Education is inversely associated with cardiovascular disease incidence in developed countries. Blood pressure may be an explanatory biological mechanism. However few studies have investigated educational gradients in longitudinal blood pressure trajectories, particularly over substantial proportions of the life course. Study objectives were to determine whether low education was associated with increased blood pressure from multiple longitudinal assessments over 30 years. Furthermore, we aimed to separate antecedent effects of education, and other related factors, that might have caused baseline differences in blood pressure, from potential long-term effects of education on post-baseline blood pressure changes.The study examined 3890 participants of the Framingham Offspring Study  from 1971 through 2001 at up to 7 separate examinations using multivariable mixed linear models.Mixed linear models demonstrated that mean systolic blood pressure (SBP) over 30 years was higher for participants with ≤12 vs. ≥17 years education after adjusting for age . Further adjustment for conventional covariates  reduced differences in females and males . Additional analyses adjusted for baseline SBP, to evaluate if there may be educational contributions to post-baseline SBP. In analyses adjusted for age and baseline SBP, females with ≤12 years education had 2.69  mmHg higher SBP over follow-up compared with ≥17 years education. Further adjustment for aforementioned covariates slightly reduced effect strength . Associations were weaker in males, where those with ≤12 years education had 1.20  mmHg higher SBP over follow-up compared to males with ≥17 years of education, after adjustment for age and baseline blood pressure; effects were substantially reduced after adjusting for aforementioned covariates . Sex-by-education interaction was marginally significant (p = 0.046).Education was inversely associated with higher systolic blood pressure throughout a 30-year life course span, and associations may be stronger in females than males. Education and other measures of socioeconomic position, such as occupation and income, are consistently inversely associated with incidence of cardiovascular disease in developed countries ,2. ElevaThe objectives of this study were to determine whether low educational attainment was associated with increased blood pressure from multiple longitudinal assessments over 30 years. Furthermore, we aimed to separate 'antecedant' effects of education, and other related factors, that might have caused baseline differences in blood pressure, from potential long-term effects of education on post-baseline changes in blood pressure. Analyses prioritized measures of systolic blood pressure (SBP) over diastolic blood pressure (DBP), as systolic hypertension is substantially more common than diastolic hypertension, and SBP contributes more to the global disease burden attributable to hypertension than DBP .The Framingham Heart Study is a community-based, longitudinal, observational cohort study that was initiated in 1948 to prospectively investigate risk factors for coronary heart disease. The Framingham Offspring Study began in 1971 with recruitment of 5124 men and women who were offspring (or offspring's spouses) of the Original Cohort of the Framingham Heart Study. The design and selection criteria of the Framingham Offspring Study have been described elsewhere.[There were 5124 participants who completed Offspring Examination 1 (in 1971-1975), of which 4989 (97%) agreed for their data to be in the open-access dataset. Of these, 1099 subjects were excluded from the present analyses because of missing education data (primarily among the participants who did not attend exams 2 or 3 when education was assessed) or being <28 years of age (n = 60) when education was assessed. Participants were restricted to those aged ≥28 years at the time education was assessed in order to allow at least 10 years from expected completion of high school , during which the participants could obtain higher levels of education. Consequently, 3890 subjects were included in the data analyses.The participants' own education was measured directly from Framingham Offspring Study participants at Examinations 2 (1979-1982) and 3 (1984-1987). Examination 3 education was used whenever available, otherwise the Examination 2 measure was used. In the original data, education was recorded in 6 categories of completed years of education: 0-4, 5-8, 9-11, 12, 13-16, ≥17 years. For current analyses, the participants' own education was collapsed into 3 groups: ≤12 years (reflecting high school or less), 13-16 years  and ≥17 years education (approximating those with more than an undergraduate college degree). This grouping was motivated by both (i) statistical power considerations (to ensure adequate number of participants in each category) and (ii) substantive reasons, whereby the education categories represent educational milestones recognized to influence earnings, occupation type, and socioeconomic position in society.Each participant rested for at least five minutes before blood pressure measurement. While the participant remained seated, a physician measured SBP and DBP each twice in the left arm with a mercury-column sphygmomanometer, according to a standardized protocol . The ave2). Current antihypertensive medication use was self-reported and modeled as a binary variable (yes/no). "Baseline age" represented age at Examination 1. "Time from baseline age" was calculated as the difference between age at a given examination and the baseline age.Covariates were measured at each exam. A binary indicator of current cigarette smoking was determined by self-report, defined as smoking regularly in the year prior to the examination (yes/no). Alcohol consumption was evaluated by self-reported average number of alcoholic drinks  per week. Body mass index was calculated as the weight in kilograms divided by the square of the height in meters (kg/ma priori. Assessment of the consistency of the AR(1) assumption is shown in the Results section. We implemented this longitudinal analysis by using PROC MIXED, with AR(1) covariance structure specified in REPEATED statement in SAS [Primary analyses focused on associations of education  with longitudinal trajectories of SBP and DBP. Analyses relied on multivariable mixed linear models, which extend multiple linear regression to longitudinal analyses of repeated measures . Accordinot used as the outcome measure, so that the number of dependent value measures for each subject was reduced by one. Adjustment for baseline blood pressure effectively implied that we compared post-baseline trajectories of blood pressure as if participants with different education had the same baseline blood pressure. This approach allowed us to separate the antecedent effects of education, and other related factors, that might have resulted in the baseline differences in blood pressure, from the potential long-term effects of education on post-baseline changes in blood pressure.The second class of models additionally adjusted all the education effects for baseline blood pressure. Accordingly, in these models, baseline blood pressure values were a priori expected that both between- and within-subject effects of aging on blood pressure may be non-linear. Accordingly, we gradually expanded the basic model, with linear effects of age and time, by adding and testing first quadratic and then cubic effects of each of the two variables, while adjusting for the use of anti-hypertensive medication and for education. Furthermore, because we expected that the impact of within-subject aging (time) on blood pressure may vary depending on the baseline age, we also tested linear and quadratic interactions between age and time. All the multivariable mixed models employed in the final analyses, described below, adjusted for only those non-linear effects of age or time, and those interactions between these effects, that were statistically significant, based on Wald test with 2-tailed α = 0.05. Once the optimal representations of the effects of age and time, as well as of their interactions, were determined, these representations were used in the final analyses of the adjusted association of education with SBP and DBP. The final representation of the effects of baseline age and time from baseline for analyses on SBP was as follows: age+age2+time+time2+age*time+age*time2+age2*time. For DBP, it was as follows: age+age2+time+ time2+age*time+age*time2+age2*time+ age2*time2. All analyses were sex-specific, as a formal test for sex-by-education interaction suggested that the effects of education may differ between males and females .Preliminary analyses were carried out to determine the most accurate representation of the effects of baseline age, and time since baseline. In particular, we Participants included in the current analyses had higher mean age , and lower smoking rates  than excluded participants. Included and excluded participants had similar distributions of sex and baseline values of SBP, DBP, body mass index, alcohol consumption and antihypertensive medication use.In females, unadjusted analyses demonstrated that education was inversely associated with baseline values of age, SBP, DBP, anti-hypertensive medication use, body mass index and smoking, and directly associated with alcohol consumption Table . In malevs. ≥17 years education was 3.26  mmHg in females, and 2.26  mmHg in males  mmHg in females, and 0.60  mmHg in males, suggesting gender differences in the association consumption between alcohol and education were not a substantial explanation for gender differences in observed associations between education and SBP.A second set of analyses adjusted for baseline SBP, in an effort to evaluate if there were educational differences in the post-baseline values of blood pressure, independent of the baseline differences. In analyses adjusted for baseline age, time from baseline age, and baseline SBP, females with ≤12 years education had 2.69  mmHg higher SBP over follow-up compared with females with ≥17 years education  mmHg in females, and 0.66  mmHg in males   assumption with our data, we estimated the Pearson correlation coefficients between measurements at different time points, for both SBP and DBP, separately for female and male. The results of Pearson correlation coefficients  aged 45 to 64 years at baseline and followed using 4 examinations over a period of 9 years, found in white participants, that education was marginally inversely associated with increases in blood pressure after adjusting for age, sex, center, medication use, and reported interactions between time and sex, and interactions between time and baseline age [Few studies have investigated sex-specific longitudinal trajectories of blood pressure, particularly over a substantial proportion of the life course. Diez Roux ort n = 855 aged 4line age . Specifiline age . Althougline age , little The primary candidate mechanisms by which education may influence longitudinal trajectories of blood pressure involve conventional risk factors for hypertension, including smoking, obesity, blood pressure medication use, and alcohol consumption. In this study, in females, education was inversely associated with anti-hypertensive medication use, body mass index and smoking, and directly associated with alcohol consumption. In males, education was inversely associated with body mass index, alcohol consumption and smoking, and not associated with antihypertensive use. Furthermore, the estimated effects of education tended to somewhat decrease after adjusting for these potential mechanisms , suggesting that they may be at least partial explanatory pathways for the observed association between educational attainment and longitudinal trajectories of blood pressure. It is important to note that biases can be induced by adjusting for variables that may partly mediate the effect of exposure; therefore, these mechanistic findings should be interpreted with caution . FurtherLow educational attainment has been demonstrated to predispose individuals to high strain jobs, characterized by high levels of demand and low levels of control, which have been associated with elevated blood pressure ,22. OtheIt has been demonstrated that although both SBP and DBP are positively associated with incidence of coronary heart disease, there are differences in the way SBP and DBP evolve over the life course. SBP tends to increase steadily with age, while DBP tends to increase until age 50 years, and to decrease steadily after that age ,8,27. Thet al. [Studies generally show consistent inverse associations between educational attainment and longitudinal changes in SBP ,6,7, witet al.  