteoprotegerin (OPG) and 25-hydroxyvitamin D3 (25-OH-D3), indicators of arterial stiffness carotid-femoral pulse wave velocity (c-f PWV) and renal resistive index (RRI), with parameters of left ventricular function in heart failure patients versus control. Materials and methods: Our case-control study compared 60 patients with ischemic heart failure and reduced left ventricular ejection fraction (LVEF) (<40%) with a control group of 60 healthy age-matched subjects (CON). Serum levels of OPG and 25-OH-D3 were determined by ELISA. Left ventricular volumes  and LVEF were measured by echocardiography. C-f PWV was determined using the arteriograph device. RRI was measured by duplex Doppler. Peak systolic velocity (PSV) and minimum end-diastolic velocity (EDV) were determined using angle correction. The estimated glomerular filtration rate (eGFR) was calculated using the MDRD equation. The Pearson’s correlation coefficient was used for interpretation of results. Results: OPG values were significantly higher in heart failure (HF) patients vs. CON . 25-OH vitamin D3 levels were significantly lower in HF patients vs. CON . Multiple regression analysis considering 25-OH D3 as a dependent variable demonstrated indicators of vascular stiffness RRI, c-f PWV and vascular calcification biomarker OPG as predictors. OPG values were significantly correlated with cardiac parameters LVEDV , LVEF , and c-f PWV, and also with 25-OH-D3 . RRI values were significantly correlated with cardiac parameters LVEDV  and LVEF , and with eGFR , c-f PWV, and 25-OH-D3 . Conclusions: This study showed significant correlations between vitamin D deficit and vascular stiffness indicators in heart failure patients with reduced ejection fraction, demonstrating the importance of these examinations for a better evaluation of these patients. Together with the evaluation of renal function, the measurement of vascular stiffness indicators and biomarkers might play a key role in identifying patients at greater risk for worsening disease prognosis and for shorter life expectancy, who could benefit from vitamin D supplementation. The abstract was accepted for presentation at the Congress of the European Society of Cardiology, Munich, 2018. Arterial stiffness is a term used to define the rigidity of the arterial wall, and also a term that refers to the viscoelastic properties of the vessel wall . IncreasPatients with cardiovascular disease often present low levels of vitamin D. Steroid hormone and vitamin D deficiency has been shown to be associated with chronic HF development in numerous studies . AssociaRenal insufficiency, common in HF patients, worsens the prognosis . However3 have been associated with high levels of OPG and high vascular calcification [Osteoprotegerin (OPG), a glycoprotein involved in phosphocalcic metabolism, considered in studies as an inflammatory biomarker, has been shown to be a biomarker of instability of atherosclerotic plaques, leading to calcification of vessels in patients with cardiovascular disease . Furtherfication .A simple, robust, and validated measure of arterial stiffness is represented by pulse wave velocity (PWV) measurement. In short, the shape of arterial blood pressure is a composite of the forward pressure wave created by ventricular contraction and a wave reflected from a distal location. The gold standard measurement of arterial stiffness is carotid-femoral PWV ,13.3 and vascular calcification biomarker OPG levels with arterial stiffness indicators measured by carotid-femoral PWV and RRI with left ventricular function parameters in heart failure patients versus control.This study aims to correlate 25-OH-DThis case-control study was conducted between July 2017 and September 2018 in the Cardiovascular Prevention and Rehabilitation Clinic of Institute of Cardiovascular Diseases Timisoara, Romania, on 60 patients with chronic heart failure with reduced LVEF (<40%) consecutive to coronary artery disease (CAD) in stable condition, selected from 482 hospitalized patients with HF of all causes. All heart failure patients included in the study underwent diagnostic coronary angiography, followed by revascularization procedures in selected cases, as documented by individual case histories. Patients with acute heart failure, degenerative valvular diseases, congenital heart diseases, cardiomyopathies of other causes than CAD, pericardial, pulmonary, or rheumatic inflammatory diseases were excluded from the study.All patients were staged at the time of hospital admission according to the New York Heart Association (NYHA) functional classification, in NYHA class II-IV. The diagnosis was based on typical signs and symptoms, as recommended by European guidelines . The HF 2 (m2). For determination of fasting blood glucose, the hexokinase test (HK) was made using Siemens Dimension RXL-MAX, Dade Behring device, Erlangen, Germany and reagents. For determining total cholesterol, triglycerides, LDL and HDL-cholesterol fractions, and photometric methods  were used. For determination of serum creatinine, the Jaffe method without deproteinization was used. Estimated glomerular filtration rate (eGFR) was calculated based on MDRD  formula. eGFR = 186 × (Creatinine/88.4)−1.154 × (Age)−0.203 × .All patients underwent clinical and biochemical evaluation. Personal data was taken: age, gender, family history of early cardiovascular disease in first-degree blood relatives (for subjects aged 55 years for masculin gender and aged 65 years for feminin gender), and smoking status. The standard objective examination included measuring systolic (SBP), diastolic blood pressure (DBP), and body mass index (BMI). Blood pressure (BP) was determined according to the European Guidelines on cardiovascular disease prevention in clinical practice . A usual3 was determined using DIAsource 25-OH Vitamin D Total Elisa 90kit ,and values were interpreted as follows: a value greater than or equal to 30 ng/mL was considered sufficient, values between 21ng/mL to 