P = 0.015). The interarm difference was greater in patients with hypertension (P = 0.002) and PAD (P < 0.0005). 443 patients were measured on two separate occasions and the interarm difference for systolic blood pressure was reproducible for differences >20 mmHg. This study confirmed the presence of a systematic but clinically insignificant difference in systolic blood pressure between arms. The interarm difference was larger in hypertension and PAD. Consistent lateralisation is present for differences ≥20 mmHg and an interarm difference >25 mmHg is a reliable indicator of PAD in the legs.The present study aimed at examining the interarm difference in blood pressure and its use as an indicator of peripheral arterial disease (PAD).Data were included from consecutive patients referred from their general practitioner to our vascular laboratory for possible PAD aged 50 years or older without known cardiac disease, renal disease, or diabetes mellitus. 824 patients (453 women) with mean age of 72 years (range: 50–101) were included. 491 patients had a diagnosis of hypertension and peripheral arterial disease (PAD) was present in 386 patients. Systolic blood pressure was 143 ± 24 mmHg and 142 ± 24 mmHg on the right and left arm, respectively ( Hypertension is a prevalent condition affecting more than one-third of the adult population in the developed world. Accordingly, measurement of blood pressure in the clinical setting is probably second to none with respect to frequency of recordings and medical consequences resulting from the measurements obtained. A number of concepts regarding technique and cut-off values for the diagnosis of hypertension have evolved, have been tested over more than a century, and have gradually become part of consensus reports and guidelines. Most recommendations on blood pressure measurements and hypertension –4 have sThe present study was aimed at a reappraisal of the possible use of an interarm difference in blood pressure as an indicator of peripheral vascular disease. In order to meet this aim, we examined data from our vascular laboratory of blood pressure measured simultaneously on both arms in a large cohort of patients and compared the results to the presence or absence of peripheral arterial disease. We used simultaneous measurements with semiautomatic, oscillometric devices to avoid possible observer bias and we studied the reproducibility of the interarm blood pressure difference in a large subgroup of patients referred for a second set of measurements.This was a retrospective observational study using data obtained from a cohort of consecutive patients aged 50 years or older referred from their general practitioner to our vascular laboratory for possible peripheral arterial disease (PAD). None of the patients had a diagnosis of ischaemic heart disease or renal disease . None of the patients had been diagnosed with diabetes mellitus (ICD-10 class E10-11) at the time of examination.Arm blood pressure was measured simultaneously on both arms three times after at least 5 minutes of rest in the supine position using two automated oscillometric devices  and the devices were used at random for the right and left arm. The devices used have passed the validation process defined by the European Society of Hypertension , 9. The t-test or the chi-squared test when appropriate, using a five per cent two-sided significance level. Predictive values of positive and negative test  using interarm differences in systolic blood pressure as a diagnostic test for PAD were calculated for values of 10, 15, 20, and 25 mmHg, respectively.Data are given as mean values with standard deviations unless otherwise indicated. Comparisons were made both for the absolute values and for the numerical difference between the two sides. All analyses were carried out using SPSS Statistics 19 . Comparisons were made with the Student's P = 0.015). Group mean value of systolic blood pressure recorded from the arm with the highest reading was 148 ± 24 mmHg. The differences in systolic blood pressure between the two arms were normally distributed with a mean value of 1.0 ± 11.7 mmHg (P = 0.015 for right versus left arm) giving 95% confidence limits of ÷21.9 to +23.9 mmHg. The numerical difference in systolic blood pressure  with a mean age of 72 years (range: 50–101 years) were included. Systolic blood pressure on arms and ankles is given in pressure  exceededP = 0.002).Hypertension was present in 491 patients (59.6%) and in these, the numerical blood pressure difference between arms exceeded 10 mmHg in 31.6%, 15 mmHg in 16.5%, 20 mmHg in 7.9%, and 25 mmHg in 5.3%. The numerical differences found in the hypertensive subpopulation were significantly higher than in those from the subgroup without this diagnosis  was 0.89 ± 0.29. The prevalence of ABI values in the different classes is given in P < 0.0005). In patients with definite PAD, the numerical systolic blood pressure difference between arms exceeded 10 mmHg in 32.1%, 15 mmHg in 18.1%, 20 mmHg in 11.1%, and 25 mmHg in 6.7%. These values were significantly higher than in non-PAD patients (P < 0.0005). When patients were stratified with respect to the presence of both PAD and hypertension, the distribution of differences in arm blood pressure only differed significantly between PAD and non-PAD patients in the hypertensive group (P = 0.013).The mean numerical interarm difference in systolic blood pressure was higher in patients with definite PAD (9.9 ± 10.5 mmHg) compared to non-PAD patients  and in the highest positive predictive value for a difference greater than 25 mmHg (PVpos = 0.81).Using a difference in arm blood pressure as an indicator of PAD resulted in the highest negative predictive value for a difference smaller than 10 mmHg (PVP = 0.004); however, this consistency disappeared for interarm differences of 20 mmHg or less (P = 0.052).The subgroup, in which arm and ankle pressures were measured on two occasions, included 443 patients with a mean age of 74 ± 9.3 years. The mean time period between measurements was 21.3 ± 17.7 months. Systolic arm blood pressure on the right side was 147 ± 24 mmHg and 146 ± 23 mmHg on the two occasions and 146 ± 24 mmHg and 145 ± 23 mmHg on the left side. The numerical differences between the two sides were 8.4 ± 8.8 mmHg and 8.4 ± 8.6 mmHg, respectively. Patients were allocated into three categories based on interarm difference at the first visit: (1) ≤10 mmHg, (2) >10 mmHg and ≤20 mmHg, and (3) >20 mmHg. A reproducible difference was found in 75.7% of cases at the second visit in category 1, in 27.0% in category 2, and in 41.2% in category 3, respectively. When all patients were included, the lateralisation of the interarm difference was consistent (This study has shown that systolic blood pressure is slightly higher in the right than in the left arm and that the pressure differs significantly more between the arms in patients with PAD than in those without. It has also shown that this dissimilarity in arm blood pressure only seems to be present in the hypertensive subgroup. In spite of this, the confidence limits of blood pressure differences in normal subjects are of a magnitude that renders this difference imprecise as a diagnostic tool in PAD. Five previous studies have analysed possible differences in blood pressure between arms using similar simultaneous measurements as in the present study –14, and A recent meta-analysis  found anWe found interarm blood pressure differences to have a low reproducibility with significant lateralization only for differences above 20 mmHg. The poor consistency of differences over time is in line with data reported by Kleefstra et al.  in patieDifferences in blood pressure between arms may have a number of causes such as subclavian artery stenosis, aortic aneurism, aortic coarctation, vasculitis, fibromuscular hyperplasia, connective tissue disorders, and thoracic outlet compression. The overall impression, though, is that the most common diagnostic entity would be subclinical atherosclerosis as suggested by the increased likelihood of finding an interarm difference in hypertension and peripheral arterial disease. This suggestion lends support to the WHO guidelines  in whichIt has been suggested that the interarm differences could be used for diagnostic purposes in suspected PAD, but based on our findings, this arm difference has to be greater than 20 mmHg in order to be reproducible and greater than 25 mmHg to attain a sufficiently high positive predictive value. According to our calculations, the negative predictive value does not become sufficiently high even at low interarm differences to suggest that the absence of an arm difference could exclude the presence of PAD.The main limitation lies in the fact that the study is of a retrospective character. However, the technique described has been the standard in our laboratory for a number of years and the staff has vast experience in blood pressure measurements and analysis. We are therefore convinced that the results obtained are of a quality that matches those that would be obtained in a prospective study.The patient group included were relatively old and were referred under the suspicion of PAD. Nevertheless, this group would most likely be the target in screening for PAD in general practice and thus a relevant population for the questions posed.Our study has confirmed others in the notion that there is a statistical but no clinical significant difference in blood pressure between arms. Our study has also shown that the interarm difference is greater in hypertensive subjects and in patients with peripheral arterial disease. We have shown that the lateralisation of blood pressure was consistent only for differences of 20 mmHg or more. Finally, we have demonstrated that an interarm difference in blood pressure could be used as an indicator of peripheral arterial disease if the difference is greater than 25 mmHg.


To determine the feasibility of adenosine stress cardiac magnetic resonance (CMR) to guide clinical management of patients with a documented intermediate angiographic coronary stenosis.A number of patients undergoing assessment for possible ischaemic heart disease proceed straight to coronary angiography without prior non-invasive functional tests. When an intermediate coronary lesion is then encountered, the functional significance of that lesion is often unclear. Invasive assessment with fractional flow reserve can clarify the situation but is not always available and involves significant expense. Non-invasive tests are then frequently requested to guide treatment. Adenosine stress perfusion imaging has been shown to have a high sensitivity and specificity for detecting ischaemic heart disease. We sought to determine the ability of stress perfusion CMR to guide management in these patients.Retrospective analysis of patients with an intermediate coronary stenosis on angiogram subsequently referred for adenosine stress CMR. Patients with previous CABG were excluded. Only those with single vessel disease were evaluated. All intermediate lesions were in the range 30-70% on angiogram. Perfusion imaging was obtained at stress (adenosine 140 µg/kg/min) and rest on a 1.5T scanner. Late enhancement was assessed with dual pass gadolinium . Patient records, hospital databases and national death registries were reviewed. We defined MACE as cardiovascular death, myocardial infarction, revascularisation, and ischaemic hospitalisation.Thirty nine patients, with follow up data for a median 25 months (IQR 22-28), were identified. Of those with a positive adenosine stress CMR, 69% (9 of 13) encountered MACE. These were all PCI events. Of those with a negative CMR, MACE occurred in 12% (3 of 26). These were also PCI events, however only two of these were symptom driven, due to lesion progression at 9 and 10 months respectively.Adenosine stress perfusion CMR may be a useful tool in the clinical management of patients with an intermediate coronary artery stenosis.