However,et al. , or evenet al.  associatStrengths of this study include having access to data on approximately 30 years of longitudinal blood pressure measurements. Furthermore, follow-up rates of the Framingham Heart Study are considered to be high for observational studies, decreasing risk of bias due to loss-to-follow-up. Finally, measurements of blood pressure were performed using methods and equipment providing good accuracy and precision, and analyses relied on statistical methods appropriate for longitudinal repeated-measures studies.With regard to weaknesses, because the historical design of the Framingham Offspring Study reflected the population of Framingham, Massachusetts at study onset in 1948, the Original and Offspring cohorts are largely composed of white participants. Consequently, the generalizability of our findings to other races/ethnicities is uncertain. Furthermore, although we had up to 7 measurements for each covariate, we expect there to be reasonable residual confounding due to imperfect measurement of obesity (body mass index), and self-reported alcohol consumption, smoking and antihypertensive medication use.This study provides evidence that education is inversely associated with systolic blood pressure throughout a 30 year life course span, and associations may be stronger in females than males. These findings provide evidence that education may be a potential risk factor for elevated blood pressure across the life course.The authors declare that they have no competing interests.EL initially conceived of the study and further developed the study objectives in collaboration with all co-authors. EL wrote much of the initial draft of the manuscript. MA was the senior biostatistics advisor and drafted the analytic approach in the Methods section. YX performed the analyses and advised on the analytic approach. JL made substantial contributions to the analytic approach, and advised on the subject matter related to socioeconomic disparities in blood pressure. All authors were involved with drafting the final manuscript, and revising it as needed for important intellectual content. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/139/prepub


Early predictive biomarkers for acute kidney injury (AKI) such as neutrophil elatinase-associated lipocalin (NGAL) could identify patients who may benefit from early initiation of treatment.We aimed to obtain a cut off point for AKI prediction by urine NGAL in kidney transplantation.In a prospective cohort study, 64 adult who underwent kidney transplantation from living or deceased donors at Baqiyatallah transplant center between April 2009 and January 2010 were included. Patients divided into two groups based on the presence or absence of graft dysfunction. In this study, early graft dysfunction (post transplantation AKI) was defined as Cr level more than 1.5 mg/dL on the second postoperative day.Post-transplant AKI was observed in 31 recipients. Mean urinary NGAL level was greater in recipients with AKI (P = 0.024). In linear regression model, AKI was only factor affected on urinary NGAL level . The best sensitivity and specificity for AKI detection by urinary NGAL observed at 2 hour after operation with cut-off point 204 ng/mL.Our study showed in those who developed early post transplantation graft dysfunction the best AUC-ROC for urine NGAL observed at a cut-off value of 204 ng/mL after 2 hour post transplantation. Acute kidney injury (AKI) occurs to some extent almost always in deceased kidney transplants due to renal ischemia-reperfusion, and even in some live donor allografts, and commonly causes varying degrees of early renal allograft impairment , 2 that According to the RIFLE criteria, AKI was defined as an abrupt increase in serum Cr of at least to more than 150% (1.5-fold from baseline) and traditionally identified by measurement of serum creatinine (Cr) . UnfortuIn addition, one of the necessities for clinical use of any AKI biomarkers is a cut-off determination for defining abnormality . RecentlIn this study, we conducted a prospective study to examine the results of the few earlier studies that evaluated diagnostic value of urinary NGAL in the prediction of early graft dysfunction in kidney transplant recipients among Iranian population. As urinary NGAL has been suggested to represent kidney damage better than plasma NGAL, we chose urine as sample material . We aimeIn a prospective cohort study, 64 adult patients aged more than 18 years old were consecutively included. They underwent kidney transplantation for the first time at Baqiyatallah transplant center between April 2009 and January 2010. The majority of patients (86%) received a kidney from a living donor. Patients who had history of recent (within one month ago) infectious diseases or inflammatory disorders were excluded from the operation and subsequently from the study. Patients divided into two groups based on the presence or absence of early graft dysfunction. The proposal of this study was approved by the local ethics committee of Baqiyatallah university of medical sciences and written informed consent was given from all patients.All patients received triple immunosuppressive therapy:  Cyclospo-1.154 × (age)-0.203 × [0.742 if female] × [1.210 if black]). We considered an excellent renal allograft function if a serum Cr level less than 1.5 mg/dL on the second postoperative day. According to previous studies , and estimated GFR (eGFR) levels within the first 10 days after transplantation. The eGFR values were calculated according to the modification of diet in renal diseases (MDRD) formula (eGFR = 186 × (serum Cr) studies , 18, 19,Data collected from all patients included age and gender of recipient and donors, donor source (living and deceased), renal function, cold and warm ischemic times, Cyclosporine level, underling disease, blood pressure, urinary out-put, sodium, potassium, calcium, magnesium, AST (aspartate aminotransferase), ALT , and hemoglobin. ºC, for 5 minutes, and the supernatant was stored at -70 ºC. In the current study, urinary NGAL was measured by means of a commercially available ELAISA test kit .We measured the urinary NGAL level in only 10 patients before transplantation, while urine sample could not be obtained in 54 cases because of oligo-anuria. The urinary samples for determination of NGAL levels were taken at 2, 6, 12, 24 and 48 hours after surgery. Almost 5 mL urine sample was collected and immediately centrifuged at 3000 rpm, 4Statistical analyses were performed using the SPSS version 17.0 for Windows. All quantitative data have been expressed as mean ± SD and the qualitative variables have been shown by percentage. Repeated measurement and ANOVA was used to evaluate the differences of markers between two groups. Independent variables with a P value ≤ 0.2 in the univariate analysis were entered into the multivariate linear regression model.To measure the sensitivity and specificity of urinary NGAL at different cut-off values, a conventional receiver operating characteristic (ROC) curve was generated at 2, 6, 12, 24 and 48 hours after kidney transplantation. We calculated the area under the curve (AUC) to ascertain the quality of urinary NGAL as an early graft dysfunction diagnostic biomarker. An area of 0.5 is no better than expected by chance, whereas a value of 1.0 signifies a perfect biomarker. The optimal cutoff level was defined by the largest sum of sensitivity and specificity. P value less than 0.05 was statistically considered significant.We enrolled 64 kidney transplant recipients. The most common known causes of end stage renal disease were hypertension (37.5%) and diabetes mellitus (10.9%). The mean age of donors was 28.6 ± 6 years with the mean hemoglobin level of 15.4 ± 1.1 g/dL and mean serum Cr concentration of 0.9 ± 0.1 mg/dL. A total of 55 patients received a kidney from a living donor, while 9 transplants were carried out using a kidney from a deceased donor. Male to female ratio was 3.9:1 (79.7% vs. 20.3%).More than 50% of our patients had excellent renal allograft function. Post-transplant AKI was observed in 31 recipients including 18 patients who had induction therapy with ATG, 4 cases with DGF. Twenty-four subjects had serum Cr level of more than 1.5 mg/dL after 48h of transplantation. The patients with AKI had higher donor age (P = 0.03), greater post-operative serum phosphorus value (P = 0.03) and lower serum calcium (P = 0.03) and hemoglobin levels (P = 0.02) compared to no-AKI individuals . There wThe mean urinary NGAL level was greater in recipients with AKI as compared to patients who had no AKI (P = 0.024) . In lineth day The best sensitivity and specificity for AKI detection by serum Cr observed at sevenAccording to our study, measurement of urinary NGAL was a better predictor for AKI after kidney transplantation than serum creatinine. It is important to note that serum creatinine is not a reliable marker of AKI in kidney transplant patients . TherefoOur study showed in those who subsequently developed AKI the best AUC-ROC observed at a cut-off value of 204 ng/mL after 2 hour post transplantation, this is in agreement with results obtained by Devarjan et al.  and HaasIn terms of diagnostic accuracy, Dent et al.  demonstrThese findings emphasize that the first hour after transplantation could be unique time for AKI revealing by urine NGAL measurement. Thus, NGAL is as an emerging tool could predict development of AKI even in various groups of recipients with multiple comorbid conditions and with unknown timing of initial kidney injury.th hour.According to Furthermore, in contrast to previous studies showed NGAL concentrations vary with age and gender , in our Limitation: In fact, urinary NGAL might be very dilute early post-transplantation due to high urine out-put . ResultiIn this study, we concluded urine NGAL at 2 h post-operation had the best sensitivity and specificity for prediction of AKI using a cut-off value of 204 ng/mL. Taken together with the fact, it is clear that the role of NGAL in the diagnosis of post-operative AKI requires further investigation.