29 ng/mL were considered insufficient, the deficit was defined by values between 10 ng/mL and 20 ng/mL, and values less than or equal to 10 ng/mL were defined as severe deficiency. OPG normal range has been established according to the Elabscience Human OPG ELISA Kitused ; levels ≥ 2 ng/mL were considered pathological.Vitamin D and OPG were determined using commercial ELISA kits. 25-OH-DTransthoracic echocardiography was performed in all patients enrolled in the study on the GE Vivid 9 ultrasound system, manufactured by GEMS Ultrasound, Tirat Carmel, Israel. M-mode, 2D, color flow, and Doppler studies were performed on all patients. M-mode ultrasound displayed the movement of all structures intersecting the beam with time and was used to accurately measure heart structures. Two-dimensional ultrasound provided morphological and functional information about dimensions, cavities, cardiac walls, presence of valvular lesions, ejection fraction, and systolic performance. LV function was assessed qualitatively as normal, or as mild, moderate, or severe dysfunction. Only the patients with reduced LVEF (<40%) were included in the study. The EF by the biplane disc summation method (Simpson’s rule) wascalculated.Carotid-femoral PWV was performed with the MedexpertArteriograph device version 3.0.0.3 manufactured by TensioMedKft., Budapest, Hungary, which determined both the central pressure, the augmentation index (Aix), and the pulse wave propagation velocity in the aorta (PWVao). The measurements were performed after a minimum period at rest of 10 min in a quiet room in a supine position. The same examiner performed repeated measurements according to the method of determination presented by expert consensus document on arterial stiffness . For a pRRI was measured by duplex Doppler in the intrarenal segmental arteries visualized in color mode . Peak syp < 0.05 was considered statistically significant.The statistical analysis was made using SPSS v17 software and included descriptive statistics results . The differences between independent groups were obtained by the Mann–Whitney test, the correlations between numerical variables were made using the multivariate regression model, and the strength of correlation was obtained with the Pearson’s correlation coefficient. Nominal variables were compared and associated by the Pearson’s chi-squared test. Any value of Clinical, biochemical, and demographic features of the patients are summarized in No difference between groups was observed regarding age, body mass index, or gender. The mean values of systolic blood pressure, diastolic blood pressure, and heart rate showed no statistically significant difference between the two groups.p < 0.001), left ventricular end-diastolic volume , left ventricular end-systolic volume , left ventricular end-diastolic diameter , left ventricular end-systolic diameter , and left atrial volume . In the HF + CAD group, T2DM was present in 26 patients (43.33%) and atrial fibrillation in 25 patients (41.66%). No difference between groups was observed regarding TC (p = 0.154), LDL-c (p = 0.072), and HDL-c (p = 0.075). A significant difference between groups was observed in TG levels . . p < 0.001)   a. The me< 0.001) b.r = −0.832, p < 0.001)   and LVTDV . There was a significant negative correlation between RRI values and 25-OH-D3  .A strong negative correlation was found between OPG values and LVEF (< 0.001) a and als< 0.001) b. OPG va< 0.001) c. RRI wap = 0.004), c-f PWV (p = 0.005), and vascular calcification biomarker OPG (p = 0.025) as predictors.  were divided into two subgroups according to vitamin D levels (≥20 ng/mL and <20 ng/mL). Numeric values were compared between the two subgroups using the non-parametric Mann–Whitney test, because values did not respect a normal distribution. Results are presented in p < 0.001). Vascular biomarker OPG was significantly increased according to vitamin D deficit (p < 0.001). Cardiac parameters LVEDD, LVESD, LVEDV, and LVESV were also significantly increased in vitamin D deficit . LVEF was significantly decreased according to vitamin D deficit (p < 0.001).Patients with HF+ CAD . These results are in line with similar published findings [In a study conducted on 4063 patients with stable CAD, Bjerre et al. observed that OPG levels were significantly increased in non-survivors (21%). Over the 6-year follow-up period, OPG proved to be a strong predictor of all-cause mortality. They concluded that serum OPG levels had a long-lasting independent predictive power for all-cause mortality and cardiovascular death in these patients . Aksu etfindings ,19,20.3 levels [Grandi et al. found that the risk of cardiovascular mortality was increased by 83% in individuals with low 25-OH-D3 levels . Al Mhei3 levels .3 were significantly lower in heart failure patients compared to CON , as confirmed in previous studies [p = 0.004) and c-f PWV (p = 0.005) as predictors, suggesting that vitamin D deficit might contribute to increased vascular stiffness in heart failure (n = 60) by applying the non-parametric Mann–Whitney test for numeric variables, we demonstrated that vitamin D deficit is not only significantly associated with increased vascular stiffness but also with significant increased cardiac diameters and volumes, as well as decreased ejection fraction  on vitamin D supplementation in high-risk cardiovascular patients demonstrated protective effects, improving blood pressure, dyslipidemia, and inflammation . AnotherCardiac and renal function are closely linked, and communication between these organs occurs through multiple common pathogenetic mechanisms that can cause HF development and aggravation . In termp < 0.001). We have also observed a significant increase of vascular rigidity expressed by c-f PWV, increased OPG levels as rigidity biomarker, and significant reductions in 25-OH-D3 levels in HF patients compared to CON  are suggestive of the fact that vascular rigidity increases with severity of heart failure. RRI