The carotid intima media thickness (cIMT) and carotid plaque score (cPS) are respective markers of early and late stage subclinical atherosclerosis. Relationships between some laboratory parameters and subclinical atherosclerosis are not yet clear in community dwelling individuals and non-diabetic subjects, so we try to elucidate these relationships and find a model to predict early and late stage subclinical atherosclerosis.We examined relationships of the cIMT and cPS with different laboratory and demographic data of 331 subjects from a community-based prospective cohort study, using univariate and multivariate analyses.In regression models and after multiple adjustments, only systolic blood pressure (SBP), age, glycated hemoglobin (HBA1c), and waist circumference (WC) were determinants of the cIMT, and only age, SBP, HBA1c, and blood urea nitrogen (BUN) were determinants of a cPS of > 2 in all individuals. Only HBA1c lost its association with regard to predicting the cIMT in non-diabetic subjects.HBA1c at > 5.9% can determine early and late stage subclinical atherosclerosis in community dwelling individuals, but only late stage subclinical atherosclerosis in non-diabetic subjects. Carotid intima media thickness (cIMT) is a measure of the intima and media layers of the carotid artery. It is performed by B mode ultrasound in clinical practice. Hypertrophy of these intima or media (or both) layers results in a thicker cIMT. Factors that are responsible for this hypertrophy also develop or lead to progression of atherosclerosis . The cIMStudies also suggest that the carotid plaque score (cPS) alongside the cIMT is a valid marker of subclinical atherosclerosis and a strong predictor of CV disease (CVD) , 5. ThicGlycosylated hemoglobin (HBA1c) was proposed as a screening and diagnostic marker for type 2 diabetes mellitus (T2DM) , as it cTo date, only a few studies have investigated relationships of the Uric acid level (URCA), HBA1c, and other tests with factors of subclinical atherosclerosis, such as the cIMT and cPS –19. As tData of individuals from a community-based prospective cohort study investigating CV and cerebrovascular risk factors on residents of 6 Villages in Shihlin District, and 6 villages in Wenshan District that are in the coverage of Shin Kong Wu Ho-Su Memorial Hospital and Wan Fang Hospital respectively in 2005 and 2006 were used in this study. Six thousand phone calls were made using the area codes of these districts. Respondents who consented to enter the study, asked about the demographic information and they were asked for the permission of keeping their contact information and to call upon them to come to the respective hospitals for further examination. Exclusion criteria were: age ≤ 30, incomplete questionnaire, prior history of cancer, chronic kidney disease, refusing to blood draw or duplex ultrasound. Individuals that had both duplex records and laboratory blood test results at the same visit were accepted in our study Fig. . All stu2), a history of stroke (STR), history of T2DM, and CVD, systolic (SBP) and diastolic blood pressure (DBP) (mmHg), pulse (beats/min), and also laboratory data including fasting blood sugar , uric acid level , blood urea nitrogen , creatinine , aspartate aminotransferase , alanine transaminase , triglyceride , cholesterol , low-density lipoprotein , high-density lipoprotein , C-reactive protein , and glycated hemoglobin  were gathered using standard methods .Simple and descriptive statistics  for continuous variables) and analysis of categorical variables based on age group  and sex were carried out with Fisher’s exact test, and continuous variables were analyzed with an analysis of variance (ANOVA) and a post-hoc (least significant difference) test. Data including demographic characteristics, such as age, sex, age (years), height (cm), weight (kg), waist circumference , body-mass index  and the following measurements were obtained for every individual: flow (ml), end diastolic velocity , and peak systolic velocity  measured in one cardiac cycle. The mean velocity (MV) and resistance index (RI) were calculated using these respective formulas: MV = (PSV + 2*EDV)/3 and RI = (PSV-MV)/PSV. The diameter of the cervical portion of the common carotid artery (CCA), the internal carotid artery (ICA) beyond the carotid bulb, and the external carotid artery (ECA) and vertebral artery (VA) sequentially on both sides and the number of plaques in the carotid arteries were measured by a cardiologist. The cPS in each person was calculated by adding the numbers of plaques on the right and left sides.The cIMT was assessed at 1 cm from the carotid bulb on the left and right sides. The mean flow and RI were determined for every subject by taking the average of all flows and RIs of the left and right carotid and vertebral arteries. The mean cIMT and diameter of each artery were calculated by taking the average of the left and right sides in each individual.Cutoff points for the cPS, cIMT, HBA1c, and SBP were set at the level of the 75% quartile of all subjects’ data. A simple Pearson’s correlation was calculated, and variables with significant correlations with the cIMT were included in a multiple linear regression to predict the cIMT. Two logistic regressions were done using variables with a significant correlation with the cIMT and cPS to calculate the odds ratio (OR) and 95% confidence interval (CI) for predicting a thick cIMT and a high cPS (using 75% percentiles as the cutoff points). Receiver operating characteristic (ROC) curves were drawn, and the Mann-Whitney test, ORs, and CIs were used to determine the significance. Multiple and logistic regressions of non-diabetic individuals were used to clarify the role of T2DM in determining the cIMT and high cPS. Observations were deleted due to missing values for the response or explanatory variables in all models. The alpha error was set to 0.05, and we used SAS version 9.4  for all data analyses.2. The mean SBP and DBP were 123.57 and 78.02 mmHg, respectively. They had 0, 1, 2  cPSs, with a minimum of 0 and a maximum of 17. The mean cIMT was 0.67 (range 0.43~ 1.125) cm. The 25%, 50%, and 75% quartiles were 0.59, 0.66, and 0.75 cm, respectively. Demographic, duplex, and laboratory data of subjects are presented in Table There were 150 (46.9%) women and 170 (53.1%) men with a mean age of 57.06 (range 32~ 85) years and a mean BMI of 23.55 kg/mResults of Pearson correlations between the cIMT and different variables and also between the cPS and different variables are presented in Table p values, ORs, and CIs of this model are also presented in Table We used the third quartiles of WC (85.5 cm), HBA1c (5.9%), age (65 years), and SBP 135 mmHg) as cutoff points to run a logistic regression, and found the OR of the variables for predicting a thick cIMT Table . We then5 mmHg asr = 0.18748 and 0.22010, respectively, both p < 0.001), and the mean RI was correlated with the cIMT , but their relationship was not independent of age and sex, as this relationship disappeared after controlling for age and sex.The ICA RI and CCA RI had significant correlations with the cIMT  and it is probable that lack of correlation between HBA1c and high cPS is also due to this fact.Few studies have investigated the relationship between HBA1c and carotid plaque in non-diabetic individuals, and there are non-consistent results in the literature , 36. LeeOur results suggest that HBA1c cannot predict the cIMT, but it can predict it with a high cPS in non-diabetic subjects. But as a general criterion, we can still use HBA1C to identify high-risk patients due to the ROC curves, and we can combine different variables to further increase the accuracy Figs.  and 3.Although it is rational to accept that carotid luminal enlargement can be used as a marker of atherosclerosis, as it should increase to preserve the space after hardening of the lumen and plaque formation, there is no proof whether these changes occur before the onset of diabetes , and morOur study used no scoring system to compare the individuals for detection of subclinical atherosclerosis. So studies that can use the proposed variables with significant determination of early or late stage subclinical atherosclerosis to generate a scoring model would be recommended to further quantify the level of association. Additionally, status of the diabetes diagnosis, whether it is newly diagnose or not, and also the duration of diabetes, can potentially have some effects on our results and should be considered as a limitation in our study.In conclusion, HBA1c can be used alongside age, SBP, WC and BUN to identify individuals at high risk of early or late stage subclinical atherosclerosis from the community. HBA1c should be removed from our prediction model if one is dealing with early stage subclinical atherosclerosis in non-diabetic subjects, although HBA1c is useful in predicting late stage subclinical atherosclerosis in non-diabetic subjects.


