Cardiac syndrome X is an important therapeutic and diagnostic challenge to physician. Study of Csx patients may help to understand the pathophysiology of coronary microcirculation and to gain an insight on the management of these group patients.We measured the flow mediated dilation of the brachial artery both endothelium dependent and independent vasodilatation by high resolution ultrasound in 30 cardiac syndrome X patients and matched with 30 healthy control subjects.Significantly decreased flow mediated dilatation was observed in patients when compared to control (9.42 ± 7.20 vs 21.11 ± 9.16 p < 0.01) but no significant difference was observed between groups in response to nitroglycerin (25.39 ± 6.82 vs 28.87 ± 8.69). Receiver operator characteristic analysis showed that value of < 11.11 had sensitivity of 80%, specificity 86.67%, positive predictive value 76.66%, negative predictive value 83.33%. In total, 46% of subjects had endothelial dysfunction and of them, CSX subjects had higher prevalence (76% vs 16% p < 0.01) than control subjects. Higher mean values of body mass index, systolic blood pressure and diastolic blood pressure was observed in subjects with FMD < 11.11 than > 11.11(p < 0.01). In logistic regression analysis, FMD was significantly associated with systolic blood pressure (Odds ratio 1.122 95% CI 1.053-1.196 p < 0.01) and body mass index (Odds 1.248 95%CI 0.995-1.56 p < 0.05).The study suggests impairment of endothelial function in cardiac syndrome X patients. Increased Systolic blood pressure and body mass index may increase the risk of impairment of endothelial function in this group of patients. Cardiac syndrome X (Csx) is defined by the presence of angina-like chest pain, a positive response to stress testing and angiographically normal coronary arteries  Csx reprIn the absence of established mechanism, multiple pathogenic mechanisms have been proposed for Csx includes: abnormal coronary flow reserve, insulin resistance, abnormal autonomic control, enhanced sodium-hydrogen exchange activity, abnormal cardiac sensitivity, microvascular spasm, extracardiac causes, psychological abnormalities, myocardial ischemia and abnormal pain perception ,7. EvaluIn this study, 30 patients with history of angina like chest pain, reported positive on tread mill test and with normal coronaries on coronary angiography, were diagnosed as Csx patients. Thirty age matched subjects, who were diagnosed healthy based on ECG and echocardiogram were treated as control. Informed consent was obtained from each of the patients and health controls following ethical guidelines of the 1975 Declaration of Helsinki. This study was approved by Institutional Ethics Committee of Sri Venkateswara Institute of Medical Sciences, Tirupti, Andhra Pradesh, India. The age of both groups of subjects ranged from 40-60 years. There were 20 male and 10 female in CSx; and 17 male and 13 female subjects in control group. Details of age, history of hypertension, ischemic heart disease, type 2 diabetes and smoking were enquired. Subjects were examined clinically for pulse, blood pressure, respiratory, cardiovascular and central nervous system followed by ECG and Echocardiogram evaluation. Height and weight were measured. Body mass index was calculated.Blood samples were drawn after 12 hr fasting. The samples were assayed for glucose, total cholesterol, triglyceride, HDL cholesterol, blood urea and creatinine. LDL cholesterol was calculated as per Fridewald et al . EndotheThe subjects were asked to lie quietly for at least 10 min before the first scan. The brachial artery was scanned in longitudinal section 2 cm above the elbow, and the center of the artery was identified when the clearest picture of the anterior and posterior intimal layers were obtained. The transmit zone was set to the depth of the near wall, because of the greater difficulty in evaluating the "M" line (the interface between the media and adventia) of the near wall as compared with that of the far wall. Depth and gain settings were set to optimize images of interface between the lumen and the arterial wall, and the obtained images were magnified. Settings for operating the machine were not changed during the study.When a satisfactory transducer position was found, the skin was marked and the arm was kept in the same position throughout the study. A resting scan was obtained. The arterial diameter was measured. Increased flow was induced by the inflation of a sphygmomanometer cuff placed around the forearm  at a pressure of 200 mmHg for 4.5 min, followed by release. A second scan was performed 90 s after deflation of the cuff. The diameter of the artery was measured at the peak of R wave (corresponding to end diastole). Flow-mediated dilation was calculated. Average of three observations was recorded. Flow-mediated dilatation was presented as the percent change from baseline to hyperemia. Fifteen minutes were allowed for vessel recovery and then a further resting scan was taken. After that sublingual glyceryl trinitrate (GTN-200 mics/puff) was administered and ten minutes later, the last scan was done. ECG was monitored through the scans and the artery diameter was measured at the peak of R wave (corresponding to end diastole). An average of 3 values was taken for each measurement. FMD (flow mediated vasodilatation) and NMD (nitrate mediated vasodilatation) in syndrome X was compared with the data of healthy control subjects. FMD was calculated using the formula FMD = (d2-d1) × 100/d1. Where d1 is the brachial artery diameter at baseline, d2 is brachial artery diameter after 90 seconds of cuff release. Changes in the diameter after both interventions i.e. after stress and GTN, was expressed as percentage change from the pre-treatment value.Means were compared with student 't" test and categorical variables with chi-square. Logistic regression was done to find the relation between dependent and independent variables. FMD Cutt-off values were determined using receiver operator curve analysis.Higher mean systolic, diastolic blood pressure and lower glucose and % FMD were observed in Csx patients when compared to the control subjects p < 0.01). Lower mean % of FMD was observed in male than female subjects (12.35 ± 7.73 vs. 19.96 ± 11.71p < 0.01). Lower mean % of FMD with increasing BMI was observed in both cases and control  subjects  table .To determine the sensitivity and specificity of FMD cut-off value in this population, we have performed receiver operator characteristic analysis (ROC). In ROC analysis Figure , we haveIn subjects with CSX, 77% had endothelial dysfunction as indicated by FMD < 11.1 as against 17% in control group (p < 0.01). When assessed in logistic regression analysis, FMD was significantly associated with Csx (Odds ratio 16.42 95% CI 4.569-59.07 p < 0.001).A logistic regression analysis was done to find out the factors contributing to the microvascular dysfunction in Csx and found that systolic blood pressure (Odds ratio 1.122 95% CI 1.053-1.196 p < 0.01) and body mass index (Odds 1.248 95%CI 0.995-1.56 p < 0.05) were significantly associated.Endothelium is the monolayer of endothelilal cells lining the lumen of blood vessels . It mainNon-invasive ultrasound test is based on the measurement of changes in brachial artery diameter in response to reactive hyperemia and is considered as a gold standard for clinical studies on conduit artery endothelial biology . It is rSeveral studies have observed lower flow mediated dilation in CSX patients when compared to healthy controls -26 but fElevated levels of total cholesterol, LDL cholesterol, apolipoprotein B100, Lp(a), aortic and fractional pulse, platelet volume, nocturnal melatonin levels, CRP, reactive oxygen species and hydroperoxides and decreased oestrogen were observed in CSX patients ,24,28-32An area under curve for cut-off value of 11.1 showed a value of 0.874 indicating that ultrasound is useful tool for identifying endothelial impairment in Csx patients and able to predict the impairment in 86% of subjects as shown by specificity of the cut-off value. This cut-off value is observed in a cross-sectional study and has to be established in longitudinal study involving larger sample size. To the best of our knowledge, no study in India reported cutt-off value for flow mediated dilation in Csx patients and this study attempts to propose the cut-off value for flow-mediated dilatation in Indian population. We have assessed the endothelial function manually using hand held probe and this is the limitation of the study.In the present study, higher mean body mass index, systolic and diastolic blood pressure in FMD < 11.11 than FMD > 11.11 group (p < 0.01) was observed. Systolic blood pressure and body mass index significantly associated with impairment of endothelial function. A 5.77 fold increase in the incidence of hypertension in the lowest than highest FMD quartile was observed over a follow up of 3.5 years in risk factor free post menopausal women . A speciLower FMD was observed with increase in BMI ,37. NuclThe results of the present study showed higher prevalence of microvascular dysfunction (78%) in the CSx patients when compared to the control subjects and suggest that early detection and management of systolic blood pressure and encouraging weight loss may be helpful in the management of CSX.The authors declare that they have no competing interests.DR designed and interpreted the study; AKN acquired and interpreted the data; SAAL statistical analysis, interpretation and drafted the manuscript. All authors read and approved the final manuscript.