There is evidence that in cirrhotic patients, certain hemodynamic parameters, such as blood pressure and heart rate, are related to the severity of liver disease. This study investigated whether non-invasive 24-hour ambulatory blood pressure and heart rate are more closely associated with markers of liver disease severity than conventional office measurements.Ambulatory patients with cirrhosis underwent office blood pressure and heart rate measurements, 24-hour ambulatory blood pressure monitoring and blood laboratory tests.Fifty-one patients  completed the study. Twenty six patients had compensated liver cirrhosis (group A) and 25 patients had more advanced liver disease (group B). Group A and B patients differed significantly both in ambulatory asleep diastolic blood pressure (p < 0.05) and office diastolic blood pressure (p < 0.01), which were lower in more advanced liver disease. Office blood pressure and heart rate correlations were similar to or even stronger than ambulatory ones. Ambulatory blood pressure and heart rate awake-asleep variation (dipping) showed a relatively flat pattern as markers of liver dysfunction were deteriorating. The strongest correlations were found with both ambulatory and office heart rate, which increased as indicators of severity of liver disease were worsening.Heart rate seems to be a more reliable marker of ongoing liver dysfunction than blood pressure. Evaluation of blood pressure and heart rate with 24-hour ambulatory measurement does not seem to offer more information than conventional office measurements. Hepatic cirrhosis is accompanied by alterations of systemic circulation, such as reduced peripheral vascular resistance, low or low-normal blood pressure (BP) and increased heart rate (HR), stroke volume and cardiac output at rest, a situation which is called "hyperdynamic circulation". These alterations deteriorate further with the aggravation of hepatocellular failure -5. It haOnly two published trials have compared non-invasive 24-hour ambulatory blood pressure (ABP) parameters of cirrhotic patients with those of healthy controls and investigated their correlation with markers of severity of liver disease ,17. It hIn this study, ambulatory cirrhotic patients underwent 24-hour ABP monitoring, as well as routine office BP and HR measurements. Additionally, biochemical and hormonal markers of liver function were tested. Patients were divided into two groups, those with Child A (group A) and those with Child B and C liver disease (group B). BP and HR parameters were compared between the two groups and statistical correlations between those parameters and aforementioned markers of liver function and portal hypertension were studied, in order to assess whether non-invasive 24-hour measurements are more closely associated with markers of liver disease severity than the conventional office measurements.This cross-sectional study included ambulatory patients with liver cirrhosis irrespective of aetiology, sex or age (> 18 years). Patients with known history of arterial hypertension, treated or untreated, heart failure, cardiac cirrhosis, bedridden, with clinical signs of hepatic encephalopathy, active infection or hemorrhage within the last 4 weeks before the study, active alcohol consumption or symptoms of withdrawal and patients with serum creatinine >133 μmol/L or serum Na <130 mmol/L on two consecutive occasions, were excluded. Twenty six patients with Child A cirrhosis formed the group A. Twenty one Child B and 4 Child C patients formed the group B. The latter 4 patients were borderline for Child C. All subjects gave written informed consent before undergoing the procedures of the study. The study protocol was approved by Local Ethics Committee.Study procedures were performed at a Day Clinic of a University Hospital. All participants gave routine medical history and underwent physical examination. The following characteristics were recorded for each subject: age, sex, body height and weight, history of diabetes mellitus, smoking habits , concomitant medical treatment, peripheral oedema or ascites, confirmed by physical examination or recent imaging examination and aetiology of cirrhosis. Child score and MELD score  were calst Korotkoff sound was recorded as systolic blood pressure (SBP) and the 5th as diastolic blood pressure (DBP). Three measurements were taken for each subject with one min interval. HR was measured once after the 1st BP measurement, with palpation of the radial pulse for 30 sec.Office BP and HR were measured on two consecutive morning visits, by physicians trained according to the British Hypertension Society Protocol, using a mercury sphygmomanometer . MeasureAmbulatory BP and HR were monitored for 24 hours, on a routine working day, using validated oscillometric devices Spacelabs 90207 or 90217  . Measurest day of the study, after medical history was obtained, physical examination was performed and office BP measurements were made and before applying the ABP device, or on the 2nd day, after withdrawing the ABP device and performing the office BP measurements. Renin and aldosterone concentration was measured after serum specimens were centrifuged and frozen at below -20°C for <6 months. Routine laboratory methods were used for INR and biochemistry tests. Serum renin and aldosterone concentration was measured with Nichols Advantage® Direct Renin and Nichols Advantage® Aldosterone chemiluminescense methods .Blood samples for international normalized ratio (INR), total bilirubin, alanine and aspartate aminotransferases , albumin, sodium, creatinine, renin and aldosterone were taken with the subject sitting on a chair for at least 10 min, fasting for 8 to 12 hours and after he/she had been awake and active for at least one hour. Samples were drawn either on the 12 test was used to evaluate frequency differences of qualitative variables among two groups. Statistical correlations of office and ambulatory BP and HR measurements with each of the following markers, i.e. Child score, MELD score, total bilirubin, albumin, INR, ALT, AST, renin and aldosterone, were studied and Pearson correlation coefficients were calculated. Quantitative variables are presented as mean ± SD. Statistical software MINITAB INC  was used for all statistical procedures. A p value of < 0.05 was considered statistically significant.For each office visit average sitting SBP, DBP and HR were included in the analysis. Ambulatory SBP, DBP and HR readings were averaged to 24-hour, awake and asleep values, according to each individual subject's sleeping hours. Logarithmic transformation was performed in not normally distributed data . T-tests were used to evaluate the difference of the mean of quantitative variables among two groups. XFrom November 2003 until May 2006 60 consecutive patients were recruited. Five refused to participate, 3 were excluded due to history of hypertension, and one due to poor general condition (not fully ambulatory). Fifty-one patients completed the study, (32 men), with mean age 57.4 ± 11.3 (SD) years. The cause of cirrhosis was alcohol abuse, viral hepatitis and miscellaneous in 23, 20 and 8 patients respectively. Twenty six, 21 and 4 patients were Child A, B and C respectively. Child B and C patients were analyzed together (group B). Mean Child score was 6.7 in all patients, 5.3 in group A and 8.2 in group B. Mean MELD score was 11.7, 8.9 and 14.7, respectively. Demographic data and other characteristics of the participants are presented in Table Ambulatory and office BP and HR values are presented in Table The relationship between office and ambulatory BP and laboratory biochemical and hormonal markers is summarized in Table Both office and ambulatory HR measurements showed stronger correlations than BP parameters, positive with Child and MELD scores, total serum bilirubin, INR, renin and aldosterone and negative with serum albumin Table . CorrelaAwake-asleep differences in ambulatory measurements (dipping) revealed a few correlations with laboratory parameters. Correlations were negative between SBP dipping, renin and aldosterone concentration , negative between DBP dipping and aldosterone concentration , positive between HR dipping and albumin concentration  and negative between HR dipping and Child score . Comparisons between group A and group B regarding BP and HR awake-asleep dipping revealed contradictory and not statistically significant differences . Two patients have died, one due to hepatocellular carcinoma and another due to progressive liver failure. None of the abovementioned 3 patients was on b-blocker therapy before the study. The rest 48 patients were alive one year after study inclusion, with no further complications related to liver disease.This is the first study that evaluated the 24-hour BP and HR profile in relation to markers of liver function in patients with cirrhosis in fully ambulatory conditions. Two previous studies have assessed the ABP profile in patients with alcoholic cirrhosis, of whom about half were at Child C stage. Both of these studies have been conducted in hospitalized patients and continued diuretic treatment, which have probably influenced the study findings. These studies showed that ABP is lower in patients than in controls, especially during the day. Awake and asleep HR was higher in cirrhotic patients and awake-asleep variation was lower than in controls. BP and HR parameters correlated with indices of liver function. Among cirrhotic patients, only the difference in DBP between Child A and C reached statistical significance ,17.This study included cirrhotic, non-hospitalized, patients, of whom only 4 marginally fulfilled Child stage C criteria. Therefore, the differences in BP and HR between study groups had to be striking, in order to be revealed. This study intended to investigate the relationship of the 24-hour ambulatory BP and HR with markers of liver dysfunction. Therefore, only fully ambulatory patients were included in whom a few days withdrawal of drug treatment (diuretics and b-blockers) was acceptable. On the other hand, severely diseased patients in whom the diurnal variation of these hemodynamic parameters was distorted due to limited physical activity, which is outside the standards of ABP monitoring  and in w2 value for the association between HR of office visit 2 and serum renin, only 31% of the variation of HR could be explained by the renin variation (Table A consistent relationship between both the degree of BP reduction and tachycardia and the severity of hepatic dysfunction was shown in the present study. These findings are in line with previous observations showing that BP is reduced and HR was elevated in advanced liver disease -5. DBP ion Table . Attempton Table  suggestiAlthough 24-hour ambulatory values are considered more reliable than office measurements in the evaluation of BP and HR in hypertensive patients, this does not seem to be the case in the setting of cirrhotic patients -25. IndeAnother interesting finding is the reduced awake-asleep variation of BP and HR in patients with more severe portal hypertension, as suggested by higher renin and aldosterone levels. Reduced awake-asleep variation of BP and HR has also been demonstrated in patients with more severe hepatocellular dysfunction, as suggested by lower albumin levels. The presence of reduced awake-asleep variation in more advanced liver disease has also been reported by previous studies ,17,35,36This was a cross-sectional study investigating associations and was not designed to assess hard end-points. Moreover, the study sample is too small to allow conclusions in relation to outcome. Further research is needed, in order to investigate the association between hemodynamic parameters and hard endpoints such as survival and hospitalization.This study showed that HR, measured either with ABP monitoring or conventional office measurement, seems to be a more reliable marker of ongoing liver dysfunction than BP. Given that normally the range of HR is wide, it is not possible to define a threshold that might indicate severe liver insufficiency. An abnormal pattern of 24-hour BP and HR daily variation was observed probably due to lack of regulation of the aforementioned hemodynamic parameters from daytime to nighttime. This abnormal diurnal pattern was evident in advanced liver disease. In conclusion, these data do not support the use of 24-hour ambulatory BP and HR as a more accurate method than office measurements for the evaluation of the severity of liver insufficiency.The authors declare that they have no competing interests.GSS had the main idea for this study and prepared the first draft of the protocol, supervised the study execution and data analysis and contributed to data interpretation and manuscript preparation. DGT collected the study data, prepared the electronic spreadsheet, performed the statistical analysis and wrote the first draft of the manuscript. SPD was involved in study design and subjects' recruitment and contributed to data interpretation. AA was involved in subjects' recruitment and contributed to data interpretation and preparation of the manuscript. