Background. Asthma-like symptoms are frequent in overweight and obesity, but the mechanism is unclear when airway hyperresponsiveness (AHR) is lacking. In this study, we focused on obese women with a clinical suspicion of asthma but negative methacholine challenge and tested distal airway hyperreactivity, explored by Forced Vital Capacity dose-response slope (FVC DRS). Objective. To question AHR at the distal airway level in obese women. Methods. A total of 293 symptomatic obese and nonobese women free of treatment were investigated. Methacholine challenge tests were undertaken, and patients were divided according to their results to the test. In hyperreactive and nonhyperreactive patients and in our total population, correlations, regression analyses, and analyses of covariance were performed to compare distal airway hyperreactivity in three groups of body mass index (BMI). Results. After adjusting for age and baseline respiratory values, the relationship between FVC and FEV1 (forced expiratory volume in one second) DRS was influenced by BMI, with a lower slope in obese than overweight and normal patients in our total population (P = 0.008) and in our nonhyperreactive one (P = 0.028). Conclusion. Distal airway hyperresponsiveness was observed in symptomatic wheezing obese women negative to methacholine challenge. The relationship between obesity and airway hyperresponsiveness (AHR) has been a great matter of interest among the scientific community for many years. Several studies have enlightened that obese patients (body mass index (BMI) > 30 kg/m²) were more likely to have a clinical diagnosis of asthma and to receive antiasthma drugs, but the effect of obesity on airway hyperresponsiveness remains debated –4. Overweight and obesity are comorbid conditions known to be associated with poorer asthma control  and pote Previous reports demonstrated that obesity was an independent risk factor for AHR , 10, but Asthma-like symptoms are frequent but not always related to AHR—with an important risk of bias in epidemiological studies, where challenges are rarely done (creating a risk of overdiagnosis). In a study by Stenius-Aarniala et al. , obese p Previous studies have hypothesized that the variations in airway calibre and pulmonary volumes, occurring during bronchoconstriction, were different in obese and nonobese asthmatic patients, due to a greater involvement of distal airways in the obese population , 13. How Airway closure has been found to be a determinant of AHR. Chapman and his team  came to The Forced Vital Capacity fall throughout a methacholine challenge test was previously reported as potential reflection of small airway closure in several studies –17.Besides, the role of gender in AHR in overweight and obese people is a potential confounder in many studies. According to epidemiological reports , bronchi In the present study, we investigated symptomatic obese women aiming at demonstrating any difference at the distal level of the airway tree. We assessed the impact of BMI on several lung function parameters derived from the methacholine challenge, such as FVC fall and FEV1 fall throughout the methacholine challenge test, and FEV1 and FVC dose-response slopes, in order to better understand the complex relationships between obesity, airway closure, AHR, and asthma-like symptoms. The study was based on the retrospective analysis of subjects from the Respiratory Department of the Arnaud de Villeneuve Hospital .  According to the French Law , this noninterventional study did not require approval by an ethics committee or informed signed consent from patients. It was reviewed and approved by our institutional review board (IRB number: 11/10-07). A total of 293 consecutive women were considered from January 2007 to December 2009. All patients had symptoms likely to suggest asthma, which include wheezing, dyspnoea, chest tightness, or cough in the following circumstances: (1) with exposure to cold air, (2) after exercise, (3) during respiratory infections, (4) following inhalant exposures in the workplace, and (5) after exposure to allergens and other asthma triggers . DiffereAll patients underwent a methacholine bronchial provocation test, and AHR was defined as a provocative concentration causing a 20% fall in FEV1 (PC20) inferior or equal to 16 mg/mL. Throughout this paper, positive patients to the methacholine test are referred to as “AHR+” and negative