was negatively correlated with eGFR  and with 25-OH-D3 . eGFR is a major determinant of accelerated progression of central and peripheral arterial stiffness. A study conducted by Kwamato et al. on 1716 participants showed that decreased eGFR is associated with an increased PWV in the general population [The present study showed significantly higher RRI values in HF patients compared to CON (0.71 ± 0.08 vs. 0.61 ± 0.05, d to CON . Moreovepulation . Moreovepulation . We studOur results demonstrate a strong connection between arterial stiffness indicators RRI and PWV with biomarkers OPG and vitamin D in heart failure with reduced ejection fraction. To this day, there are unconclusive data to assess the impact of vitamin D supplementation on indicators of arterial stiffness, due to inappropriate study design, insufficient duration of supplementation, and insufficient power ,38.Limitations of the study: This study had a relatively small sample size. We investigated the correlation between vitamin D status and vascular stiffness without focusing on pathophysiological aspects and mechanisms that could explain this association.This study demonstrated significant correlations between vitamin D deficit and vascular stiffness indicators in heart failure patients with reduced ejection fraction, demonstrating the importance of these examinations for a better evaluation and follow-up of these patients. Multiple regression analysis considering 25-OH D3 as a dependent variable demonstrated indicators of vascular stiffness RRI, c-f PWV, and biomarker OPG as predictors, suggesting that the correction of vitamin D deficits could improve vascular rigidity. Together with an evaluation of renal function, the measurement of vascular stiffness indicators and biomarkers might play a key role in identifying patients at higher risk for worsening disease prognosis and for shorter life expectancy.The clinical implications of vitamin D supplementation to improve the life course of these patients are still under scrutiny. Assessment of vitamin D and vascular stiffness in heart failure is needed, because vitamin D deficiency and its consequences for increased cardiovascular risk are well documented. Large, well-designed RCTs are needed to confirm dosage recommendations and benefits, in order to provide a solid base of evidence for guideline recommendations in heart failure.


This prospective study aimed to evaluate the value of the cardiac cycle time-corrected electromechanical activation time (EMATc) measured at admission for predicting major cardiac adverse events (MACEs) in hospitalized patients with chronic heart failure (CHF). N = 145) were enrolled in this study. Documented clinical end-points (MACEs) included cardiogenic death, onset of acute HF as assessed with invasive and noninvasive mechanical ventilation, and cardiogenic shock. According to the different clinical end-points, patients were divided into two groups: a MACE group (n = 22) and a nonMACE group (n = 123). EMATc, LVEF, and circulating levels of B type natriuretic peptide (BNP) and Troponin I (TnI) were measured. Multivariate logistic regression analysis was used to examine the association between EMATc and MACEs. The parameters adjusted in the multivariable model included EMATc, BNP, and heart rate. The predictive value of EMATc was evaluated by receiver operating characteristic (ROC) curve analysis.  CHF patients with a left ventricular ejection fraction (LVEF) lower than 50% . The area under the ROC curve for EMATc was 0.799 . The optimal cutoff EMATc value was >13.8% with a sensitivity of 81.8% and a specificity of 65.9%.  Elevated EMATc was an independent risk factor for MACEs (ChiCTR1900021470. We demonstrated that an elevated EMATc measured at admission is an independent risk factor for MACEs among hospitalized CHF patients. Acoustic cardiography measured at admission may provide a simple, noninvasive method for risk stratification of CHF patients. This trial is registered with  Although advances in the diagnostic technologies and treatment of heart disease have been made over the past decade, the readmission and mortality rates among chronic heart failure (CHF) patients remain high. According to one report, the all-cause mortality of CHF patients was 17%, and the readmission rate within 12 months was 44% , 4.Echocardiography is a valuable tool for CHF diagnosis, as it noninvasively measures the structure of the heart chambers and the left ventricular ejection fraction (LVEF), and it is well-recognized that a decrease in the LVEF is associated with the severity of HF as well as a decrease in the survival rate . HoweverLeft ventricular (LV) systolic time intervals, including the preejection period (PEP), ejection time (ET), and their ratio (PEP/ET), are determined by the LV systolic and diastolic function and ventriculo-arterial coupling . The eleA total of 145 patients who were treated for acute decompensation of CHF with a decreased LVEF between August 1, 2017 and December 31, 2018 were consecutively enrolled. HF patients with a LVEF <50% and New York Heart Association (NYHA) classification of III or IV were registered in this study. Patients who met one of the following criteria were excluded from this study: age <18 years, acute myocardial infarction, acute myocarditis, structural heart disease, acute episode of chronic obstructive pulmonary disease, plans for coronary intervention or cardiac surgery during this hospitalization, or the use of an angiotensin receptor-neprilysin inhibitor (ARNI). Informed consent was obtained from each participant, and the study was approved by the Institute Ethics Committee.The demographic and baseline clinical data of all patients, including gender, age, medical history, and medications delivered and events that occurred during the course of the hospitalization, were recorded. The documented clinical data included resting heart rate (HR), blood pressure, and the levels of creatinine, BNP, and troponin I (TnI).Acoustic