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/10/143/prepub


Monitoring of continuous blood pressure and cardiac output is important to prevent hypoperfusion and to guide fluid administration, but only few patients receive such monitoring due to the invasive nature of most of the methods presently available. Noninvasive blood pressure can be determined continuously using finger cuff technology and cardiac output is easily obtained using a pulse contour method. In this way completely noninvasive continuous blood pressure and cardiac output are available for clinical use in all patients that would otherwise not be monitored. Developments and state of art in hemodynamic monitoring are reviewed here, with a focus on noninvasive continuous hemodynamic monitoring form the finger. The primary evaluation of the hemodynamic condition is done by assessing heart rate (HR) and mean blood pressure (BP) as a surrogate of tissue perfusion. When these parameters change rapidly, a single measurement conveys insufficient information, making continuous measurement desirable . For con®  allows hemodynamic monitoring with both BP and CO continuously available in patients without an arterial line. Continuous BP is measured with a cuff around a finger and a pulse contour method calculates beat-to-beat CO. This review summarizes past and present developments in BP and CO measurement with a focus on continuous noninvasive finger cuff technology and its clinical applications.Although giving vital information, BP and HR due to their regulated nature frequently do not respond to substantial changes in intravascular volume, e.g. fluid administration or blood loss. Age and pre-existing cardiovascular morbidity complicate interpretation of these parameters further –9. In suThe first quantitative measurements of blood pressure were performed in animals by Hales in 1733 , 25. EarPractical noninvasive (intermittent) BP measurement became possible when Riva-Rocci presented his air-inflatable arm cuff connected to a manometer in 1896 , 33. By “Semi-continuous noninvasive methods” based on radial arterial tonometry require an additional arm cuff to calibrate arterial pressure –43. The ®”, developed by Wesseling et al. Physiocal analyzes the curvature and sharpness of the plethysmogram during short periods of steady cuff pressure levels [Continuous noninvasive measurement of BP is possible using finger cuff technology. The first generation using this technology was introduced with the Finapres™ device developed by Wesseling et al.  in the ee levels . A set oe levels . Generale levels .The Finapres device showed the arterial pressure as measured at the finger. However, since the brachial site is the clinical standard for noninvasive BP measurement later devices such as the Finometer  and the Nexfin  show the brachial pressure reconstructed from the finger pressure. Reconstruction reverses the physiological waveform transformation that waves experience while travelling through the arterial system see Fig. . The proBoth the Finometer and the Nexfin use a system that automatically corrects for hydrostatic differences in pressure when the hand is not at heart level. The “finger side” of the heart reference system is fixed next to the finger on which the cuff is applied and the “heart side” at right atrial level. The hydrostatic difference is measured and the recordings are continuously corrected to give BP at heart level. The CNAP device uses repeated upper arm cuff measurements to compensate for hydrostatic pressure differences.Tracking of changes in BP was already considered good in earlier devices using the finger cuff technology . With thThe BP measurement with the latest generation finger cuff technology device, the Nexfin, was validated against both invasive and noninvasive methods , 63, 64.The Nexfin has also been evaluated in an emergency care setting where the authors concluded that continuous BP and HR measured by the Nexfin device showed reasonable agreement when compared with the intermittent values obtained by automated ED equipment . HoweverVarious methods to measure CO are being used and can be characterized by their invasiveness or their ability to measure continuously. Table Indicator dilution techniques use the Stewart-Hamilton  equationDetermination of CO with the thermodilution method is in general restricted to the critically ill patients or patients at high risk associated with an intervention or with serious comorbidities. The use of intermittent estimation of CO by thermodilution is decreasing –22 owing® system applies a bolus indicator dilution method for CO measurement using lithium chloride as an indicator. Detection of the indicator in arterial blood through a lithium-sensitive electrode produces a lithium concentration–time curve [® system also utilizes pulse contour analysis of intra-arterial BP for continuous CO monitoring, whereas transpulmonary thermodilution is used for calibration [In their publication of 1904 Erlanger and Hooker determined cardiac SV from characteristics of the arterial pressure pulse . Pulse cibration . Althougibration –77, but In general, calibration may improve the accuracy of the absolute values, but is not essential as long as changes in CO are accurately tracked. Continuous tracking is necessary to assess the response to a relatively fast hemodynamic change, such as a fluid challenge or passive leg-raising. Responding to the challenge with a certain increase in CO indicates that the patient is fluid responsive and thus may benefit from receiving additional fluid , 9, 78. Noninvasive and (semi-)continuous tracking of changes in SV can be accomplished by thoracic electrical impedance –82, ultrc represents the impedance that the ventricle encounters during ejection. Its value is determined by the interaction of the capacity of the proximal aorta to store volume  and the blood mass that needs to be accelerated (inertance L). Zc is equal to the square root of L/C. Windkessel compliance Cw is equal to the sum of the compliances of all arteries, mainly the ascending and descending aorta, and it represents the ability to elastically store the stroke volume ejected by the heart. Peripheral resistance Rp equals the sum of all resistances of small arteries and arterioles, representing the resistance to the flow of blood. In Wesseling’s Modelfow method a Windkessel model is used in which Zc and Cw are nonlinear functions of pressure, age, gender, height and weight [In order to determine beat-to-beat SV and CO from noninvasive continuous BP from the finger a pulse contour method based on a physiological model of the circulation is used. In the early 1970s Wesseling developed the cZ pulse contour method making use of the systolic part of the pressure curve  unmonitored. Examples include orthopedic surgery in the elderly, abdominal surgery and bariatric surgery. In obese patients upper arm cuffs for BP measurement often do not fit, and thigh cuffs are needed, or a brachial cuff is used on the forearm. While the arms and legs can increase significantly in circumference, fingers do get larger but usually not up to the degree that the finger cuff does not fit.For surgical patients volume treatment corrects a perioperative volume deficit and attenuates negative influences on the central blood volume (corresponding to the diastolic volume of the heart) caused by, e.g. hemorrhage, repositioning of the patient, anesthesia and ventilation. Interpretation of the heart rate (HR) and arterial pressure responses to a reduced central blood volume is complex. Cardiovascular variables are regulated and affected by influences other than central blood volume, including surgical stress and anesthesia . This maNoninvasiveness and ability for quick assessment allows the characterization of hemodynamic profiles of patients in the Emergency Department and following of possible changes. It was demonstrated by Nowak et al.  that emeIn cardiac resynchronization therapy, the atrioventricular delay or the inter-ventricular delay can be chosen to optimize SV. In a study comparing noninvasive pulse contour SV with echo Doppler aortic velocity–time integral while optimizing the atrioventricular delay, a good agreement was found and the authors concluded that Nexfin is a promising tool in individual optimization .During invasive electrophysiology procedures, it is common practice to use an intra-arterial line to monitor BP in critical situations of hypotension caused by tachyarrhythmias or by intermittent incremental ventricular temporary pacing till to the maximally tolerated systolic BP fall. During such procedures Nexfin recorded reliable BP waveforms notwithstanding the presence of tachyarrhythmia . The autNoninvasive BP with finger cuff technology has been used for a long time in the diagnosis and management of syncope  and is uAs indicated by De Waal et al.  the idea