patients as “AHR−.”2, overweight subjects as having a BMI ≥ 25 kg/m2 and < 30 kg/m2, and obese subjects as having a BMI ≥ 30 kg/m2 [ Three groups of patients were considered according to their BMI. BMI-normal subjects were defined as having a BMI < 25 kg/m Methacholine challenges were performed according to the American Thoracic Society Guidelines , with th Furthermore, in order to keep the cumulative effect of methacholine, the waiting time between each dose was kept under 2 minutes. When an FEV1 fall greater or equal to 20% was reached, a bronchodilator was administered and FEV1 was measured after a 15-minute wait and until complete recovery was reached.AHR was defined by a PC20 lower or equal to 16 mg/mL.  AHR was measured as the FEV1 dose-response slope (DRS) throughout the methacholine challenge test. Distal airway closure was estimated by the FVC DRS. These DRS were obtained from a calculation based on the last value minus the baseline value, divided by the last methacholine dose in mg. With this methodology, we could take into account the methacholine dose when considering the fall in respiratory parameters. The relationship between changes in FVC and FEV1, each represented by their dose-response slope, provided an estimate of the proportion of FEV1 change that was attributable to airway closure.The closing index was the percentage fall in FVC divided by the percentage fall in FEV1. The percentage falls were defined as /last value.Implemented Variables First, a Kolmogorov-Smirnov test was used to assess the normality of our variables. Because variables were not normally distributed, the comparison of population characteristics between normal weight, overweight, and obese patients was studied via nonparametric Kruskal-Wallis tests, and the results were expressed as medians and interquartile ranges. Nonparametric Spearman correlation tests were also executed, in order to quantify the strength of the relationship between FEV1 and FVC fall.The effect of BMI on the relationship between the fall in FEV1 and the fall in FVC throughout the methacholine test was examined using a linear regression of FVC DRS against FEV1 DRS for the three levels of BMI , with BMI-normal patients as our control group. FEV1 DRS was considered as the predicted variable, and FVC DRS as the independent parameter. This allowed us to calculate the contribution of the FVC DRS to the FEV1 DRS.In order to compare the slopes calculated in the linear regressions and represented in the graphic representations, we carried out analyses of covariance (ANCOVA), with FEV1 DRS as the predicted variable and FVC DRS and BMI as the independent parameters. We focused particularly on the interaction term, which described significant differences between the slopes.This has been done for the AHR+ patients, the AHR− patients, and the whole population. In order to achieve normality and a clearer graphic representation, log (FEV1 DRS) and log (FVC DRS) were used instead of the variables themselves. P value lower than 0.05 was considered statistically significant.All these results were adjusted for age and baseline respiratory values, and a Statistical tests were performed with R 2.10  and SAS 9.2 .P < 0.0001) and had lower values in baseline FVC and FEV1 (P < 0.0001) and FEV1/FVC ratio (P = 0.0375). Obese patients also had higher values in FEV1 fall (P = 0.0230), FEV1 DRS (P = 0.0008), FVC fall (P = 0.0011), and FVC DRS (P = 0.0008)  .P < 0.0001) and had lower values in baseline FEV1 (P < 0.0001) (P = 0.0003) and had lower values in baseline FEV1 and FVC (P < 0.0001). AHR+ patients differed only by age and baseline FEV1. In this subgroup, overweight and obese women were significantly older ( 0.0001) . Conside 0.0001) , overweiR2 = 0.90), and the Spearman coefficient was 0.97  and 0.93 (obese patients).R2 of 0.77 and a Spearman coefficient of 0.87.In the AHR− population, the values were again high, particularly for the obese patients, with an Entire Population. The relationship between FVC DRS and FEV1 DRS was significantly different according to BMI, with a lower slope in obese than overweight and normal patients (0.74 (sd: 0.04) versus 0.91 (0.04) and 0.90 (0.05), resp., P = 0.008)  .AHR+ Patients. No difference was found in the AHR+ population, with slope values of 0.87 (0.06), 1.04 (0.06), and 0.94 (0.06) (P = 0.409) for the BMI-normal, the overweight, and the obese patients, respectively  versus 0.78 (0.14) and 