Noninvasive cardiovascular magnetic resonance (CMR) techniques including arterial spin labeling (ASL), blood oxygenation level-dependent (BOLD), and intravoxel incoherent motion (IVIM), are capable of measuring tissue perfusion-related parameters. We sought to evaluate and compare these three CMR techniques in characterizing skeletal muscle perfusion in lower extremities and to investigate their abilities to diagnose and assess the severity of peripheral arterial disease (PAD).f, diffusion coefficient D, and pseudodiffusion coefficient D*, were measured in the anterior, lateral, soleus, and gastrocnemius muscle groups. Friedman, Mann-Whitney, Wilcoxon signed rank, and Spearman rank correlation tests were used for statistical analysis.Fifteen healthy young subjects, 14 patients with PAD, and 10 age-matched healthy old subjects underwent ASL, BOLD, and IVIM CMR perfusion imaging. Healthy young and healthy old participants were subjected to a cuff-induced ischemia experiment with pressures of 20 mmHg and 40 mmHg above systolic pressure during imaging. Perfusion-related metrics, including blood flow, T2* relaxation time, perfusion fraction P < 0.05), blood flow, T2*, and D values gradually decreased, while f values showed a tendency to increase in healthy subjects under cuff compression. No significant correlations were found among the ASL, BOLD, and IVIM parameters . Blood flow and T2* values showed significant positive correlations with transcutaneous oxygen pressure measurements , while f values showed a significant negative correlation in healthy young subjects . T2* was independent of age in every muscle group. T2* values were significantly decreased in PAD patients compared with healthy old subjects and severe PAD patients compared with mild-to-moderate PAD patients . Significant correlations were found between T2* and ankle–brachial index values in all muscle groups in PAD patients . Other imaging parameters failed to show benefits towards the diagnosis and disease severity evaluation of PAD.In cases of significant differences determined by the Friedman test  contains supplementary material, which is available to authorized users. Peripheral arterial disease (PAD) is a highly prevalent and severe atherosclerotic condition characterized by progressive peripheral arterial development of lower extremeity stenosis/occlusions . PatientNoninvasive testing of flow-limiting stenosis typically includes measurement of the ankle–brachial index (ABI), the ratio of ankle systolic blood pressure to arm systolic pressure . PAD is Medical imaging has emerged as an important tool in the diagnosis and management of PAD. Imaging modalities, including computer tomography (CT) angiography, cardiovascular magnetic resonance (CMR) angiography, and digital subtraction angiography, are commonly used to assess abnormal blood vessels and blood flow to the lower extremities. These techniques fail to provide information regarding skeletal muscle microvascular perfusion in the affected extremity . HoweverSeveral CMR techniques can noninvasively measure microvascular perfusion using endogenous tracers, including arterial spin labeling (ASL), blood oxygenation level-dependent (BOLD), and intravoxel incoherent motion (IVIM). ASL magnetically tags arterial blood using radiofrequency pulses, and the perfusion contrast is given by the signal difference between the tagged image and the nontagged control image obtained without net magnetization perturbation in arterial blood . BOLD usHence, this study aimed to 1) test the feasibility of using ASL, BOLD, and IVIM to measure perfusion changes in the lower extremities of healthy subjects under different external compression statuses; 2) validate the associations between ASL-, BOLD-, and IVIM-derived parameters and TcPO2 measurements; 3) evaluate the effects of age on imaging parameter measurements of ASL, BOLD, and IVIM in healthy subjects at rest; 4) use ASL, BOLD, and IVIM to compare perfusion in affected and contralateral (asymptomatic) lower extremities in PAD patients at rest; 5) compare the capabilities of resting-state ASL, BOLD, and IVIM in detecting perfusion differences between PAD patients and age-matched healthy subjects and between mild-to-moderate and severe PAD patients; and 6) investigate the associations between ASL-, BOLD-, and IVIM-derived parameters and ABI in PAD patients.The local institutional review board approved the prospective study, and written consent was obtained from all subjects prior to participation. Technical support for imaging sequence optimization was provided by a GE Healthcare employee (JQ). Authors not associated with GE Healthcare had full control of the data and information submitted for publication.n = 15); 2) PAD patients (n = 14); and 3) age-matched healthy old subjects (n = 10). None of the healthy subjects showed clinical evidence of PAD, cardiac insufficiency, hypoxic pulmonary diseases, or lower extremity venous disorders. Each of these subjects had a normal peripheral pulse status and an ABI > 0.90, and they were all non-smokers. The healthy old group was age-matched to the PAD group to eliminate the confounding effect of age on CMR perfusion parameter measurements. Patients with PAD were recruited from the department of vascular surgery with symptoms of intermittent claudication, rest pain, or critical limb ischemia and an ABI ≤ 0.90. The PAD group was then stratified into two disease severity subgroups based on ABI: 1) the mild-to-moderate group corresponded to an ABI of 0.51 to 0.90 (n = 7); and 2) the severe group corresponded to an ABI ≤ 0.50 (n = 7). Details for each group are listed in Table Between February 2016 and October 2017, three groups of subjects were enrolled: 1) healthy young subjects , cuff compression with a pressure of 20 mmHg above systolic pressure (Cuff-20), cuff compression with a pressure of 40 mmHg above systolic pressure (Cuff-40), and recovery period (Post). Two different cuff pressures were used to verify whether different air pressures could modulate the perfusion signal intensity and thus provoke different degrees of ischemia. The pressure of 40 mmHg above systolic pressure was chosen in accordance with the previously reported range of 30–50 mmHg above systolic pressure, which is recommended for provoking complete and reproducible ischemia . During 2; slice thickness = 5 mm; number of slices = 12) were acquired for use as anatomical landmarks. A FOV of 32 × 32 mm2 could cover both legs without leaving anything outside, thus prohibiting wrapping artifacts , where S(b) is the measured signal intensity obtained with a nonzero b-value and Sb0 is the measured signal intensity for b = 0. With this equation, perfusion fraction f together with diffusion coefficient D and pseudodiffusion coefficient D* were calculated using a nonlinear biexponential fit based on the Levenberg-Marquardt technique [The multi-echnique .R2 = 1 − ESS/TSS, where ESS is the sum of squared errors between the data points and the fitting curve and TSS is the sum of squared differences between the data points and the mean value of all data points. Additional computations were performed to assess the signal-to-noise ratios (SNRs) of the images obtained with TE of 65.5 ms for BOLD and b-value of 800 s/mm2 for IVIM. Noisy images were excluded from curve fitting.For BOLD and IVIM analysis, goodness of fit was assessed using Regions of interest (ROIs) were manually drawn on T1-weighted images around the 4 muscle groups  at the largest cross-sectional area of the calf on both the experimental and control sides  in an air-conditioned room maintained at 22 °C. The cuff-induced ischemia paradigm followed the same process as that described for the CMR experiments. One author  placed the electrode at the same spot at which the CMR measurements were taken  .P-values less than 0.05 were considered to indicate statistical significance.Statistical analyses were performed using SPSS version 20 , OriginPro 2016 , and Prism 5 . All data were expressed as the median (range) owing to non-normal data distributions. To assess interreader and interscan reproducibility, the intraclass correlation coefficient (ICC) was calculated. ICC values less than 0.40 indicated poor reproducibility, those ranging from 0.40 to 0.75 indicated fair to good reproducibility, and those higher than 0.75 indicated excellent reproducibility.U test. The Wilcoxon signed rank test was used for comparisons of imaging parameter measurements between the left and right lower extremities in PAD patients. Then, imaging parameters were compared between PAD patients and healthy old subjects, as well as between mild-to-moderate and severe PAD patients using the Mann-Whitney U test. Finally, correlations between imaging parameters and ABI in PAD patients were assessed using the Spearman rank correlation test. Bonferroni correction for multiple comparisons for the number of muscle groups was applied when necessary.To determine whether differences existed in each imaging parameter value under different statuses (Pre/Cuff-20/Cuff-40/Post) in the experimental and control lower extremities, the Friedman test was used. In cases of statistical significance, further pairwise comparisons with the Dunn test were performed. The Wilcoxon signed rank test was used to compare imaging parameter measurements between left and right lower extremities in all healthy subjects under different statuses. The non-parametric Spearman rank correlation test was performed to assess correlations between imaging parameters derived from different methods, as well as between imaging parameters in gastrocnemius and TcPO2 measurements. Strength of correlation based on the Spearman rank correlation coefficient (ρ) was interpreted as follows: 0.00 to 0.20, very weak to negligible correlation; 0.21 to 0.40, weak correlation; 0.41 to 0.70, moderate correlation; 0.71 to 0.90, strong correlation; and 0.91 to 1.00, very strong correlation . The effThe sample size of patients included in this study was estimated using one-sided calculations with α of 0.05 and a power of 80% to detect an absolute T2* decrease of 4 ms  with a standard deviation of 2 ms based on the results of previous studies , 25. AssR2 values for BOLD and IVIM fittings were 0.90  and 0.98 , respectively. The median SNR values on the TE = 65.5 ms and b = 800 s/mm2 images were 19.2  and 17.2 , respectively. The overall interreader reproducibility was fair to excellent, with ICC values of 0.83 for blood flow, 0.93 for T2*, 0.77 for f, 0.92 for D, and 0.64 for D*. The overall interscan reproducibility was fair to excellent, with ICC values of 0.73 for blood flow, 0.85 for T2*, 0.67 for f, 0.84 for D, and 0.55 for D*.All subjects successfully completed the CMR examinations Table . Cuff coChanges in quantitative imaging parameters under the cuff compression paradigm in the healthy young and healthy old groups are illustrated in Figs. P < 0.01 for blood flow, and all P < 0.001 for T2*). f and D values showed significant differences in the lateral, soleus, and gastrocnemius muscle groups, and D* values were significantly different in the soleus and gastrocnemius muscle groups . Under the Cuff-20/Cuff-40 compression statuses, T2* values were significantly lower than the baseline measurements in all muscle groups , and blood flow, f, D, and D* values showed marked differences in only some muscle groups. No significant differences for any parameter in either muscle group were observed between the Post and Pre statuses  . D* values showed significant differences in the soleus and gastrocnemius muscle groups (both P < 0.01). Blood flow values did not significantly differ in any muscle group . Under the Cuff-20/Cuff-40 compression