Background. We investigated the association between blood pressure control and common cardiometabolic risk factors from a global and regional perspective. Methods. In the present analysis of a large cross-sectional i-SEARCH study, 17.092 outpatients receiving antihypertensive treatment were included in 26 countries. According to clinical guidelines for the management of arterial hypertension, patients were classified based on the level of seated systolic/diastolic blood pressure (SBP/DBP). Uncontrolled hypertension was defined as SBP/DBP ≥140/90 mmHg for non-diabetics, and ≥130/80 mmHg for diabetics. Results. Overall, mean age was 63.1 years, 52.8% were male, and mean BMI was 28.9 kg/m2. Mean SBP/DBP was 148.9/87.0 mmHg, and 76.3% of patients had uncontrolled hypertension. Diabetes was present in 29.1% with mean HbA1c of 6.8%. Mean LDL-cholesterol was 3.2 mmol/L, HDL-cholesterol 1.3 mmol/L, and triglycerides 1.8 mmol/L; 49.0% had hyperlipidemia. Patients with uncontrolled hypertension had a higher BMI (29.4 versus 28.6 kg/m2), LDL-cholesterol (3.4 versus 3.0 mmol/L), triglycerides (1.9 versus 1.7 mmol/L), and HbA1c (6.8 versus 6.7%) than those with controlled blood pressure . Conclusions. Among outpatients treated for arterial hypertension, three quarters had uncontrolled blood pressure. Elevated SBP/DBP and uncontrolled hypertension were associated with increasing BMI, LDL-cholesterol, triglycerides, and HbA1c, both globally and regionally. Arterial hypertension represents a major cause of cardiovascular morbidity and mortality, and affects approximately 1 billion individuals worldwide . Despite2), WC (cm), diabetes mellitus (%), HbA1c (%), LDL/HDL-cholesterol (mg/dL), triglycerides (mg/dL), and C-reactive protein . Furthermore, cardiometabolic risk was determined according to blood pressure control. Uncontrolled hypertension was defined as SBP/DBP ≥140/90 mmHg for non-diabetic and ≥130/80 mmHg for diabetic patients.A large cross-sectional International Survey Evaluating microAlbuminuria Routinely by Cardiologists in patients with Hypertension (i-SEARCH) study was conducted in 2005-2006 in cardiology outpatient clinics in 26 countries world-wide as described previously . 21.794 All analyses were performed both globally and separately for the following 5 geographical regions: Northern Europe , Southern Europe , North America (Canada), Middle East  and Asia . The analysis population comprised patients with no missing data for SBP/DBP and the respective metabolic parameter. A linear model was used to estimate the least square means of BMI, WC, HbA1c, LDL-cholesterol, HDL-cholesterol, triglycerides, and CRP for each level of SBP/DBP and by region. The model was adjusted for age and gender ; for age, gender, and antidiabetic treatment (HbA1c); and for age, gender, and the presence of diabetes . A logistic regression analysis was conducted to estimate the prevalence of diabetes for each level of SBP/DBP and region, adjusted for age and gender . Continuous variables are depicted as adjusted means (least square means) ± standard deviations and categorical variables as percentages .Overall, mean patient age was 63.1 years out of which 52.8% were male. Mean SBP/DBP was 148.9/87.0 mmHg, and 76.3% of patients had uncontrolled blood pressure. Diabetes was present in 29.1% of patients with mean HbA1c of 6.8%. Mean LDL-cholesterol was 3.2 mmol/L, mean HDL-cholesterol 1.3 mmol/L, and mean triglycerides 1.8 mmol/L, and 49.0% of patients had hypercholesterolemia. MAU was present in 58.8% of patients, and mean CRP was 0.92 mg/dL. 38.8% of patients were present or past smokers, and 28.6% had a family history of a myocardial infarction. For concomitant cardiovascular disease and regional distribution of individual parameters, see 2), in patients with DBP ≥110 versus <90 mmHg (30.3 versus 28.5 kg/m2), and in patients with uncontrolled versus controlled blood pressure (29.4 versus 28.6 kg/m2) . Mean WC was higher in patients with SBP ≥180 versus <120 mmHg (101.2 versus 97.5 cm), in patients with DBP ≥110 versus <90 mmHg (103.2 versus 98.8 cm), and in patients with uncontrolled versus controlled blood pressure (100.7 versus 98.8 cm) . By comparing the association of BMI and WC across the regions, an increase in BMI with increasing SBP/DBP could be observed for Northern, Southern Europe and the Middle East region, whereas in North America and Asia, BMI decreased with increasing SBP, and increased with DBP . Only in Northern and Southern Europe, uncontrolled versus controlled blood pressure was associated with an increase in BMI (P < 0.0001). With increasing SBP/DBP an increase in WC could be observed for Northern Europe, Southern Europe, North America, and Middle East , whereas an inverse relationship between SBP/DBP and WC was observed for Asia (P < 0.0001). For details see Tables Globally, the mean BMI was higher in patients with SBP ≥180 versus <120 mmHg (29.5 versus 28.2 kg/mP < 0.0001). Diabetes was present in 30.9% of patients with a DBP <90 mmHg and 28.1% of patients with a DBP ≥110 mmHg (P < 0.0001). There was no difference in the prevalence of diabetes in patients with uncontrolled versus controlled hypertension in the overall population . Mean HbA1c increased from 6.7% in patients with an SBP of <120 mmHg to 7.0% in patients with an SBP of ≥180 mmHg (P < 0.0001), from 6.8% in patients with a DBP <90 mmHg to 6.9% in patients with a DBP ≥110 mmHg (P < 0.0027), and from 6.7% in patients with controlled to 6.8% in patients with uncontrolled blood pressure (P < 0.0001). A significant increase in HbA1c with SBP and DBP was observed in Northern and Southern Europe, but not in Northern America, Middle East, and Asia. For details, see Tables The prevalence of diabetes was 28.4% in patients with an SBP <120 mmHg and 32.6% in patients with an SBP ≥180 mmHg . Mean HDL-cholesterol was 1.3 mmol/L, and there was no association between HDL in patients with uncontrolled versus controlled hypertension (P = 0.13). Triglycerides increased from 1.5 mmol/L in patients with an SBP <120 mmHg to 1.9 mmol/L in patients with an SBP ≥180 mmHg, and from 1.7 mmol/L in patients with a DBP <90 mmHg to 1.9 mmol/L in patients with a DBP ≥110 mmHg (P < 0.0001 for both parameters). Triglycerides were also higher in patients with uncontrolled versus controlled blood pressure . The regional comparison revealed an increase in LDL-cholesterol as well as triglycerides with increasing SBP and DBP for all 5 regions, whereas no association between HDL-cholesterol and blood pressure levels was observed. For details see Tables The mean LDL-cholesterol was higher in patients with SBP ≥180 versus <120 mmHg (3.4 versus 2.9 mmol/L), in patients with DBP ≥110 versus <90 mmHg (3.5 versus 3.0 mmol/L), and in patients with uncontrolled versus controlled blood pressure (3.4 versus 3.0 mmoL) . An increase in CRP with SBP and DBP was observed in Northern Europe and Northern America only. For details see The mean CRP was higher in patients with SBP ≥180 versus <120 mmHg (1.1 versus 0.7 mmol/L), in patients with DBP ≥110 versus <90 mmHg (1.0 versus 0.8 mmol/L), and in patients with uncontrolled versus controlled blood pressure (1.0 versus 0.8 mmol/L) (In the present analysis of a large international study of patients treated for arterial hypertension, both an elevated SBP and DBP, and uncontrolled hypertension were associated with increasing BMI, WC, LDL-cholesterol, triglycerides, HbA1c, and CRP, whereas there was no association between HDL-cholesterol and blood pressure levels. Furthermore, the presence of diabetes was associated with an elevated SBP only. The observed associations between blood pressure levels and metabolic parameters were consistent across all 5 geographic regions, even though some associations were not significant, especially in regions with a low sample size for individual parameters, such as the Middle East, Asia, and—partly—North America. Based on the data presented herein, it appears difficult to draw any firm conclusions on stronger and weaker associations of individual cardiometabolic parameters with blood pressure for some regions as compared to the overall population or the European region. Furthermore, regional samples cannot be necessarily considered as ethnically/culturally homogenous and any regional analysis might be confounded by differences in the genetics or dietary habits of study participants. Overall, our data are consistent with findings from other investigations, where the prevalence of additional cardiometabolic risk factors among hypertensive patients was as high as 82% and was associated with poor blood control in the United States . Of inteOur results confirm the significant association between systemic hypertension and other cardiometabolic risk factors, including visceral obesity, diabetes, and hyperlipidemia. Obviously, the vast majority of patients with arterial hypertension are at multiple risk of cardiovascular disease. Therefore, our data emphasize the statement of current joint guidelines of the European Society of Hypertension and European Society of Cardiology concerning an intensified diagnostic and therapeutic measures in patients with an elevated SBP and DBP . Reasons for the observed association between increasing blood pressure and the presence of cardiometabolic risk factors remain to be determined. It is a subject of an ongoing debate, whether patients with an elevated SBP and DBP simply more frequently have an unfavorable cardiometabolic risk profile with poorly treated cardiovascular parameters or whether there is a causal relationship between a high systemic blood pressure and the deterioration of multiple cardiometabolic markers. The intra-abdominal obesity and recently discovered endogenous gland activity of adipose tissue producing various hormones and cytokines, such as angiotensinogen, insulin, resistin, lipoprotein lipase, leptin, lactate, plasminogen activator inhibitor, adipsin, and interleukin, seem to play a central role in the development of disadvantageous cardiometabolic profile and may represent the causal link between arterial hypertension, atherogenic dyslipidemia, diabetes, thrombosis, and inflammation . This hyProinflammatory mechanisms are thought to be a hallmark of the cardiovascular disease process, notably in disease states such as hypertension. These findings are often exacerbated by the increasing prevalence of obesity worldwide. Obesity is often accompanied by high plasma levels of nonesterified fatty acids that cause insulin resistance in skeletal muscle and overload the liver with lipids, producing fatty liver and atherogenic dyslipidemia . Fat accLifestyle changes, including an increased prevalence of obesity and the metabolic syndrome contribute to the incidence of hypertension , 22. At The strengths of our study include the prospective enrollment of a large sample of treated hypertensive patients and the collection of detailed information on systemic blood pressure and cardiometabolic parameters. P-values should be interpreted with caution. Neither a uniform methodology nor a central laboratory was used for measurements of blood pressure and cardiometabolic parameters. Thus, differences in region-specific techniques and measurements may have influenced the comparability of results. Another study limitation is the fact that the present analysis of lipid measurements was not adjusted for statin use. However, the analysis was adjusted for age and, therefore, for age-dependent rise of LDL-cholesterol and triglycerides, and indirectly also for statin use because the elderly more often receive statin treatment. Finally, our study was not designed to explore reasons for the observed association between an elevated blood pressure and cardiometabolic risk factors.One study limitation is the fact that the numbers of enrolled patients differ substantially between the 5 regions. Therefore, the regional comparisons and An elevated SBP and DBP, but also uncontrolled hypertension, are associated with an increase in cardiometabolic risk, independently of the geographic region. These findings not only highlight the importance of a thorough risk-stratification of patients with arterial hypertension, but also the necessity of treating concomitant cardiometabolic risk factors in order to decrease the overall cardiovascular risk of patients with arterial hypertension.