0.62 (0.09), resp., P = 0.028) (= 0.028)  and 6. In obese women tested for AHR, we observed increased dose-response slope of FVC plotted against FEV1, in the whole population and in AHR− patients. According to the graphic representations, the regressions, and the analyses of covariance, we observed a greater contribution of FVC fall to the FEV1 fall for obese women. Our results highlight the importance of obesity on the involvement of distal airways. On the patients with asthma-like symptoms but negative challenge, obesity could increase airway resistance via distal airways , thus le Increased closing index and classical improvement at exercise of a certain degree of hypoxia at rest are other reflections of small airway involvement . But to Nitrogen slopes or respiratory CT scan in these patients might be worth investigation to achieve a better understanding of the mechanisms involved in the impact of obesity on distal airways. This could lead to better treatments for wheezing obese patients, who are clearly a complex phenotype. A more specific medication, treating especially distal airways, might be worth investigation in these patients.  Unfortunately, symptoms were not quantified, and lung volumes were not prospectively recorded. But rigorousness of the protocol and methacholine dosage nonetheless allowed us to observe an expected difference. As in every functional study dedicated to BMI influences, result expression is a critical issue to address, as equations are including the BMI. Changes in percentage of flows and volumes are then highly affected by the pretest values, that is to say that FEV1 fall is easier to observe in the obese with lower starting FEV1 values. Most of our results were clearly influenced by basal values of flows and volumes, and an adjustment was required. Some authors –17 reporPrevious studies already suggested that increased abdominal pressure on the diaphragm in the obese can lead to a stronger contribution of airway closure , 30. Eve Whether currently available treatment dedicated to small airways may help these patients is rather unknown. Most lines of evidence suggest a negative answer as neither inhaled corticosteroids (ICS) nor long-acting beta agonists tended to improve symptoms, because of their inability to reach the distal area of the lung . On the At a glance, we identified a different level of methacholine-induced bronchoconstriction only at distal airway level of symptomatic nonasthmatic women of a nonestablished cause.


Abnormal circadian blood pressure patterns have been associated with cardiovascular disease in diabetes mellitus. We have described that the acrophase of diastolic blood pressure (DBP) registered in type 1 diabetes (T1D) patients was significantly earlier than normal and DBP ecphasia was more pronounced in patients with lower heart rate variability during deep breathing. The aim of this study was to compare the circadian rhythm characteristics of BP among different groups: normotensive (NT) control subjects, patients affected by T1D and type 2 diabetes (T2D), and patients with essential hypertension (HT).We retrospectively evaluated ambulatory blood pressure monitoring records in 30 NT, 20 T1D, 20 T2D, 20 HT whose fasting plasma glucose and HbA1c were contemporaneously measured. The four groups were well-matched regarding age, gender, and BMI.Systolic blood pressure (SBP) and DBP midline-estimating statistic of rhythm were higher in T1D, T2D, and HT groups. DBP ecphasia was present only in the diabetic individuals: the acrophase of DBP occurred four hours earlier than normal in T1D group, whereas two hours earlier in T2D group. In a multiple regression analysis, only HbA1c and SBP acrophase were statistically significant correlates of DBP acrophase.People with diabetes mellitus, both type 1 and type 2, have their circadian acrophase of DBP occurring 2–4 hours earlier than normotensive and hypertensive subjects. Altered circadian timing of DBP, potential trigger of cardiovascular events, seems to be a distinguishing feature of diabetes mellitus and correlates with the previous 2–3 months of glycaemic control. Abnormal patterns of circadian blood pressure (BP) variation, evaluated by ambulatory blood pressure monitoring (ABPM), predict cardiovascular prognosis in diabetes mellitus . We have. Subjects where excluded if they had incomplete clinical records or if their fasting plasma glucose (FPG) and