Introduction. Intradialytic hypotension (IDH) is a common complication during hemodialysis which may increase mortality risks. Low dose of Korean red ginseng (KRG) has been reported to increase blood pressure. Whether KRG can improve hemodynamic stability during hemodialysis has not been examined. Methods. The 8-week study consisted of two phases: observation phase and active treatment phase. According to prehemodialysis blood pressure (BP), 38 patients with IDH were divided into group A  and group B . Patients were instructed to chew 3.5 gm KRG slices at each hemodialysis session during the 4-week treatment phase. Blood pressure changes, number of sessions disturbed by symptomatic IDH, plasma levels of vasoconstrictors, blood biochemistry, and adverse effects were recorded. Results. KRG significantly reduced the degree of blood pressure drop during hemodialysis (P < 0.05) and the frequency of symptomatic IDH (P < 0.05). More activation of vasoconstrictors (endothelin-1 and angiotensin II) during hemodialysis was found. The postdialytic levels of endothelin-1 and angiotensin II increased significantly (P < 0.01). Conclusion. Chewing KRG renders IDH patients better resistance to acute BP reduction during hemodialysis via activation of vasoconstrictors. Our results suggest that KRG could be an adjuvant treatment for IDH. Intradialytic hypotension (IDH) is a common complication which occurs in 20–30% of all dialysis treatments . It has The mechanism responsible for IDH is an inappropriate response of cardiovascular and neurohormonal systems to the acute plasma volume removal during dialysis –5. HemodPanax ginseng, a naturally occurring compound that has been used for several thousand years in the orient [Panax ginseng have confirmed its effect on regulating blood pressure [Panax ginseng at low-doses can elevate blood pressure, while high-dose Panax ginseng has hypotensive effect in healthy subjects [Panax ginseng in patients with IDH has not been examined.e orient , is one e orient . Previoupressure . Interessubjects –19. HowePanax ginseng with preserved major constituents, has been shown to possess more biological activity than Panax ginseng [Korean red ginseng (KRG), a steamed form of  ginseng –22. Here The study was conducted at the hemodialysis center in Taoyuan Chang Gung Memorial Hospital (TCGMH), Taiwan. The study was approved by Chang Gung Memorial Hospital Ethical Review Committees. Each patient signed informed consent before enrollment. Patients aged from 20- to 80-year-old on thrice-weekly hemodialysis, with a treatment time of at least 180 minutes, and had at least three symptomatic episodes of IDH in the 30 days preceding enrollment, were enrolled in the study. IDH was defined as a decrease in systolic blood pressure (≥20 mmHg) or a decrease in mean arterial pressure (≥10 mmHg) accompanied by symptoms , according to Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients . The excThe prospective study was designed to evaluate the pre- and posttreatment differences, and each patient served as his/her own control. The 8-week study consisted of two phases: an observation phase (phase I) and an active treatment phase (phase II). Each phase was composed of twelve consecutive HD treatments (4 weeks). Patients were given standard treatment for IDH during phase I. These enrolled patients were divided into two groups according to their prehemodialysis blood pressure. Patients with average prehemodialysis blood pressure more than 140 mmHg systolic or 90 mmHg diastolic during phase I were clustered to group A, while patients with normal or low prehemodialysis blood pressure to group B.During the active treatment phase (phase II), patients were instructed to chew 3.5 gm KRG slices at each hemodialysis session. Each slice of KRG was put into the mouth until melted, then chewed and swallowed. Patients in group A (hypertensive at baseline) were given KRG slices 60 minutes after the onset of hemodialysis to prevent late onset of hypotension after ultrafiltration. In contrast, patients in group B (normotensive or hypotensive at baseline) were given KRG slices 30 minutes before hemodialysis to prevent early onset of hypotension . Cheong-Arterial blood pressure was measured with an electronic digital sphygmomanometer every 60 minutes from the beginning to the end of each dialysis session. In the event of IDH, the blood pressure was checked every 10 minutes. Prehemodialysis (pre-HD), posthemodialysis (post-HD), and intradialytic lowest (nadir) blood pressure at each dialysis session were recorded. The difference of SBP, DBP, and MAP between prehemodialysis and nadir, and between prehemodialysis and posthemodialysis, were calculated. The number of sessions disturbed by symptomatic IDH was defined as hypotensive episodes that require medical intervention including transient reduction or premature stop of ultrafiltration, infusion of isotonic or hypertonic saline, or glucose solution. These parameters during each study phase were recorded by the nurses at the hemodialysis center. Any adverse effects that might be related to KRG were recorded.In the last dialysis sessions of each study phase, plasma levels of ET-1, PRA, AngII, and NO products were checked before and after dialysis. Blood samples were collected with prechilled polypropylene tubes containing 1 mg/mL of K2-EDTA and 500 KIU/mL aprotinin (Sigma). Plasma was separated by centrifugation at 3000 rpm for 15 minutes at 4°C and stored at −70°C until assayed. Specific antibodies and radioimmunoassay kits were used to assay PRA , AngII , and ET-1 . The final products of NO metabolism were examined using an assay for detecting the plasma levels of the nitrate+nitrite (NT) . Hematocrit, albumin, electrolytes, and alanine aminotransferase were monitored at the beginning and end of the study by autoanalyzer. χ2 test for dichotomous variables. The Mann-Whitney U test is applied to compare intergroup differences. The Wilcoxon signed-rank test is used for intragroup comparison between phase I and phase II. A two-tailed P < 0.05 is considered statistically significant. Statistical analysis is performed with analytical Software SPSS 12.0 version.All numerical values are expressed as mean±standard deviation (SD). Baseline variables are compared with the n = 1 in group A; n = 2 in group B), catheter infection (n = 1 in group B), and death due to sepsis and cerebrovascular accident (n = 1 in group A) which was not directly related to KRG use. For the statistical analyses, three patients were excluded due to adjustment of antihypertensive medications (n = 1 in group A) and changes of dry weight exceeding ±1% (n = 2 in group B). Finally, 18 patients in the group A and 20 patients in the group B were included for analysis.Of the 46 enrolled patients, 21 patients were grouped into group A and 25 patients to group B according to prehemodialysis blood pressure in the observation phase (phase I) . In totaP = 0.016) and a higher percentage of diabetes mellitus .Baseline patient characteristics of the 38 patients of the analysis population are listed in P = 0.016) and from 3.9 ± 3.9 times to 2.7 ± 3.5 times in group B (P = 0.035)  to 2.7 ± 3.1 times in group A (= 0.035) . The ave= 0.035) . Thus, wP = 0.045). A similar trend of increased nadir SBP was noted in group A . However, the administration of KRG did not significantly change prehemodialysis or posthemodialysis blood pressure.We looked at the effects of KRG in regulating the blood pressure changes during hemodialysis . We founP = 0.045; −13.2 ± 7.1 mmHg of nadir-pre-DBP in phase I to −10.4 ± 6.6 mmHg in phase II, P = 0.011; −16.9 ± 7.1 mmHg of nadir-pre-MAP in phase I to −13.8 ± 7.7 mmHg in phase II, P = 0.015; −11.0 ± 6.3 mmHg to −7.8 ± 6.3 mmHg in post-pre-DBP, P = 0.025). A similar trend was also noted in group A after KRG treatment . When all patients were included for analysis, the blood pressure drop reduced significantly in the KRG-treated period . These results indicate that KRG may help to keep hemodynamic stability in IDH patients.Furthermore, we calculated the differences of blood pressure measured at different time points  . NotablyP = 0.004) but less evident in group A (P = 0.071). The level of ET-1 and AngII did not significantly increase despite an average ultrafiltration of 2.6 ± 1.0 kg with removal of fluid in both groups (P > 0.05).To investigate the action mechanism of KRG, we examined the plasma levels of PRA, ET-1, AngII, and NT (nitrite + nitrate). In the observation phase (phase I), PRA levels increased significantly after hemodialysis in group B  , which is in contrast to the trend in phase I (P = 0.033), but not in group B (P = 1.000). A previous study has shown that NT can be removed by hemodialysis [P < 0.05 in group A) (After four weeks of KRG treatment (phase II), the posthemodialysis PRA levels increased significantly in both groups (group B) . Similar phase I . The levdialysis . As expegroup A) . These rP = 0.014; 2.042 ± 1.127 to 1.023 ± 1.190 ng/mL in group B, P = 0.047) as shown in P < 0.001; 1.616 ± 1.387 to 0.694 ± 0.859 ng/mL in group B, P < 0.001). In contrast, the predialysis PRA levels remained unchanged in the group A but elevated in group B (P = 0.012) with KRG treatment. There were no significant changes in the prehemodialysis NT levels during the two study phases.Unexpectedly, we observed a two- to threefold declination of prehemodialysis ET-1 levels in both groups with KRG treatment  and thirsty (n = 1 in group B). Serum potassium levels increased slightly from 4.3 ± 0.5 to 4.6 ± 0.7 mEq/L (P = 0.016) in group B with KRG administration, but the difference were not significant when data from both groups was pooled  (P = 0.04) with KRG treatment, but the levels were still within the normal range. No other significant changes in hematologic or biochemical parameters were observed  . Serum pobserved .The current treatments for IDH include stopping ultrafiltration, increasing dialysate sodium and glucose concentrations, and administration of hypertonic solutions and vasoconstrictor agents , 12–14. Panax ginseng on regulating blood pressure were controversial due to its complexity of major components and different actions in various pathological conditions [Panax ginseng have strong CNS excitatory actions that may cause hypertension, while dammarenediol glycosides in Panax ginseng have sedative and antihypertensive effects [Panax ginseng could cause hypertension [Panax ginseng was shown to increase NO production in recent clinical trials and laboratory experiments [Panax ginseng induced different responses in different blood vessels taken from rabbits, dogs and humans qualitatively and quantitatively [The effects of nditions , 28, 29. effects . Three drtension . Howevereriments . Furthertatively . Our datThe mechanism of IDH has been partly attributed to endothelial dysfunction in response to hemodynamic instability, with increased NO and decreased ET-1 during hemodialysis , 32–34. Previous studies have shown that hypotension-prone patients have higher baseline AngII levels compared to hypotension resistant dialysis patients . This inDespite the promising results obtained in this trial, several limitations should be acknowledged. First, the study had a relative small sample size, and further studies are needed to confirm the results. Second, the study is a phase I pilot study, and we could only observe the differences within the same patient although this also help to eliminate the variation of blood pressure changes among different patients. Third, the long-term effects of KRG in hemodialysis patients were not studied, and further investigations are warranted.Chewing low-dose KRG renders patients better resistance to acute BP reduction during hemodialysis. KRG treatment improves the compensatory response to acute volume change during hemodialysis via activation of vasoconstrictors (ET-1 and AngII). Our results suggest that KRG could be an adjuvant treatment for IDH.