Background. It has been widely suggested that analyses considering multilocus effects would be crucial to characterize the relationship between gene variability and essential hypertension (EH). Objective. To test for the presence of multilocus effects between/among seven polymorphisms (six genes) on blood pressure-related traits in African-derived semi-isolated Brazilian populations (quilombos). Methods. Analyses were carried out using a family-based design in a sample of 652 participants (97 families). Seven variants were investigated: ACE (rs1799752), AGT (rs669), ADD2 (rs3755351), NOS3 (rs1799983), GNB3 (rs5441 and rs5443), and GRK4 (rs1801058). Sensitivity analyses were further performed under a case-control design with unrelated participants only. Results. None of the investigated variants were associated individually with both systolic and diastolic BP levels  or EH (as a binary outcome). Multifactor dimensionality reduction-based techniques revealed a marginal association of the combined effect of both GNB3 variants on DBP levels in a family-based design (P = 0.040), whereas a putative NOS3-GRK4 interaction also in relation to DBP levels was observed in the case-control design only (P = 0.004). Conclusion. Our results provide limited support for the hypothesis of multilocus effects between/among the studied variants on blood pressure in quilombos. Further larger studies are needed to validate our findings. Common polymorphisms at multiple blood pressure-related loci from distinct biological pathways are likely to contribute to the genetic component of essential hypertension (EH) in humans –3. Althoquilombos (presently known as quilombo remnants), were founded in isolated areas, in different Brazilian regions, by either runaway or abandoned African slaves [quilombos, such as a decrease in the intensity of agricultural activities and the nutrition transition, are associated with a larger frequency of common diseases such as obesity and essential hypertension [Approximately 4 million Africans were brought to Brazil as slaves over a period of four centuries. Before the abolition of slavery in Brazil in 1888), many communities, named n slaves . Recent rtension , 888, many quilombos. We hypothesized that multilocus effects between or among seven widely studied polymorphisms in six genes of major importance for blood pressure regulation might modulate the risk of essential hypertension in this peculiar population, characterized by historical inbreeding and high prevalence of cardiovascular risk factors [In this paper, we present the results of a carefully conducted family-based association study (652 participants from 97 informative families) in semi-isolated Brazilian populations of African ancestry, which includes individuals from remnants of  factors .quilombos, which encompass partially genetically isolated communities [quilombos share a particularly homogeneous rural lifestyle and environment. Further information on these populations are found elsewhere [Participants were ascertained from African-derived Brazilian populations named munities , 10. Themunities , 8. Impoquilombo communities , located in the Vale do Ribeira region, São Paulo State (Southern Brazil). Figure S1  presents the numbers of participants at each stage of the study.Briefly, the sample consisted of individuals aged over 17 years with clinical and anthropometric data. Participants were sampled from 12 quilombos are isolated populations, a detailed clinical evaluation was not feasible. However, participants with diabetes or suspected secondary forms of hypertension were excluded.Clinical evaluation occurred at multiple visits performed between 2003 and 2010. Due to the fact that Blood pressure was measured after 15 min of rest in a sitting position. Two measurements were obtained by a physician from each participant at 5 min intervals. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) values were means of the two physician-obtained measurements.The primary phenotype was the risk of essential hypertension classified according to the World Health Organization (WHO) criteria (SBP ≥ 140 and/or DBP ≥ 90 and/or use of antihypertensive medication). Blood pressure was also evaluated as a continuous trait. In order to avoid shrinkage in estimated effects for continuous variables, blood pressure levels in participants taking antihypertensive drugs were adjusted by adding 15 mmHg and 10 mmHg to the SBP and DBP, respectively, as recommended previously .Normotensive control participants were defined as those individuals with a SBP < 140 and DBP < 90 and no history of use of antihypertensive drugs. We used the same rational described previously to choose the set of seven variants from six genes . BrieflyACE, insertion/deletion in intron 16—rs1799752), and angiotensinogen ; (2) sodium balance: β-adducin ; (3) NO-dependent vasodilatation: nitric oxide synthase endothelial ; (4) intracellular signal transduction ; (5) dopaminergic system: G protein-coupled receptor kinase type 4  might be associated with blood pressure traits under a multilocus perspective. Further information on markers investigated is provided in Table S1 .We hypothesized that seven variants from six major candidate genes directly involved in the (1) renin-angiotensin-aldosterone system: angiotensin-I-converting-enzyme (Alu insertion in the ACE were determined by polymerase chain reaction (PCR) and electrophoresis in agarose gels; all carriers of DD genotype (without Alu insertion) were genotyped twice. Genotypes for marker in the GNB3 (G-350A) were determined by PCR followed by restriction fragment-length polymorphism analyses; all carriers of A allele were regenotyped by direct sequencing. The markers in AGT, NOS3, GNB3 (C825T), ADD2, and GRK4 were genotyped following a minisequencing method using the MegaBace SnuPe Genotyping Kit . Primers sequences are available as Supplementary Material . Positive (previously tested samples with known genotype) and negative (buffer only) controls were included in each batch as a quality control measure. Genotyping was performed blinded to clinical status. DNA was extracted from whole blood using standard procedures. Genotypes for the t-test for independent samples was used to investigate differences between groups for approximately normally distributed variables. When the distribution of the variables was skewed, the nonparametric Mann-Whitney U test was applied. Deviations from the Hardy-Weinberg equilibrium were tested by an exact approach [Data were expressed as means ± standard deviation (SD), median (interquartile range), or absolute number (percentage) when appropriate. The approach . We performed two approaches of analysis: (i) a family-based design and (ii) an unrelated case-control design .Family-based association test (FBAT) analyses were performed with the FBAT program. The FBAT framework uses a variety of generalized linear models to perform tests similar to the transmission-disequilibrium test, allowing for the analysis of complex pedigrees . We assuhigh risk, low risk or no evidence based on the direction and magnitude of the association [P values were computed by a resampling approach with 10,000 permutations. A full description of this technique is presented in detail elsewhere [Under a family-based design, we investigate all possible two-way multilocus effects using the recently proposed flexible family-based multifactor dimensionality reduction (FAM-MDR) approach . The curociation . FAM-MDRlsewhere , 15.http://www.r-project.org/), THESIAS 3.1 (http://ecgene.net/genecanvas/), and GMDR . Statistical significance was set at the 5% level (one-tailed for GMDR-based models and two-tailed for the remaining tests). In sensitivity analyses, we also performed analysis considering 384 unrelated participants. For single-locus analysis, we used the MAX3 statistic which selects the largest test statistic from the dominant, recessive, and additive models . To examquilombo communities, we included 652 participants with complete data, representing approximately 43% of the total quilombo population. There were 97 informative families with an average number of subjects per family of 10.5 (ranging from 3 to 313). The largest family with 313 members represents a complex pedigree with a strong historical founder effect. This family has been partitioned accordingly in FBAT analysis. From a total of 1521 potentially eligible inhabitants across 12 P = 0.169). The prevalence of essential hypertension (EH) was 40.5% in women and 44.6% in men, a higher frequency when compared to admixed Brazilian populations –21 and AGNB3 variants on blood pressure (data not shown).In the single-locus FBAT analysis, no variant was significantly associated with any of the three examined blood pressure-related phenotypes, namely systolic and diastolic blood pressure  levels and EH . FBAT-baGNB3 variants (C825T and G-350A) on DBP levels (P = 0.04).The family-based multifactor dimensionality reduction (FAM-MDR) method was applied to blood pressure as a continuous phenotype . As shown in We next performed a case-control study with unrelated subjects only, which yielded a total of 384 unrelated participants, whose clinical characteristics are shown in GNB3 variants based on unrelated participants (P = 0.152).Haplotypic analyses of both G-350A and C825T icipants  indicatequilombos  and had a high cross-validation consistency (90%).GMDR-based models were constructed to exhaustively identify all possible two- to four-locus models that potentially have an influence on the risk of hypertension and/or modulate SBP and DBP levels in uilombos . These aIt has been shown that analyses focusing on biologically plausible candidate genes might be a strategy to circumvent the problem of limited coverage of current genome-wide association (GWA) platforms. This strategy holds the promise of increasing the density of markers in regions coding for known blood pressure-related effectors that are likely to be missed by GWA studies in hypertension .quilombos). As described previously, quilombos may be an important target population for genetic studies of complex diseases, since this population displays peculiar genetic and environmental characteristics [quilombos are known not only to have a large contribution of African genes, but also strong founder effects, a substantial degree of inbreeding, and high prevalence of essential hypertension as well as overweight [ Here, we present a comprehensive investigation about the potential role of seven variants (from six candidate genes directly involved in the blood pressure regulation) in the susceptibility of essential hypertension in a semi-isolated, African-derived population  the effect of both GNB3 variants (C825T and G-350A polymorphisms) on DBP levels in a family-based design and (ii) the significant NOS3-GRK4 interaction also in relation to DBP levels in the unrelated case-control design. Using different methodological approaches  and study designs (family-based and unrelated case-control designs), our investigation did not suggest an important contribution of the studied markers in the risk of essential hypertension in GNB3 locus in hypertension provide evidence for heterogeneity in the genetic effects across populations [GNB3 variants on blood pressure levels [Meta-analyses addressing the role of the C825T polymorphism at the ulations . Howeverulations . Althouge levels . Thus, oNOS3 markers as significant factors influencing blood pressure levels [NOS3-GRK4 model was the only combination found to achieve nominal significance with an adequate cross-validation consistency. Recently, despite the use of different markers, the NOS3-GRK4 synergistic effect on blood pressure was also observed in an African American sample [GRK4 are associated with both impaired natriuresis and salt-sensitive hypertension [NOS3-GRK4 model might be the cumulative effect from both pathways. Indeed, a diminished natriuresis along with an impaired endothelium-dependent  vasodilatation might lead to increased blood pressure levels. Nonetheless, the plausibility of the observed multilocus effects along with its generalizability across different populations requires further and detailed investigations.Recently, gene-centric approaches have revealed e levels . These oe levels , 29. Intn sample , suggestn sample , and genrtension , 32. ThuMajor limitations of our study include: first, the small number of participants investigated, that is, our samples are underpowered to detect typical main effects of genetic variants associated with common traits and second, lack of information on serum lipids as well as accurate information on smoking habits. In fact, lipids were not investigated due to technical restrictions. Furthermore, we observed that there was inaccurate reporting of smoking status by participants mainly due to heterogeneity in the definition of smoking. For example, a high proportion of participants reported to smoke homemade cigarettes, but failed to consider this as a “smoking habit”. As a result, both lipids and smoking status were not included in adjusted analyses.Furthermore, our results should be carefully interpreted because correction for multiple testing was not performed in our analyses. As this is a hypothesis testing study, we considered that correction for multiple testing would be overly conservative and might lead to a substantial loss of statistical power.Finally, it is worth of mentioning that the present study does not invalidate the hypothesis of gene-gene interactions/multilocus effects between or among the studied variants nor single-loci effects on blood pressure. Our null associations might plausibly be associated with low statistical power and the reduced panel of markers investigated. quilombos but highlight potential multilocus association signals that should be investigated in further studies with larger samples.In conclusion, our results do not support the hypothesis of significant association between the seven investigated variants and the risk of essential hypertension in The supplementary material includes one figure  and one Table (Table S1). Figure S1 shows all the steps in the selection of subjects for the different types of analyses, both family-based studies and case-control studies. Table S1 provides complete information about the molecular markers selected for association studies with phenotypes related to hypertension, including nucleotide sequences of primer pairs and genomic identification of the polymorphisms.Click here for additional data file.Click here for additional data file.