To assess relationships between blood pressure hemodynamic measures and outcomes after acute ischemic stroke, including stroke severity, disability and death.The study cohort consisted of 189 patients who presented to our emergency department with ischemic stroke of less than 24 hours onset who had hemodynamic parameters recorded and available for review. Blood pressure (BP) was non-invasively measured at 5 minute intervals for the length of the patient's emergency department stay. Systolic BP (sBP) and diastolic BP (dBP) were measured for each patient and a differential (the maximum minus the minimum BP) calculated. Three outcomes were studied: stroke severity, disability at hospital discharge, and death at 90 days. Statistical tests used included Spearman correlations (for stroke severity), Wilcoxon test (for disability) and Cox models (for death).Larger differentials of either dBP (p = 0.003) or sBP (p < 0.001) were significantly associated with more severe strokes. A greater dBP (p = 0.019) or sBP (p = 0.036) differential was associated with a significantly worse functional outcome at hospital discharge. Those patients with larger differentials of either dBP (p = 0.008) or sBP (0.007) were also significantly more likely to be dead at 90 days, independently of the basal BP.A large differential in either systolic or diastolic blood pressure within 24 hours of symptom onset in acute ischemic stroke appears to be associated with more severe strokes, worse functional outcome and early death Stroke is associated with a high mortality and significant long-term functional disability. Of the 15 million patients affected by stroke worldwide yearly, the World Health Organization reports almost a third of these patients die, and another third are permanently disabled. Hypertension accounts for nearly 12.7 million strokes worldwide [Close to 80% of acute ischemic stroke (AIS) patients have an elevated blood pressure . The eleTreatment strategies for hypertension post-AIS are centered on the aim to salvage the ischemic penumbra , but theIt is well known that normally cerebral auto-regulation maintains perfusion over a wide range of systemic blood pressures. During the acute phase of stroke, cerebral auto-regulation becomes dysfunctional , and cerPreviously published data demonstrate that acute blood pressure variability within early hours of presentation to the emergency department (ED) is associated with an increased risk of death at 90 days . Both veWe sought to determine if there was any association between fluctuations in systolic (sBP) or diastolic (dBP) blood pressure within 24 h of the onset of AIS and stroke severity, functional disability and mortality.The study cohort for this IRB  approved prospective cohort follow-up study consisted of prospectively enrolled consecutive adult patients presenting to our academic ED with AIS. Patients with AIS onset > 24 h prior to presentation/indeterminable time of onset and patients with non-reviewable consecutive vitals were excluded from the final cohort.Blood pressure (BP) was non-invasively measured at 5-min intervals for the length of the patient's ED stay with the Philips M3046A Patient Monitoring System . The system design uses the oscillometric method, measuring the pulsed amplitude of pressure changes in the cuff as it deflates, to demarcate the systolic and diastolic blood pressures. The 24-h differential pressure, defined as the difference between the maximum and the minimum pressures, was calculated for both the sBP and the dBP.Besides the routine demographics, data on stroke severity on arrival, disability at hospital discharge and death at 90 days were collected for the study cohort. Stroke severity on arrival was measured by the National Institutes of Health Stroke Scale (NIHSS), and disability at discharge was measured by the modified Rankin score (mRS). Poor functional outcome was defined as a mRS ≥ 3 at discharge. Death at 3 months was ascertained by scripted telephone follow-up, state death certificates and electronic medical records with prior patient authorization.JMP 8.0 was used for the analysis using Spearman correlations (for stroke severity), Wilcoxon test (for disability) and Cox models (for death).Demographics and characteristics of the cohort are summarized in Table The median number of blood pressure readings was 7, with an inter-quartile range (IQR) of 4 to 10. The median systolic blood pressure on arrival (baseline sBP) was 161 mmHg (IQR 144 to 188 mmHg), and the median diastolic blood pressure (baseline dBP) was 80 mmHg (IQR 70 to 90 mmHg). The median diastolic BP differential was 27 mmHg (IQR 16 to 41 mmHg), and the median systolic BP differential was 33 mmHg (IQR 19 to 53 mmHg).p = 0.038).A statistically significant relation was found between baseline hypertension and death at 90 days, when defining baseline hypertension as baseline sBP = 170 mmHg and/or baseline dBP = 110 mmHg. A total of 41.07% patients had baseline hypertension using the above definition. The relative risk of mortality at 90 days for patients with baseline hypertension was 2.05 with a 95% confidence interval of 1.02-4.10 when compared to patients presenting with lower BP  and differential sBP (p < 0.001) . There was no association found between baseline hypertension and NIHSS score on arrival (p = 0.4734).The median NIHSS score at arrival was 6.0, with an interquartile range of 3.75 to 15.0. Patients with more severe strokes had larger differential dBP (p = 0.019) or sBP (p = 0.036) differential was associated with a significantly worse functional outcome at hospital discharge (Table p = 0.486).A total of 129 patients (68.3%) had a Rankin score of 3 or more at hospital discharge (bad outcome). The median differential dBP for a Rankin score 0-2 was 22.5 mmHg, while for a Rankin score of 3 or more was 29 mmHg. The median differential sBP for a Rankin score 0-2 was 26 mmHg, while for a Rankin score of 3 or more was 36 mmHg. A greater dBP (p = 0.008) or sBP (0.007) were significantly more likely to be dead at 90 days  occurred within the first 90 days. Those with larger differentials of either dBP , a follow-up to our earlier study. We questioned whether it was indeed the BP differential that resulted in poor outcomes or rather an episode of hypotension during the early ED course that was the culprit. When we compared the hypotensive and non-hypotensive groups, we found that there was no difference in the outcomes of death or functional Rankin scores, suggesting that BP fluctuation was an independent predictor of poor outcome. The VISTA collaboration presented similar findings, highlighting that fluctuations in systolic blood pressure were associated with worse outcome post-stroke .Our study also found that patients with more severe strokes had greater fluctuations in blood pressure, but not the initial baseline blood pressure. This led to the argument that it was the initial severity of the stroke that translated to the worse outcome. However, when we adjusted for the NIHSS severity of strokes, we found that the sBP differential and dBP differential co-related independently with death at 90 days.Hypotension relative to the baseline, causing regional hypo-perfusion, is an increasingly understood concept immediately following an ischemic stroke. The results of the present study and ensuing discussion may tempt one to surmise that blood pressure variability is bad and that therefore somehow tightly controlling it within a specified range is the next logical step. Caution must be exercised here. One cannot assume that "correcting" the association will result in improved outcome. It is indeed the next step in clinical investigation, but not quite ready for implementation into clinical practice before the hypothesis is definitively investigated in a controlled trial.Fluctuations in blood pressure in the setting of acute ischemic stroke appear to impart a negative impact on stroke severity, functional outcome and death at 90 days. This is a hypothesis-generating study that asks whether pharmacologic control of these blood pressure fluctuations would result in improved clinical outcomes.This protocol was approved by the department of Emergency Medicine Research Committee (minute excerpt attached). It was also approved by the Mayo Clinic Institutional Review Board as protocol 1054-04.LGS conceived the study, collected the data and wrote the paper. SE, MFB, AJ, LV, RG, and RK collected data and reviewed the paper. ALW analyzed the data. RDB supervised the project. All authors read and approved the final manuscript.The authors declare that they have no competing interests.


We investigated the association between heart rate and its variability with the parameters that assess vascular, renal and cardiac target organ damage.A cross-sectional study was performed including a consecutive sample of 360 hypertensive patients without heart rate lowering drugs . Heart rate (HR) and its standard deviation (HRV) in clinical and 24-hour ambulatory monitoring were evaluated. Renal damage was assessed by glomerular filtration rate and albumin/creatinine ratio; vascular damage by carotid intima-media thickness and ankle/brachial index; and cardiac damage by the Cornell voltage-duration product and left ventricular mass index.There was a positive correlation between ambulatory, but not clinical, heart rate and its standard deviation with glomerular filtration rate, and a negative correlation with carotid intima-media thickness, and night/day ratio of systolic and diastolic blood pressure. There was no correlation with albumin/creatinine ratio, ankle/brachial index, Cornell voltage-duration product or left ventricular mass index. In the multiple linear regression analysis, after adjusting for age, the association of glomerular filtration rate and intima-media thickness with ambulatory heart rate and its standard deviation was lost. According to the logistic regression analysis, the predictors of any target organ damage were age (OR = 1.034 and 1.033) and night/day systolic blood pressure ratio (OR = 1.425 and 1.512). Neither 24 HR nor 24 HRV reached statistical significance.High ambulatory heart rate and its variability, but not clinical HR, are associated with decreased carotid intima-media thickness and a higher glomerular filtration rate, although this is lost after adjusting for age.NCT01325064ClinicalTrials.gov:  Traditionally, high heart rate (HR) at rest has been directly associated with a risk of cardiovascular (CV) disorders, both in the general and in the elderly population , as wellThe aim of the present study therefore was to assess the association between office and ambulatory HR and its variability with the parameters that assess the presence of vascular, renal and cardiac target organ damage.This was a cross-sectional study performed in a primary care