HbA1c measurements were not available. Were included 90 patients: 30 NT, 20 HT, 20 subjects with T1D, and 20 with T2D. The four groups were well matched regarding age, gender, and BMI  as previously described [The study protocol was approved by the ethical committee of the hospital and all patients provided written informed consent.Analysis was performed using Aabel 3 . Results are given as mean±SD. Statistical comparison was by chi-square test, ANOVA or Kruskal-Wallis tests. The cut-off level for statistical significance was set at p <0.05. Pearson’s correlation coefficient or Spearman’s rho was computed to determine the correlation between variables. Multivariate regression analysis was used to determine independent predictors of the variables of interest; candidate predictors selected in the multivariate model were the variables significantly associated by simple univariate correlation analysis.Subjects in the T1D and T2D groups had significantly higher FPG levels than NT and HT; the highest value of HbA1c was in the group T1D , FPG , AASI , and PP , while positively with SBP acrophase , and DBP amplitude   out-of-office BP values correlated with organ damage and cardiovascular events, 2) nondipping or reverse dipping patterns were related to autonomic dysfunction and/or nephropathy, and 3) the levels of both SBP and proteinuria-creatinine ratio in the morning were mainly associated with the progression rate of diabetic nephropathy -11. Our roblasts  and protus clock . The conus clock , of multus clock , is one us clock . FurtherNo financial competing interest to declare.Elena Matteucci and Ottavio Giampietro contributed in the planning and designing of the study and writing the manuscript. Luca Della Bartola contributed to data collection. All Authors have read and approved the final manuscript.


Plasmodium falciparum malaria occurs in up to 40% of adult patients. The case fatality rate reaches 75% in the absence of renal replacement therapy (RRT). The precise pathophysiology of AKI in falciparum malaria remains unclear. Histopathology shows acute tubular necrosis with localization of host monocytes and parasitized red blood cells in the microvasculature. This study explored the relationship of plasma soluble urokinase-type plasminogen activator receptor (suPAR), as a proxy-measure of mononuclear cell activation, and plasma P. falciparum histidine rich protein 2 (PfHRP2), as a measure of sequestered parasite burden, with AKI in severe malaria.Acute kidney injury (AKI) complicating severe PfHRP2 concentrations were assessed in Bangladeshi adults with severe falciparum malaria (n = 137). Patients were stratified according to AKI severity based on admission creatinine clearance.Admission plasma suPAR and PfHRP2 concentrations increased with AKI severity (test-for-trend P <0.0001) and correlated with other markers of renal dysfunction. Admission plasma suPAR and PfHRP2 concentrations were higher in patients who later required RRT . In a multivariate analysis, both increasing suPAR and PfHRP2 were independently associated with increasing urine neutrophil gelatinase-associated lipocalin concentration, a marker of acute tubular necrosis (β = 16.54 (95% CI 6.36-26.71) and β = 0.07 (0.02-0.11), respectively).A total of 106 (77%) patients had AKI; 32 (23%), 42 (31%) and 32 (23%) were classified into ‘mild, ‘moderate’ and ‘severe’ AKI groups, respectively. Plasma suPAR and Both sequestered parasite burden and immune activation contribute to the pathogenesis of AKI in severe falciparum malaria. The iPlasmodium falciparum histidine-rich protein 2 (PfHRP2) is released in distinct amounts at the moment of schizont rupture and is quantitatively related to parasite density [PfHRP2 estimates total body P. falciparum burden, including the sequestered biomass that causes obstructed microcirculatory flow in vital organs. Unlike the peripheral parasitaemia level, plasma PfHRP2 concentration correlates strongly with disease severity and outcome [ density ,9. The p outcome -12.Plasma soluble urokinase–type plasminogen activator receptor (suPAR) reflects the systemic level of cell surface urokinase-type plasminogen activator receptor (uPAR) expression, and has been proposed as a marker of immune activation via modulation of mononuclear cell adhesion and migration -15. CellNeutrophil gelatinase-associated lipocalin (NGAL) is secreted predominantly in damaged distal tubular renal