cardiography  was performed after the patient had been admitted to the hospital for 2 hours and allowed to rest in a supine position for 5–10 minutes. Simultaneous electrocardiogram (ECG) and heart sound data from the V3/V4 standard precordial position were analyzed by the computerized algorithm to calculate the EMAT and the HR corrected variable EMATc. Three recordings were taken for each patient, and the average EMATc value was used in this study.The modified biplane Simpson's rule was used to measure LVEF. LV end diastolic volume (LVEDV) and LV end systolic volume (LVESV) were obtained from apical four- and two-chamber views (PHILIPS Affiniti 50). The investigator who interpreted the echocardiographic findings was blinded to all clinical data and acoustic cardiographic findings.MACEs were defined as exacerbation of acute left HF that required invasive or noninvasive ventilator-assisted ventilation, cardiogenic shock, or cardiac death. Exacerbation of acute HF requiring invasive or noninvasive ventilator ventilation was referred to as the onset of dyspnea and/or severe hypoxemia during the course of standardized drug treatment . Cardiogenic shock generated from a cardiogenic cause was defined by a systolic pressure <90 mmHg for more than 30 min, or when a patient needed to be under the support of vasoactive drugs or intra-aortic balloon counter pulsation to maintain a blood pressure >90 mmHg or had pulmonary congestion when combined with symptomatic low perfusion of vital organs .t-test or Mann Whitney U test were used for comparison of continuous variable data. Categorical variables were expressed as frequency (proportion), and the Chi-square test was used for data comparison between groups. Multivariate logistic regression analysis was used to analyze the independent risk factors of MACEs. Receiver operating characteristic (ROC) curves were used to analyze the predictive value of selected variables for MACEs among in-hospital HF patients. A two-sided P value <0.05 was considered statistically significant. All statistical analyses were performed using SPSS, version 22.0 .Continuous variables with a normal distribution were expressed as mean ± standard deviation (SD), whereas those variables with a skewed distribution were expressed as median with interquartile range [M ]. Two-sample Student's P = 0.011, 0.004 and 0.010, respectively] than in the nonMACE group. However, the MACE group had a significantly lower LVEF (P = 0.006) but higher EMATc (P < 0.001) than the nonMACE group.A total of 145 patients  with an average age of 57.9 ± 15.3 years were enrolled in this prospective study. These patients were divided into two groups according the different outcomes. The mean in-hospital duration was 7.50  days. The MACE group had 22 patients with MACEs, of whom 12 (54.5%) had exacerbation of acute left HF, 9 (40.9%) had cardiogenic death, and 1 had cardiogenic shock (4.5%). The nonMACE group two had 123 patients who did not experience any MACEs. There were no statistically significant differences with regard to age, gender, or prior medical history including hypertension, diabetes, myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, or chronic renal insufficiency between the two groups . HR and β receptor antagonist was significantly lower , with an optimal cutoff point of 13.83%, a sensitivity of 81.8%, and a specificity of 65.9%. The AUC for BNP was 0.700 , with an optimal cutoff point of 811.5 pg/ml, a sensitivity of 67.7%, and a specificity of 65.8%.We next performed ROC curve analyses to determine the value of BNP and EMATc for predicting MACEs in the hospitalized HF patients. As shown in OR 8.679, 95% CI 2.760–27.291,P = 0.000), BNP , and HR  were significantly different. There were no statistical differences in the parameters LVEF  and TnI .Clinical indicators that were analyzed for statistically significant differences  by univariate logistic regression are presented in EMATc and BNP were transformed into categorical variables according to the cuttoff points, 13.8% and 811.5 pg/ml, respectively. TnI and LVEF were transformed into categorical variables according to the upper limits, 0.04 ng/ml and 40%, respectively.OR 6.578, 95% CI 1.931–22.416,P = 0.003), and BNP >811.5 pg/ml  were independent risk factors for MACEs . Efstratiadis et al. [Roos et al. examined s et al.  also evas et al. . In lineXu et al.  studied P = 0.001for cutoff of 811.5 pg/ml), which was consistent with a previous report [Previously, Carubelli et al. found that TnI level and LVEF were independent risk factors affecting the long-term prognosis of HF patients. In our study, the differences in HR, BNP level, TnI level, and LVEF between the MACE and nonMACE groups were statistically significant. However, the above variables were not independent risk factors for in-hospital MACEs . ESC guis report . HoweverWe noted that a previous study conducted by Chao et al. showed that approximately 45% patients had a normal ejection fraction . Also, iSome limitations of the present study need to be noted. First, we only studied the association of prolonged EMATc with MACEs in the hospitalized patients; future studies should be performed to examine the value of EMATs in the prognosis of HF patients over the long term. Second, we did not perform a long-term follow-up to examine the significance of EMATc in the management of patients with stable CHF. Third, this study was carried out in one institute with a small sample size. Fourth, the 2016 European Cardiology Association's HF guidelines redivided the classification of HF, classifying a LVEF level between 40% and 49% as intermediate zone HF (HFmrEF) . We did In conclusion, we demonstrated that EMATc is an independent risk factor for MACEs among in-hospital HF patients and holds prognostic value. We believe that bedside acoustic cardiography detection of EMATc is simple, fast, and effective and should be used for screening hospitalized HF patients to stratify those more likely to suffer MACEs.