To examine if mild carotid stenosis correlates with silent vascular brain changes, we studied a prospective population-based cohort “Men born in 1914.” Data from followups at ages 68 and 81, have been used. Carotid ultrasound was performed at age 81, and cerebral blood flow (CBF) was measured with SPECT at age 82. Out of 123 stroke-free patients, carotid stenosis <50% was observed in 94% in the right and 89% in the left internal carotid arteries (ICAs). In these subjects, Peak Systolic Velocities in ICA correlated negatively with CBF in a majority of several brain areas, especially in mesial temporal area. Results were limited to normotensive until their seventies, who developed late-onset hypertension with a subsequent blood pressure, pulse pressure, and ankle-brachial index growth. Elderly with asymptomatic carotid stenosis <50% and peak systolic velocities in ICA 0.7–1.3 m/s, should be offered an intensified pharmacotherapy to prevent stroke or silent cerebrovascular events. Stroke risk in patients with symptomatic internal carotid artery (ICA) stenosis greater than 70% can be reduced effectively by carotid endarterectomy. In most cases, carotid ultrasound is performed in association with TIA or stroke and, in case of significant stenosis, an operative treatment or pharmacotherapy is initiated as a secondary prevention. Additionally, asymptomatic patients with carotid stenosis could benefit from primary preventive operative treatment with carotid endarterectomy in presence of a hemodynamically significant 60–99% ICA stenosis –3. A numCalculating carotid stenosis to less than 50% could be made by radiologic or sonographic methods. Measurement of peak systolic velocities (PSVs) in ICA has been used worldwide, and maximal PSV, defined between 1.25–1.4 m/s, was used delimitate stenosis to maximum 50%, sometimes with mandatory plaque or intimal thickening visible . When esThe aim of our study was to estimate the presence of silent changes in cerebral blood flow (CBF) in a populations sample of stroke-free elderly men without carotid stenosis or less than 50% and to examine if there was a dose-response relationship between PSV in ICA and a grade of CBF decline.  A prospective population sample study, “Men born in 1914,” has been in progress since 1968. It includes all men born in the even months of 1914 in the city of Malmö, Sweden. A total of 809 men were invited to participate in the study, and 703 men took part in the first health examination. When they were 68 years old, 465 men in the cohort and an additional 95 new residents were invited to attend a new examination. Five hundred of them agreed to participate in this first followup . The mosVascular risk factors, including hypertension, levels of blood glucose, cholesterol, and triglycerides during fasting conditions as well as body mass index (BMI) were measured at age 68. Blood pressure was measured sphygmomanometrically with Korotkoff method in the upper right arm in the supine position after 15 min of rest (at age 68) and in the sitting position (at age 81), using a calibrated mercury manometer and rubber cuffs . The participants were also classified as nonsmokers/former smokers and current smokers. Peripheral circulation in the lower extremities was estimated using the ankle-brachial pressure index (ABI) at age 68 and 81 (see below). At the recent followup at age 81, the medical examination was repeated, and 185 men answered a questionnaire focusing on lifestyle and health markers. Possible dementia was classified according to the DSM-IV criteria and, according to them, one subject was diagnosed as being demented. The Mini-Mental State Examination (MMSE) was performed on 171 men, giving a mean value of 28.23 ± 1.85  (SD); range 18–30. Eight subjects had MMSE scores ≤24. Hypertension was defined as systolic and diastolic brachial BP ≥ 160 mmHg or ≥ 90 mmHg, respectively, or medication for hypertension. These hypertension criteria have been used previously and were valid until the World Health Organization drew up new ones in 1999. All the subjects had been monitored and treated during their lifetime according to these hypertension criteria, and therefore they were used for the statistical analysis.y = 0.54 · ex0.021, where  y  is the peak systolic velocity in the ICA in m/s, and  x  is the degree of stenosis expressed as the diameter reduction in percentage. Diameter reduction in percent = [b − a] · 100, where “a” is the smallest diameter in the stenotic zone, and “b” is the diameter of normal common carotid artery proximal to the stenosis [The carotid arteries were examined at age 81, using a computed sonography system  with a 7 MHz B-mode real-time linear scanner, including a 5 MHz pulsed and color-coded Doppler. The color-coded Doppler was used to identify areas with high flow velocities in the internal carotid artery (ICA), and the maximum flow velocity (m/s) was measured with the pulsed Doppler. The angle between flow direction and Doppler signal was carefully corrected and always kept below 65°. The degree of stenosis in the ICA was determined from the peak systolic velocity to the equation:  stenosis . Each subject received an intravenous injection of 800 MBq 99mTc-HMPAO . The acquisition was performed under resting conditions on a triple-headed gamma camera system  with fan beam low-energy collimators and in 360° rotation . The energy window used had a 15% window centered over the 140 keV peak. Image processing included reconstruction of 10 transaxial 1 cm-thick slices, from 1 cm below the orbitomeatal line and upwards. Regions of interest were delineated in each slice and defined as right or left: frontal, temporal medial, temporal lateral, parietal superior, parietal inferior, basal ganglia, and subcortical as in Ankle blood pressure was estimated, at the ages of 68 and 81 years, by placing a cuff around the ankle and using a Doppler signal on the tibial posterior artery or dorsal foot artery to detect peripheral blood flow. Both ankle pressure and the reference pressure in the arm were calculated using the strain gauge system. The occluding cuff was placed on the arm, and finger blood flow was continuously recorded by mercury-in-silastic strain gauge pulse sensor placed on the proximal phalanx of the first digit. Wheatstone bridge with amplifier was used to record the resistance of the strain gauges, and a pressure transducer (Siemens-Elema EMT 746 with amplifier EMT 311) was used to record cuff pressures. Arithmetic average of a two recordings was used. The ankle-brachial pressure index (ABI) was calculated for each leg by dividing the ankle SBP by the highest individual upper arm SBP value. U  test for independent samples was used to analyze differences. A two-tailed P value of less than 0.05 was considered statistically significant. All data analyses and statistical calculations were performed using the SPSS  data package. The study was approved by the local ethics committee at Lund University (LU 111-82). All subjects gave their informed consent. Summary values were expressed as means ± standard deviation. Correlation analyses were performed using the Spearman correlation tests. Partial correlation has been calculated between variables when controlling for the grade of carotis stenosis. The Mann-Whitney  The data of the cohort “Men born in 1914” are presented in In a whole cohort, CBF values did not correlate with carotid PSV. The presence of long-term/early hypertension has been chosen as a grouping factor, and the cohort has been divided into hypertensive and normotensive subgroup at age 68. In subjects who were found normotensive at 68, both left and right carotid PSV at age 81 correlated negatively with CBF in several brain areas. In 110 subjects with left-sided carotid stenosis <50%, 59 were normotensives, and negative correlation has been observed between PSV in left ICA and CBF in frontal, mesial temporal, inferior and superior parietal and subcortical areas . In thosP = 0.455; right ICA: 0.67 ± 0.19 versus  0.67 ± 0.16,  P = 0.978). When comparing PSVs in all 160 survivors, who were examined by ultrasound but before inclusion in the CBF, normotensive subjects presented significantly higher PSVs in left ICA  and slightly larger, but nonsignificant, difference in right ICA . In normotensive subjects at age 68, left-sided PSV correlated positively with SBP at age 81 and with time difference in SBP between ages 81 and 68, showing highest left-sided PSV values in those subjects who developed largest SBP-increase during 13-year followup , and at 81 . Normotensives had also more stable blood pressure during 13-year followup, compared to a marked blood pressure decline in hypertensives  . ABI at age 68 did not differ between normo- and hyper-tensives, but at age 81, ABI was higher in normotensives in the left leg , and ABI time decline from age 68 to 81 was lower than in hypertensives . Values of CBF did not differ between normotensive and hypertensive subjects diagnosed at age 68  with increasing SBP values over time had slightly higher PSV, mainly on the left side and a clear relationship between high PSV in carotids, the grade of systolic blood pressure increase and CBF defects of arteriosclerotic origin probably due to dynamic effect of high pulse pressure, which simultaneously affects cerebral circulation. Secondly, subjects with early-onset hypertension, with blood pressure decline over time, either due to dysautonomia or heart failure, where lower blood pressure in the eighth decade express higher vascular lifetime-load, and where higher peripheral resistance in cerebral vessels and lower cardiac output could blur the pulse pressure related PSV increase and its effect on CBF . To our knowledge, this is a first study showing a correlation between high peak systolic velocities in the internal carotid artery and a widespread cerebral blood flow defects in stroke-free very elderly men with carotid stenosis less than 50%. This observation was limited to those who were normotensive and untreated until their seventies and in majority developed late-onset hypertension with subsequent blood pressure and pulse pressure growth. Elderly men with velocities between 0.7–1.3 m/s should be offered an intensified pharmacotherapy and lifestyle modification.


The responder group presented lower age , Framingham risk score (FRS) , values of peripheral , and central pulse pressure (PP) . FMD response showed negative correlation with FRS , baseline FMD , baseline reactive hyperemia index , and central PP . However, after linear regression analysis, only FRS and baseline RHI were associated with FMD response. In conclusion, one-week dark chocolate intake significantly improved endothelial function and reduced BP in younger hypertensive with impaired endothelial function in spite of lower cardiovascular risk.Recent findings indicate an inverse relationship between cardiovascular disease and consumption of flavonoids. We aimed to identify clinical and vascular parameters of treated hypertensive who present beneficial effects of dark chocolate for one-week period on vascular function. Twenty-one hypertensive subjects, aged 40–65 years, were included in a prospective study with measurement of blood pressure (BP), brachial flow-mediated dilatation (FMD), peripheral arterial tonometry, and central hemodynamic parameters. These tests were repeated after seven days of eating dark chocolate 75 g/day. Patients were divided according to the response in FMD: responders ( Hypertension notably contributes to the worldwide cardiovascular morbidity and mortality. Hypertensive disease seems to have a complex association with endothelial dysfunction, a phenotypical alteration of the vascular endothelium that precedes the development of adverse cardiovascular events and anticipates future cardiovascular risk . SeveralLifestyle modifications, including dietary habits, have substantial effects on risk factors for cardiovascular disease such as hypertension . EpidemiSome individuals may have positive health benefits when chocolate is ingested in moderation as part of a balanced diet . Thus, tClinicaltrials.gov (NCT01314924).Twenty-one hypertensive patients recruited from