setting. We included 360 hypertensive patients without heart rate lowering drugs, aged 30-80 years, and seen in their primary care clinics between January 2008 and June 2010 through consecutive sampling. All patients enrolled agreed to take part in the study. The protocol was approved by an independent ethics committee of Salamanca University Hospital , and all participants signed the corresponding informed consent forms.Sample size calculation indicated that the 360 patients included in the study were sufficient to detect a minimum correlation coefficient between heart rate or its variability and subclinical organ damage parameters of 0.15 in a two-sided test, with a significance level of 0.05 and a power of 0.81.Clinical blood pressure and heart rate measurements were obtained by performing three measurements of systolic blood pressure (SBP) and diastolic blood pressure (DBP), with a validated sphygmomanometer, OMRON M7 model , following the recommendations of the ESH . For theAmbulatory blood pressure monitoring (ABPM) was performed on a day of standard activity with a cuff adequate for the size of the patient's arm. A control system, the Spacelabs 90207 model , was used and validated according to the protocol of the British Hypertension Society . Of the The electrocardiography examination was performed with a General Electric MAC 3.500 ECG System  that automatically measures the voltage and duration of waves and estimates the criteria of the Cornell voltage-duration product (Cornell VDP)  to assesKidney damage was assessed by measuring the glomerular filtration rate estimated (eGFR) by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation  and protCarotid ultrasonography to assess IMT was performed by two investigators trained for this before starting the study. The reliability of which was evaluated before the study began using the intraclass correlation coefficient, which showed values of 0.974 (95%CI: 0.935 - 0.990) for intra-observer agreement on repeated measurements in 20 subjects, and 0.897 (95%CI:0.740 - 0.959) for inter-observer agreement. According to the Bland-Altman analysis, the limit of inter-observer agreement was 0.022 (95%CI: -0.053 - 0.098) and the limit of intra-observer agreement was 0.012 (95%CI: -0.034 - 0.059). A Sonosite Micromax ultrasound device paired with a 5-10 MHz multifrequency high-resolution linear transducer with Sonocal software  was used for performing automatic measurements of IMT for optimizing reproducibility. Measurements were taken from the common carotid artery after the examination of a 10-mm longitudinal section at 1 cm away from the bifurcation. We performed measurements of the anterior or proximal walls and of the posterior or distal walls in the lateral, anterior and posterior projections, following an axis perpendicular to the artery to discriminate two lines, one for the intima-blood interface and the other for the media-adventitious interface. Six measurements were obtained of the right carotid and another six of the left carotid, using mean values (mean IMT) and maximum values (maximum IMT) calculated by the software automatically. The measurements were obtained following the recommendations of the Manheim Carotid Intima-Media Thickness Consensus . Mean IMThis parameter was evaluated using the ankle-brachial index (ABI) and was performed in the morning in patients who had not consumed coffee or tobacco for at least 8 hours prior to measurement in an ambient temperature of 22-24°C. With the feet uncovered and the patient in a supine position after 20 min of rest, the pressure in the upper and lower extremities was measured using a portable Minidop Es-100Vx Doppler system . The probe was applied at posterior tibial artery at an angle of approximately 60° relative to the direction of blood flow. The transducer's cuff was quickly inflated on each ankle to about 30 mm Hg above the systolic pressure, and the pressure was then allowed to descend (by about 2 mmHg per second) until the first sound corresponding to the systolic pressure was heard. Blood pressure was also measured in both arms . The ABI was calculated separately for each foot by dividing the higher of the two systolic pressures in the ankle by the higher of the two systolic pressures in the arm. Target organ damage was considered present if the ABI was lower than 0.9  and missContinuous variables were expressed as the mean ± standard deviation (SD), while qualitative variables were expressed on the basis of their frequency distribution. The Pearson correlation coefficient was used to estimate the relationship between quantitative variables. The multivariate analysis involved eighteen multiple linear regression models with mean IMT (nine models) and CKD-EPI (nine models) as dependent variables. We included as independent variables, clinical HR, 24-hour HR, awake HR, sleep HR, 24-hour HRV, awake HRV, sleep HRV, N/D HR ratio and N/D HRV ratio, one in each model, and age as the adjusted variable. Logistic regression analysis was performed, including as dependent variable the absence "0" or presence "1" of any TOD and as independent variables, using the enter method, age, gender, antihypertensive drugs, systolic N/D (night/day) ratio, office systolic blood pressure, waist circumference, atherogenic index , smoking, diabetes mellitus and 24-hour HR in the first model and 24-hour HRV in the second model. An α risk of 0.05 was established as the limit of statistical significance. The SPSS/PC+ version 15.0  statistical package was used throughout.Table Tables These correlations were stronger in diabetics patients and the subgroup without antihypertensive treatments and weaker in the subgroup with antihypertensive drugs, losing statistical significance in some of the correlations of HR and HRV with IMT and systolic and diastolic blood pressure night/day ratio. The statistics signification of the association found between HR and HRV with IMT and eFGR was lost after adjusting for age.2.Figure According to the logistic regression analysis Table , the preThe data obtained in our study suggest that there is an association between ambulatory, but not clinical, HR and its variability with respect to IMT and eGFR, whereas no association was observed with respect to albumin/creatinine index, Cornell VDP, LVMI or ABI in patients without heart rate lowering drugs. However, this association is lost after adjusting for age. On the other hand, the variable with the greatest capacity to predict the presence or absence of target organ damage was night/day systolic ratio, without HR or HRV reaching statistical significance in the logistic regression models.The association found with ambulatory HR but not with office HR could be due to white coat phenomenon that increases and modify the basal HR in the office.The association between HR and its variability with respect to the development of target organ damage or vascular conditions has not been clearly established. Barrios et al.  noted thFácila et al.  studied Gottsäter et al.  found a Brotman et al.  noted anMartini et al.  found a They also concluded that there is a continuous negative association between left ventricular mass and HRV, while Cuspidi et al.  found siFinally, in our study the most important predictive variable of damage to any target organ was the night/day systolic ratio (OR = 1.418). A fact that had already been suggested in 1997 by Mancia et al. , indicatThe main limitation of this study is its cross-sectional design, which precludes longitudinal analysis between HR, HRV and TOD. Another limitation is the selection of the study population, since sampling was performed consecutively with pragmatic and broad inclusion criteria; thus, the study population included hypertensive patients, some with diabetes and hyperlipidemia, and many patients receiving drug therapy (not HR lowering drugs). This could modify blood pressure levels and thus limit the validity of some results. Consequently, the heterogeneity of the sample could lead to some limitations when interpreting the results, though it is quite similar to the distribution of the general population of hypertensive patients with some cardiovascular risk factors.In conclusion, high ambulatory HR and its variability, but not clinical HR, were associated with a decreased carotid intima-media thickness and a higher glomerular filtration rate, although it was lost when adjusted for age. We found no association of HR with albumin/creatinine ratio, Cornell VDP, left ventricular mass index or ankle/brachial index. In summary, the data from this study indicate that the associations found between HR and its variability with the parameters that assess target organ damage is mediated principally by age. This would be contrary to consider the HR as an independent risk factor for the appearance of TOD.However, given the discrepancies found in the literature, we consider that further prospective studies are needed in order to determine the association between HR and its variability with cardiovascular risk in the early stages of hypertension and prior to the development of TOD.The authors declare that they have no competing interests.AGG and LGO devised the study, designed the protocol, participated in fund raising, and prepared the draft manuscript. CPA collaborated in protocol design and data interpretation. JIRR, ERS and CAC participated in study design, data collection, and manuscript review. MAGM participated in protocol design, fund raising, analysis of results, and final review of manuscript. Finally, all authors reviewed and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/12/19/prepub


Due to a lower risk of complications, non-invasive monitoring methods gain importance. Measuring arterial blood pressure belongs to the standard hemodynamic monitoring. A newly developed continuous non-invasive arterial blood pressure (CNAP) measurement method is available and has been validated perioperatively . We compWe performed a prospective study on 49 critically ill patients at a medical ICU. All patients were sedated and mechanically ventilated . Furthermore, all patients were under vasopressor therapy. CNAP was applied on two fingers of the hand contralateral to the invasive arterial blood pressure catheter in the A. radialis. All measurements were digitally recorded with a sample frequency of 100 Hz, every pulse beat was automatically identified by an algorithm  and subsIn total we analysed 500,000 beats. Overall we observed a bias in mean pressure of -7.49 mmHg with a standard deviation of 10.90 mmHg. The Bland-Altman plot (Figure In our study we detected a good overall agreement between CNAP and IBP. The future perspective of this study is to investigate whether the continuous non-invasive blood pressure waveform is suitable for deriving further hemodynamic parameters of fluid responsiveness.