Elevated arterial stiffness is associated with increased cardiovascular mortality. The relationship between arterial stiffness and critical limb ischemia (CLI) is not well established.  The objective of this study is to analyze the relationship between arterial stiffness indices and the degree of limb ischemia measured by the ankle-brachial index (ABI).  A cross-sectional study comparing patients with CLI and controls. Arterial stiffness was measured using brachial artery oscillometry. The arterial stiffness indices pulse wave velocity (PWV) and augmentation index normalized to 75 beats/min (AIx@75) were determined. Multiple linear regression was applied to identify predictors of arterial stiffness indices.  Patients in the CLI group had higher PWV  and AIx@75  than controls. Central systolic pressure was higher in the CLI group . There was an inverse relationship between AIx@75 and ABI , but there was no relationship between ABI and PWV . In multiple regression analysis, reduced ABI was a predictor of elevated levels of AIx@75 .  Patients with CLI have high arterial stiffness measured by brachial artery oscillometry. The degree of limb ischemia, as measured by the ABI, is a predictor of increased AIx@75. The increased AIx@75 observed in CLI may have implications for the prognosis of this group of patients with advanced atherosclerosis.  Lower limb peripheral artery disease (PAD) is common in the elderly and its worldwide incidence is increasing. , An ankle/brachial index (ABI) ≤ 0.90 is considered abnormal and when associated with ischemic pain at rest or ischemic wounds it confirms a diagnosis of CLI. , Arterial stiffness reduces the elasticity of the arterial system and its ability to adjust to volume changes during the cardiac cycle. - Arterial stiffness measured by PWV and AIx has been analyzed in patients with PAD to establish criteria for determination of risk and prognosis.  We evaluated patients seen at the Angiology and Vascular Surgery Department of a tertiary level hospital from May 2016 to April 2017. Patients aged 50 to 90 years were included in the study. Patients with no symptoms of PAD and with ABI between 0.91 and 1.30 were included in the control group. Those who presented with CLI characterized by pain at rest or by the presence of ischemic wounds and ABI ≤ 0.90 were included in the CLI group.  The sample size was calculated to enable comparison of AIx and PWV between groups using independent samples. Given a significance level of 5% and a medium effect size, the number of individuals required to achieve a power of 90% was 70 in each group. The medium effect size was selected based on a study by Catalano et al., who found a 0.55 standard deviation difference in AIx between groups.  Patients were examined by the lead author and by trained research assistants. Epidemiological data, biochemical parameters, measurements of arterial stiffness, and ABI were recorded. Smokers were defined as those who smoked at the time of the interview or who had stopped smoking at least 6 months prior to the study. Diabetes was defined as fasting glucose ≥ 126 mg/dL or use of insulin or oral hypoglycemic drugs. Hypertension was defined as systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg during the interview or use of antihypertensive drugs. Dyslipidemia was defined as serum cholesterol above 200 mg/dL or use of a statin. History of coronary intervention or acute myocardial infarction (heart disease), cerebrovascular accident or transient ischemic attack, and congestive heart failure were all considered in the analysis.  Blood pressure (BP) at brachial level was measured in both arms with an aneroid sphygmomanometer and stethoscope, with the patient sitting and the limb resting on the examination table. Two pressure measurements were taken for each arm and the mean was considered for analysis.  Arterial stiffness indices were measured with a Mobil-O-Graph device . Brachial artery pulse wave capture was performed with a high-fidelity sensor  incorporated into the cuff. After oscillometric measurement of BP, the cuff reinflates to diastolic BP level for 10 s and records information from the pulse waves. The aortic pulse wave is generated using a mathematical transfer function.  Several parameters were calculated. The AIx@75 was assessed from the central aortic pressure wave, which is characterized by two pressure peaks. The first peak is caused by contraction of the left ventricle and the second is the result of the reflection wave. The difference between the peaks represents the augmentation pressure (AP), which reflects the degree to which systolic blood pressure increases due to the reflection wave. AIx@75 is defined as the ratio of AP to central pulse pressure . AIx@75 reflects the increase in systolic pressure due to early return of reflected waves. The PWV is estimated using mathematical models that consider the parameters obtained by analysis of the pulse waves. The arterial stiffness indices PWV and AIX@75 were evaluated. The formula for AIx@75 is AIX@75 = AIx - 0.39 × (75 – heart rate).  Data were obtained for stiffness indices, peripheral systolic blood pressure (SBPp), peripheral diastolic blood pressure (DBPp), peripheral pulse pressure (PPp), and mean arterial pressure (MAP), defined as MAP = (2DBPp+SBPp)/3. Central pressures and hemodynamic data, including central systolic blood pressure (SBPc), central diastolic blood pressure (DBPc), central pulse pressure (PPc), systolic volume, cardiac output, total vascular resistance (TVR), and the cardiac index (CI) were obtained. Medications in use by the patients were not suspended for data measurement.  