statuses, significant differences were found for T2* values compared with those at baseline in all muscle groups except for the anterior muscle group under the 20-mmHg status . Furthermore, f, D, and D* values were significantly different in several muscle groups under these statuses . Additionally, no significant differences between Pre and Post measurements were observed for any of the parameters   Fig. .D values gradually decreased under the Cuff-20 and Cuff-40 compression statuses, while f values showed a tendency to increase. During the recovery period, all parameters nearly returned to normal  . Most muscle groups exhibited significant differences in perfusion-related parameter values especially when the cuff compression pressure was increased to 40 mmHg above systolic pressure.Results of Wilcoxon signed rank test comparing functional imaging parameters between the experimental and control sides under different statuses are illustrated in Table P > 0.05)  and ρ = 0.522 (P < 0.001), respectively). A significant negative correlation was observed between f and TcPO2 measurements (P = 0.018), although the correlation was weak (ρ = − 0.351). No significant correlation was found for D (P = 0.054) or D* values (P = 0.340).The normalized CMR imaging parameters blood flow, T2*, and nts Fig. . Blood ff for the soleus and gastrocnemius groups, and D and D* for the gastrocnemius group demonstrated significant differences between the healthy young and healthy old groups at rest . Only T2* was found to be independent of age in every muscle group   Table .Table 3CP = 0.005), and no significance was reached in the lateral, soleus, or gastrocnemius muscle groups  . No significant differences in other parameters in any muscle group were observed except D* values between PAD patients and healthy old subjects in the lateral muscle group.Results of Mann-Whitney P < 0.001), lateral , soleus , and gastrocnemius  muscle groups .Spearman rank correlation analysis showed that in PAD patients, T2* was significantly correlated with ABI in the anterior  blood flow, T2*, and f values were all correlated with TcPO2 measurements; 3) ASL of all muscle groups and IVIM of the gastrocnemius group were influenced by age; only BOLD was independent of age in every muscle group; 4) BOLD could detect perfusion differences between the affected and contralateral lower extremities in PAD patients; 5) BOLD could separate PAD patients from healthy old subjects and PAD patients with different severities; and 6) BOLD-derived T2* was correlated with ABI in PAD patients.Noninvasive monitoring of skeletal muscle perfusion in the lower extremities is critical for PAD patient management as perfusion can provide insight into microvascular function and endothelial integrity . Advancef, D, and D* values were reported to be 3%, 1.45 × 10− 3 mm2/s, and 28.5 × 10− 3 mm2/s, respectively, in the forearm muscle at rest by Filli et al. [− 3 mm2/s, and 11.7× 10− 3 mm2/s, respectively, in the shoulder muscle by Nguyen et al. [− 3 mm2/s, and 18.6 × 10− 3 mm2/s, respectively, in the soleus muscle in healthy young subjects).Similar to the results in published literature , 27, basi et al. , and 6.6n et al. . These fD values also showed a decreasing trend under cuff-induced ischemic conditions. Local ischemia leads to decreased diffusivity of water molecules within muscles, and this decreased D was mostly likely attributed to this physical effect. Conversely, the perfusion fraction f derived from IVIM showed a tendency to increase in the case of arterial occlusion. Given that f reflects the signal fraction of capillary blood flow in entire water molecule diffusion pool within each voxel [f values. In addition, it has been suggested that decrease in venous oxygen saturation may release relaxing factors than can cause microvascular dilation [f value. In healthy old subjects, changing trends for the imaging parameters were similar to those observed in the healthy young group except for ASL. ASL is limited by the intrinsic low SNR in skeletal muscle, wherein the ASL signal represents only 0.5%–1% of the raw image intensity [n = 10).Under cuff compression conditions, negative ASL and BOLD contrasts in healthy young subjects developed due to ischemic insult, which agreed with previous studies , 25, 31.ch voxel , it can dilation , which mntensity . This noInterestingly, we also observed aberrant T2* signal changes on the control sides of healthy subjects during the cuff compression experiment on the other lower extremity, in accordance with the findings of a previous study . Yeung ef values were also found to correlate with TcPO2 measurements in our study, with correlation coefficients of 0.465 and − 0.351, respectively. The correlation between BOLD-derived T2* and TcPO2 measurements was stronger than those between the other parameters, which may be attributed to the fact that both BOLD CMR imaging and TcPO2 examination are directly associated with the oxygenation state at the microvascular level.Ledermann et al. reported that BOLD CMR imaging correlated with TcPO2 measurements in healthy volunteers during muscle ischemia , which wAge effects on parameter measurements varied among the different sequences and muscles. In our study, no significant differences between the healthy young and healthy old groups were observed for the baseline T2* value, indicating that age did not appear to affect BOLD in healthy subjects at rest. This finding was in accordance with other observations . In contThe ABI is a measure providing objective data for diagnosing PAD. When applying these imaging techniques on PAD patients, we found that BOLD was capable of detecting perfusion deficits at rest better than ASL and IVIM. Lower T2* values were related to the presence of PAD and more disease severity stratified by ABI. As discussed earlier, BOLD effect is generally assumed to reflect blood oxygenation state influenced by the ratio of oxygenated to deoxygenated hemoglobin, which is determined by the balance between oxygen supply and consumption . In PAD,In the cuff-induced arterial occlusion experiment on healthy subjects, varying degrees of ischemia were factitiously induced by different pressures above the systolic pressure, and CMR imaging techniques were able to detect these changes. However, in healthy old subjects and PAD patients with differing degrees of ischemia, only BOLD was effective for this discrimination at rest. One possible explanation for this finding could be that the degree of ischemic insult in PAD patients was less severe than that induced by cuff occlusion. Additionally, collateral arteries developed in skeletal muscles in PAD patients would compensate for the perfusion deficit. BOLD is more sensitive to these less dramatic changes, which may be ASL- or IVIM-insensitive.Numerous previous studies have used ASL or BOLD to monitor dynamic perfusion changes in skeletal muscles at rest and during ischemia and hyperemia, which allows the measurement of key parameters, such as peak hyperemic value (PHV) and time-to-peak (TTP). In our study, we did not measure continuous temporal changes of ASL, BOLD, and IVIM in our subjects mainly because it was not technically feasible to perform these three sequences sequentially at a high temporal resolution. Nevertheless, our protocol can be regarded as a simplified approach to the dynamic scanning method; a similar approach was also used in a previous study . Althoug31P CMR spectroscopy is a useful tool to noninvasively probe skeletal muscle energetics, including adenosine triphosphate and creatine phosphate metabolism [The present study has several limitations. First, the number of study subjects was relatively small. Second, no gold standard for blood flow, oxygenation, or microvascular perfusion in skeletal muscle could be established in our subjects. For example, mixed venous oxygen saturation measurements would be informative regarding the confirmation of BOLD results. Nevertheless, our results revealed significant relationships with TcPO2 measurements, which are commonly used in clinical routines. However, the use of TcPO2 measurement is limited since it is confined to the skin microvasculature and thus fails to directly analyze the skeletal muscle . Therefotabolism , which wIn conclusion, the present study shows that multi-parametric CMR techniques including ASL, BOLD, and IVIM provide useful and complementary information regarding tissue perfusion in the lower extremities of healthy subjects. Perfusion-related metrics derived from these techniques correlate with TcPO2 measurements. In PAD patients, BOLD is a more reliable imaging technique for the detection and stratification of alterations in microvascular function at rest compared with ASL and IVIM.Additional file 1:Figure S1. Example of source images and processed maps for arterial spin labeling (ASL), blood-oxygen level dependent (BOLD), and intravoxel incoherent motion (IVIM) cardiovascular magnetic resonance (CMR). (PPTX 11134 kb)Additional file 2:Figure S2. Graphs depicting serial measurements of imaging parameters from ASL, BOLD, and IVIM for the anterior, lateral, soleus, and gastrocnemius muscle groups in the control side in healthy young subjects. (PPTX 727 kb)Additional file 3:Figure S3. Graphs depicting serial measurements of imaging parameters from ASL, BOLD, and IVIM for the anterior, lateral, soleus, and gastrocnemius muscle groups in the control side in healthy old subjects. (PPTX 654 kb)Additional file 4:Table S1. Spearman rank correlation coefficients for ASL, BOLD, and IVIM imaging parameters. (DOCX 16 kb)Additional file 5:Table S2. Comparison of functional imaging parameters between affected and contralateral lower extremities in PAD patients. (DOCX 18 kb)


Physical examination and B-type natriuretic peptide (BNP) have been used toestimate hemodynamics and tailor therapy of acute decompensated heartfailure (ADHF) patients. However, correlation between these parameters andleft ventricular filling pressures is controversial.This study was designed to evaluate the diagnostic accuracy of physicalexamination, chest radiography (CR) and BNP in estimating left atrialpressure (LAP) as assessed by tissue Doppler echocardiogram.Patients admitted with ADHF were prospectively assessed. Diagnosticcharacteristics of physical signs of heart failure, CR and BNP in predictingelevation (> 15 mm Hg) of LAP, alone or combined, were calculated.Spearman test was used to analyze the correlation between non-normaldistribution variables. The level of significance was 5%.Forty-three patients were included, with mean age of 69.9 ± 11.1years,left ventricular ejection fraction of 25 ± 8.0%, and BNP of 1057± 1024.21 pg/mL. Individually, all clinical, CR or BNP parameters hada poor performance in predicting LAP ≥ 15 mm Hg. A clinical score ofcongestion had the poorest performance [area under the receiver operatingcharacteristic curve (AUC) 0.53], followed by clinical score + CR (AUC0.60), clinical score + CR + BNP > 400 pg/mL (AUC 0.62), and clinicalscore + CR + BNP > 1000 pg/mL (AUC 0.66).Physical examination, CR and BNP had a poor performance in predicting a LAP≥ 15 mm Hg. Using these parameters alone or in combination may leadto inaccurate estimation of hemodynamics. In this study we tested the hypothesisthat BNP values add diagnostic accuracy to physical examination in detectingcongestion in patients with ADHF, using echocardiogram-derived hemodynamicassessment as a reference method for comparison.Elevated levels of B-type natriuretic peptide (BNP) reflect increased LV fillingpressures, secondary to myocyte stretch, due to volume or pressureoverload.A prospective convenience sample of patients admitted to the emergency departmentor coronary