Pedro Ernesto Hospital on stable drug therapy over at least 4 weeks, aged 40–65 years, were included in a prospective study. Exclusion criteria were evidence of secondary hypertension, body mass index ≥ 35 Kg/m², coronary artery disease, kidney or thyroid disease, hormone replacement therapy, diabetes or impaired tolerance glucose, severe dyslipidemia (LDL-cholesterol ≥ 4.14 mmol/L and/or triglycerides ≥ 3.39 mmol/L), use of lipid-lowering drugs, using restricted diets , allergy to chocolate or cocoa, and use of nutritional supplements  for up to seven days before the study beginning. The protocol was approved by the local Ethics Committee Research (2415-CEP/HUPE), and all patients gave written informed consent. This study was registered in After overnight fasting, without smoking or drinking coffee for a least 12 h before tests, patients were examined in the supine position in a dark, quiet, and air-conditioned room (22–24°C). A linear-array transducer operating at 10 MHz was used to acquire longitudinal images of the right brachial artery. A standard BP cuff was positioned around the right arm, 5 cm above the antecubital fossa. After obtaining baseline images of end-diastolic diameter of the brachial artery, the cuff was inflated to 50 mmHg above systolic BP for 5 minutes. Longitudinal images of the brachial artery were captured continuously for 30, 60, and 90 seconds after cuff deflation to document the vasodilator response. FMD was calculated as the percentage change in diameter from the baseline value to the peak value after cuff release. Volunteer patients meeting the selection criteria underwent clinical and laboratory evaluation. For laboratory tests and vascular assessment, patients were asked to fast for eight to twelve hours. At the first visit, patients were instructed to maintain the habitual physical activity, usual diet, but avoiding consumption of foods rich in flavonoids  during the intervention. All patients then received 75 g of dark chocolate with 70% cocoa, rich in flavonoids, daily for seven days.After 1-week consumption of dark chocolate and reexamination, patients were divided according to the response in brachial FMD into responders (RESP) when there was at least an increase of 1% in FMD and nonresponders (N-RESP) when this improvement in FMD was not observed.Total polyphenol content of the chocolate used in this study was measured by spectrophotometry in the Laboratory of Pharmacology at our institution. We found 42.7 mg of polyphenols/g of dark chocolate, resulting in 3202 mg of polyphenols in the total daily dose.Office brachial systolic and diastolic BP were measured in the sitting position using a validated electronic device  with an appropriate cuff size. Three consecutive readings, one minute apart, were obtained, and the average value was used as the clinic BP. Routine biochemical assessment included fasting glucose and lipid profile . The Framingham risk score was estimated for each patient .Endothelial function was also assessed by PAT using the Endo-PAT2000 device . PAT is a noninvasive technique, to assess peripheral microvascular endothelial function by measuring changes in digital arterial pulse volume during reactive hyperemia .Probes were placed on index finger of each hand, and a BP cuff was placed on nondominant (study arm), while the contralateral arm served as a control. Continuous recording of pulsatile blood volume responses from both hands was initiated. After a 10 min equilibration period, the BP cuff on the study arm was inflated to 60 mmHg above systolic pressure. The changes in arterial tone were elicited by a standard 5 min occlusion of the brachial artery. The cuff was then deflated to induce reactive hyperemia, while PAT recording was continued. Reactive hyperemia index (RHI) was analysed by a computer in an operator-independent manner. Radial artery applanation tonometry and pulse wave analysis were carried out to derive central BP and other parameters using dedicated system SphygmoCor v.7 . This method generates central aortic pressure waveforms from the radial pressure waveform using a previously validated transfer function. The central pressure waves were analyzed to identify the outgoing and reflected components and to calculate the augmentation index (Aix), that is, the proportion of the central pulse pressure that is attributable to pulse wave reflection which is calculated as augmentation pressure (AP).One goal of the proposed study is to test the null hypothesis that the mean difference (or change) within pairs is zero. The criterion for significance  has been set at 0,050. The test is 2 tailed, which means that an effect in either direction will be interpreted. With the proposed sample size of 20 pairs of cases, the study will have power of 80% to yield a statistically significant result.t-test with a confidence interval of 95%, and the value of P < 0.05 was considered statistically significant. Student's t-test for independent samples was used for intergroup analysis. Pearson coefficient was obtained in correlation tests between continuous variables. Multiple linear regression, stepwise model, was done considering FMD response as dependent variable and those significantly correlated to this parameter as independent variables. Statistical analysis was performed using the Statistical Package for Social Sciences  version 18.0.The results were expressed as mean ± standard deviation (SD) or as percentages when appropriate. In the intragroup analysis, continuous variables obtained before and after chocolate consumption were compared by paired Twenty-four eligible patients were identified for this study. One patient was excluded due to high levels of fasting glucose, and another 2 patients failed to complete the intervention period. Thus, 21 individuals completed the study of whom 16 (76%) were female. Baseline characteristics and vascular profile of the study population are given in Data on drug therapy show that classes of antihypertensive drugs used by patients were thiazide diuretics (95%), angiotensin receptor blocker (10%), angiotensin converting enzyme inhibitor (5%), and calcium channel antagonist (5%). From the total sample, 81% were on monotherapy (76% on thiazides), and 19% were on a combination of two drugs.The clinical and lipid profiles of responders and nonresponders are shown in P < 0.05) and diastolic  BP and in mean arterial pressure .Besides improvement in FMD, the responder group presented significant changes in clinical parameters such as systolic , baseline FMD , baseline RHI . However, after multiple linear regression analysis, only the Framingham risk score and baseline RHI were independently associated with FMD response.FMD response was inversely correlated with Framingham risk score (This study demonstrated that treated hypertensive subjects responding to 7-day dark chocolate intakes with improved endothelial function and reduced blood pressure were younger and had less cardiovascular risk than nonresponders.In contrast to our study, other protocols commonly included only naive hypertensive patients with never-treated raised BP levels or a washout period with discontinuation of drug therapy before the intervention with chocolate , 17–19.  Nonresponders were older and had higher cardiovascular risk scores than responders as reported previously in patients of similar ages to those in our study . RecentlTo date, the gold standard noninvasive technique for measuring endothelial function in clinical studies is the FMD of the brachial artery , 24. It Our responders also showed reductions in blood pressure after eating chocolate as others have with untreated hypertension and in longer studies , 17, 20. In a recent prospective study, Buijsse et al. investigated the effects of chocolate consumption on BP and incidence of cardiovascular disease after 8-year followup and found chocolate eating reduced cardiovascular risk, largely due to the reductions in blood pressure . A new mOur study had some limitations, especially concerning the sample size and lack of a control group. Nevertheless, the findings are in line with other recent observations. There is as yet no way to identify those who will benefit from dark chocolate consumption, but the present study provides data that could be examined in larger randomized controlled studies for the selection of subjects likely to benefit from increased intakes of dark chocolate.In conclusion, the intake of dark chocolate significantly improved endothelial function and reduced blood pressure in some individuals who were younger hypertensive patients with impaired endothelial function in spite of lower cardiovascular risk.


Elevated blood pressure (BP) is a major risk factor for the progression of chronic kidney disease (CKD). However, little is known about the influence of prehypertension on CKD. In this study, we investigated the relationship between prehypertension and CKD in a middle-aged Korean population. Furthermore, we prospectively evaluated the effect of active BP control on deterioration of kidney function during the two-year follow-up.2. A multivariable logistic regression model was used to identify associations between BP and CKD.The Korean Genome and Epidemiology Study is a community-based prospective cohort study started in 2001, with a follow-up survey conducted every two years. A total of 9509 participants aged 40–69 years were included in a baseline study. BP was classified according to the Seventh Report of the Joint National Committee on High BP (JNC-7) categories and CKD was defined as the presence of proteinuria or eGFR< 60mL/min/1.73mThe overall prevalence of CKD was 13.2%, and significantly increased with BP level. The multivariable-adjusted odds ratio of CKD was 1.59 for prehypertension and 2.27 for hypertension, compared with a normal BP. At the two-year follow-up, among the participants with prehypertension, subjects whose BP was poorly controlled had a significantly higher risk of eGFR drop , as compared to controls. The prevalence of eGFR drop was 57.8% in the controlled BP group and 66.0% in the poorly-controlled BP group.Prehypertension, as well as hypertension, is significantly associated with CKD among middle-aged Koreans. Our results indicate that active control of the blood-pressure of prehypertensive individuals is needed to prevent deterioration of kidney function. Chronic kidney disease (CKD) is associated with all-cause mortality, progression to end-stage renal disease (ESRD), cardiovascular disease (CVD), and many chronic diseases, such as diabetes-5.2 for at least three months; in addition, GFR is usually estimated from serum creatinine (Scr) values alone or prediction equations that take into account the Scr, age, gender and race[The prevalence of CKD in the United States has increased from 10.0% in 1988–1994 to 13.1% in 1999–2004. In a poet al. found that a BP above 110/75 mmHg was significantly associated with albuminuria in a Japanese population without hypertension, but not with eGFR[Elevated blood pressure (BP) is closely associated with CKD progression, and lowering of BP may slow down GFR decline,11. A nuith eGFR.Although several studies have suggested that hypertension is a significant risk factor for CKD, little is known of its association with prehypertension and CKD. In this study, we investigated the relationship between prehypertension and CKD in a middle-aged Korean population. To determine the effect of BP control on deterioration of kidney function, we prospectively evaluated eGFR drop according to the change of BP during the two-year follow-up.2), 9509 participants were included for baseline study. At the 2-year follow-up examination, 8603 participants were enrolled in this study after exclusion of 92 death and 814 lost to follow-up. Of those, 8149 people with complete data were selected to participate in a follow-up survey. We excluded 2108 and two participants with missing Scr and BP values, respectively. Thus, 6039 subjects were included in the present study . We obtained baseline and 2-year follow-up data from the Center for Genome Science in the National Institute of Health, Korea. The details of the present cohort have been described