The ABI was measured with the patient in the supine position, using portable continuous wave Doppler ultrasound with a 7.5-mHz probe . Systolic pressures were measured bilaterally in the dorsalis pedis and posterior tibial arteries using Doppler ultrasound and an aneroid sphygmomanometer. The ABI of each lower limb was calculated by dividing the highest pressure in the tibial arteries by the highest systolic brachial pressure measured with the same sphygmomanometer. An ABI ≤ 0.90 was considered abnormal. t test or the Mann-Whitney test, as appropriate. Categorical variables were compared using the chi-square test and Fisher's exact test. Linear regression models were used to evaluate the effect of variables on AIx@75 and PWV. Variables with p<0.20 in the univariate analysis were included in a saturated model and assessed with a stepwise strategy. The quality of fit was assessed by the R2 value and residual analysis. Analyses were performed using the R program , version 3.3.2, and a significance level of 5% was adopted.  Categorical variables were expressed as counts and percentages and quantitative variables as means ± standard deviation. Quantitative variables were compared using Student's  A total of 312 patients were evaluated at first visit between May 2016 and April 2018. One hundred and two patients did not meet the inclusion criteria and 2 refused to participate. Complete hemodynamic analysis and arterial stiffness measurements were conducted for 142 patients: 70 in the control group and 72 in the CLI group. Two patients in the CLI group had pain at rest (Rutherford category 4), 68 had ischemic ulcers and were classified as Rutherford category 5, and 2 patients were considered category 6.  Patients in the control group were significantly taller than those in the CLI group (p = 0.01)   . Althou CLI patients had higher peripheral and central arterial blood pressure and TVR than those in the control group   . Ischem The variables that influenced AIx@75 after multiple linear regression analysis are shown in  This study showed that patients with CLI had higher values of arterial stiffness indices compared to controls, matched by gender and age. There was a correlation between the degree of limb ischemia as measured by ABI and arterial stiffness as measured by AIx@75. These data suggest that the more advanced the limb ischemia measured by ABI, the greater the magnitude of reflected waves measured by AIx@75. Central arterial pressures were also higher in the CLI group, which is consistent with advanced atherosclerotic disease. - Arterial stiffness has been analyzed in groups of patients with advanced atherosclerotic disease, such as those with coronary disease or on hemodialysis, with the objective of risk classification and to determine prognosis of cardiovascular events.  The main explanation for the association between low ABI levels and high AIx@75 levels is the fact that multisegmental arterial obstruction in the lower limbs can lead to early pulse wave reflections from the peripheral circulation to the aorta. Additionally, the reduction of the capillary bed in the distal circulation that occurs in advanced atherosclerosis increases pulse wave reflections.  In the current study, patients with limb ischemia had higher PWV than those in the control group. However, there was no relationship between PWV and the degree of ischemia measured by ABI. It’s important to consider that even the control group had an elevated PWV value, of 12.1±1.9 m/s. A PWV above 10 m/s has been associated with increased mortality.  In the only study we found with CLI patients, Brand et al. reported different findings. , Our finding of an inverse correlation between male sex and the AIx@75 is consistent with published data. Populational studies show that women have higher PWV and AIx than men. , Advanced age is associated with increased stiffness of the arterial wall.  Diabetes has been linked to increased arterial stiffness for several reasons. There is a reduction of the distensibility of muscular arteries due to the progression of atherosclerosis, reduction of capillaries in target organs, and thickening and calcification of the tunica media of small and medium-sized arteries.  High levels of SBPp were associated with high PWV. Increased systolic pressure with maintenance of diastolic pressure is associated with an increase in pulse pressure, which is a determinant of PWV, in addition to being associated with cardiovascular complications. , Measurement of pulse waves by brachial artery oscillometry, as used in this study, is a validated method when compared with other invasive and noninvasive methods of arterial stiffness measurement.  One limitation of this study is its cross-sectional character, which prevents determination of any temporal association between PAD and increased arterial stiffness. We chose to include patients with the ABI ≤ 0.90 in the CLI group because this is the most commonly used definition for patients with peripheral arterial disease. However, patients with critical ischemia are expected to have lower ABI values. Measurement of toe pressure would be more accurate for characterization of CLI, but this measurement was not performed, which was a limitation of the study. Additionally, the sample included patients who were referred due to circulatory problems and many were scheduled for surgery. Their medications were therefore not discontinued for evaluation of arterial stiffness.  In conclusion, this study shows that the degree of limb ischemia as measured by ABI is related to the intensity of pulse wave reflections as measured by AIx@75. This relationship helps to classify the risk of cardiovascular events in patients with PAD, since the increase in arterial stiffness is associated with several cardiovascular complications. Since this relationship has been established, defining the prognostic value of arterial stiffness indices in longitudinal studies may help to define therapeutic measures in the population with advanced PAD.