care unit of three hospitals  due to ADHF was studied. The study was conducted accordingto the Declaration of Helsinki standards for human research. Institutionalreview boards approved the research protocol, and all participants providedwritten informed consent before enrollment.Patients with ADHF due to LV systolic dysfunction, with LV ejection fraction(LVEF) <40% by Simpson's method, New York Heart Association (NYHA) functionalclass III or IV on admission and sinus rhythm were included within 24 hours ofemergency care.The exclusion criteria were as follows: ADHF due to acute coronary syndrome;echocardiographic window precluding adequate analysis of hemodynamic parameters;primary valve disease; mechanical prosthetic valve; single mitral flow pattern;and presence of cardiac pacing.The following physical findings were evaluated: jugular venous distension;hepatojugular reflux; hepatomegaly; ascites; lower extremity edema; third heartsound (S3); pulmonary rales; arterial blood pressure; and proportional pulsepressure. Patients were examined in a quiet emergency or critical care room. Thejugular venous distension was evaluated with the patient sitting upright and thepresence of a visible internal jugular vein above the clavicle was consideredelevated. The hepatojugular reflux was tested in patients with no visiblejugular vein, applying a firm right abdominal pressure. The liver was examinedwith the patient in recumbent position. Hepatomegaly was considered when theliver had more than 10cm of length, considering percussion technique initiatingon the third intercostal space, along the midclavicular line. Liver palpationwas the method of choice to assess the lower margin of the liver if it waspalpable in the abdomen.Patients with chest radiography showing any sign of congestion were considered tobe congested. The radiological evaluation was done through theposterior-anterior and left lateral chest radiography. In cases of inability totake chest radiography in posterior-anterior and lateral positions, ananterior-posterior position with the patient sitting in bed was performed. Thechest radiography was performed immediately prior to the echocardiogram.14 and with levels of BNP < 200 pg/mL were considered“dry”.15Simultaneously to echocardiography, blood sample was drawn for measurement ofBNP. Samples were drawn in EDTA tubes and BNP was measured in whole blood, byimmunofluorescence technique, using a commercially available kit . All measurements wereperformed within 30 minutes of blood sampling. Patients with levels of BNP >400 pg/mL were considered congested,16 All Doppler profiles were recorded in an apical4-chamber view.All patients were submitted to a transthoracic echocardiography with tissueDoppler imaging  within a maximum of 30 minutesafter completion of the physical exam. In each center, only one examiner (themost experienced) performed all echocardiographic evaluations. Echocardiographicmeasurements were performed in a blinded manner: the examiner was unaware of thephysical findings. Images were obtained from patients in the left lateral andrecumbent position, and measurements followed the recommendations of theAmerican Society of Echocardiography.The estimated left atrial pressure (LAP) was calculated as follows: calculationof the E/E' ratio by measuring the intra-myocardial flow velocity with tissueDoppler. The early diastolic mitral annular velocity (E') was obtained by tissueDoppler in the LV lateral wall and in case of technical impossibility ofobtaining the velocity in this wall, as in ischemic involvement, it was measuredin the interventricular septum. At least three consecutive cardiac cycles wereused and an average was used as the final result. This measurement, whencombined with the trans-mitral flow obtained with pulsed Doppler in earlydiastole (E) results in the relationship E/E'. The LAP was then estimated by theformula: LAP: 1.24 x (E/E’) + 1.9. Indication of increased LV filling pressurewas defined as LAP ≥ 15 mm Hg. Although patients with values below 15 mmHg may have congestion, values ≥ 15 mm Hg have high specificity forincreased LV filling pressure. Ejection fraction was evaluated through theSimpson’s method.Descriptive statistics were expressed as frequency (%) for categorical variables.For continuous variables data are presented as means ± standard deviationfor normally distributed data or median and interquartile range (IQR) fornon-normally distributed data. Measures of diagnostic performance  were used toevaluate the diagnostic utility of physical exam signs of heart failure and/orBNP in predicting LAP ≥ 15 mm Hg (defined as indication of increased LVfilling pressure).The Spearman test was used to analyze the correlation between non-normaldistribution variables. The level of significance was 5%.To determine the best cut-off value for BNP to estimate elevation in LAP, areceiver operating characteristic (ROC) curve was constructed. A clinical score(CS) was built by giving 1 point to each positive sign of decompensated heartfailure . Patients with ≥ 2 points were considered witha positive CS, according to analysis of ROC curve. To evaluate the capacity ofphysical exam and noninvasive diagnostic tests for the prediction of elevatedLAP (LAP ≥ 15 mm Hg), separate models were built using combination of CS,CS + chest radiography, CS + chest radiography + BNP > 400 pg/mL, and finallyCS + chest radiography + BNP > 1000 pg/mL . Each of these diagnostic tests was dichotomized and compared to determinethe incremental predictive value. Statistical analyses were performed usingSPSSÒ .Forty-three patients were included in the study. Patients were predominantly male(75%), elderly (69.9 ± 11.1 years) and had ADHF of ischemic etiology(65%). The mean serum creatinine was 1.3 ± 0.4 mg/dL, and the mean BNPwas 1057 pg/mL ± 1024 pg/mL. Nine patients had LAP < 15 mm Hg as assessed by echocardiogram. The mostfrequent sign of decompensation was the presence of rales (27 patients),followed by S3 (19 patients), edema, hepatomegaly and hepatojugular reflux (12patients each). Prevalence of all clinical signs is show in Elevated jugular venous pressure was the most specific (88%) clinical sign topredict LAP ≥ 15 mm Hg, and rales were the least specific (33%). Accuracyof each sign to predict LAP ≥ 15 mm Hg is shown in Levels of BNP > 400 pg/mL had a suboptimal diagnostic capability to estimatecongestion. In fact, chest radiography showed a slightly better accuracy than BNP levels topredict congestion. Accuracy of CS and its combinations with chest radiography and BNP with cut-offvalues of 400 pg/mL or 1000 pg/mL are illustrated in In this study, we have assessed the diagnostic accuracy of heart failure clinicalsigns to predict elevation of cardiac filling pressures as derived fromechocardiogram-based parameters. Additionally, we have combined information fromclinical signs and chest radiography regarding congestion and finally added the BNPvalue in order to augment the diagnostic accuracy in assessing congestion. Thisstrategy reflects a “real world” practice to clinically evaluate the hemodynamics ofADHF patients, and we compared this clinical approach with objective measurements ofhemodynamics derived from tissue Doppler echocardiogram. We have shown that a CS ofcongestion, chest radiography and BNP, alone or in combination do not accuratelypredict elevation of LAP.17 In a study with 35 patients in a critical care unit,the jugular venous pressure was accurate in estimating low or high fillingpressures.18 Inanother study, after evaluating a thousand patients referred for cardiactransplantation, the authors observed that estimated right atrial pressurebelow or above 10 was concordant with a pulmonary capillary wedge pressure(PCWP) below or above 22 mm Hg in 79% of patients.19 Other studies also have shown prognosticinformation about elevated jugular venous pressure in patients with heartfailure. Its presence was associated with adverse outcome, includingprogression of heart failure, even after adjustment for other prognosticfactors.20 Butseveral factors limit its power in predicting filling pressures. There isnot a universal method to estimate the jugular venous pressure. Controversyexists regarding the position (sitting upright or semirecumbent position of30-45º), the jugular vein being used , and thetechnique of measurement .22 Inpatients with heart failure with preserved systolic function, the jugularvein pressure is far less studied.24 Inaccordance with these observations, we have also found that elevated jugularvenous pressure had the best specificity (88%) of all physical findings forelevated LAP. Additionally, in patients with no elevated jugular venouspressure, but with a positive hepatojugular reflux, we were able to identifyan elevated LAP in 10 out of 12 patients. However, as expected, the absenceof elevated jugular venous pressure was not able to exclude elevatedLAP.The jugular venous pressure is the most important and probably the onlyphysical examination sign that is relatively accurate in estimatingventricular filling pressures.25 havestudied patients with dyspnea in the emergency department and found that S3did not improve diagnostic accuracy for ADHF, with a sensitivity of only14.6%. Moreover, in that study, a low diagnostic accuracy (58%) for thediagnosis of ADHF when utilizing all signs together was observed. In ourstudy, S3 was present in less than half of patients and, when present,showed a positive predictive value of 79% for LAP > 15 mm Hg. Whenabsent, an elevation of filling pressures could not be ruled out. Inaddition, S3 did not add any information regarding hemodynamic status. Thisis in accordance with other studies.26 Of note,in our study, all physical examinations were done by a heart failurespecialist. In the setting of a less experienced professional, the accuracyof physical exam (particularly S3) can be low, since studies suggest pooragreement between medical interns or residents and phonocardiographicfindings.27 On theother hand, reasonable agreement in S3 detection has been found amongprofessionals of heart failure clinics.28Collins et al.29 and to assessprognosis.31 For other BNP purposes,data are less clear. In the Escape Trial,32 the ROC curve for the performance of BNPin estimating an elevation in PCWP > 22 mm Hg showed a poor performance(AUC = 0.55). Another study with 40 critically ill patients utilizinginvasive hemodynamic monitoring has shown a weak correlation between BNP andPCWP (r = 0.58).33 Ourdata were consistent with these studies, showing a weak correlation betweenBNP and LAP (r = 0.29). BNP was also tested for guiding treatment, because,theoretically, lowering BNP is a consequence of lowering fillingpressures,34 butthis strategy failed to show clinical benefit.35 In contrast, in the recent PROTECTtrial,36 a similarstrategy of guiding treatment according to amino-terminal-Pro-BNP levelsagainst standard of care resulted in decreased incidence of events,improvement in quality of life and in cardiac remodeling. However, thattrial was conducted in an outpatient setting, involving very few heartfailure patients in more advanced functional classes.The strongest evidence for clinical use of BNP is to discriminate the causeof dyspnea in patients admitted in the emergency department35 We have observed that BNPlevels > 400 pg/mL had a poor prediction performance to identifyelevation in LAP, similar to other physical findings or chest radiographyperformances when taken individually. No valuable information on fillingpressures was observed when BNP levels were below 400 pg/mL. Using the AUC,we found that BNP levels of 1000 pg/mL had the best specificity to predictLAP ≥ 15 mm Hg. Therefore, we have also utilized this cut-off