elsewhere,19. Of 1Measurement of BP was performed after a 5 min period of rest using a mercury sphygmomanometer, and two BP readings were taken from both arms at 30 s intervals. The average systolic and diastolic BP values of two measurements taken in a sitting position were recorded.BP was classified according to the Seventh Report of the Joint National Committee on High BP (JNC-7) categories; normal Controlled BP was defined as participants who maintained a normal BP, and poorly-controlled BP as those with prehypertension or hypertension at the two-year follow-up.Demographic, medical and behavioral characteristics were obtained using a standardized questionnaire, and included age, sex, cigarette smoking and alcohol intake.Body weight and height were measured to the nearest 0.1 kg or 0.1 cm and body mass index (BMI) was calculated as body weight (kg) divided by height (meters) squared. Waist circumference (WC) was measured at the midpoint between the ribs and the iliac crest in the standing position.Blood samples were collected after an 8–14 h fast. Fasting plasma glucose (FPG), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and Scr levels were measured enzymatically, and low-density lipoprotein cholesterol (LDL-C) levels were estimated by the Friedwald formula. Protein2 for at least three months[2. CKD stages were classified as follows: stage 1, proteinuria (≥ 1 +) with eGFR ≥ 90 mL/min/1.73 m2; stage 2, proteinuria (≥1 +) with eGFR 60–89 mL/min/1.73 m2; stage 3, eGFR 30–59 mL/min/1.73 m2, and stage 4, eGFR 15–29 mL/min/1.73m2. eGFR was calculated using the following equation[-1.154 × Age- 0.203 × . Changes in kidney function were evaluated using baseline and two-year follow-up eGFR values. eGFR drop denotes a decline in eGFR between baseline and the two-year follow-up.According to the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, CKD is defined as a marker of kidney damage and/or GFR < 60 mL/min/1.73 me months. We defi1C (HbA1C) ≥6.5%, or use of oral hypoglycemic agents using the 2010 criteria of the American Diabetes Association (ADA)[DM was diagnosed as an FPG ≥126 mg/dl or 2-h post-challenge plasma glucose (2 h PG) ≥200 mg/dl or hemoglobin Aon (ADA).P <0.05 were considered to be statistically significant. The data were analyzed using the SAS software .The baseline characteristics of subjects were expressed as means and standard deviations for continuous variables. Statistical differences between groups were performed by one-way analysis of variance (ANOVA) for continuous variables and the chi-square test for categorical variables. A multivariable logistic regression model was used to identify associations between BP and CKD. C-statistics were calculated to compare the ability of different logistic models to discriminate participants with and without CKD. After two-year follow-up, the odds ratio of eGFR drop according to BP change was calculated by multivariable logistic regression analysis. Values of 2. The BMI, WC, FPG, TC, LDL-C and TG levels were increased when BP level was high. Hypertensive participants were more likely to have a history of DM (11.5% in the prehypertension group and 19.3% in the hypertension group). Of all subjects, 25.8% were current smokers and 47.7% were alcohol drinkers. The mean GFR estimated using the Modification of Diet in Renal Disease (MDRD) equation was 74.0 ± 14.0 mL/min/1.73 m2, and was lowest in the hypertension group. The proportion of individuals with eGFR <60 mL/min/1.73 m2 in the normal BP, prehypertension and hypertension groups were 5.6%, 11.4% and 23.3%, respectively. Two-hundred and seventeen subjects (2.3%) had proteinuria (≥1+), which was more prevalent in subjects with hypertension than in those with a normal BP.The baseline characteristics of the participants according to BP category are shown in TableP trend <0.001). CKD prevalence according to stage was 13.8% in stages 1 and 2, 85.4% in stage 3, and 0.8% in stage 4. Participants with hypertension showed the highest CKD prevalence. There was a gender difference in CKD prevalence . Females had a higher prevalence of CKD in all categories  equation, the meaWe found that CKD prevalence increased with BP level; normotensive subjects showed the lowest prevalence and hypertensive subjects the highest .Hypertension is a well-known risk factor for CKD progression-14. HoweSeveral cohort studies provided strong epidemiologic evidence regarding the risk of ESRD across the BP categories. Our results were consistent with those of an earlier study, which reported that the risk of ESRD was increased even with normal but not optimal and high-normal levels, as well as hypertension,33. In oOur follow-up results showed that subjects with poorly-controlled BP were more likely to have a decreased eGFR compared with those with controlled BP. The risk of eGFR drop was significantly increased among the poorly-controlled BP group in all, and prehypertensive participants Table. These fInterestingly, the risk of CKD significantly increased in prehypertensive subjects, and those with poorly controlled BP had a higher risk of eGFR drop at the two-year follow-up. That is, the increased CKD risk begins at a near-normal BP; therefore, those individuals may be considered for active BP control to reduce the burden of kidney disease.The strength of this study was that it was a prospective community-based cohort study which evaluated the association between BP and CKD across the range of BP.2 or kidney damage for at least three months; therefore, Scr and proteinuria should be evaluated more than once. Thus, there might be an underestimation or overestimation of the prevalence of CKD in both males and females. Third, the MDRD equation has not been validated in the Korean population. Therefore, eGFR calculation using the MDRD equation might be inaccurate. Fourth, each participant’s BP measurement was based on only two readings of a single day. Also, we only evaluated in a state of BP control with BP values and self-reported medication at a baseline and 2-year follow-up. Therefore, the misclassification of BP may be possible and it might be underestimated or overestimated the prevalence of controlled BP and poorly-controlled BP.However, there were also some limitations to this study. First, the study population consisted only of those aged 40–69 years. Nevertheless, our results may be representative of the general population in Korea because the data were from a community-based prospective cohort study, which may have minimized the sampling bias effect. Second, Scr and proteinuria were measured only once. According to the K/DOQI guidelines, CKD is defined as a GFR <60 mL/min/1.73 mPrehypertension, as well as hypertension, is significantly associated with CKD among middle-aged Koreans. Our results indicate that active control of the blood-pressure of prehypertensive individuals is necessary to prevent deterioration in kidney function. Therefore, we suggest that active blood-pressure control may play an important role in prevention of CKD.1C: Hemoglobin A1C; ADA: American Diabetes Association ; ANOVA: One-way Analysis Of Variance ; MDRD: Modification of Diet in Renal Disease ; SBP: Systolic Blood Pressure ; DBP: Diastolic Blood Pressure .BP: Blood Pressure ; CKD: Chronic Kidney Disease ; ESRD: End-Stage Renal Disease ; CVD: CardioVascular Disease ; KDOQI: Kidney Disease Outcomes Quality Initiative ; eGFR: Estimated Glomerular Filtration Rate ; Scr: Serum creatinine ; KEEP: Kidney Early Evaluation Program ; NHANES: National Health and Nutrition Examination Survey ; BMI: Body Mass Index ; WC: Waist Circumference ; FPG: Fasting Plasma Glucose ; TC: Total Cholesterol ; TG: Triglyceride ; HDL-C: High-Density Lipoprotein Cholesterol ; LDL-C: Low-Density Lipoprotein Cholesterol ; DM: Diabetes Mellitus ; 2 h PG: 2-h Post-challenge plasma Glucose ; HbAThe authors declare that they have no competing interests.MJK and HYP participated in the design of the study, performed the statistical analysis and participated in drafting the manuscript. NKL performed the statistical analysis. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/12/960/prepubMean GFR according to different estimating equations.Click here for filePrevalence of CKD according to the CKD-EPI equation.Click here for filePrevalence of CKD according to the MDRD equation with the Korean coefficient.Click here for filePrevalence of CKD according to the novel equation for Korean.Click here for file


Patients with diabetes mellitus are at increased risk for microvascular complications. Early changes in microcirculation are characterized by hyperperfusion (e.g. in the retina and kidney) and increased pulse wave reflection leading to increased aortic pressure. We investigated the effects of the DPP-4-inhibitor saxagliptin on early retinal microvascular changes.In this double-blind, controlled, cross-over trial 50 patients  with type-2 diabetes (mean duration of 4 years) were randomized to receive placebo or 5 mg saxagliptin for 6 weeks. Retinal arteriolar structure and retinal capillary flow (RCF) at baseline and during flicker-light exposure was assessed by scanning laser Doppler flowmetry. Central hemodynamics were assessed by pulse wave analysis.Postprandial blood glucose  and HbA1c (6.84 ± 0.15 (51 ± 1.6) versus 7.10 ± 0.17% (54 ± 1.9 mmol/mol); p < 0.001) were significantly reduced with saxagliptin treatment compared to placebo. RCF was significantly reduced after treatment with saxagliptin . This was most pronounced in a subgroup of patients (n = 32) with a fall in postprandial blood glucose . No significant changes in RCF were seen during flicker-light exposure between placebo and saxagliptin, but the vasodilatory capacity increased two-fold with saxagliptin treatment. Central augmentation pressure tended to be lower after treatment with saxagliptin (p = 0.094), and central systolic blood pressure was significantly reduced .Our data suggest that treatment with saxagliptin for 6 weeks normalizes retinal capillary flow and improves central hemodynamics in type-2 diabetes.NCT01319357).The study was registered at (ID:  Diabetes mellitus is associated with microvascular complications such as diabetic retinopathy and nephropathy ,2. EarlyExamination of the retinal circulation offers the unique opportunity to directly visualize and investigate the microvasculature in vivo non-invasively -9. ScannSaxagliptin is a potent, selective, reversible, and competitive dipeptidyl peptidase-4 (DPP-4) inhibitor ,16. SaxaEffects of Saxagliptin on ENdothelial function in patients with type-2 Diabetes (ESENDI)-study was to analyze the impact of saxagliptin on early microvascular changes due to type-2 diabetes by non-invasively measuring the retinal circulation, documenting hemodynamic changes and assessing early vascular remodelling.The aim of the ESENDI was a randomized, double-blind, placebo-controlled investigator sponsored cross-over trial conducted in Erlangen-Nuremberg, Germany between November 2010 and July 2012. The study protocol was approved by the Ethic Committee of the University of Erlangen-Nuremberg and the study was performed according to Declaration of Helsinki and “good clinical practice” (GCP) guidelines. Written informed consent was obtained from all patients before study entry.The study was registered at clinicaltrials.gov, ID: NCT01319357.Patients of either gender and age between 18 and 75 years were eligible for inclusion into the study given they were diagnosed with type-2 diabetes mellitus (defined by fasting glucose ≥ 7.0 mmol/L or HbA1c ≥ 6.5% (48 mmol/mol) or receiving anti-diabetic pharmacotherapy). Selected exclusion criteria included being on more than one blood glucose lowering medication, insulin or (current or within the previous 6 months) treatment with any incretin-based treatment strategy such as DPP-4 inhibitors or GLP-1 agonists. Furthermore patients with micro- or macrovascular complications such as diabetic retinopathy, macroalbuminuria, an acute cardiovascular event , unstable angina or stroke within 6 months prior to enrollment were excluded. Female subjects of child bearing potential or within two years of the menopause were excluded unless a pregnancy