Omega-3 fatty acids carry major roles in mediating inflammation, immune response, lipid peroxidation and lipoprotein metabolism. Diversity of health benefits have been attributed to dietary supplementation with omega-3 fatty acids in transplant and nontransplant settings. Several studies in renal transplantation have suggested that supplementation with omega-3 fatty acids may lead to significant clinical benefits. However, the extents of these benefits are variable and published data had not coincided with positive findings.The aim of this study was to evaluate the effectiveness of omega-3 supplementation on the lipid profile and lipid peroxidation in patients underwent kidney transplant.Thirty cases had been selected with stable allograft function following at least six months of transplantation. The serum levels of lipids including triglyceride, low density lipoprotein (LDL), high density lipoprotein (HDL), very low density lipoprotein (VLDL), total cholesterol and indices of lipid peroxidation  were measured by biochemical techniques at the baseline. Two months following prescription of oral omega-3 (3 g/day), the biochemical measurements were repeated and the differences were analyzed.Of thirty patients, 12 were male and 18 were female with the mean age of 45.3 ± 13.0 (18-65) years. At the baseline, the serum levels of MDA and APO B were 3.5 ± 1.3 and 148.3 ± 20.4 ng/dL respectively. At the end of two months following intervention, they were 3.2 ± 1.2 and 145.7 ± 19.0 ng/dL, respectively (P > 0.05). Correspondingly, at the baseline the serum levels of triglyceride, LDL, VLDL and total cholesterol were 171.1 ± 58.7, 106.9 ± 31.8, 42.2 ± 4.0, 145.7 ± 33.2 and 181.2 ± 35.1 mg/dL and after intervention they were 162.4 ± 82.5, 99.4 ± 35.1, 44.6 ± 6.3, 140.3 ± 33.1 and 170.9 ± 38.3 mg/dL, respectively (P > 0.05). There was no significant difference between the males and females in this instance.Our results seem to indicate that oral omega-3 may promote the lipid profile and indices of lipid peroxidation in patients following kidney transplantation however extents of these effects are not significant. One of the common metabolic disorders following kidney transplantation is hyperlipidemia and lipid profile disorder and it is associated with poor prognosis . In kidnThe aim of this study was to assess effect of omega-3 on lipid profile in kidney transplanted patients. If there is a positive effect of omega-3 on serum lipids, unwanted complications can be prevented in these patients with a prophylactic prescription.In this study, 30 kidney allograft recipients who had the necessary inclusion criteria's were selected. Omega-3  as 1 gram soft gel capsule was administered three grams per day after meals for two months. This study was performed from February 2009 to February 2010 in university hospitals of Tabriz University of Medical Sciences. Inclusion criteria were defined as 1) Individual consent to participate in this study; 2) Adult kidney allograft recipients; 3) No history of treatment with omega-3 or consumption of fish; 4) A period of at least 6 months after kidney transplantation. We excluded patients who had drug intolerance, active infectious or inflammatory disease. These patients were on maintenance immunosuppressive therapy including Cyclosporine  Mycophenolate mofetile  and Prednisolone. Serum level of malonyl dialdehyde (MDA), apo protein A1 (APO A1), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), very low density lipoprotein (VLDL) and total cholesterol, Na+, K+, serum creatinine (Cr) and blood urea nitrogen (BUN) were measured at baseline and following two months at the end of the study. Lipid profile and lipid peroxidation status and other laboratory parameters were measured by standard biochemical methods. Malonyl dialdehyde was assessed as malonyl dialdehyde like material (MDA-LM) by the thiobarbituric acid assay, according to the method which was defined by Smith et al. . Mean serum MDA was 3.5 ± 1.3 ng/mL before omega 3 administration and reached 3.2 ± 1.2 ng/mL following two months of omega 3 supplementations that, at the end of study, showed no significant change (P > 0.05). Serum Apo B level was 148.3 ± 20.4 ng/mL before the study and 145.7 ± 19 ng/mL at the end of study without significant changes (P > 0.05). There was a non-significant change in lipids level, serum creatinine (Cr) and blood urea nitrogen (BUN) and other laboratory results at the end of the study (P > 0.05) . There wChronic kidney disease (CKD) is one of the most important public health problems which leads to dialysis and transplantation . The incIn this study, we assessed lipid profile and peroxidation changes in kidney transplantation, 2 months following omega-3 prescriptions with doses of 3 g/day. Although, several studies were done regarding the effect of omega-3 (fish oil) in kidney transplanted patients, but there was no study regarding parameters related to lipid peroxidation change after omega-3 intake. Lim and et al in a meta-analysis assessed the results of 16 studies. Their findings showed that omega-3 prescriptions in kidney allograft recipients did not have a significant effect on organ or patients’ survival, acute rejection rate or kidney’s function. When compared with a placebo, omega-3 was associated with a lower diastolic blood pressure and higher HDL level. Therefore there was no sufficient evidence from this study to recommend omega-3 intake to improve renal function . Our resIn a study by Kooijmans et al. 25 kidney transplanted patients that ingest cyclosporine were assessed. Omega-3 supplementation was prescribed with dose of 6 g/day in these patients and followed up for 12 months. This study demonstrated that there were no significant differences between two groups (case and control groups) regarding kidney function parameters, blood pressure and acute rejection and laboratory parameters. For that reason, they recommended that omega-3 should not be used for kidney transplanted patients . Our stuIn conclusion, consistent with previous studies, this study didn’t show any significant effect of omega 3 supplementation on lipids profile and lipid peroxidation. Further studies with more sample size and a longer duration follow up is recommended.