valuein our subsequent combined analysis. Patients with moderate or severe renalimpairment had higher BNP values, in our study the mean values of urea andcreatinine were only slightly elevated and should not have influenced theresults.In the present study, we used a cut-off point of 400 pg/mL for BNP as amarker of congestion, since this value was employed in previousstudies.Although there is a time difference between the change in ventricular fillingpressures and the corresponding change in BNP levels, this time lapse doesnot seem to have clinical significance. The half-life of BNP is short, about20 minutes, and, in addition, the treatment-induced decrease in pulmonarycapillary pressure leads to a rapid reduction in BNP levels (30 to 50pg/mL/hour).37 A recent studywith 50 patients utilized a very similar strategy to our study, comparing a CS,BNP and a hand carried ultrasound in estimating elevation of ventricular fillingpressures, but the gold standard in that study was right heartcatheterization.14 Asin ours, that study used a cut-off value for BNP > 400 pg/mL and for PCWP≥15 mm Hg as referencing parameters. The clinical symptom score had verylittle predictive utility for an elevated PCWP. Combining the information ofjugular venous pressure, BNP and ultrasound, the best diagnostic characteristicsfor predicting elevated LV filling pressure was achieved (AUC 0.98). In ourstudy, combining the findings of physical examination with chest radiography andBNP augmented progressively the sensitivity  fordetecting an elevated LAP, achieving a positive predictive value of 81%,although with a poor specificity. Still, combining these tools showed a modestpower in predicting high filling pressures (AUC: 0.62). Thus, ours and the studyby Goonewardena et al.14showed that clinical examination and BNP are not fully capable to preciselydetect elevated filling pressures, and echocardiographically-derived hemodynamicassessment can reliably be incorporated into clinical practice of ADHF, avoidingthe traditional invasive right heart catheterization method. The increasingutilization of hand carried ultrasound can be of great value in this area.In patients with intermediate BNP levels (100-500 pg/mL), adding the informationabout the presence of S3 increases the positive predictive value from 54% to80%.40We have used the echocardiogram as the gold-standard method for defining fillingpressures instead of right heart catheterization. Nonetheless, hemodynamicechocardiogram-derived parameters are well validated in the medical literaturewhen correlated with invasive measurements.We primarily use the lateral annulus to measure E/e' ratio. Although the mostrecent recommendations suggest using the mean of the lateral and septal annulusvalues, this was mainly validated in normal subjects. The most recent 2016guideline of the American Society of Echocardiography and the EuropeanAssociation of Cardiovascular Imaging recognizes that at times only the laterale’ or septal e’ velocity is available, and it is clinically valid.In addition, we did not follow patients during the hospitalization or in thepost-discharge period to observe whether the initial hemodynamic profile wascompatible with the clinical course.In this study, we showed that in ADHF patients, clinical assessment alone or inconjunction with chest radiography and BNP may lead to inaccurate estimation ofechocardiographically-derived hemodynamic profiling.


The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reducing risk of cardiovascular events (CVEs) and preserving kidney function in patients with chronic kidney disease is well-documented. However, the efficacy and safety of these agents in dialysis patients is still a controversial issue.We systematically searched MEDLINE, Embase, Cochrane Library and Wanfang for randomized trials. The relative risk (RR) reductions were calculated with a random-effects model. Major cardiovascular events, changes in GFR and drug-related adverse events were analyzed.2, 0.38 to 1.47 mL/min/1.73 m2) and urine volume . No difference in drug-related adverse events was observed in both treatment groups.Eleven trials included 1856 participants who were receiving dialysis therapy. Compared with placebo or other active agents groups, ARB therapy reduced the risk of heart failure events by 33%  with similar decrement in blood pressure in dialysis patients. Indirect comparison suggested that fewer cardiovascular events happened during treatment with ARB . The results indicated no significant differences between the two treatment regimens with regard to frequency of myocardial infarction , stroke , cardiovascular death  and all-cause mortality . Five studies reported the renoprotective effect and revealed that ACEI/ARB therapy significantly slowed the rate of decline in both residual renal function  contains supplementary material, which is available to authorized users. Cardiovascular events (CVEs) are the leading causes of death among dialysis patients, with mortality rates 7 to 30 times higher than in the general population , 2. ObseWe therefore undertook a meta-analysis to evaluate the effect of ACEIs and ARBs on cardiovascular events and residual renal function decline in patients receiving dialysis.Trials.gov website for randomized trials that were registered as completed but not yet published. All completed RCTs that assessed the effects of ACE-Is or ARBs compared with placebo or other antihypertensive drugs in dialysis patients, and which reported cardiovascular, renal or adverse outcomes, were eligible for inclusion.We undertook a systematic review of the literature according to the approach recommended by the statement for the conducting of meta-analysis of intervention studies . RelevanPublished reports were obtained for each eligible trial, and relevant information extracted into a spreadsheet. The data sought included dialysis modality, number of patients, country in which the study was performed, patient age, mean baseline systolic and diastolic blood pressure values, residual GFR, Kt/v, mean duration on dialysis, follow-up duration, change in blood pressure, outcome events . Major cardiovascular events were defined as a composite of fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, heart failure, or comparable definitions used by individual authors or cardiovascular mortality. Residual renal function was measured by GFR or endogenous creatinine clearance (CrCl), or urine volume, and drug-related adverse events if sufficient data were available. The literature were searched and identified by two investigators (LYX and MXX) independently. Data extraction and quality assessment   was unde2 to describe the percentage of variability. We made graphic representations of potential publication bias using Begg Funnel plots of the natural logarithm of the RR versus its standard error (SE) and assessed them visually. A 2-sided p value less than 0.05 was considered statistically significant, and statistical analyses were performed using STATA, version 12.0 and Review Manager 5.1.The relative risk (RR) and 95% confidence interval (CI) for each outcome was calculated before pooling by the random-effects model. For the continuous measurement of change of GFR, blood pressure and urine volume, we used the weighted mean difference between groups. Heterogeneity across the included studies was analyzed using the In = 397) compared ACE-Is with placebo [n = 82) [n = 352) compared ACE-Is with active control [n = 1025) compared ARBs with active control [Our literature search yielded 2502 relevant articles, of which 49 were reviewed in full text Fig. . A total[n = 82) , three s control , 18, 20, control –17, 19. The quality of the included studies was estimated using the Cochrane Collaboration tool for assessing the risk of bias; low versus high risk of bias is indicated for each study in Table p = 0.13; and MD 0.83 mmHg, 95% CI -0.68 to 2.35 mmHg; p = 0.28; for systolic and diastolic blood pressure, respectively).There was no significant difference in blood pressure over time between patients treated with ACEI/ARB and those treated with placebo or other antihypertensive drugs . Subgroup analysis indicated that the presence of heterogeneity was due to the different RASI category (ACEI or ARB), shown in Fig. 2 = 74.6%, p = 0.008, Fig. 2 while did not affect the association of ACEI/ARB with lower risk of heart failure events . There were no significant differences between ACEI/ARB and placebo or active agents therapy on the outcomes of myocardial infarction , stroke  and cardiovascular death   and 143 deaths of the 873 patients with placebo or active agents therapy (16.4%) .0% and 1–20. Overn = 82) conducted in hemodialysis patients and 4 in peritoneal dialysis patients (n = 170). The average residual GFR declined by 1.44 ml/min per 1.73 m2 in the ACEI/ARB group versus 2.37 ml/min per 1.73 m2 in the placebo or active control group. The average decline in residual GFR was 0.93 ml/min per 1.73 m2  less in patients receiving ACEI/ARB than in placebo or active control group patients (p < 0.001) with no evidence of heterogeneity   , which was displayed in Additional file Formal statistical testing showed no evidence of publication bias for major cardiovascular events Additional file 2: Figure S2.Change of urine volume in ACEI/ARB group versus placebo or other active agents group. (PPTX 70 kb)Additional file 3: Figure S3.Funnel plots with pseudo 95% confidence limits for CVEs among the included trials. (PPTX 48 kb)Additional file 4:Search strategy. (DOCX 18 kb)


Oleuropein, a polyphenolic compound enriched in olive oil and leaves of the olive tree, has attracted scientific attention in recent years because of a variety of reported health benefits. While the mechanisms by which oleuropein functions stigated , more stOleuropein is best known for its blood pressure-lowering effect. When administered via intraperitoneal or intravenous injections, oleuropein significantly reduces systolic and diastolic blood pressure in animal models. The ability of oleuropein to lower blood pressure may justify the traditional use of olive leaf in the treatment of mild to moderate hypertension. Our recent study provides significant insight into the mechanism whereby oleuropein reduces blood pressure. We find that oleuropein protects the hypothalamus from oxidative stress by improving mitochondrial function through activation of the Nrf2-mediated signaling pathway [Beyond hypertension, oleuropein has been shown to have cardioprotective, anti-inflammatory, antioxidant, anti-cancer, anti-angiogenic and neuroprotective functions, and thus may be of therapeutic potential for a variety of human disorders. Oleuropein reduces oxidative damage in the substantia nigra of aged rats, a region of the brain that is most affected by neurodegeneration in Parkinson's disease . OleuropDespite the many benefits of oleuropein, considerations about detrimental effects in certain individuals should not be neglected. Oleuropein may exacerbate low blood pressure in individuals who already have low blood pressure. Oleuropein could also interact with other pharmaceutical drugs that are designed to lower blood pressure or regulate diabetes. Patients should consult their physician before use and keep their physician informed of each medication being used in order to avoid additive or antagonistic drug interactions and side effects.The unexpected benefits and unique properties of oleuropein provide ample rationale for continued use and study of this key component of the Mediterranean diet to promote human health. Future studies are needed for a more comprehensive understanding of the cellular networks involved in the diverse protective effects of oleuropein.