Home blood pressure (BP) and unattended automated BP (uAOBP) monitoring have been recommended by guidelines for the care of hypertensive subjects. However, BP measurements in the peripheral arteries cannot serve as direct substitutes for their central counterparts. Moreover, the comparative effectiveness and safety of BP-guided strategies using these BP measuring devices have never been evaluated.Patients with uncontrolled or newly diagnosed hypertension aged 20–90 years will be recruited via outpatient clinics and allocated into three arms by stratified randomization (baseline systolic BP 130–155 mmHg and 155–180 mmHg): home BP, uAOBP, and central BP-guided treatment. At each scheduled visit to the clinic, a patient’s BP will be measured by each of the three methods of measuring BP. The blood pressure from three different methods will be confirmed available at each visit. Patients and physicians will be blinded to the allocated interventions because they will use measured BP values in the clinic through a standardized report format. A common BP target for systolic blood pressure (SBP) of 130 mmHg is adopted for these BP-guided strategies. The primary outcome is the change of 24-h mean ambulatory SBP at 3 months. A key secondary outcome is to determine the percentage achieving their target BPs at 3 months and the decrease of left ventricular mass at 12 months.To our knowledge, this is the first prospective double-blind randomized controlled trial to assess the optimal guiding strategy for hypertension. It will help to define which BP monitoring method is the most effective for guiding the clinical management of hypertension. It will provide good evidence to support future guideline recommendations for BP monitoring devices.NCT03578848. Registered on 4 June 2018.ClinicalTrials.gov, The online version of this article (10.1186/s13063-019-3366-8) contains supplementary material, which is available to authorized users. Throughout middle and old age, blood pressure (BP) is strongly and directly related to vascular and all-cause mortality . LowerinMoreover, BP measurements in the peripheral arteries cannot serve as direct substitutes for their central counterparts because of the long-recognized differences in blood pressure waveforms  and valuConsidering that there are many better strategies for guiding hypertension management than traditional office BP, there is an apparent need to investigate their comparative effectiveness and safety in the management of hypertension. We hypothesize that home BP may be non-inferior to uAOBP and central BP-guided in reducing ambulatory BP, which the present randomized controlled trial is designed to test.This is a 12-month prospective double-blind parallel-group randomized trial. The study is scheduled to commence in June 2018. We plan to enroll a total of 252 patients with 84 subjects allocated to each of the three arms. The uAOBP and CBP groups will be compared to the Home BP group for data analysis. Details of the sample size calculation is provided in the statistics section (Section 2.6).20 to 90 years of agenot pregnantreceiving antihypertensive therapy for uncomplicated essential hypertension and taking one or two types of antihypertensive drugs (to rule out complicated or resistant hypertension) or with hypertension newly diagnosed by uAOBP (uAOBP > 130 mmHg at the screening visit)Patients with hypertension will be recruited at outpatient clinics, from advertisements, and at Taipei Veterans General Hospital. The inclusion criteria are as follows:poor adherence to medicationunable to conduct self-measurement of blood pressurehistory of polycystic kidney diseasecongestive heart failure (a recent assessment of left ventricular (LV) ejection fraction <40% prior to the screening visit)-1 1.73 m-2  at the screening visitchronic kidney disease with estimated glomerular filtration rate <30 mL min2.7 in women and >64 g/m2.7 in men) prior to the screening visitrecently recorded severely abnormal LV mass index (>59 g/msecondary causes of hypertensionuncontrolled hypertension (uAOBP > 180/100 mmHg at the screening visit)history of severe aortic valve diseasehistory of upper limb obstructive atherosclerosishistory of atrial fibrillationBP differences more than 5 mmHg between both arms at the screening visitThe exclusion criteria are as follows:Patients will be asked to sign the informed consent by the designated investigator before the interview. Eligible participants will be paid US $16.5 in cash at the baseline visit and at the end of study visit. Routine blood and urine tests will be analyzed at baseline and at the end of the study.Patients will be randomized to have hypertension management decisions made based on uAOBP, home BP, or central BP monitoring. Permuted block randomization will be done using computer-generated randomization codes in two stratums with baseline systolic BP (uAOBP) 130–155 mmHg and 155–180 mmHg. Whether the BP measurements are made on the left or right arm will also be determined by randomization codes. The BP for each patient will be measured by the three different methods of measurement at each visit. To guide the management of hypertensive patients, adjustments to medication will be based on a published guideline .An overview of the study protocol comply with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines  will be increased and if the difference is above 40 mmHg, the doses or three drugs (or a single-pill combination) will be increased. If the BP is low (less than 90/70 mmHg) or there are possible drug-related side effects, a cautious adjustment of the prescribed antihypertensive will be made.The patients are asked to bring their medication to each visit so that their pills can be counted. All dose adjustments and side effects will be recorded throughout the whole study period. A sub-study will test the level of agreement between the different methods of measuring BP.At the initial visit, the patient’s BP will be measured simultaneously from both upper arms by an oscillometric BP monitor . Subjects with SBP differences between both arms of more than 5 mmHg will be excluded. The procedure for BP measurements will adhere to the standard procedure .For uAOBP and central BP, the measurements will be conducted in a quiet room without the presence of clinical personnel. The patients will be seated without talking. The BP used will be the average of three measurements taken with an automated device  that has been preset to wait 5 min between measurements . SimultaFor the home BP measurements, a validated device  will be given to all subjects allocated to measure BP at home BP. Subjects are requested to take their BP in the morning (within 2 h after awakening) and evening (between 6 pm and midnight), before taking their medication, for 7 consecutive days before each scheduled clinical visit. The assistant will check the record of home sphygmomanometer at each visit. The BP taken on the first day of the measurements will be discarded and an average of all BP readings taken in the morning and in the afternoon will be calculated and given to the clinicians to guide treatment.The ambulatory BP of all subjects will be measured at baseline, at 3 months, and at the end of the study by a validated device (WatchBP O3 AFIB Ambulatory). Similarly, the choice of right or left arm for the measurement of ambulatory BP will be determined randomly. All the automated BP