P<0.05) respectively. The amplitude of individual blood pressure fluctuation with temperature throughout a year (a 29 degrees centigrade range) was 9.4/7.3 mmHg. Medication with angiotensin converting enzyme inhibitor benazepril attenuated the blood pressure fluctuation by 2.4/1.3 mmHg each year, though the inverse association of temperature and blood pressure remained. Gender, drinking behavior and body mass index were also found to modify the association between temperature and diastolic blood pressure. The results indicate that ambient temperature may negatively regulate blood pressure. Hypertensive patients should monitor and treat blood pressure more carefully in cold days, and it could be especially important for the males, thinner people and drinkers.Several studies have suggested an association between ambient air temperature and blood pressure. However, this has not been reliably confirmed by longitudinal studies. Also, whether the reaction to temperature stimulation is modified by other factors such as antihypertensive medication is rarely investigated. The present study explores the relationship between ambient temperature and blood pressure, without and with antihypertensive medication, in a study of 1,831 hypertensive patients followed up for three years, in two or four weekly check ups, accumulating 62,452 follow-up records. Both baseline and follow-up blood pressure showed an inverse association with ambient temperature, which explained 32.4% and 65.6% of variation of systolic blood pressure and diastolic blood pressure ( For hypertensive patients, optimal control of blood pressure (BP) helps maintain low and stable level of BP, and may decrease the risk of adverse events, including stroke and heart failure This study was approved by the institutional review boards of Peking University. All subjects provided written informed consent.The research is a secondary analysis of a longitudinal study with 3-year follow-up of 1,831 hypertensive patients, which was a part of the Chinese Community-based Comprehensive Prevention and Control of Hypertension (CCPACH), a project consisting of 34,770 permanent residents over 35 years old in the Nanshi District, Shanghai, China th week , 72.5% of the patients  remained in the study, with an accumulation of 62,452 follow-up records, of which 60,463 were at the fourth week and after.During baseline and the following interviews, BP was measured in the right arm of seated participants after a 5-minute rest by mercury sphygmomanometer with appropriately sized cuff. Measurement was performed at three 1-minute intervals according to standard protocol th week . At the Daily ambient temperatures  were monitored at Hongqiao airport meteorological station, Shanghai, which was about 16 kilometers away from the clinics and the patients’ residence. Data from June 1997 to April 2001 were retrieved to cover the entire follow-up period.The dataset was divided into a baseline (before the prescription of benazepril) and a follow-up dataset. Linear regression was used to investigate the association between temperature and baseline BP, adjusted for gender, age, body mass index (BMI), urine protein, smoking behavior and drinking behavior. Multilevel modeling was implemented to analyze the association between the temperature and the repeated measurement data of the follow-up dataset. Random effects for the duration of medication and intercept were included in the model. The covariance structure was defined as unstructured, and the estimation method was maximum likelihood. Besides the covariates mentioned above, the baseline BP and the medication duration was also included. Interactions of temperature and other covariates were examined as product terms.2) were used to indicate the proportion of variance that could be explained by ambient temperature; the R2 of medication duration was also investigated.To estimate the contribution of temperature to the average change of BP in aggregated weeks, the association between the ambient temperature and the average weekly BP was examined by linear regression. The average BP of the subjects who were recruited in the same week was calculated, so was the mean of temperature. Multiple correlation coefficients . To exclude the possible bias from the intake of dihydrochlorothiazide, the analyses were repeated after the 57 patients involved were dropped.As BP dropped quickly in the first few weeks of benazepril medication and more slowly in the later period, association analyses were conducted only with BP records from the 4The statistical analyses were performed in SPSS for windows  and SAS .β = −0.266 in SBP model, 95% CI: −0.352 to −0.181, P<0.001; β = −0.173 in DBP model, 95% CI: −0.220 to −0.126, P<0.001) after adjustment for gender, age, BMI, urine protein, smoking behavior and drinking behavior. Those associations were also significant in the individual follow-up analysis  in which multilevel models were used and baseline BP and medication duration were additionally adjusted. The average amplitude of temperature change in the follow-up years was 29.0 degrees (2.3 to 31.2 centigrade), so the average amplitude of BP fluctuation each year with ambient temperature was estimated to be 6.2/4.2 mmHg. The highest and lowest temperature was also examined, showing quite similar results (data not shown). There was no significant association between diurnal temperature range and SBP or DBP. Hence, only daily average temperature was chosen to represent the effect of ambient temperature in the follow-up analyses.The relationship between ambient temperature and BP was examined with the baseline and follow-up datasets of individual BP records. As expected, daily average temperature was significantly associated with baseline SBP and DBP (P<0.001), so under the benazepril therapy, the reaction of SBP to the change of ambient temperature (29.0 degrees throughout a year) was estimated to decrease by 2.4 mmHg each year. To confirm these interactions, medication duration and age were transformed into ordinal categories and the follow-up dataset was stratified into subsets in which the effects of daily average temperature on BP were estimated separately. In that process, there seemed to be a linear trend in the medication categories but not for the age categories , so the change in DBP to the ambient temperature change (29 degrees over a year) was estimated to decrease by 1.3 mmHg each year. When stratified by medication duration (in unit of year) the effect of temperature also decreased. The fluctuation of DBP was 7.8, 6.4 and 4.4 mmHg in each year. For males, this fluctuation was 8.4, 7.0 and 4.4 mmHg, while for females it was 7.2, 5.5 and 4.4 mmHg (P<0.05). The temperature regression coefficients are smaller in the higher BMI group  and −0.252  respectively, which meant a 9.4/7.3 mmHg increase in BP as the ambient temperature decreased by 29.0°C in a year.After these interactions were adjusted (the age-temperature interaction was not included in the SBP model), the regression coefficients of daily average temperature were −0.325  and 65.6%  of the variation of SBP and DBP, respectively.Linear regression was used to investigate the association between the average baseline BP of patients recruited in the same week and the mean of weekly ambient temperature . Signifiβ = −0.189 in SBP model, 95% CI: −0.219 to −0.159, P<0.001) and 39.0%  of BP variation. The full follow-up models (including temperature and medication duration) explained 86.5% and 88.4% of SBP and DBP variation.To investigate the BP fluctuation of the same subjects as temperature changes, the temperature-BP relationship was also examined in the three-year follow-up dataset . Similarth, the 100th and the 150th week, BP of the first group reached its lowest, while the second group was at its highest.To further confirm the fluctuation of BP with temperature, subsets of patients recruited around October  and February , when the ambient temperatures were highest and lowest in the year of recruitment, were selected separately to investigate the trends. These two groups showed opposite BP trends : at arouTo exclude the potential influence of dihydrochlorothiazide on the results, the analyses were repeated in a dataset without the 57 subjects involved, and the results did not appreciably change (data not shown).Based on 1,831 patients with 3-year follow-up, the present research suggests that BP is negatively associated with ambient temperature throughout the year both before and after starting antihypertensive medication , and no If ambient temperature has an effect on BP, a change in ambient temperature may lead to an increase in the incidence of hypertension, and raise public health concerns. Also, it may help explain the increased mortality of cardiovascular diseases in cold seasons However, Alpérovitch et al. reported a large longitudinal study with a 2-year follow-up, with interviews made quarterly. Although they found significant differences between BP under the highest and lowest quintile of temperature, they could not address whether there was a threshold above which this fluctuation occurs Hozawa et al. reported that an inverse association between outside temperature and BP was only observed in warmer seasons in Japan We also investigated there are factors that modify the association of ambient temperature and BP. Alpérovitch examined the interaction between antihypertensive medication and temperature, but their subjects were taking several kinds of drugs and the researchers did not find significant differences Some researchers have reported that older people’s BP is more sensitive to temperature change Unlike some reports which suggested that women are more sensitive to cold stimulation than men P = 0.655, so we combined them together) and higher than the non-drinking group.Drinking behavior is another potential effect modifier of temperature-BP association. The drinkers’ DBP fluctuated slightly more than the non-drinkers’ DBP as ambient temperature changed. This may result from the effect that alcohol increases superficial blood flow and emission of heat, leading to higher sensitivity to ambient temperature stimulation. Drinking behaviors of the subjects were primarily recorded as no drinking, drinking less than 100 g wine per day, or drinking at least 100 g per day in the study. A “J” curve of the effect of drinking was once suspected for the association between drinking and BP or coronary heart disease We also found that BMI may modify the temperature-BP association. We found people with higher BMI seemed to experience a smaller fluctuation of DBP with ambient temperature. Generally, BMI was not consistent with our original hypothesis that obese people who often had worse cardiovascular function had to face more difficulties in adapting to environmental stimulations. Possibly people with more fat maintained their body temperature more easily, so feel milder stimulation of cold. This was supported by Kingma’s study which reported that large body fat proportion help protect against the adverse effect of cold Temperature has been reported to be associated with mortality in a study with over 169,000 clinic visits Our data was collected a decade ago so ambient temperature during that period do not necessarily reflect the current conditions. But since our aim is the relationship of blood pressure and temperature, whether the data is old seems of secondary importance. Nevertheless, it would be meaningful to study the health effects of the temperature in recent years as the climate today may be somewhat different to that of ten years ago.In summary, the present research suggests that ambient temperature appeared to affect BP. Medication with ACEI benazepril may help to keep BP stable when ambient temperature changes. Thinner male patients who drink may need to monitor and treat BP more rigorously. The findings of the present research may have implications for clinical management of hypertension.Table S1Stratified analyses of temperature-BP association (regression coefficients). The significant interactions found in multilevel models were further examined by this method: the regression coefficient of temperature was calculated separately in each stratum (divided by the factor suspected to interact with temperature) and the regression coefficients among different stratum were compared by examining the confidence intervals for their difference with the following formula: where β1 and β2 were the regression coefficients of temperature, and SE1 and SE2 were their respective standard errors.(DOC)Click here for additional data file.Table S2Stratified analyses of temperature-BP association (sensitivity). Besides the examination of overlap between confidence intervals Click here for additional data file.