In the development of new drugs for severe asthma, it is a challenge from an ethical point of view to randomize severe asthma patients to placebo, and to obtain long-term safety data due to discontinuations. The aim of this study was to evaluate the feasibility of using electronic health record (EHR) data to create a real-world reference population of uncontrolled asthmatic patients to supplement the concurrent control/placebo group in long-term studies of asthma.EHR data from 36 primary care centres and a University hospital in Sweden were linked to Swedish mandatory health registers (2005–2013), creating a population covering 33 890 asthma patients, including data on co-morbidities, risk factors and laboratory/respiratory measurements. A severe asthma EHR reference cohort was established. We used logistic regression to estimate the propensity score (probability) of each RCT or EHR patient existing in the EHR cohort given their covariates.2 versus 27.3 kg/m2; and consisted of 40% versus 34% males.We created an EHR-derived reference cohort of 240 patients, matching the placebo group (N = 151) in an RCT of severe asthma. The exacerbation rate during follow-up in the EHR study population was 1.24 (weighted) compared to 0.9 in the RCT placebo group. Patients in the EHR cohort were of similar age as in the RCT placebo group, 50.6 years versus 50.1 years; had slightly higher body mass index 27.0 kg/mThe results indicate that EHRs provide an opportunity to supplement the control group in RCTs of severe diseases. Asthma is a common but complex heterogeneous chronic inflammatory disease of the airways, which presents with variable symptoms of cough, breathlessness, and wheeze, with episodic acute worsening of symptoms known as exacerbations, particularly in severe asthma . The preThere is a broad spectrum of novel therapeutic agents currently under development for the treatment of severe asthma. Development of a new drug requires extensive documentation of effectiveness and safety, usually by comparison with a placebo control group in a RCT. When the indication involves severe asthma, it may be an ethical challenge to randomize patients to a long-term safety follow-up in a control group receiving placebo . DifficuIn parallel, clinical research is on the threshold of a new era in which electronic health records (EHR) are gaining an important novel supporting role . The traAnother common health data source for clinical research, especially in the US, is health insurance administrative data, or claims data. Claims data include diagnostic information, treatments given, and providers used, in addition to a variable number of financial measures . This maCurrently, we see an increasing pace of implementation of modern quality-controlled EHRs with growing evidence that EHRs can support clinical research including but certainly not limited to clinical trials for new medicines  . To furtThe aim of this propensity score weighted, retrospective, observational cohort study was to evaluate the feasibility of creating an EHR/registry-based reference cohort comparable to the placebo group of a previously completed randomized clinical trial (RCT) in severe asthma.This was a propensity score weighted, retrospective study where the placebo group population and its outcome in an RCT was compared to an observational cohort, linking data from national mandatory Swedish registries to primary care EHR data.The Swedish National Board of Health and Welfare performed data linkage and the Department of Medical Sciences, Respiratory Medicine at Uppsala University, Sweden managed the linked database.Thirty-six centres and one university hospital were included, with a catchment area covering 4% of the Swedish population. No stratification of primary healthcare centres was performed, but effort was made to reflect Swedish asthma healthcare by selection of centres that covered a representative sample of the Swedish asthma population, by a mix of rural and urban areas, public and private providers, and centre size . EHR datData were also extracted retrospectively from Swedish national registers, covering mandatory individual health data on a full population level. Data regarding morbidity and mortality were collected from the National Patient Register, including inpatient hospital care  and outpatient hospital care , and the Cause of Death register, including date and cause[s] of death, respectively. Data on drug prescriptions from hospital and primary care were collected from the Swedish Prescribed Drug Register. We were able to follow patients for up to nine years (2005-2013). The regional ethics committee in Uppsala, Sweden approved the study protocol.n = 33890) and sent it to the Swedish National Board of Health and Welfare, which linked this database to the pre-defined national registers   (mean with 95% CI) at visit 13 at 52 weeks. Only 74 EHR patients had spirometry performed during the 1-year post-index period. The average FEV1 for these patients was 78.2  (mean with 95%CI). The corresponding weighted average with 95% CI was 68.0  which again is much closer to what is observed in the placebo group of the RCT.The patients in the RCT had spirometry performed at each visit. The average FEV1 was observed under controlled conditions at scheduled visits leading to a large number of repeated observations per patient. In the EHR population FEV1 was observed as part of routine spirometry as needed by the treating physician and hence not all patients in the EHR population have any observations on FEV1 during the 12-months post index period and those who do have one or perhaps two observations  which has reasonable similarity to an RCT placebo group (N = 151) in severe asthma. This was accomplished both by finding an adequate number of patients and by creating high data quality . We used asthma exacerbation frequency, which also was the primary outcome in the RCT study, as a key indicator to evaluate the comparability achieved between the RCT and EHR placebo groups.In the present retrospective, observational cohort study based on a population of 33 890 asthma patients, with up to nine years of follow-up in Sweden, we showed that it is technically feasible to create a reference cohort  based on a study protocol. There can be substantial differences in the timing of assessments, as well as in the actual measurements used. Furthermore, patients participating in a RCT are not in fact as assumed by our method a true random sample from the population found in an EHR source. While between subject differences in sampling probability due to observed variables might be adjusted for, as was done in this analysis, there can easily be differences due to unobserved variables. Having access to detailed information on diseases and medications pre index from the trial for the RCT patients and from in-hospital and pharmacy claims registries will increase the likelihood of successfully adjusting for differences in selection probabilities related to disease severity and co existing conditions. Other factors such socioeconomic factors are much harder to account for. While there are registries containing socioeconomic data such as income, education and ethnicity in terms of country of origin available in some countries  these data would rarely be available for the patients in the RCT even if the study was done in such a country, mainly depending on the strict rules of data integrity surrounding an RCT.1 in the EHR cohort may differ from those obtained in the RCT in timing and frequency. Exacerbations are partly defined by use of OCS, and the distinction between continuous use and acute use may not be completely clear in registry data while it is unambiguously recorded in the case report form for an RCT.Lastly, the way that outcome measures are observed needs to be consistent for the EHR and RCT populations. There are commonly accepted standards for performing spirometry, but this test is performed less consistently in regular practice than in an RCT. Consequently, observations on FEVQuestionnaire approaches to assessing patient reported outcomes are commonly used in RCTs but infrequently are included in EHRs. Issues like these might lead to systematic differences in the observed outcome that are impossible to statistically account for and for future studies hard clinical endpoints such as death of other well defined events may be better choice if relevant.1, were captured for a sufficiently large number of patients, similar to the RCT sample size. However, some laboratory variables were sparsely collected in the EHR population and there were difficulties in finding relevant observations on some of the laboratory variables key to the RCT, such as neutrophils and eosinophils. This mainly reflects that these variables only rarely are used in general clinical practice. Further details of captured data variables in the EHR reference cohort can be found in The use of actual EHR data linked to various sources, prescription data and laboratory data including spirometry data, presents a unique opportunity to create a dataset that is sufficiently rich to address the difficulties mentioned above. Both of the two most important confounders, the number of exacerbations during the 12 months preceding the index date and the pre index FEVThere are several important assumptions that underpin the analysis. Firstly, the inclusion and exclusion criteria need to be equivalent. In the RCT placebo cohort, we had the opportunity to assess pre-randomization variables according to a specific protocol. In the EHR cohort, the corresponding criteria had to be operationalized based on routinely available observations recorded in the EHR. Therefore, the inclusion criteria may not be equivalent, which may lead to systematic differences in the RCT and EHR population.no unobserved” confounders commonly used in epidemiology. Although capturing data on the most obvious confounding variables, such as the number of pre-index exacerbations, pre index GINA classification and spirometry, we cannot be certain that there are no unobserved confounders. The analysis technique used here is also not able to adjust for the notion of a placebo effect arising from the very participation in an RCT.Secondly, we assumed that the RCT study population was a random sample conditional on the patient characteristics used to estimate the weights that we used to create the EHR reference. This is equivalent to the assumption of “Furthermore, we must assume that the outcome measure is recorded in the same way in the RCT and EHR population. Exacerbations are partly defined as increased acute use of OCS, which is difficult to distinguish from continuous use based on the drug dispense registry. Lastly, the results for the RCT placebo cohort used in this study were taken from a large multicentre trial with patients from 16 countries not including Sweden. The EHR data used comes from primary care centres in Sweden. Asthma care in most countries generally follows international guidelines  but asthAnother potential limitation when using EHR data for creating a reference group is the risk of overestimating the treatment effect. This is due to the fact that in RCTs there is often an improvement in the control groups because the patients have improved asthma care due to regular visits. Thus the effect in the treatment group is combination of the improved asthma care and the drug treatment. This limitation is supported by the fact that the prevalence of exacerbations was higher in the EHR groups than the RCT control group.This study demonstrates the feasibility of capturing high quality health data in EHRs and offers the possibility of creating a real-world reference population of uncontrolled severe asthma patients to supplement or even potentially replace the control/placebo group in long-term studies. Results provide evidence for the value of EHR data to improve the design and interpretation of clinical trials. Moreover, our results support the opportunities to conduct registry-based trials or so-called mixed trials where a placebo cohort can prospectively go alongside a RCT study especially in disease areas where it is problematic to assign patients to placebo treatment. For instance long term extension studies are presently often uncontrolled one-armed designs without an internal reference. One concern with this study design is unanticipated adverse events. Adding an external reference cohort based on registry data using the technique presented in this paper may aid the interpretation of such a finding in this type of study. Further research should validate the methodology within other disease areas. For the future, the PACEHR approach would render important value like for example long term safety study for asthma in which the patient is receiving a biologic agent in development, a control group is simply not be feasible, or for other diseases like atopic dermatitis. For both these cases, among others, identifying an appropriate control group from EHRs to be followed prospectively would be perfectly suitable and helpful.This study demonstrate that an adequate large number of severe uncontrolled asthma patients, comparable to the placebo group in a RCT, can be found in Swedish EHRs based on pre-defined criteria for uncontrolled asthma. Causal inference methodology based on propensity score analysis and weighting methods adjusted for differences in observed confounders, and can provide a useful tool to aid the interpretation of RCTs. The results indicate that EHRs provide an opportunity to supplement, the control group in RCTs of severe diseases.