test at the screening visit was negative and adequate contraceptive precautions made during the study.The principal objective was to investigate the effect of saxagliptin compared to placebo on early vascular remodeling and on the retinal capillary flow (RCF). By applying SLDF, objectives of the study were therefore: to analyze RCF at baseline, after flicker light, and after i.v. NG-monomethyl-L-arginine (L-NMMA) application, as well as to assess wall to lumen ratio (WLR) of retinal arterioles 6 weeks after saxagliptin treatment compared to placebo. In addition we evaluated the effect of saxagliptin on carotid-to-femoral pulse wave velocity (PWV) and on central systolic pressure by aortic pulse wave contour analysis, and on urinary albumine-to-creatinine ratio (UACR). The effect of saxagliptin on metabolic parameters , was also measured.It was pre-specified that results were to be validated in a subgroup of patients with a reduction of postprandial blood glucose, since the reduction of postprandial blood glucose is thought to represent a direct measure of the pharmacologic action of saxagliptin in humans.All patients entered a run-in / wash-out phase of 4 weeks given they were on any prior anti-diabetic treatment and of 2 weeks if they were treatment-naïve Figure . PatientRCF was assessed using SLDF at 670 nm . Measurements were performed in the juxtapapillary area of the right eye, 2-3 mm lateral to the optic nerve. The average of three single measurements was recorded for analysis. Data were analyzed using “SDLF version 4.0”, which has shown to be a reliable tool for the measurements of retinal arteriolar in vivo in humans .For measurement of flicker-light-induced vasodilatation RCF was determined at baseline (after 30 minutes of rest) and after flicker light stimulation . The repeated flashes increase retinal blood flow at least in part via NO-dependent vasodilatation and it represents a non-pharmacological tool to investigate vasodilatory capacity of retinal capillaries  thereby Measurement of basal NO activity of the retinal vasculature was conducted after a resting phase of 10 minutes to ensure that blood flow was at its baseline. The NO synthase inhibitor L-NMMA  was administered intravenously as a bolus infusion at a dose of 3 mg/kg of body weight over 5 minutes. Changes of RCF reflect basal NO activity of retinal vasculature, which is an independent determinant of arteriolar remodeling in the retina .Measurement of vessel and lumen diameter of retinal arteriols, wall thickness and WLR were assessed using an arteriole with a size between 80 and 140 μm of the superficial retinal layer in a retinal sample of 2.56 × 0.64 × 0.30 mm, which was scanned within 2 seconds at a resolution of 256 points × 64 lines × 128 lines as described previously . AnalyseThe central aortic pressure waveform can be used to determine central systolic and diastolic blood pressure (BP), central pulse pressure (PP) and augmentation pressure (AP). Central PP and augmentation index (cAIx) (AP as a proportion of PP) are markers of arterial stiffness and have been shown to correlate with cardiovascular morbidity and mortality ,26. The PWV is a direct measure of arterial stiffness of large arteries. For the determination of aortic PWV, waveforms of the common carotid artery and the femoral artery were obtained again using the SphygmoCor™. PWV was calculated as the distance between the suprasternal notch and the femoral artery recording site, and divided by the time interval between the feet of the flow waves.To perform a formal sample size calculation the primary endpoint was set to be the effect of saxagliptin compared to placebo on the change of RCF after i.v. L-NMMA application. We estimated that at least 38 fully evaluable patients would be needed . Assuming a drop-out rate of 15% and about 10% non-evaluable patients we determined a sample size of 50 subjects to be included.Data were entered in duplicate into a Microsoft Access  database and the analysis was performed using SPSS .Normal distribution was confirmed by Kolmogorov-Smirnow tests prior to further analyses. Normally distributed data were compared by paired t-tests and expressed as mean ± standard error of the mean (SEM). Non-parametric data (UACR) where compared using the Wilcoxon test and are presented as median and interquartile range. A two-sided P-value < 0.05 was considered statistically significant.2, and the mean duration of diabetes 4 years. HbA1c prior to randomization was 6.99% (53 mmol/mol) and BP 132/79 mmHg.A total of 50 patients were recruited for the study. Four patients dropped out prior to randomization. A further four patients were excluded from the per protocol analysis because either after randomization SLDF measurements were not evaluable (n = 3) or due to high blood glucose levels that required study discontinuation for safety reasons (n = 1). Therefore the analysis was based on a total of 42 patients which had a mean age of 60.3 ± 7.2 years and 13 of these were female (31%). The average body mass index (BMI) was 30.6 ± 5.6 kg/mBy analysing our data stratified according first treatment (placebo versus saxagliptin) at baseline (week 0) as well as stratified according chronological phases (phase 1 versus phase 2) we were able to ensure successful randomization and to rule out a carry-over effect on the presented results, respectively (data not shown).After  6 weeks of saxagliptin treatment HbA1c was significantly lower in the saxagliptin group than in the placebo group (6.84 ± 0.15 (51 ± 1.6) versus 7.10 ± 0.17% (54 ± 1.9 mmol/mol); p < 0.001). A significant reduction with saxagliptin was also noted for postprandial glucose  compared to placebo. The nominal comparison in fasting blood glucose  did however not reach statistical significance. Adiponectin concentrations tended to be higher in the saxagliptin group . Total as well as LDL- and HDL-cholesterol was lower in the saxagliptin group than in the placebo group. There was no significant effect of saxagliptin on insulin levels, the HOMA index, office systolic and diastolic BP, weight, or BMI  . The basal NO activity in the retinal circulation in the saxagliptin group was not significantly higher than in the placebo group (p = 0.442).After treatment of saxagliptin for 6 weeks no significant changes were seen in WLR, wall thickness (WT) and in vessel and lumen diameter Table .No significant changes were seen for PWV, cAIx@75 and UACR Table . CentralTo evaluate the pharmacologic action of saxagliptin more precisely, we analyzed the results of those 32 patients who responded with a reduction in postprandial blood glucose upon treatment with saxagliptin  and unresponsiveness of type-2 diabetic patients to the pharmacological effects of DPP-4 inhibitors. Our data indicate that treatment with saxagliptin resulted in a lower RCF which should be considered as a sign towards normalization of RCF in early type-2 diabetes. Our results are in disagreement with a previous open label trial that reported a mean increase in RCF from baseline to 24-weeks with vildagliptin compared to glimepiride on top of metformin . There aBetween treatment groups we found no significant difference in the change of RCF in response to L-NMMA treatment. While L-NMMA inhibits basal NO synthase activity flicker light stimulation results in partially NO dependent vasodilation and overall serves as a vasodilatory test of retinal arterioles. Dorner et al found that about 50% of the flicker light-induced increase in retinal arteriolar and venular vasodilatation can be blocked by L-NMMA infusion . The retWe hypothesized that the ability of the retinal microvascular respond to these stimuli can be improved by saxagliptin -22. The This beneficial effect of saxagliptin in the retina was observed in parallel to other vascular signals indicative of improvement, i.e. normalization of vascular function. In the macrocirculation central (aortic) systolic pressure decreased significantly , and central PP and AP tended to decrease towards normal values. These discrete changes in the macrocirculation points towards to a normalization of wave reflection in the arterial tree in the saxagliptin group. While one should be cautious in extrapolating these results to potential macrovascular benefits of DPP-4 inhibitors overall, or saxagliptin in particular, there is a plausible mechanistic link between these observations and data recently published by Rathmann  and MonaRecently The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) - Thrombolysis in Myocardial Infarction (TIMI) 53 trial comprising 16,492 patients with type 2 diabetes who had a history of, or were at risk for cardiovascular events, a reported unchanged risk of the pre-specified macrovascular (e.g. cardiovascular) composite primary endpoint, but an increased rate of hospitalization for heart failure, which is not explainable and subject of ongoing analysis. The former is not surprising, since with a median of 2.1 years of follow-up no such effect can be expected in this short period. Interestingly, saxagliptin treatment resulted in both less worsening and higher rate of normalization of microalbuminuria (both p < 0.001), indicating an improvement of microvascular damage .This is in line with previous findings. In the Steno-2 study, a multifactorial approach of intensive treatment significantly reduced microvascular complications (including diabetic nephropathy and retinopathy) already after a mean monitoring period of 3.8 years , whereasOur study was not designed for determining the underlying mechanism, but looking at the literature and our own data it appears that various DPP-4 inhibitors are also able to improve endothelial function pointing to a class effect. Previously, it was shown that alogliptin increased both postprandial endothelial function and lipidemia, indicating anti-atherogenic effects . HoweverTo sum up, treatment with saxagliptin for 6 weeks resulted in a reduction of RCF in microcirculation and reduced central systolic pressure. In accordance with these data, we noted signals that the vasodilatory capacity of the retinal arterioles may increase, and central PP and AP decrease. Thus, data suggest that compared to placebo the DPP-4 inhibitor saxagliptin may reverse early hemodynamic and vascular remodeling processes in type-2 diabetes.AD: Outer arteriole diameter; ADVANCE: The action in diabetes and vascular disease: Preterax and diamicron modified release controlled evaluation; cAIx(@75): Central augmentation index ; AP: Augmentation pressure; AU: Arbitrary units; BP: Blood pressure; DDP-4: Dipeptidyl peptidase-4; ESENDI: Effects of saxagliptin on ENdothelial function in patients with type-2 diabetes; GLP-1: Glucagon-like-peptide 1; HbA1c: Glycated hemoglobin; HOMA: Homeostasis model assessment; LD: Lumen diameter; L-NMMA: NG-monomethyl-L-arginine; NO: Nitric oxide; RCF: Retinal capillary flow; PP: Pulse pressure; PWV: Pulse wave velocity; SAVOR-TIMI: The saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus - thrombolysis in myocardial Infarction 53 trial; SLDF: Scanning laser Doppler flowmetry; UACR: Urinary albumin-to-creatinine ratio; WLR: Wall-to-lumen ratio; WT: Wall thickness.Saxagliptin is a drug developed by Bristol-Myers Squibb and Astra Zeneca. PB and RES receive research funding and consulting honoraria from both companies beyond the scope of the present study. All other authors have no competing interests to disclose.CO participated in conception of research design, researched data, analyzed data, wrote the manuscript and reviewed/edited the manuscript. UR participated in conception of research design, researched data, contributed to the discussion and reviewed/edited the manuscript. SS researched data and reviewed/edited the manuscript. IK researched data and reviewed/edited the manuscript. SF researched data and reviewed/edited the manuscript. PB participated in data analysis and wrote the manuscript. JMH researched data, contributed to the discussion and reviewed/edited the manuscript. RES participated in conception of research design, analyzed data, wrote manuscript and reviewed/edited the manuscript. All authors read and approved the final manuscript.