Objective. The objective of this study was to determine the frequency of pulmonary arterial hypertension (PAH) in congenital heart disease (CHD) with an isolated, large left-to-right shunt and to indicate the factors in the development of PAH. Methods. The pressure measurements in the cardiac chambers and the calculations based on the Fick's principle were compared among 3 separate groups of patients, respectively, with PAH, with hyperkinetic pulmonary hypertension (HPH), and with neither PAH nor HPH. Results. PAH was diagnosed in 30 (12.3%) patients, HPH in 35 (14.4%), while 177 (73.1%) were free of either. The highest risk for the development of PAH was found in the presence of perimembranous ventricular septal defect. A statistically significant difference was seen among these groups as to their left atrial pressure (p = 0.005) and the mean pulmonary arterial pressure . While a correlation was present between RpI on one hand and age on the other (p = 0.014), a multiple linear regression could not evidence any correlation among age (p = 0.321), gender (p = 0.929). Conclusion. Our findings do not allow establishing a correlation between the duration of the high pulmonary flow and pulmonary vascular resistance increase or PAH development in isolated left-to-right shunts with congenital heart diseases. The moss of PAH . ConsideThe objective of this study was to determine the frequency of PAH in our CHD patients without genetic pathology who had undergone cardiac catheterization for an isolated, large left-to-right shunt and to characterize the variables correlating with RpI. Identifying the parameters which correlate with the pulmonary vascular resistance index could provide very helpful indications for the management and the prognosis of these patients.mean) > 25 mmHg, pulmonary capillary wedge pressure (PCWP) < 15 mmHg, pulmonary vascular resistance index (RpI) > 3 WU/m² (250 dyn·s·cm−5) [mean of ≥25 mmHg as measured at rest during right heart catheterization and RpI < 3 WU/m². Patients with a PAPmean < 25 mmHg measured as described above were assigned to group III [A total of 242 patients aged 4–198 months with a diagnosis of CHD and isolated, large left-to-right shunt who had been seen between October 2006 and November 2011 at the Pediatric Cardiology Department of the Gazi University Medical School were included in this retrospective evaluation. The cases were evaluated in three separate groups. Group I consisted of patients with a diagnosis of PAH. Criteria for the diagnosis of PAH were a mean pulmonary artery pressure (PAP·s·cm−5) . PH in gPatients who had been evaluated by invasive hemodynamic diagnostics by cardiac catheterization in view of an intervention necessitated by heart failure and cardiomegaly were included in the surgical treatment plan, as well as patients who fulfilled the criteria decribed below. The inclusion criterion for the presence of a large left-to-right shunt at evaluation by transthoracic echocardiography (TTE) was a diameter of >2 cm for an atrial septal defect (ASD) and >1 cm for a ventricular septal defect (VSD) . The incPremedication for cardiac catheterization was performed with intravenous midazolam, 0.1 mg/kg; patients who received additional sedative or anesthetic agents were excluded from the study in order to avoid measurement errors on which to base calculations after the Fick's principle. Pressure recordings and blood samples were obtained from the heart chambers and the large vessels in all patients following catheterization of femoral vein and artery. Pulmonary blood flow (Qp) and systemic blood flow (Qs) was calculated on the basis of Fick's principle. Hemodynamic measurements consisted of left atrial pressure, left atrial pressure or PCWP, systolic, diastolic and mean pulmonary artery pressures, pulmonary and systemic blood flow, flow ratio, pulmonary and systemic resistance, and resistance ratio. These values were divided by the body surface area for use as standardized indexes. Estimated values according to age, sex, and heart rate were used for oxygen consumption.P-value inferior to 0.05 was considered statistically significant.Data analysis was performed using SPSS for Windows, version 15.0. The normality of continuous variable distribution was tested by the Shapiro-Wilk test. Homogeneity of variance was evaluated by the Levene test. Data were expressed either as mean ± 1 SD or median (minimum-maximum), as appropriate. Differences in the group means were evaluated using one-way analysis of variance (ANOVA), while differences among median values were evaluated by the Kruskal-Wallis test. Tukey's post hoc procedure or Conover's multiple comparison test was used in case of a statistically significant result of ANOVA or Kruskal-Wallis tests to determine the different groups. Categorical variables were evaluated using Pearson's chi-squared test. After correcting for age and sex, the continuation of the effect on RpI in both the PAH and PH groups was evaluated by multivariable linear regression analysis. A A total number of 242 subjects were included in the study. Their average age was 61.6 ± 51.2 months. The patient's number, central values, and age range for the three groups were as follows: group I, 30 patients aged 32.5 ± 46.4 months (6–156); group II, 35 patients aged 25.9 ± 33.2 months (6–132); group III, 177 patients aged 73.7 ± 49.8 months (6–216).There was no significant difference between the first two, while age in group III was higher than in both of these . Even thThe most frequent anatomic condition in both groups I and II was perimembranous VSD, while in Group III it was ASD . PAH wasThere was no difference among groups as to Qp . Qs, on the other hand, differed among the three groups. Qp, Qs, and the Qp/Qs ratio were not found to be a determining factor in the development of PAH. There was no statistically detectable difference between Groups I and II for RsI, RpI/RsI, or left atrial pressure even though there was a perceived difference .P = 0.014 with a 95% confidence interval of 0.011–0.074).Stepwise multivariable linear regression analysis of all those variables that had a statistically significant correlation with RpI  showed tP = 0.321, P = 0.929), while the significant elevation of RpI in both the PAH and PH groups remained. The results of multivariable linear regression analysis are shown in After correcting for age and sex, the significant effect on RpI disappeared (Correct management of heart defects with left-to-right shunt is important in the prevention of progressive pulmonary vascular disease. It is estimated that pulmonary vascular disease develops in 15% (10–18%) of all CHD. The uncorrected CHD defects in these cause a left-to-right shunt; the resulting continual increase in pulmonary flow increases tensile stress, which leads to an elevation of Rp and finally to pulmonary vascular damage . In the The estimated prevalence, in developed countries, of PAH in adults with CHD including a left-to-right shunt is 1.6–12.5 cases per million . AccordiThe size and location of the septal defect are an important determinant of PAH in the presence of CHD both in children and adults. Simple defects are considered in two groups according to location, pretricuspid and posttricuspid shunts . PretricPulmonary resistance index (RpI) cannot be measured directly; it is calculated by the ratio of pulmonary pressure variation to pulmonary arterial flow. While right heart catheterization measurements are helpful, in fact the best available tool to date, they are not always reliable. Even patients who are in the interval recognized as predicting a good outcome of surgery may show a persistent postoperative PAH. More manageable and less invasive tools are needed, especially for patients who are a borderline for operability according to their hemodynamic profile. Lévy et al. report recent developments which could justify hopes of new tools for determining operability . The ademean, increased mean right atrial pressure, and reduced cardiac index. No significant difference was seen between Groups I and II with regard to PAPmean, systolic and diastolic pulmonary arterial pressure  and left atrial pressure. As a result, these parameters were not considered risk factors for the development of PAH. The significant single-pair correlations shown in Published literature indicates that hemodynamic values obtained by cardiac catheterization are the principal prognostic factor. An analysis based on records of the US National Institute of Health (NIH) shows a particularly high prognostic importance of three hemodynamic variables for survival . These aThe influence of individual conditions like the type of lesion and genetic predisposition on the result remained incompletely understood. Studies have been performed on the prognostic value of other investigations than catheterization, including lung biopsy, a more rarely used invasive procedure, and the high risk of irreversible PAH after CHD correction indicated by circulating endothelial cells as reported by Smadja et al. , 16.Along with intimal thickening of the pulmonary artery and increased bcl-2 expression in endothelial cells in lung biopsy, patients with irreversible PAH seemed to have a higher number of circulating endothelial cells than those with a reversible disease. Findings other than CEC, like endothelial activation, regeneration, and injury biomarkers, do not differentiate between reversible and irreversible PAH.Finally, it is not possible as of today to predict exactly when and under the influence of which risk factors PAH is likely to develop; numerous studies including many more cases are needed to understand this complex disease.As for the limitations of the study, the lack of genetic marker data of the patients is an important one, even though, with the knowledge of studies performed to date, genetic markers were found in small numbers in nonhereditary PAH patients. Such determinations are not yet at the point of being part of the routine evaluation of patients with left-to-right shunts. Another limitation is the fact that, even though vasoreactivity had been tested in our PAH patients, it has not been presented as various methods, and various agents had been employed for the test.In conclusion, patients followed up with a diagnosis of VSD are the most at risk for PAH among those with isolated large left-to-right shunt. PAH developed in 12.3% of cases of isolated left-to-right shunt. A correlation could not be established between pulmonary vascular resistance increase, provoked by the patient's age or the exposure duration of the pulmonary vascular bed and the development of PAH. Considering the probable effect of factors other than age, particular attention should be paid to following up these cases for the development of irreversible pulmonary vascular remodeling, a situation to be kept in mind also in determining the follow-up periods.