The variability of visit-to-visit (VVV) in systolic blood pressure (SBP) and diastolic blood pressure (DBP) is proved as a predictor of renal function deterioration in patients with non-diabetic chronic kidney disease. The purpose of this study was to investigate the relationship of the variability in SBP and the magnitude of renal function impairment for normal renal function patients in the first 10-years diagnosed with type II diabetes mellitus (DM).We retrospectively reviewed the electronic medical records of 789 patients who were first diagnosed with diabetes mellitus during 2000–2002 and regularly followed for 10 years with a total of 53,284 clinic visits. The stages of Chronic Kidney Disease (CKD) of every patient were determined using estimated glomerular filtration rate. The occurrence of nephropathy was defined in those patients whose CKD stages elevated equal or larger than three.p < 0.001) increased risk of renal function impairment compared with patients with low VVV of both SBP and DBP. Risk of renal function impairment for patients with high VVV of either SBP or DBP had a 1.43-fold increase  compared with patients with low VVV of both SBP and DBP. Cox regression analysis also demonstrated that every 1-year increase of DM diagnosed age significantly raised the risk of renal function impairment with a hazard ration of 1.05 .Patients were categorized according to the VVV of systolic and diastolic BP into three groups. Patients with high VVV of both SBP and DBP had a 2.44 fold (95% CI: 1.88–3.17, Not only VVV of SBP but also VVV in DBP is correlated with diabetic nephropathy in the first decade for patients diagnosed with type 2 DM. Diabetes mellitus (DM) is the primary cause of end stage renal disease . In adulIn diabetic patients with CKD, the decline of the glomerular filtration rate (GFR) is highly variable, ranging from 2 to 20 mL/min/year . The risRecently, the visit-to-visit variability (VVV) of systolic BP (SBP) has been shown to be a novel risk factor for development of renal function decline in non-diabetic CKD , progresWe retrospectively collect the 10-year measurements of blood pressure, body weight, body height, and laboratory datas at every outpatient clinic visit of 789 patients who were first diagnosed with type 2 DM during 2000–2002 at Chang Gung Memorial Hospital, Keelung. Type 2 DM was diagnosed in accordance with the criteria of American Diabetes Association . Body ma1c was assayed using high-performance liquid chromatography and expressed with the unit defined by the National Glycohemoglobin Standardization Program.We then evaluated relationships of variability in blood pressure to change of CKD stage during the 10-year follow-up period. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Chang Gung Memorial Hospital; informed consent was waived. Blood pressure measurements at every outpatient clinic visit throughout the follow-up period were recorded. Fasting serum total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglyceride concentrations were assessed using standard enzymatic methods. Hemoglobin AThroughout the 10-year consecutive visits from the beginning of the observation period, the mean office BP and the VVV of SBP and DBP  were calculated. The BP instability indice was expressed as the delta BP, which was defined as a difference between the maximum and the minimum BP, through all 10-year visits .2 or commencement of dialysis therapy, respectively. Renal function impairment was defined as two or more CKD stages  deterioration without recovery.Serial serum creatinine data were collected and eGFR was determined by the abbreviated CKD Epidemiology Collaboration equation . CKD wasP value <0.05 was considered statistically significant. The area under each receiver operating curve (ROC) and 95% confidence intervals (CI) were estimated to compare the relative ability of SD of SBP and DBP to identify risk of renal function impairment in diabetic patients. Optimal cut-off points for SD of SBP and DBP indicator were determined [Means and frequencies of potential confounding variables were calculated. The relationships between variability in SBP and DBP, as well as other variables, and renal function impairment were examined by Pearson’s correlation analyses. To examine the effects of various factors on the deterioration of renal function, the following factors were considered simultaneously as independent variables for Cox multiple regression analysis: age of DM diagnosed, sex, BMI, average SBP and DBP, SD of SBP and DBP, hemoglobin A1c, total cholesterol, triglyceride, smoking status, presence of CVD, hypertension and dyslipidemia. All continuous variables are presented as the mean ± SD or absolute number. A termined . The coltermined .1c, lipid profile, and serum creatinine throughout 10- year of data collection was 49739, 35432, 27424, 9327, and 14123, respectively. The characteristics of the study patients were shown in Table Eight hundred and twenty-five patients were first diagnosed with DM from 2000 to 2002. Thirty-six patients who were died or loss of follow-up were excluded. None of these patients died from renal failure. The characteristics of the 789 patients, who were first diagnosed with DM from 2000 to 2002 and followed for 10 years, enrolled in this study are shown in Table P < 0.001, Hazard ratio (HR) = 1.063, 95% CI = 1.028–1.100), as well as the SD of DBP . The age of DM first diagnosed had also positively correlated with the occurrence of renal function impairment after 10-year follow-up . Our results found that maximum, minimum or delta of SBP and DBP had no significant independent correlations between renal function impairment after 10-year of DM diagnosed. And multiple regression analysis demonstrated that other factors, such as mean or SD of hemoglobin A1c, BMI, total cholesterol, low-density lipoprotein, high-density lipoprotein, triglyceride, were not independently correlated with the occurrence of renal function impairment, as shown in Table Cox regression analyses revealed that the SD of SBP was positively correlated with the occurrence of renal function impairment  and DBP (0.85 ± 0.03) and categorized patients into high or low SD of SBP or DBP. The best cut-point BP was calculated based on the Youden Index , which wp < 0.001, 95% CI = 2.128–3.612) compared that of patients with low VVV of both SBP and DBP. Whereas the risk of renal function impairment in patients with wither high VVV of SBP or DBP increased 1.587 fold  compared that of patients with low VVV of both SBP and DBP. The renal function intact survival curve for these three groups of patients was shown in Fig. After 10 years of DM diagnosis, the patients with high VVV of both SBP and DBP had the highest percentage of peripheral artery disease, cerebrovascular disease, coronary artery disease or myocardial infarction, transient ischemic attack or stroke, and the highest percentage of patients with renal function impairment, which all were significantly different among these three groups. Cox multivariate regression revealed that only the age of DM diagnosed and the group of VVV of SBP and DBP were significant risk factors for development of renal function impairment after 10-year follow-up, as shown in Table 1c concentration, and SD of hemoglobin A1c concentration were not correlated with the occurrence of renal function impairment. To the best of our knowledge, this is the first study to explore the association of the VVV of SBP and DBP and renal function decline in the first decade of patients with DM.This study showed that VVV of both SBP and DBP were significantly associated with the change to CKD stage in the first decade of patients diagnosed with DM, whereas mean office SBP/DBP, delta SBP/DBP, mean serum lipid profile, mean hemoglobin AIn the present study, not only the VVV of SBP was significantly associated with the change of CKD stage, but the VVV of DBP was also significantly associated with the occurrence of renal function impairment in our study patients group. For the first time, our result demonstrated that a VVV of SBP higher than 16.3 mmHg or a VVV of DBP higher than 7.6 mmHg would significantly increase the risk of decline of renal function in the first decade of patients diagnosed with DM. Furthermore, with both high VVV of SBP and DBP would even increase the risk of renal function impairment to 2.773 fold compared with those patients with both low VVV of SBP and DBP.Our results are in accordance with other study findings, which showed a significant association between VVV of BP and progression of nondiabetic CKD , 9. HoweMany studies proved that an increase in VVV of SBP was one of the factors which may contribute to the progression of renal function deterioration , 10. ManThe retrospective nature of the present study and the sample size are two of the limitations of the present study. The possibility of type 2 error existed. Other limitations are the standardized procedure of blood pressure measurement and the medication prescription record through 10-year follow-up period. Certain classes of antihypertensive regimens, such as non-β-blocker-based and non-rennin-angiotensin system-based  or calciNevertheless, this study has several strengths including the one-decade follow-up of patients initially diagnosed with DM with CKD and available information on demographic, clinical, and long-term BP data. In addition, the use of the electronic medical record database provided real-world evidence on the status of hypertension control in the first decade renal function prognosis of diabetic patients and minimizes selection bias related to self selection into the study. Our results prove that VVV of SBP and DBP has significant prognostic value. However, prospective investigations in stabilization of VVV of SBP and DBP are in need to identify the optimal therapeutic strategies and potentially modify the clinical practice in hypertensive patients with type II DM.In conclusion, the present study showed, in patients with intact renal function, significant association between high VVV of SBP and DBP with renal function decline in the first decade of DM diagnosed.