Whether a given integrin-ligand pair mediates cell adhesion and migration depends on the activation state of the integrin. Integrins exist in an inactive bent, an intermediate-activity extended closed, and a high-activity extended open conformation. Integrin activation states can be monitored by conformation-specific monoclonal antibodies (mAbs). Studies in mice indicate that both β1 and β2 integrins mediate eosinophil recruitment to the lung. In vitro studies indicate that α4β1 and αMβ2 are the principal integrins mediating eosinophil adhesion, including to vascular cell adhesion molecule-1 and the novel αMβ2 ligand periostin. In vivo, blood eosinophils have intermediate-activity β1 integrins, as judged by mAb N29, apparently resulting from eosinophil binding of P-selectin on the surface of activated platelets, and have a proportion of their β2 integrins in the intermediate conformation, as judged by mAb KIM-127, apparently due to exposure to low concentrations of interleukin-5 (IL-5). Airway eosinophils recovered by bronchoalveolar lavage (BAL) after segmental antigen challenge have high-activity β1 integrins and high-activity αMβ2 that does not require IL-5. Here we review information on how the activation states of eosinophil β1 and β2 integrins correlate with measurements of eosinophil recruitment and pulmonary function in asthma. Blood eosinophil N29 reactivity is associated with decreased lung function under various circumstances in non-severe asthma and KIM-127 with BAL eosinophil numbers, indicating that intermediate-activity α4β1 and αMβ2 of blood eosinophils are important for eosinophil arrest and consequently for recruitment and aspects of asthma.Eosinophil arrest and recruitment to the airway in asthma are mediated, at least in part, by integrins. Eosinophils express α Eosinophilic airway inflammation is frequent pattern in different phenotypes or endotypes of asthma  via αLβ2 and αMβ2; laminin via α6β1; fibrinogen/fibrin via αMβ2 and αXβ2; and vitronectin via αMβ2  to some with high N29 signal   of ≥15% during the late-phase 3–8 h after whole-lung antigen challenge, in addition to the common initial early-phase fall within 15–30 min), N29 reactivity was increased 48 h after segmental lung antigen challenge  have a low but detectable KIM-127 signal but very low reactivity with mAb24 and CBRM1/5, indicating that a fraction of their β2 integrins, including αMβ2, is in the intermediate- (but not high-) activity conformation , the eosinophil counter-receptor for P-selectin   induces blood eosinophil reactivity with CBRM1/5 and mAb24, and adhesion to αab Table , indicat1 integrin state. We speculate that it may be the result of the eosinophils having undergone arrest, transendothelial migration, and encounters with adhesive ligands. Current thinking in the leukocyte integrin field includes the possibility that outside-in signaling following ligand-binding by integrin in the intermediate conformation brings about the final stage of activation to the high-activity conformation  withdrawal study in subjects with non-severe asthma. N29 reactivity of blood eosinophils was found to correlate inversely with forced expiratory volume in 1 s  after ICS withdrawal or across all visits during the whole study   on circulating eosinophils is associated with a higher degree of airway inflammation and decreased pulmonary function in non-severe asthma, presumably because subjects with a more activated α4β1 would have a higher degree of eosinophil arrest and recruitment to the airway.Although it was known that purified blood eosinophils adhere “constitutively” to VCAM-1 dy Table  . As there was no baseline in this observational study, we examined correlations with FEV1 corrected for forced vital capacity (FVC). The correlation between N29 reactivity of blood eosinophils with FEV1/FVC did not reach significance in the whole asthma study population   and periostin (for αMβ2). It is difficult to say much more without knowing the histories of the sampled cells as the cells responded to the challenge. Interestingly, degree of activation of both β1 and β2 integrins on airway eosinophils correlates with number of eosinophils found in BAL.Airway eosinophils obtained by BAL 48 h after segmental antigen challenge have α4β1 and αMβ2 on blood eosinophils cooperate in eosinophil arrest in vessels of inflamed bronchi and movement of eosinophils into lung tissue. α4β1 may dominate in arrest on VCAM-1, and αMβ2 may dominate at the later stage by mediating extravasation and migration in the ECM. It should be stressed that some of the observations in humans are correlational in nature and have not yet been replicated by others, and a number of predictions based on the observations have not been tested. For instance, identification of the vascular beds in which partial eosinophil integrin activation takes place will firm up the observations. These need not to be the beds into which eosinophils ultimately extravasate. We have suggested that eosinophils may encounter activated platelets and P-selectin (Johansson and Mosher, 2 integrin activation by anti-IL-5 is due to neutralization of IL-5 present in low concentration in the general circulation or at higher concentrations in certain vascular beds. Longitudinal studies are needed to relate changes in integrin activation to the natural history of asthma and thus supplement correlations done on values obtained at a single time point. Such studies may give insight into why β1 integrin activation on blood eosinophils correlates with pulmonary function in younger adults with non-severe asthma but not in patients with severe disease or older patients. Murine experiments are needed to assess the arrest and extravasation of eosinophils in intact blood vessels imaged in real time and relate eosinophil behavior to integrin activation state. Similar experiments have provided important information about the behavior of platelets and neutrophils in injured or inflamed vessels. Finally, more needs to be known about roles of eosinophil integrins in modulating the movement and behavior of eosinophils in lung tissues. Such studies may reveal important roles for the five eosinophil integrins that are largely ignored in this review.Observations on human blood eosinophils and genetically manipulated mice indicate that partially activated αThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Objectives. In traditional Chinese medicine, Yu-Zhi  constitution describes a body that tends to express abnormal circulatory conditions. This study identified the linkage between YZ constitution and peripheral arterial disease (PAD) in patients with type 2 diabetes. Methods. Patients over 20 years of age who had had type 2 diabetes for 5 years or longer were recruited. PAD was diagnosed if the ankle-brachial index score was ≤0.9 in either leg. Level of YZ constitution was accessed by an YZ Constitution Questionnaire. Results. A total of 712 patients (354 men and 358 women) with a mean age of 61.5 ± 10.6 years and diabetes duration of 13.1 ± 6.7 years were recruited. The prevalence of PAD among our patients was 7.2%. Multivariate logistic regression revealed significant correlations between PAD and, respectively, YZ score, age, diabetes duration, current smoking, and hs-CRP. Conclusion. In addition to traditional risk factors, YZ constitution was statistically associated with PAD in patients with type 2 diabetes. This result invites further research into the effectiveness of traditional Chinese medicine to treat YZ constitution. Atherosclerosis is a leading cause of mortality and morbidity in the developed world. Peripheral arterial disease (PAD), one clinical manifestation of atherosclerosis, is an independent risk factor of mortality and morbidity in patients with cardiovascular diseases . The comHuang Di Nei Jing, specific constitutions develop from both congenital and environment factors. The patient's constitution affects his or her susceptibility to and the development and prognosis of a specific disease. The classification method in TCM differs from the clinical practice of conventional Western medicine. Thus, different TCM constitutions may be encountered in patients diagnosed according to Western practices as having the same disease.Constitutional diagnosis has been used for more than 2000 years by traditional Chinese medicine (TCM) to classify patients. According to a textbook of TCM internal medicine, The Yu-Zhi (YZ) constitution is one of the TCM body constitutions and represents a tendency to stasis or stagnation. It tends to express blood stasis syndrome (BSS), a morbid state caused by blood stagnation, which is considered a link to cardiovascular disturbance. One study found that BSS was associated with increased thickness of the carotid intima-media in dyslipidemia patients . In TCM,Nonaboriginal Taiwanese type 2 diabetes patients were recruited at the outpatient clinic of China Medical University Hospital between September 2006 and June 2007. All study patients were older than 20 years and had had DM for 5 years or longer. Type 2 diabetes was diagnosed according to the American Diabetic Association Criteria . Ankle-b2). After patients had fasted overnight, their blood samples were drawn between 8:00 and 10:00 in the morning, and the separated serum was stored at −70°C until assaying. Fasting plasma glucose (FPG) was determined by the hexokinase method . Hemoglobin A1c was measured using high-performance liquid chromatography . Serum levels of total cholesterol (TC), triglyceride, high- (HDL) and low-density lipoprotein (LDL) cholesterol, creatinine, and uric acid were examined by standard laboratory methods . High-sensitivity C-reactive protein (hs-CRP) was gauged by immunoturbidimetry . The albumin-to-creatinine ratio (ACR) was obtained from morning spot urine samples, and data were categorized as normoalbuminuria (ACR ≤ 30 mg/g), microalbuminuria (30 < ACR < 300 mg/g), or macroalbuminuria (ACR ≥ 300 mg/g). Biochemistry analysis was conducted in the Taipei Institute of Pathology.Questionnaire collection, ABI measurement, and data management were performed by various personnel. Demographic data  were collected by a questionnaire. Systolic, and diastolic blood pressure (SBP and DBP) were obtained by averaging 2 measurements taken at least 5 min apart, with an interval of rest in between. The participants' body height and weight (while wearing light clothing and no shoes) were measured by experienced research staff, and the body mass index (BMI) was calculated as a ratio of body weight (kg) divided by the square of body height . After patients had rested for 5 min in the supine position, their blood pressure was measured from bilateral arm and ankle, and pulse volume was measured from the brachial and posterior tibial arteries. The highest arm pressure was used to calculate an ABI score. PAD was diagnosed if the ABI score (which is the lowest ratio of ankle-to-arm SBP) was equal to or less than 0.90 . Patientα of 0.7827, which is considered acceptable for clinical use. Validity of the instrument was measured by assessing its construct validity. Two principal components explained 54.7% of the total variance. The 8 questionnaire items probed self-reported symptoms, with responses being rated on a 5-point Likert scale . The final YZ score was obtained by summing the scores for all items, with higher scores indicating stronger intensity of YZ constitution.The questionnaire used to assess YZ body constitution contains 8 items (see the appendix) and was originally developed through a psychometrically sound method . Its intt-test for continuous variables and by χ2 test for categorical variables. The association between YZ score and PAD was assessed by the logistic regression model to calculate the odds ratios (OR) and their 95% confidence intervals (CIs). All analyses were performed using SPSS 12.0 software , and P values of less than 0.05 were considered statistically significant.Continuous variables were expressed as mean ± standard deviation. Categorical variables were expressed as percentages. Differences in the results for type 2 diabetes patients with or without PAD were compared by Student's In all, 718 unrelated people were recruited. Six people were excluded because of an ABI > 1.3, yielding a final study group of 712 patients with type 2 diabetes (354 men and 358 women). The demographic and anthropometric traits as well as plasma and urine biochemical data of the patients are presented in P = 0.006). In addition, compared with the non-PAD group, the PAD patients were significantly older (P = 0.003), had experienced a longer duration of diabetes (P = 0.008), and included more current smokers (P = 0.033). The PAD group displayed a significantly higher SBP (P = 0.002), higher hs-CRP (P = 0.049), higher creatinine (P = 0.016), higher uric acid (P = 0.004), and higher proportions of micro- and macroalbuminuria (P < 0.001). Sex, DBP, body height, body weight, BMI, FPG, hemoglobin A1c, TC, triglycerides, HDL cholesterol, and LDL cholesterol did not significantly differ between the PAD and non-PAD group.The results of this cross-sectional study revealed that YZ constitution was a predictor for PAD in type 2 diabetes patients. This finding indicated a relationship between YZ constitution and cardiovascular complications of type 2 diabetes. Based on results of this study, type 2 diabetes patients who exhibit symptoms and signs of YZ constitution, including limb numbness; chest tightness; tingling pain; bruises without an apparent cause; dry, cracked, scaly, or tough skin; dull and lustreless face, and dull purple color or petechiae on the lips or tongue, might have a higher risk of PAD.People with a YZ constitution tend to express BSS, which is a morbid state of blood stagnation usually considered relevant to cardiovascular complications. Prior researches found that BSS was related to increased carotid intima-media thickness in dyslipidemia patients . The sevFurther investigation is needed to ascertain how YZ constitution influences PAD development in type 2 diabetes. The mechanisms related to the formation of YZ constitution are known to be complex. Associated pathogenesis of BSS includes microcirculation disturbance, hemodynamic change, and abnormal hemorheologic factors such as eicosanoid-controlled functions; fibronectin; the fluidity of human erythrocyte membranes, and plate activation, aggregation, and adhesion. Microcirculation disturbance is also considered fundamental to cardiovascular diseases . In DM pTraditionally, the therapeutic methods of TCM for the treatment of BSS are termed “promoting blood circulation to remove stasis.” Promoting blood circulation to remove stasis was adopted by TCM as main treatment components to manage cardiovascular complications of DM. Studies reported that this therapeutic principle may reduce blood clot formation by lowering levels of fibrinogen and D-dimer , as wellOther independent factors which we found to be associated with PAD included age, duration of diabetes, current smoking status, and hs-CRP. Another research has also found age to be an independent risk factor for PAD , and theDyslipidemia and blood pressure have frequently been reported as risk factors for PAD . In thisOur study was subject to two main limitations. First, to avoid subjective effects on the diagnosis of YZ constitution, we used a patient self-report questionnaire as the diagnostic tool. This meant forgoing some important TCM clinical diagnostic procedures, such as pulse diagnosis. We similarly did not use modern examination techniques and laboratory data that are usually considered when making the diagnosis of blood stasis. These deliberate omissions might have yielded lower diagnostic accuracy of YZ constitution in this study than would generally occur during clinical practice. Second, although an abnormal constitution usually occurs before a disease is diagnosed, the cross-sectional design of our study limited our ability to plot a causal relationship between YZ constitution and the development of PAD. Our results revealed only the statistical relationship between these two conditions and their associated variables.Several independent factors were associated with the development of PAD in type 2 diabetic patients, namely, age, duration of diabetes, current smoking status, and hs-CRP value. In addition, we found that YZ constitution, as conceptualized by TCM, was independently associated with PAD. Our results suggested that a combination treatment for promoting blood circulation to remove stasis might prevent PAD in type 2 diabetes patients with a YZ constitution. Further investigation is needed to clarify how YZ constitution influences the development of PAD in diabetic patients.