Albuminuria is a marker of glomerular damage in Sickle Cell Disease (SCD). In this study, we sought to determine the possible predictors of albuminuria in the two more prevalent genotypes of SCD among the Jamaica Sickle Cell Cohort Study participants.An age-matched cohort of 122 patients with HbSS or HbSC genotypes had measurements of their morning urine albumin concentration, blood pressure, body mass index, haematology and certain biochemistry parameters done. Associations of albuminuria with possible predictors including hematological parameters, reticulocyte counts, aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels were examined using multiple regression models.A total of 122 participants were recruited . 25.9% with HbSS and 10.8% with HbSC disease had microalbuminuria  whereas 16.5% of HbSS and 2.7% of HbSC disease had macroalbuminuria . Mean arterial pressure, hemoglobin levels, serum creatinine, reticulocyte counts and white blood cell counts were statistically significant predictors of albuminuria in HbSS, whereas white blood cell counts and serum creatinine predicted albuminuria in HbSC disease. Both markers of chronic hemolysis, i.e. AST and LDH levels, showed no associations with albuminuria in either genotype.Renal disease, as evidenced by excretion of increased amounts of albumin in urine due to a glomerulopathy, is a common end-organ complication in SCD. It is shown to be more severe in those with HbSS disease than in HbSC disease. Rising blood pressure, lower hemoglobin levels and higher white blood cell counts are hints to the clinician of impending renal disease, whereas higher rates of hemolysis do not appear to play a role in this complication of SCD. Chronic renal failure is common in the Jamaican population with a prevalence of 327 per million persons Proteinuria is known to be a frequent finding in SCD A descriptive, observational, cross- sectional study was performed at the Sickle Cell Unit (SCU) of the Tropical Medicine Research Institute, The University of the West Indies from January - February 2006.The study was granted ethical approval by the University of the West Indies/University Hospital of the West Indies Ethical Committee. The study was designed and performed in adherence with the Declaration of Helsinki. Written, informed consent was obtained from all participants involved in the study.These patients have attended the SCU and have participated in the JSCCS since birth The participants had measurements of their morning urine albumin concentration using an immunoturbidimetric assay on Alcyon™ 300 Falcor. Three measurements of sitting blood pressure and pulse rate were taken at 5-minute intervals using a Dynamap®. The averages of the three determinations were used in the study. Mean arterial pressure was calculated from the mean systolic and diastolic blood pressure values as [1/3(Systolic pressure) + 2/3(Diastolic pressure)].Height was measured with a wall- mounted Staidiometer and weight was measured using a lever balance.Blood samples were collected from each subject for various hematological and biochemical measurements and stored at −70°C until analysis was done.Descriptive statistics e.g. means, standard deviations and frequency counts were used as appropriate. We used two sample t-tests to test for differences between means in continuous outcome measurements by genotype.Random urine albumin values were left censored at <4.0 mg/L as this represented the lower limits of detection for the albumin assay. Fifty seven (47%) observations were censored and for them, we set the value of albumin concentration to 2.0 (4.0/2) mg/L. Albumin- creatinine ratios (ACR) were calculated using this value for albumin concentrations. Microalbuminuria was defined as ACR 30–300 mg/g of creatinine, and macroalbuminuria as >300 mg/g of creatinine. As the distribution of the ACR was right skewed, it was normalized using log transformation. To determine the predictors of albuminuria, a series of multiple linear regressions with log ACR as outcome were performed. The potential predictors included hematology, anthropometry, blood pressure, age, and gender. Predictors of albuminuria were selected using a manual procedure after adjusting for gender. Models were compared using the partial F statistic. As the distributions of hematological variables were different by genotype, regressions models incorporating these variables were performed separately by genotype. Significance was defined at an alpha level of 0.05.Data was analyzed using Stata Software version 10.0 for Windows™ .A total of 122 participants were included in the study. Of these, 69.7%  were of HbSS genotype and 30.3%  were HbSC. The mean age of the sample was 28.6 +/− 2.5 years with a range from 24.1–32.5 years. There was no statistical significant difference in age between the two genotypes.There were statistically significant differences between all the potential predictor variables by genotype with the exception of age, height, systolic blood pressure and serum iron. HbSS patients had lower weight, BMI, diastolic blood pressure, mean arterial pressure, hemoglobin, lower sodium and serum creatinine than their HbSC counterparts. However, they had higher fetal hemoglobin, absolute reticulocyte counts, white blood cell counts, lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) (the last two as a markers of hemolysis) . Almost HbSS patients had significantly higher urinary albumin/creatinine ratios than those with HbSC disease . MicroalThe distribution of the hematological variables by genotype was distinct, i.e. overlap was minimal. Hence separate multiple linear regression analyses were performed for each genotype to facilitate inclusion of these variables. For persons with HbSS, higher mean arterial pressure , higher white blood cell counts , lower hemoglobin , lower absolute reticulocyte counts  and lower serum creatinine  were significant predictors of higher albumin excretions in the urine . This moFor persons with HbSC, higher white blood cell counts  and higher serum creatinine levels  predicted greater levels of albuminuria . This moIn this study, albuminuria was present in 42.3% of HbSS and 13.5% of HbSC patients. This compares quite well to past studies Mean arterial pressure is seen to be associated with increasing albuminuria in persons with HbSS. Higher blood pressures have been shown to be associated with increased mortality LDH is known to be a marker of increasing severity in SCD and there are strong epidemiological associations between its elevation and both endothelial activation and pulmonary hypertension We are further reporting that absolute reticulocyte counts are significant negative predictors of albuminuria in those with HbSS disease. This is contrary to the findings of Guasch et al. who reported no association of reticulocytes with albuminuria. They however conducted their analyses using percentage of reticulocytes which may not necessarily indicate reticulocytosis. Haymann et al. White blood cell count is also known to be a marker of severity in SCD and is a strong predictor of mortality In summary, even though the cross-sectional design of this study does not allow for causal inferences to be drawn, patients with rising blood pressure, higher white blood cell counts and those with HbSS may be more prone to renal dysfunction and an early marker of disease is albuminuria. Prospective studies are needed to establish a causal relationship as regular screening may then help identify renal disease early and timely interventions may help delay the progression of nephropathy.


The purpose of the present study was to investigate microcirculatory blood flow in patients with septic shock treated with levosimendan as compared to an active comparator drug (i.e. dobutamine). The primary end point was a difference of ≥ 20% in the microvascular flow index of small vessels (MFIs) among groups.-1·min-1 (n = 20) or an active comparator  for 24 hours. Sublingual microcirculatory blood flow of small and medium vessels was assessed by sidestream dark-field imaging. Microcirculatory variables and data from right heart catheterization were obtained at baseline and 24 hours after randomization. Baseline and demographic data were compared by means of Mann-Whitney rank sum test or chi-square test, as appropriate. Microvascular and hemodynamic variables were analyzed using the Mann-Whitney rank sum test.The study was designed as a prospective, randomized, double-blind clinical trial and performed in a multidisciplinary intensive care unit. After achieving normovolemia and a mean arterial pressure of at least 65 mmHg, 40 septic shock patients were randomized to receive either levosimendan 0.2 μg·kgP = .02; MFIs 2.9  vs. 2.7 ; P < .001). The relative increase of perfused vessel density vs. baseline was significantly higher in the levosimendan group than in the control group % vs. 0 %; P = .007; dMFIs 47 % vs. 10 ; P < .001). In addition, the heterogeneity index decreased only in the levosimendan group % vs. 0 %; P < .001). There was no statistically significant correlation between systemic and microcirculatory flow variables within each group (each P > .05).Microcirculatory flow indices of small and medium vessels increased over time and were significantly higher in the levosimendan group as compared to the control group  vs. 2.9 ; -1·min-1 of dobutamine, levosimendan at 0.2 μg·kg-1·min-1 improved sublingual microcirculatory blood flow in patients with septic shock, as reflected by changes in microcirculatory flow indices of small and medium vessels.Compared to a standard dose of 5 μg·kgNCT00800306. Microvascular dysfunction plays a pivotal role in the pathophysiology of septic shock and may occur even in the presence of normal systemic oxygen supply and mean arterial pressure . In thisATP)  [Microvascular blood flow was visualized by means of an SDF imaging device (MicroScanion lens . The option lens . The 'Deion lens  and is bion lens . Vessel ion lens . Both inion lens . The proion lens . Microvaion lens  was usedion lens . Since oion lens . To asseion lens . PercentBL) - 1] .n = 20). The consort diagram is presented in Figure Patients were enrolled within the first 24 hours from the onset of septic shock after having established normovolemia (PAOP = 12 to 18 mm Hg and CVP = 8 to 12 mm Hg) [a priori analysis of sample size revealed that at least 17 patients per group were required to demonstrate a minimum difference of 20% between groups in the primary endpoint with an estimated standard deviation of 20%, a test power of 80%, and an alpha error of 5%. Data are expressed as median  if not otherwise specified. Sigma Stat 3.10 software  was used for statistical analysis. Baseline and demographic data were compared with a Mann-Whitney rank sum test or chi-square test, as appropriate. Microvascular and hemodynamic variables were analyzed with a Mann-Whitney rank sum test. The correlation between systemic and microcirculatory flow variables within each group was tested by means of Spearman rank order correlation. A P value of less than 0.05 was considered statistically significant for all tests.An Baseline characteristics, including age, gender, body weight, and origin, as well as onset time of septic shock, Simplified Acute Physiology Score II (SAPS II), and mortality were not different among groups Table . In addi2 and arterial pH tended to be higher whereas NE requirements tended to be lower in the levosimendan group .Activated protein C was administered in five patients in the control group and in four patients in the levosimendan group. Three patients in each group required continuous renal replacement therapy during the study period. These treatments were equally distributed among groups  and heterogenity index was lower after 24 hours of treatment with levosimendan versus dobutamine . Since baseline data varied (non-significantly) among groups, relative changes from baseline were calculated and compared between groups. Relative increases from baseline of MFIs, MFIm, PPV, and PVD  were significantly higher in the levosimendan group  revealed no statistically significant results  following levosimendan infusion may be compensated by a simultaneous increase in myocardial contractility.The role of levosimendan in severe sepsis or septic shock is still not fully elucidated and remains controversial -16,20-26The hypothesis that constituted the basis of our study was that  levosimendan - by its vasodilatory effects - improves microcirculatory blood flow by increasing the driving pressure of blood flow at the entrance of the microcirculation . In factWhereas the increases in MFI suggest that levosimendan ameliorated blood flow within the perfused vessels, the increase in PPV with a concomitant decrease in heterogeneity index indicates a recruitment of non-perfused vessels and hence a reduction of the diffusion distance between capillaries. In light of these findings, it is most likely that levosimendan enhanced both convection and diffusion, thereby improving oxygen delivery at the level of the microcirculation.2 and pH noticed in the levosimendan group may further indicate an improvement in microcirculatory blood flow, it has to be considered that an improvement in pulmonary function  following levosimendan administration might have contributed to these changes. This assumption is supported by recent experimental and clinical studies showing that levosimendan in fact improves pulmonary function and gas exchange [Although the increases in SvOexchange ,20,25,26Our results are in line with those of an experimental study by Schwarte and colleagues , who repNotably, the lack of modifications in the proportion of perfused vessels observed in the control group (in which the patients were treated with dobutamine as an active comparator at a dose of 5 μg/kg per minute) varies from the study of De Backer and colleagues , who repThe present study has some limitations that we would like to acknowledge. First, we administered a fixed dose of 5 μg/kg per minute of dobutamine and cannot exclude the possibility that a higher dose would have resulted in different findings. However, it is important to note that our intention was not to perform a direct comparison between dobutamine and levosimendan but to use the selected dobutamine dose as an 'active comparator' to facilitate blinding of the study drugs. Indeed, randomization of levosimendan versus placebo would have unmasked group allocation because of the strong hemodynamic effects of levosimendan. Second, in the present study, the improvement in microvascular perfusion was independent from changes in CI. However, it is also possible that these variables might correlate in a way that is more complex than the linear correlation of percentage changes in CI and oxygen delivery. Therefore, a possible correlation should be clarified in future larger studies. Third, owing to the lack of investigation of specific variables, we cannot conclude whether anti-ischemic and anti-inflammatory effects, as well as effects at the cellular level , have coThis is the first prospective, randomized clinical study investigating the effects of levosimendan on sublingual microcirculation in patients with septic shock. Our results demonstrate that levosimendan at 0.2 μg/kg per minute (when compared with a standard dose of 5 μg/kg per minute of dobutamine) improves sublingual microcirculatory blood flow in volume-resuscitated septic shock patients and that this effect was not correlated with changes in systemic flow variables.• Levosimendan improves sublingual microcirculatory blood flow in volume-resuscitated septic shock patients.• Levosimendan enhances convection and improves diffusion, thereby improving oxygen delivery at the level of the microcirculation.• Levosimendan at 0.2 μg/kg per minute may be more effective than a standard dose of 5 μg/kg per minute of dobutamine for improving microcirculatory blood flow.• Under normovolemic conditions, levosimendan administration did not influence arterial blood pressure or norepinephrine requirements.2I: systemic oxygen delivery index; dPVD: relative increase in perfused vessel density; ICU: intensive care unit; KATP: ATP-dependent potassium; MAP: mean arterial pressure; MFIm: microvascular flow index of medium vessels; MFIs: microvascular flow index of small vessels; NE: norepinephrine; PAOP: pulmonary arterial occlusion pressure; PPV: proportion of perfused vessels; PVD: perfused vessel density; SDF: sidestream dark-field; SvO2: mixed-venous oxygen saturation.CI: cardiac index; CVP: central venous pressure; dMFIm: relative increases of microvascular flow index of medium vessels; dMFIs: relative increases of microvascular flow index of small vessels; DOThe authors declare that they have no competing interests.AM and MW planned the study, were responsible for its design and coordination, and drafted the manuscript. J-LT and GL participated in the study design and helped to draft the manuscript. CE, ML, SR, and HVA participated in the design of the study, performed the statistical analysis, and helped to draft the manuscript. AO, VC, AD, P Pelaia, and CI analyzed SDF images and helped to draft the manuscript. P Pietropaoli participated in the study design, helped to draft the manuscript, and obtained funding. All authors read and approved the final manuscript.