readings will be stored digitally for analysis and the BP values for each arm will be given to clinicians to guide hypertension management.Each patient will be randomly assigned, using a standard computer protocol at the General Clinical Research Center, Taipei Veterans General Hospital, Taipei, Taiwan, to the interventions in a 1:1:1 ratio using sealed opaque envelopes . The study coordinator will oversee the enrollment and intervention assignment and maintain the concealment of the allocation.The primary outcome is the change in 24-h mean ambulatory SBP at 3 months. The secondary outcomes include: (1) the change in 24-h mean ambulatory diastolic blood pressure (DBP) at 3 months, (2) decrease in LV mass at 12 months, (3) change in SBP/DBP measured by uAOBP monitoring, home BP monitoring, or central BP monitoring, (4) change in quality of life, (5) changes in medication, and (6) side effects. Any possible treatment-related side effects, including hypotension, injurious falls, dizziness, electrolyte imbalances (serum Na < 130 meq/L and serum K > 5.5 or < 3.0 meq/L), syncope, acute renal failure , and bradycardia (heart rate <50 bpm detected by electrocardiogram or ECG), will be recorded and evaluated. The quantity of medication taken will be recorded using the daily defined dose (DDD) calculated as per the World Health Organization standard. The DDD is a statistical measure of drug consumption used to standardize comparisons across drug classes, e.g., 1 × DDD = 150 mg irbesartan or 5 mg amlodipine .2.7 [Patients will be interviewed by well-trained interviewers using a structured questionnaire. Questions are on sociodemographic characteristics, smoking habits, consumption of alcohol, tea, and coffee, vegetarian habits, sleep, physical activity, medical history, and medication history. The quality of life will be assessed by the Taiwan version of the Short Form 36 (SF-36) . The Tai2.7 .The attending physicians will remain blinded to the allocation because they will be given the measured BP through a standardized report form and will not know which BP monitoring device was used. Except for patient-reported outcomes and adverse events, the investigators and participants are blinded to all outcome variables . The assessment of LV mass will be conducted on side-by-side images by a technician blinded to allocation.Based on data from our previous work , the sam2 test will be used to determine the relation between categorical variables. Intra-class correlations and a paired t-test will be used to assess the agreement between different strategies.A clinical study information system is used to manage this clinical trial. Access to the data system is restricted to members of the research team only. We will test the normality of all parameters using the Shapiro–Wilk test. Categorical data will be presented as proportions, and continuous data as means and standard deviations or as medium and interquartile ranges when appropriate. Data for all randomized patients in the three arms will be analyzed based on the intention-to-treat principle. For continuous variables , the analysis will be undertaken using linear regression, with the dependent variable calculated as the change over time. We will analyze DDD medication data recorded at all visits using mixed regression models to account for repeated measures on individuals over time, with outcome variables log-transformed to correct for heteroskedasticity where necessary. We will present back-transformed means and confidence intervals. Recommendations for medication use at each visit were categorized as maintain, increase, decrease, or cease . A log-mserum sodium ≤132 or >150 meq/Lserum potassium <3.0 or >5.5 meq/Lserum creatinine increased by at least 50% to ≥1.5 mg/dL since the last blood sample testheart rate <40 bpmECG shows complete heart block or bradycardia <40 beats/mininjurious fallssyncopeany unexpected event that the investigator believes could be attributed to the interventionWe have established a data and safety monitoring board to monitor all aspects of the study. All issues related to participant safety will be reported by the medical safety officer to the independent data and safety monitoring board, which will monitor data and oversee participant safety. The board will meet twice a year to monitor safety. It will advise the research steering committee on study progress and performance, and make recommendations regarding whether the study should continue or if there should be a protocol change. The data and safety monitoring board will attempt to identify any major adverse outcomes due to the therapy. The following are possible safety events relating to the intervention:fatal or life-threateningresulting in significant or persistent disabilityrequiring or prolonging hospitalizationany events that investigators judge are significant hazards or harm to the participantsSerious adverse events are any adverse events that meet any of the following criteria:The GYMNs trial was approved by the institutional review board at Taipei Veterans General Hospital (2018–05-009A) on 29 May 2018. The findings of this study will be published in peer-reviewed journals. It will provide good evidence to inform future guideline recommendations for BP monitoring devices.Taking BP measurements is a clinical procedure of considerable importance because it serves as an imperative foundation in the management of hypertension, which is the most significant cardiovascular risk factor across the globe . HoweverUsing conventional office BP in the management of hypertension is heavily affected by the busy and hurried clinical environment. In a previous review article, it was demonstrated that routine office BP is substantially higher than research office BP, uAOBP, and daytime ambulatory BP . TherefouAOBP, with its potential to eliminate the whitecoat effect, has been adopted in the SPRINT study , 36. OneWe designed this study as a double-blind study. Clinical information will be provided to clinicians without them knowing which method was used to measure their patients’ BP. The allocation concealment and blinding of patients, caregivers, and outcome accessors will be rigorously kept to avoid any possible placebo or performance bias. To our knowledge, this may be the first double-blind randomized controlled trial to evaluate the best BP monitoring strategy.We adopt a common BP target based on the recommendation of the latest hypertension guideline for uAOBP and home BP . UsuallyAlthough we will count the pills held by a patient at each visit, poor medication adherence patients may be a limitation of this trial.The GYMNs trial is ongoing and due to complete in 2021. The trial should be fully powered to test its primary hypothesis. It is the first double-blind randomized controlled trial to evaluate the optimal guiding strategy for hypertension and it will help define which method of BP monitoring is the most effective in guiding the clinical management of hypertension. Whatever the outcome, the findings of GYMNs are likely to influence future international guidelines for the choice of BP monitoring strategy in routine clinical practice in the care of hypertensive subjects.This protocol is version 1, dated 19 March 2018. Recruitment began on 6 June 2018. We planned to achieve the recruitment target by December 2021.Additional file 1:SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents. (DOC 120 kb)