This special issue is related to the main concern in hypertensive disease: the target-organ damage. The selected papers approach some aspects of renal and cerebral disease associated to hypertension but the principal focus is on the arterial vessel as the main organ involved in hypertensive patients. Although hypertensive cardiopathy is not specifically included in this issue, the heart disease might be considered as one of the principal consequences of vascular dysfunction discussed in many papers.Cardiovascular disease has been associated to a low level of chronic inflammatory state which may be an important mechanism leading to organ damage in hypertensive patients. Interestingly, the paper by D. A. B. Kasal and E. L. Schiffrin provides new evidences about the role of the T-regulatory lymphocytes, showing that this population of lymphocytes may inhibit the inflammatory process resulting in beneficial effects on vascular disease in hypertension. This review also establishes the linkage between the immune response, renin angiotensin aldosterone system, and oxidative stress. Recently, the same authors published original papers reporting that T-regulatory lymphocytes were able to prevent vascular injury mediated by angiotensin II and aldosterone by suppressing inflammation and oxidative stress and improving endothelial function in experimental models of hypertension , 2.Vascular disease is the main topic in three review papers of this collection. In the first review, methods to evaluate endothelial dysfunction were considered in experimental models of hypertension. It is important to recognize that a large range of knowledge of changes in microcirculation came from vascular studies using resistance arteries mounted in wire or pressurized myograph in different animal models of hypertension and more recently in clinical settings of hypertensive disease. In the second review, A. R. Cunha et al. describe the controversial role of magnesium in the pathogenesis and vascular complications of hypertension. In spite of heterogeneity of study populations, the authors suggest that magnesium is more involved in the functional vascular changes and also on local metabolic stability with no influence on the vascular structure. Accordingly, experimental and epidemiological studies reported a connection between intracellular concentrations of ions and development of hypertension and other cardiovascular diseases , 4. In tVascular stiffness was the concern of the original study carried out by I. Farro et al. in Uruguayan subjects. The main objective of that study was to discriminate the reference values of pulse wave velocity in a Uruguayan population. To our knowledge, this is the first study that evaluates normal values of pulse wave velocity in this population, which may help to characterize the vascular aging in these individuals. Unlike the pulse wave velocity determination, which has been used more in research area, carotid intima-media thickness (IMT) and ankle-brachial index (ABI) measurements have been more commonly obtained since they represent a relationship with atherosclerosis process. Indeed, both values may be used for cardiovascular risk stratification in hypertensive patients and therefore are included in recent guidelines of hypertension , 9. FollThe strong connection between hypertension and chronic kidney disease is clear when we recognize the kidney as an important source of changes involved in the pathogenesis of essential hypertension and at the same time a frequent target for organ damage in hypertensive patients. The original paper by R. A. Gismondi et al. addresses the relationship between kidney disease and vascular stiffness. In a case-control study, comparing to hypertensive subjects with normal renal function, hypertensive patients with low glomerular filtration rate (<60 mL/min) presented higher ambulatory arterial stiffness index which was correlated to pulse pressure, suggesting increased vascular stiffness in this population. And last but not least, the brain was the focus in the last review paper. F. Medeiros et al. provide evidences concerning the influence of dietary interventions that can reduce the risk of stroke in hypertension. The authors raise the controversial benefit of carotenoids, flavonoids, n-3 polyunsaturated fats, and lower salt and high glycemic index intake in risk of stroke. In summary, this special issue covers a wide range of target organ damage associated to hypertension, with a special attention to the vessel as the central key not only for vascular disease but also for cardiac, cerebral, and renal complications in hypertensive patients. Taken together, these papers point out the importance of a complete approach of each hypertensive subject beyond the mere blood pressure measurement.Mario Fritsch NevesMario Fritsch NevesAgostino VirdisAgostino VirdisWille OigmanWille Oigman


This study aimed to determine the prevalence of Self-Monitoring Blood Pressure amongst people with hypertension using a cross-sectional survey. Of the 955 who replied (53%), 293 (31%) reported that they self-monitored blood pressure. Nearly 60% (198/331) self-monitored at least monthly. Diabetic patients monitoring their blood glucose were five times more likely than those not monitoring to monitor their blood pressure. Self-monitoring is less common in the UK than internationally, but is practiced by enough people to warrant greater integration into clinical practice. Monitoring of blood pressure (BP) is a key aspect of the diagnosis and management of hypertension . Self-moInternational surveys have found that over 70% of people with hypertension self-monitor blood pressure –7. AvailThis study aimed to determine the prevalence of self-monitoring of BP in primary care hypertensive patients and to highlight the characteristics of those that self-monitor blood pressure.A questionnaire was sent to 1815 patients with hypertension registered with four general practices in the West Midlands, UK between November 2008 and April 2009, to determine the prevalence and patterns of use of self-monitoring of blood pressure. Self-monitoring was defined in the questionnaire and information sheet as “taking your own measurements of blood pressure outside your usual visit to your GP practice, usually within the home.” Participating practices were chosen to represent a range of ethnic diversity and affluence of the patient population using the Index of Multiple Deprivation, an estimate of the socioeconomic deprivation of the practice population  linked thttp://www.spss.com). The results presented are descriptive, reported as percentages and odds ratios with 95% confidence intervals. Demographic characteristics including age, gender, ethnicity, and current status of employment were collected. Some descriptive categories were collapsed for the analysis.Analyses were undertaken using SPSS . To estOf the 1815 questionnaires mailed, 1062 were returned giving a return rate of 59%. Of these, 107 (10%) were returned blank and excluded from analysis, 955 were returned and analysable, giving an overall response rate of 53%. Of these 421/874 (48%) were male, and the age range was 21 to 81+. Of the 931 respondents reporting ethnicity, 81% were white, 6% Asian or Asian British, 7% Black British, 3% were Chinese and 3% were Mixed or other not stated. In view of the small numbers of nonwhite ethnicities, these have been collapsed into one group for the rest of the analysis.293 reported currently self-monitoring blood pressure . A quarter of respondents  had concurrent diabetes, of whom 155 (67.4%) monitored blood glucose and 75 (32.6%) monitored blood pressure. There was no difference in the prevalence of self-monitoring of blood pressure in people with or without diabetes . Amongst the 230 people with diabetes, 156 (68%) monitored blood glucose. This group was 5 times more likely to monitor their blood pressure compared to those that do not monitor their blood glucose . Characteristics of those measuring their own BP are shown in Most people who self-monitored used an automated electronic BP device  with a small percentage  indicating they monitored using a manual machine. At least 65% reported monitoring at least once per month, most commonly once or twice a week (85/198 43%). Self-reported frequencies are shown in This survey has found that approximately 30% of primary care patients with hypertension self-monitored blood pressure whether or not they had diabetes. People who self-monitored were more likely to be younger (18–60), in employment (full time or part time), and from minority ethnic backgrounds  than those who did not self-monitor. People with diabetes who self-monitored blood glucose were more likely to also self-monitor blood pressure.These findings, in common with those of a local community study  support In our study the frequency of monitoring for many respondents was low (42% monitoring more than monthly). This may reflect uncertainty of the appropriate frequency of monitoring; in the UK, National guidelines do not specify regimes for self-monitoring of blood pressure other than for diagnosis . PatientThe high uptake of self-monitoring in ethnic minority groups could perhaps reflect an increased awareness of the risks of cardiovascular disease amongst this group or by their GPs who may have recommended self-monitoring . An alteThe response rate for this study was not as high as hoped and responders may have differed from the rest of the population. However, the proportion of males in the sample  was similar to the 2001 census of West Midlands (49%) although the proportion of the people from a White ethnic background  was lower than the corresponding 2001 census figure (89%).The results of this short survey identify a group of individuals with hypertension who currently self-monitor blood pressure with or without GP recommendation. Whilst this could reflect a healthy self-empowered population where hypertensive patients are taking more responsibility for their own health, previous research also suggests that patients may not be reporting this data to their GP or health professional and also monitoring under minimal or no supervision , 16. ThiSelf-monitoring is practiced by an appreciable minority in UK primary care. In accordance with the findings from our study, people diagnosed as hypertensive could be potentially three times more likely to self-monitor than the general population. General Practitioners should be aware that around a third of their patients with hypertension could be monitoring their own blood pressure and of the opportunities that this could bring to daily management.