Cardiac output (CO) is an important determinant of the hemodynamic state in patients with congestive heart failure (CHF). We tested the hypothesis that CO can be estimated from the right ventricular (RV) pressure waveform in CHF patients using a pulse contour cardiac output algorithm that considers constant but patient specific RV outflow tract characteristic impedance.In 12 patients with CHF, breath-by-breath Fick CO and RV pressure waveforms were recorded utilizing an implantable hemodynamic monitor during a bicycle exercise protocol. These data were analyzed retrospectively to assess changes in characteristic impedance of the RV outflow tract during exercise. Four patients that were implanted with an implantable cardiac defibrillator (ICD) implementing the algorithm were studied prospectively. During a two staged sub-maximal bicycle exercise test conducted at 4 and 16 weeks of implant, COs measured by direct Fick technique and estimated by the ICD were recorded and compared.-5, respectively. During sub-maximal exercise, the total pulmonary arterial resistance decreased  but the characteristic impedance was unaffected . The algorithm derived cardiac output estimates correlated with Fick CO  with a limit of agreement of 1.7 L/min and tracked changes in Fick CO (R2 = 0.73).At rest the total pulmonary arterial resistance and the characteristic impedance were 675 ± 345 and 48 ± 18 dyn.s.cmThe analysis of right ventricular pressure waveforms continuously recorded by an implantable hemodynamic monitor provides an estimate of CO and may prove useful in guiding treatment in patients with CHF. Cardiac output (CO), together with measures of cardiac filling pressures and peripheral resistance, is a key variable to describe hemodynamic pathophysiology in patients with heart failure. At rest, heart failure patients often maintain a normal CO until later stages of the disease, when CO becomes too low to meet the metabolic demands of the body . HoweverCO can be affected by disorders that affect both left and right ventricular (RV) function ,5. CHF pRecently, continuous monitoring of right ventricular pressure parameters, recorded either from an implantable hemodynamic monitor (IHM)  or usingThe present study aims to investigate if this assumption remains valid in exercising heart failure patients and to assess if this algorithm can also be used to derive estimates of CO for continuous measurements in patients with heart failure who are implanted with an IHM or an ICD with pressure monitoring capabilities. For this purpose, retrospective hemodynamic data obtained during stationary bike tests were pooled with data from prospective chronic studies in patients implanted with an ICD implementing the algorithm to further validate these assumptions and to assess the bias and agreement of this method to the Fick method.® Phase I technical feasibility study [Hemodynamic data from six male patients who were enrolled in a pilot trial   which was implanted in the left subclavicular region using standard techniques for pacemaker insertion [Patients in Group I and II received an IHM system . Group II patients were studied at least one month after the implant and performed a two-staged upright bicycle exercise protocol (6 minutes at 25 watts followed by 3 minutes at 50 watts). Group III patients were studied at one and four months after implant at rest in supine position, standing and during upright bicycle exercise at 50 and 70% of the maximal work load. The maximal workload was determined during an exercise test one week before the one month test.During exercise, pulmonary artery (PA) pressure, and mixed venous oxygen saturation were measured by an oximetric probe . The ventricular pressure waveforms and arterial oxygen saturation were recorded by the IHM and by finger probe oximetry, respectively.Oxygen consumption was measured breath-by-breath, using a metabolic assessment system . For Groups I and II, breath-by-breath CO was calculated according to the Fick principle, using mixed venous oxygen saturation from the optical catheter, arterial oxygen saturation from the finger probe oximeter and oxygen consumption. For Group III, CO was calculated at the end of each intervention according to the Fick principle, using arterial and mixed venous blood samples and oxygen consumption. Beat-by-beat RV pressure waveforms, RV pressure derived estimated cardiac output (Group III) and breath-by-breath oxygen consumption values were saved to a computer disk for subsequent analysis.estimate of the cardiac output, eCO, as:A beat-by-beat estimate of the CO was calculated using a previously established RV pressure waveform based pulse contour CO algorithm, PCCO ,11. Thismax and dP/dtmin. We have previously shown that the small error (<2%) introduced by triangular approximation of the outflow waveform can be ignored [1st and PES denote pressures at the time of peak flow and at the dP/dtmin, respectively. The coefficient Zc is considered to be the patient specific RV outflow tract characteristic impedance unaffected by changes in pressure or flows. Note that if the value of Zc is unknown but assumed to be constant, Equation 1 denotes the cardiac output normalized to Zc, [c can easily be calculated empirically as the ratio of cardiac output (measured using a gold standard method) to first two terms of the Equation 1.where the ejection duration (ED) corresponds to the time interval between dP/dt ignored . The P1sd to Zc, ,11. The c was assumed to be unknown) and stored in the ICD memory to allow measurements in chronic ambulatory settings. Using custom software, these stored eCO data were subsequently retrieved and analyzed.In Groups I and II, Equation 1 was implemented in dedicated software which was used to analyze the recorded RV pressure waveforms on a personal computer. In Group III, the PCCO algorithm was implemented in the hardware of the ICD which had the capability of recording the RV pressure waveform. Using this algorithm, beat-by-beat eCO values were calculated  was calculated as the ratio of eMPAP to mCO. Once PAR and the Zc, were known, the coefficient of wave reflection, Γ, was calculated as [Baseline and exercise values of steady and oscillator components of the RV afterload were calculated to assess differences between patients and influence of exercise. In particular, the changes in characteristic impedance due to exercise was calculated to verify the assumptions of the algorithm. Both the IHM and the ICD can analyze the RV pressure waveform on a beat-by-beat basis, extract and store the values of right ventricular diastolic pressure (RVDP), right ventricular systolic pressure (RVSP) and the estimated mean PA pressure (eMPAP) -15,20. Ulated as ,15:(2)The differences between baseline and exercise hemodynamic parameters were assessed using paired-t tests. Because the cardiac output measured by the breath-by-breath Fick technique (mCO) was highly variable (SD/mean = 35 ± 14%), measured and estimated parameters corresponding to rest and submaximal exercise were averaged over two minutes.c, were analyzed and when it was found to be negligible, the average Zc for each patient, irrespective of the exercise stage was calculated using all beat-by-beat values. This average Zc was then entered in Equation 1 to calculate beat-by-beat eCO values.In Groups I and II, the effects of exercise on patient specific characteristic impedances, Zc for each patient, irrespective of the posture and exercise stage was calculated using data generated during the first exercise study at one month. This average Zc was then utilized to calculate beat-by-beat eCO values for the data collected at the four month exercise study using Equation 1.In Group III, an average ZA linear regression and Bland-Altman analyses were performed to assess the correlation coefficient, the mean bias and the limits of agreement of the eCO compared to mCO . Finally-5) and oscillatory components of the RV afterload  were elevated compared to normal [Table o normal .-5 and a significant decrease in the coefficient of wave reflection of -0.02 ± 0.04 units but no statistically significant change in Zc of 3 ± 9 dyn.s.cm-5 during exercise . The corresponding modified Bland-Altman plot indicated a mean bias of the estimate of -0.6 L/min. The limits of agreement were -3.0 to 1.9 L/min (30%)  Figure  and therIn this study, we used right ventricular pressure waveforms recorded with an implanted hemodynamic monitor, to estimate the cardiac output at rest and during bicycle exercise in patients with CHF. The results indicate that the PCCO algorithm and a single estimate of the characteristic impedance, individualized for each patient, are sufficient to provide estimates of the cardiac output at rest and during exercise. Given the important role of cardiac output in the hemodynamic pathophysiology of heart failure, continuous monitoring of this parameter over time using an implantable device may be helpful to improve the long-term management of CHF patients.2 = 0.73) [Critchley and Critchley suggested that in order to accept a new cardiac output measurement technique for clinical use, the limits of agreement should be within ± 30%, The pre = 0.73) . It has  = 0.73) . Howeverc, and the coefficient of wave reflection, Γ) components of the RV afterload were already elevated in these patients with moderate HF [c of the RV outflow tract essentially remains constant for a given individual [c of the RV outflow tract remained unchanged, confirming our initial hypothesis. Although the Zc appear to have quite large increase with exercise in some patients, this observation was not consistent in all patients , and oscillatory  and the medications  on these findings. Further systematic studies with larger sample sizes are needed to address the influence of such parameters on these findings.In this study of patients with chronic heart failure, the RV pressure waveform recorded by an implantable hemodynamic monitor accurately and repeatedly measured cardiac output at rest and during exercise in an acute setting. This information, together with the corresponding data on cardiac filling pressures derived from the RV pressure sensor, could be useful in the long-term assessment of hemodynamic status and therapy response in heart failure patients.CL and FB have received research grants and been a consultant advisory and board member for Medtronic. MK, BK, VS and TB are employees of Medtronic, Inc.MK has conceived the original study, its design and coordination, contributed to the gathering and critical analysis of data and has written the manuscript. TB helped in the study design and coordination, and helped with the manuscript. MS has contributed to the cardiopulmonary exercise tests and to the interpretation of data. VS contributed to the gathering and the statistical analysis of data and the drafting of the manuscript. BK has contributed to the study design and coordination and cardiopulmonary exercise tests and the drafting of the manuscript. CL helped in recruiting the patients and coordination of the study and critical review of the manuscript. FB helped its design and coordination, performed catheterizations and contributed to the gathering and critical analysis of data and has helped write the manuscript. All authors read and approved the final version of the manuscript.