The Nihon Kohden linear inflationary non-invasive blood pressure (iNIBP) monitoring technology is an oscillometric device that measures blood pressure by detecting oscillations during inflation. Systolic blood pressure can be recorded without overinflating the cuff higher than the true systolic pressure. Thus, total time taken for inflation and deflation is shorter than that by the conventional deflation devices. In this study, the ability of iNIBP to detect maternal hypotension during cesarean section faster than deflationary non-invasive blood pressure (dNIBP) monitoring devices under clinical settings was evaluated prospectively.Z test was performed to statistically analyze the difference between iNIBP and dNIBP measurement results.A prospective study of singleton planned cesarean sections at a tertiary center was conducted from August 2015 to April 2016. The combined spinal-epidural anesthesia (CSEA) technique through a single puncture was performed for cesarean section at the center where the study was carried out. An iNIBP cuff was placed on the same arm as the intravenous line, and a dNIBP cuff was placed on the other arm. Due to left uterine displacement by approximately 10° tilt of OR table, hypotension in this study was defined as systolic pressure of 107 mmHg or less, when measured in the left arm, which was about 10 cm lower, and pressure of 92 mmHg or less in the right arm which was about 10 cm higher. This setup was done to evaluate which device detected hypotension faster under clinical settings. A two-tailed One hundred singleton planned cesarean deliveries under CSEA were included after 36 weeks of gestation. Out of the 100, 76 women (76%) experienced maternal hypotension. Of these, iNIBP detected hypotension faster than dNIBP in 47 cases (61.8%).It was found that iNIBP detected hypotension faster than conventional dNIBP without compromising the reliability of measurement. This may lead to early treatment of maternal hypotension and prevention of adverse events related to the mother and the fetus. Nowadays, spinal anesthesia is the first choice for anesthesia during cesarean sections. Pregnant women tend to experience a drop in blood pressure because of supine hypotensive syndrome and decreased peripheral vascular resistance. Maternal hypotension is an adverse event for the mother and the fetus and can cause fetal bradycardia . TherefoThe Nihon Kohden linear inflationary non-invasive blood pressure (iNIBP®) measurement technology is an oscillometric device used to measure blood pressure by detecting oscillations during inflation. We can read systolic blood pressures without the need to overinflate the cuff higher than the true systolic pressure. Thus, the total time taken for inflation and deflation is shorter than that taken by conventional deflationary devices.In this study, we prospectively evaluated whether iNIBP can detect maternal hypotension during spinal anesthesia earlier than deflationary non-invasive blood pressure (dNIBP) in clinical settings in which noise and vibration could lead to inaccurate measurement, requiring re-measurement of blood pressure.Approval of the Institutional Review Broad and written informed consent from the patients were obtained for this study. We conducted a prospective study of singleton planned cesarean sections at a tertiary center from August 2015 to April 2016 (UMIN000027385).At our center, the combined spinal-epidural anesthesia (CSEA) technique is performed for cesarean sections. The L3-4 interspace was selected. The CSEA was initiated with 0.5% hyperbaric bupivacaine (8 mg) and fentanyl (20 μg) via a 27-gauge spinal needle placed via a 16-gauge Tuohy needle, and the epidural catheter was inserted.The iNIBP® cuff was wrapped around the arm with an established intravenous line, and the dNIBP cuff was wrapped around the other arm Fig. . Blood pZ test was performed to statistically analyze the differences between the iNIBP and dNIBP measurements.A two-sided We included 100 singleton planned cesarean deliveries under spinal CSEA, after 36 weeks of gestation.The demographic and clinical characteristics of the cases are described in Table p = 0.03).Out of the 100, 76 women (76%) experienced maternal hypotension, as measured by iNIBP or dNIBP. Of these, iNIBP detected hypotension faster than dNIBP in 47 cases (61.8%) and dNIBP detected faster than iNIBP in 29 cases (38.2%). This comparison is shown in Table We conducted the prospective study to evaluate which method between iNIBP and dNIBP could detect the post-spinal maternal hypotension during cesarean section faster. It was found that iNIBP could detect maternal hypotension faster even under clinical settings, in which noise and vibration could lead to inaccurate measurement and require re-measurement of blood pressure.The spinal anesthesia for cesarean section is likely to cause maternal hypotension because of the spine hypotensive syndrome and decreased peripheral vascular resistance. Hypotension during cesarean section is defined as systolic blood pressure ≤ 100 mmHg or ≤ 20% below the baseline blood pressure .The conventional non-invasive blood pressure monitoring devices are designed to detect oscillations during deflation. Therefore, they require elevation of the cuff pressure higher than the true systolic pressure. This excessive cuff pressure may cause adverse events such as pain, venous stasis, thrombophlebitis, peripheral neuropathy, and compartment syndrome , 5. MeanFurthermore, previous studies suggested that the hemodynamic changes caused by pregnancy and pre-eclampsia may attribute to inaccuracy of the devices. Immediate detection of the oscillations during inflation may provide accurate measurements without transmission of the pressure wave. Therefore, inflationary oscillometry may be more accurate than deflationary oscillometry and mercury sphygmomanometry in pregnancy and pre-eclampsia cases , 8.A limitation of this study is its small sample size. Further research is required to have a clear understanding of the advantages of iNIBP for cesarean section cases. A further limitation was that blood pressure was measured not every minute but 2 min. The BP measurement every minute until delivery of the baby is recommended.Through this study, we conclude that iNIBP detects hypotension faster than conventional dNIBP, without compromising the reliability of measurement. This may lead to early treatment of maternal hypotension and prevention of maternal and fetal adverse events.


Hypertension is a widespread chronic condition which is usually treated with hypertensive drugs. However, 50% of hypertensive patients do not achieve control of their blood pressure below the standard target of 140/90 mmHg when treated with a single antihypertensive drug. Generally, hypertension specialists have a key role in managing hypertensive patients.® . Twenty-four hour blood pressure profiles were monitored a fortnight and six months later.A retrospective case note review based on observations made in a cardiological outpatient clinic in Germany was carried out to assess whether the recommendation given by hypertension specialists were followed. The aim was to lower the blood pressure to < 130/85 mmHg over a period of six months by administering the new antihypertensive drug Zaneril® therapy six months later. Eighty-four patients (65%) did not turn up for follow-up examinations. The blood pressure of patients who were under Zaneril® therapy for the whole six months was better adjusted than that of patients who changed their treatment in the meantime (133/78 mmHg vs. 139/80 mmHg).Of the 130 patients, whose average blood pressure was 163/87 mmHg before receiving hypertensive treatment, only 44 (34%) were still on ZanerilSpecialists have only little influence on the long-term therapy of hypertensive patients. High blood pressure or hypertension is a chronic condition affecting about one billion people worldwide . It contOver the past years, extensive guidelines have been developed for therapy of arterial hypertension , 4. In t® which combines lercanidipine  and enalapril (angiotensin converting enzyme (ACE) inhibitor). Patients with signs of decompensation, unstable angina pectoris or rhythmological problems were not included in the study. As to the costs, Zaneril® is about half as expensive as established antihypertensive angiotensin-blocking drug/diuretic combinations. The administered dose was 1 tablet per day of Zaneril® 10/10 or 20/10. The aim was to lower the blood pressure to < 130/85 mmHg over a period of six months. To determine the efficacy of the treatment, 24-h blood pressure profiles were monitored a fortnight later. On this occasion, the therapy was adapted if necessary. Six months later, 24-h blood pressure profiles were checked again.The outline of this retrospective case note review is shown in ®, their mean 24-h blood pressure was reduced to 134/78 mmHg. The therapy of most of the remaining 70 patients was changed to other antihypertensive drugs by their GPs (see below). The main reason for the change was adverse reactions to Zaneril®. However, some patients could not state any reason why their GP changed their medication. For the six month follow-up examination, only 46 patients turned up  was 29.8 ± 13.1. Twenty-five patients were diabetics. The average blood pressure before introduction of antihypertensive drug therapy was 163/87 mmHg. Of the 130 patients, only 60 turned up for the two week follow-up examination . Under turned up . Of thes® while 30 patients took other antihypertensive drugs. Eight patients did not take any medication anymore. Fifteen patients provided information about their blood pressure which was on average 137/77 mmHg. No difference was observed between patients taking Zaneril® and patients taking other antihypertensive drugs. Only one patient had a blood pressure below the target of 130/85 mmHg  achieved in free combination of beta blocker and ACE inhibitor (metoprolol/lisinopril).Of the patients who failed to turn up for the follow-up examinations, 59 were contactable by telephone. Twenty-one patients were still under Zaneril® therapy for the whole six months was better adjusted compared to those patients whose therapy was changed in the meantime. Although the difference in blood pressure between the two groups of patients was only 6/2 mmHg, 2 mmHg reduction in diastolic blood pressure is associated with a reduction in the rate of stroke (40%) and myocardial infarction (25%) in high risk patients [t-test and Mann-Whitney test, no statistical significance was found between the two groups of patients regarding systolic blood pressure, diastolic blood pressure and blood pressure amplitude. This may be due to the small sample size (only those patients were included in the statistics who turned up for the follow-up examinations) and that the data were not normally distributed.The blood pressure of those patients who were under Zaneril®. However, in all cases the attending GP did not consult the cardiologist to discuss the discontinuation of the Zaneril® therapy. Possible reasons are actual adverse reactions, lack of knowledge of the guidelines and fears about the available medication budget (note that the medication budget of GPs in Germany is capped). As demonstrated here, the cardiologist has only little influence on the long-term therapy of hypertensive patients; only 34% (44 out of 130) of the patients originally put on Zaneril® were still under this guideline-recommended drug regime six months later. The therapy of almost half of the patients was changed to single agent although the initial blood pressure values suggested that combination therapy was required. Also the high proportion of patients who were treated with beta blockers despite having diabetes or a high BMI raises the question of possible long-term complications of the monotherapy. Recent studies have shown that an effective collaboration between professionals would achieve significant better mean and overall blood pressure control rates [As already mentioned above, the main reason for therapy change was adverse reactions to the new antihypertensive drug Zanerilol rates -10. In a