P = 0.015) and a higher incidence of cardiovascular events . Our findings illustrated that ABI is a powerful predictor of cardiovascular events and renal outcome in patients with CKD.Ankle-brachial index (ABI) is an accurate tool to diagnose peripheral arterial disease. The aim of this study was to evaluate whether ABI is also a good predictor of renal outcome and cardiovascular events in patients with chronic kidney disease (CKD). We enrolled 436 patients with stage 3–5 CKD who had not been undergoing dialysis. Patients were stratified into two groups according to the ABI value with a cut point of 0.9. The composite renal outcome, including doubling of serum creatinine level and commencement of dialysis, and the incidence of cardiovascular events were compared between the two groups. After a median follow-up period of 13 months, the lower ABI group had a poorer composite renal outcome (OR = 2.719,  Chronic kidney disease (CKD) is a growing health concern worldwide. According to several epidemiologic studies, the prevalence of CKD ranges from 11.9% to 16.2% in different countries . CKD is The ankle-brachial index (ABI) is a good tool to evaluate systemic atherosclerosis  and the 2, as calculated by the modification of diet in renal disease equation. Patients undergoing renal replacement therapy or those who had undergone renal transplantation or bilateral leg amputation were excluded from the study. The study protocol was approved by the Institutional Review Board of our hospital. All participants provided written informed consent.This prospective observational study was conducted between October 2008 and January 2010 in a tertiary referral center. We enrolled patients older than 18 years of age with a GFR of less than 60 ml/min/1.73 mAfter enrollment, the subjects' ABI was measured at the outpatient clinic. Measurements of ABI were obtained using an ABI-form device , which automatically and simultaneously measures blood pressure in both the arms and the ankles by using an oscillometric method. The ABI was calculated as the ratio of the systolic blood pressure of the ankle to that of the arm. The lowest ABI obtained from either leg was taken as the patient's ABI value. The ABI measurement was done once in each patient.Demographic data, including age, gender, diabetes mellitus status, hypertension status, and use of prescribed antihypertensive agents, were obtained from the patients' medical records. A patient was considered to have hypertension if the systemic blood pressure was more than 140 mmHg or diastolic blood pressure was more than 90 mmHg or if the patient was currently using antihypertensive agents. A patient was considered to have diabetes mellitus if the fasting blood sugar was more than 7 mmol/L or if the patient was using oral antidiabetic agents or insulin. Systemic blood pressure, diastolic blood pressure, pulse pressure, and body mass index (BMI) were recorded during the same visit when ABI was measured. The BMI was calculated as the ratio of the body weight in kilograms to the square of height in meters. Laboratory data, including levels of serum albumin, cholesterol, uric acid, calcium, phosphate, and hemoglobin, were measured from fasting blood samples. Urine protein/creatinine ratio (UPCR) was measured from the first morning voiding. These data were acquired within 1 month of the measurement of ABI.All participants received regular followup in our nephrology clinic. Serum creatinine levels were measured every 3 months to determine the decline in renal function. The composite renal outcome was defined as doubling of serum creatinine or commencement of renal replacement therapy . Another study outcome was the occurrence of cardiovascular events, defined as mortality or hospitalization because of cerebrovascular events, myocardial infarction, congested heart failure, or peripheral vascular diseases.t-test was used for continuous variables. Multivariate forward logistic regression analysis was applied to identify the independent determinant factors of low ABI. To determine the influence of ABI on renal and cardiovascular outcome, we used the Kaplan-Meier analysis. Cox regression model was used to evaluate the effect of presumed risk factors on renal and cardiovascular outcome. Variables with a P value less than 0.1 in univariate Cox regression analysis were included in a multivariate Cox regression analysis.All statistical analyses were performed using SPSS 16.0 for Windows . Data were expressed as mean ± standard deviation or as a percentage. For analysis of the determinants of low ABI, a chi-square test was used for categorical variables, and an independent 2. Patients with ABI < 0.9 tended to be older and have a higher prevalence of diabetes and hypertension, higher systolic blood pressure and pulse pressure, lower serum albumin level, higher UPCR, and a higher prevalence of calcium channel blocker usage. Multivariate logistic regression analysis was performed to analyze the determinants of low ABI in our subjects. The results are listed in P = 0.001), low GFR , diabetes mellitus , and high pulse pressure .In this study, we enrolled 436 patients. The baseline characteristics of the study population are shown in P = 0.002) and higher incidence of cardiovascular events (P < 0.001), as revealed by the Kaplan-Meier analysis (P = 0.015) (P = 0.001) , where as six patients died in the ABI > 0.9 group (1.6%). Nine patients (16.7%) with ABI < 0.9 and sixteen patients (5.0%) with ABI ≥ 0.9 reached composite renal endpoint, and thirteen patients (24.1%) with ABI < 0.9 and twenty-three patients (6.0%) with ABI ≥ 0.9 developed cardiovascular events. Compared to those with ABI ≥ 0.9, the low ABI group had poorer composite renal outcome   and card= 0.001) .ABI has been well recognized as a diagnostic index of PAOD  and a maIn addition to progressive renal failure, cardiovascular diseases are a major concern in patients with CKD. Several studies have implicated poor renal function as a factor in increasing cardiovascular events and mortality , 17, 18.2, a decline in GFR of more than 4 ml/min/1.73 m2 per year, which is the definition for rapid decline in renal function as in K/DOQI guideline [Although results from our study suggest that ABI is a good indicator of renal and cardiovascular outcomes in patients with CKD stage 3–5, our study population was selected from a single center, and hence may not be fully representative of the CKD population at large. Therefore, similar studies are required to confirm the predictive power of ABI in other populations. Furthermore, in our study, we defined cardiovascular events as either hospitalization or death due to cardiovascular disease. Since hospitalization may partly reflect disease severity and has been used as a surrogate endpoint in several large clinical trials, we thought that this would be an adequate definition of cardiovascular endpoint. However, since hospital admission criteria for cardiovascular disease may differ from place to place, redefining a cardiovascular event as cardiovascular mortality may reduce the variability introduced by such differences. In our follow-up period, we observed very few cardiovascular mortalities. Therefore, extended follow-up studies are needed to determine whether defining a cardiovascular event as cardiovascular mortality might better define the association between ABI and cardiovascular events. Similarly, because of differences in age, gender, and baseline renal function in our study population, defining renal endpoint as a doubling of serum creatinine may not be as accurate as defining it as a decline in GFR. However, since all the enrolled subjects had a GFR less than 60 ml/min/1.73 muideline , was lesOur study shows that patients with stage 3–5 CKD who have a lower ABI have a rapid decline in renal function and a high incidence of cardiovascular events. Since ESRD and cardiovascular diseases are major risks in patients with CKD, we suggest that ABI, a noninvasive and convenient tool to diagnose PAOD and systemic atherosclerosis, be used in all these patients.Fu-An Chen contributed to the paper processing by (1) conception and design of the study and collection and analysis of data, (2) drafting the paper, and (3) final approval of the version to be published; Wu-Chang Yang by (1) analysis and interpretation of data, (2) revising the paper, and (3) final approval of the version to be published; Chih-Yu Yang by (1) analysis and interpretation of data, (2) revising the paper, and (3) final approval of the version to be published; Jinn-Yang Chen by (1) patient referral, care, and acquisition of data and (2) final approval of the version to be published; Yee-Yung Ng by (1) patient referral, care, and acquisition of data and (2) final approval of the version to be published; Szu-Yuan Li by (1) patient referral, care, and acquisition of data and (2) final approval of the version to be published; Wen-Sheng Liu by (1) acquisition of data and (2) final approval of the version to be published; Shiao-Ti Cheng by (1) collection and analysis of data and (2) final approval of the version to be published; Yu-Jen Wang by (1) collection and analysis of data and (2) final approval of the version to be published; Chih-Ching Lin by (1) conception and design of the study and analysis and interpretation of data, (2) revising the paper, and (3) final approval of the version to be published.