Abnormalities in nocturnal blood pressure dipping are well known for its relationship to cardiovascular diseases. Cerebral microbleeds are frequently observed in patients with hypertension and are known to be potent risk factors for stroke. However, there are scanty reports about the relationship between nocturnal dipping and cerebral microbleeds.We recruited consecutive patients with both hypertension and ischemic stroke within 7 days after symptom onset, and those with cardioembolism were excluded. We applied 24-hour ambulatory blood pressure monitoring two weeks after stroke onset, and we used brain MRI to detect cerebral microbleeds. Various blood pressure parameters such as mean 24-hour blood pressure, awake/sleep blood pressure, and morning surge were compared between cerebral microbleeds (+) vs. (-) groups. Subjects were further classified according to nocturnal dipping status and were analyzed by logistic regression to determine its association with cerebral microbleeds with adjustment for age, gender, and cardiovascular risk factors.p-value = 0.01).A total of 162 patients  were included. Cerebral microbleeds were detected in 65 patients (40.1%). Most ambulatory blood pressure parameters except morning surge were significantly higher in those who had cerebral microbleeds. After adjusting for the confounding factors, the reverse dippers were prone to have cerebral microbleeds (odds ratio, 3.81; 95% confidential interval, 1.36-10.65; Cerebral microbleeds are independently associated with reverse dipping on ambulatory blood pressure monitoring in hypertensive stroke patients. Cardiovascular events such as stroke, myocardial infarction, and sudden cardiac death showed diurnal variations in their occurrences . Based oCerebral microbleeds (CMB) are known as focal accumulations of hemosiderin-containing macrophages in the perivascular spaces of small blood vessels in the brain, which result from blood extravasation, due to microvasculature structural changes in the brain caused by a high BP load . This isSubjects who had cerebral infarctions within one week were consecutively recruited from two university hospitals - from August 2007 to July 2011, according to the following criteria.  classifications . We alsoThis study was approved by a local institutional review board with Boramae Hospital; additionally, we obtained written informed consents from all patients participating in the study.Due to possible reactive BP increment after stroke, we applied ABPM  two weeks after the ictus. Antihypertensive medications were suspended from stroke ictus per routine clinical protocol. BP was assessed every 30 minutes in the non-paretic upper extremity. Subjects who obtained less than 80% of valid BP readings were excluded.The following parameters were calculated from raw data for the mean and standard deviations (SD): 24-hour mean systolic/diastolic BP (SBP/DBP), awake SBP/DBP, sleep SBP/DBP, morning SBP/DBP, evening SBP/DBP, lowest sleep SBP/DBP, pre-wake SBP/DBP, morning SBP surge, nocturnal BP falls, and pulse rate .Each individual parameter was defined as follows: Sleep BP was an average of all values from the beginning of sleep until awakening based on the activity sheet. Awake BP was defined as the average for the remaining time excluding sleep BP. Morning BP was designated as an average BP over 2 hours after awakening. Evening BP was an average BP during the 2 hours before bedtime. The lowest sleep BP was defined as an average BP during 1 hour that included the lowest sleep BP. Pre-wake BP was an average BP during the 2 hours before awakening.Morning BP surge (MBPS) was defined in two different ways; First, we calculated sleep-trough MBPS as the mean SBP during the 2 hours after awakening minus the mean SBP during 1 hour including the lowest SBP during sleep . Second,Nocturnal BP falls was also defined by two different means. First, the awake nocturnal fall was calculated as the awake SBP minus sleep SBP  * 100]). Second, the evening nocturnal fall was calculated as the evening SBP minus sleep BP  * 100]) .According to the magnitude of the BP falls, subjects were divided into subgroups: dippers were those who showed ordinary nocturnal BP falls , extreme dippers were those who had over 20% nocturnal BP falls, non-dippers were those who did not meet the ordinary magnitude of BP falls , and reverse dippers were those who showed BP increments during nighttime.On the day of admission, diffusion-weighted imaging, apparent diffusion coefficient, axial T2, fluid-attenuated inversion recovery (FLAIR), T2*-gradient echo, sagittal T1, contrast-enhanced axial/sagittal T1, contrast-enhanced FLAIR, intracranial and extracranial MR angiography were obtained for each subject with a 1.5 Tesla superconducting magnet . CMB were defined as round-shaped homogenous foci of low signal intensity lesions on T2*-weighted gradient echo images, which were less than 5 mm in diameter . The focIn addition, acute stroke locations were also reviewed on diffusion-weighted images. Lesion locations were classified as cortex, corona radiata, basal ganglia/internal capsule, and infratentorial. Furthermore, the insular cortex and amygdala were separately inspected, because there was prior evidence that disruption of those structures were associated with impaired BP variability in patients with acute stroke .T-tests for continuous variables. In order to assess the relationship between various ABPM parameters and CMB, we applied logistic regression analyses; and calculated the odds ratios at one standard deviation increment in BP parameters. Models were adjusted for age, gender, and additionally for those which showed p-value < 0.20 in the bivariable analysis.We performed Chi-square tests for categorical variables, and Student’s A total of 162 subjects were enrolled in this study. Mean time interval between the ictus of stroke and ABPM was 15.5 days (standard deviation 4.9 days). CMB were detected in 65 (40.1%) patients. About 61% of CMB were located in the central gray matter, 27% in lobar, and 12% in infratentorial regions.p-value = 0.02; 107.2 ± 32.1 vs. 115.7 ± 35.1, p-value = 0.12; for CMB (+) vs. (-) respectively); otherwise, there were no significant differences between the two groups.Baseline characteristics of subjects with or without CMB are described in Table The distribution of stroke lesions is shown in Table p = 0.73), and those medications were suspended in all patients after stroke.One hundred four (64.2%) subjects had pre-existing hypertension and 58 were diagnosed with hypertension de novo. About half of the patients were prescribed antihypertensive medications before index stroke (82 (50.6%) in total; 34 (52.3%) in CMB (+) patients; 48 (49.5%) in CMB (-) patients; p = 0.01) according to the definition of evening nocturnal BP falls, and after adjusting for age, gender, LDL, and 24-hour mean SBP/DBP. Awake nocturnal BP falls were not significantly associated with CMB. Additionally, morning surge did not show any significant differences between the two groups, according to both definitions.Every individual ambulatory BP component in relation to CMB is presented in Table In this present work, we demonstrated that acute ischemic stroke patients who had a reverse-dipping phenomenon were prone to have CMB. Although most of the ABPM parameters lost their significances after adjusting for the cardiovascular risk factors and 24-hour mean SBP/DBP, the association between reverse dipping and CMB was still significant.There are few reports that deal with the pathophysiologic link between dipping and CMB. Pathologically, CMB are located around the deep perforating arteries showing moderate to severe lipohyalinosis and amyloid deposits . RuptureIn our results, the significant differences were observed only in the reverse dipping with the evening nocturnal BP falls, not the awake nocturnal BP falls that is the conventional definition of nocturnal dipping. Evening nocturnal BP falls were calculated with evening BP during 2 hours prior to bedtime . We haveThe exact mechanism of reverse dipping is open to validation. Several explanations such as persistent activation of autonomic nervous system, sympathetic tone, and α1-adrenergic activities during the night may account for this . Sheer sThe prevalence of CMB was higher than the previous studies in hypertensive patients , cross-sIn the previous studies, 63 (11.0%) patients among 575 subjects with sustained hypertension who aged over 50 years were reverse dippers . AnotherThere are several limitations in our study. A case can be made to call into question the eligibility criteria of our study. For the practical reason, we limited our study to hypertensive patients. CMB were regarded as hypertensive target organ disease , and morp = 0.01).After stroke, BP can show a reactive elevation due to increased catecholamine levels and previous hypertension and pain ; so the Physical dependence caused by recent stroke could be another confounding factor. However, when we compared stroke severities using initial NIHSS between two groups, there were no significant differences in the stroke severity.The small number of subjects should also be considered. Though there were statistical significances, the small numbers of patients in the subgroups of dippers and reverse dippers could actually weaken the strength of our conclusion. The possibility of increased type I error is another consideration of our study. When we readjusted minimum p-value for statistical significances using Bonferroni methods, the statistical significances were mostly compromised. Considering the conservative nature of Bonferroni correction, there were some possibilities that true associations were also compromised by this correction. However we admit the possibility of increased type I error, we thought that our results should be validated through hypothesis-driven research with larger sample size.For practical reasons, we applied ABPM only once for each patient. Ideally, a repetitive ABPM application would increase data reliability; however, patient discomfort and high application cost were too much to bear in actual practice. In addition to that, the possible confounding factors such as sleep apnea were not measured. Finally, the cause-effect association cannot be referred in the present study.In conclusion, our study revealed that reverse dipping in ABPM was significantly associated with high prevalence of CMB in hypertensive patients with ischemic stroke. This has an implication of underscoring the importance of sustained nighttime hypertension for its association with CMB, which represents hypertensive target organ disease. Nighttime reverse dipping often goes unnoticed by patients, and, or physicians. Strategies to overcome these silent issues might be helpful in preventing CMB-associated cerebrovascular diseases. In future research, these associations should be reproduced and confirmed in more generalized subjects.None of the authors have any conflict of interest.HMK and HN participated in the design of the study. HMK, JSL, YSK, JM, HP, HYK, YHL and HN collected the data. HMK and JSL performed the statistical analyses and drafted the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/14/8/prepub


The relationship between systemic hemodynamic parameters and microcirculatory perfusion remains unclear. This is especially apparent in the concept of fluid responsiveness, where stroke volume (SV) can fluctuate strongly without being paralleled by changes in microcirculatory perfusion. Therefore, we hypothesized that large decreases in volume status due to ultrafiltration (UF) with intermittent hemodialysis in patients with end-stage kidney disease (ESKD) would decrease systemic hemodynamics but would not affect parameters of microcirculatory perfusion.Consecutive patients on chronic intermittent hemodialysis for ESKD were eligible for our study. SV and heart rate were measured continuously and non-invasively using NICOM, a technique based on chest bioreactance. Blood pressure was measured intermittently with a sphygmomanometer. Peripheral and microcirculatory perfusion were measured intermittently with sidestream dark-field (SDF) imaging , and continuously with forearm-to-finger temperature gradient (Tskin-diff) and photopletysmography (PPG) (finger). All parameters were assessed before (baseline) and after 4 hours at the end of UF.P < 0.01) and from 102 (88 to 109) mmHg to 85 (75 to 95) mmHg (P < 0.001), respectively, while heart rate did not change. At baseline all parameters of peripheral and microcirculatory perfusion were undisturbed. During UF, Tskin-diff and the PPG of the finger did not change. Sublingual microvascular flow index and vessel density measured with SDF slightly decreased from 3.0 (3.0 to 3.0) to 2.8 (2.7 to 2.9) (P < 0.001) and from 10.6 (9.9 to 11.1) n/mm to 9.9 (9.2 to 10.5) n/mm (P < 0.05), respectively.Data are presented as median (IQR). Twenty-one patients  years) were included in our study. A median volume of 2,200  ml was removed. SV and mean arterial pressure decreased during UF from 75 (58 to 84) ml to 51 (37 to 67) ml (UF leads to a significant and uniform decrease in volume status in patients with ESKD but surprisingly this was not associated with large decreases in peripheral and microcirculatory perfusion. Therefore caution is warranted when interpreting systemic hemodynamic parameters in terms of hypovolemia and hypoperfusion when peripheral perfusion is not evidently impaired.