epithelial cells prior to neutrophil activation, and is an early marker of renal tubular cell damage -20. NGALPfHRP2, as a measure of sequestered parasite burden, with AKI in adult patients with falciparum malaria was assessed in this study. Severity of kidney dysfunction and damage was measured quantitatively by creatinine clearance and urine NGAL (a marker of acute tubular necrosis), respectively. Since kidney failure in severe malaria is a consequence of severe ATN, severe kidney tubular damage was assessed qualitatively by RRT requirement.The relationship between plasma suPAR, as a proxy-measure of mononuclear cell immune activation, and plasma The study was an analysis of a subset of patients enrolled in two clinical trials assessing N-acetylcysteine (2003–2005) and levamisole (2006–2010) as adjuvant therapy in severe falciparum malaria ,22. Of tP. falciparum malaria were recruited. Criteria for severe malaria included: coma (Glasgow Coma Score <11), shock (systolic blood pressure (SBP) <80 mmHg with cool extremities), severe anaemia , severe jaundice , hyperparasitaemia , acidosis (venous bicarbonate <15 mmol/L), hyperlactataemia (venous lactate >4 mmol/L), hypoglycaemia (blood glucose <40 mg/dL), convulsions (≥ two in 24 hours), pulmonary oedema, and/or renal failure (serum creatinine >3 mg/dL).Adults (≥16 years) with slide-confirmed severe Patients were treated with parenteral artesunate  and managed according to WHO treatment guidelines . SupportOn enrolment, a complete medical history and examination were performed, and venous blood and urine collected. Admission venous sodium, potassium, chloride, glucose, blood urea nitrogen, haemoglobin, haematocrit, pH and bicarbonate were assessed using a portable, handheld analyzer . Peripheral parasitaemia was assessed on admission and every six hours until parasite clearance, defined as two consecutive negative blood films. Plasma, serum and urine samples were processed and stored at -80°C for further analysis in Bangkok, Thailand and Amsterdam, the Netherlands. The time and indication for RRT was recorded.PfHRP2 was assessed by commercial sandwich ELISA , according to the manufacturer’s instructions with minor modifications [PfHRP2 standard curves . Concentrations in duplicate plasma dilutions  were determined according to the linear component of the standard curve. Cases where duplicates differed by more than 50% were re-assayed.Plasma suPAR concentrations were measured using suPARnostic™ ELISA , according to the manufacturer’s instructions. Specimens were diluted to read within the calibration curve defined by quantitative standards. Reported results are the mean suPAR concentration (ng/ml) of duplicate wells for each specimen. Urine NGAL concentrations were measured using Human Lipocalin-2/NGAL ELISA  according to the manufacturer’s instructions. Multiple dilutions were tested in duplicate. The final urine NGAL concentration (pg/ml) was normalized to urinary creatinine and expressed as pg/mg of creatinine (uNGAL/Ucr). Plasma ications . Pooled AKI was defined by the estimated creatinine clearance, which is an accepted surrogate of kidney function measured by the glomerular filtration rate (GFR). Severity of AKI was classified as mild, moderate or severe dysfunction based on admission creatinine clearance (CrCl): mild (CrCl = 60–89.9 ml/min), moderate (CrCl = 30–59.9 ml/min) and severe (CrCl <30 ml/min). No AKI was defined as CrCl ≥90 ml/min. CrCl was calculated using the Cockcroft-Gault formula . No patiPfHRP2 results, independently reviewed each patient file to determine whether patients met pre-defined criteria for RRT: hyperkalaemia (K >5.5 mmol/L), acidosis , fluid overload refractory to diuretics, uncontrolled seizures, pericarditis or rapid deterioration of renal function [Three clinicians  blinded to suPAR and function . RRT wasfunction .t-test and Mann–Whitney-U test for normally and non-normally distributed variables, respectively. Data were transformed to achieve a normal distribution where possible. A non-parametric test-for-trend, which is an extension of the Wilcoxon rank-sum test, was used to identify increasing or decreasing associations with AKI severity. Correlations between variables were assessed using Pearson’s correlation coefficient. A robust regression model was constructed to assess the contributions of suPAR, PfHRP2, suPAR x PfHRP2 interaction, age and SBP to the variation in uNGAL/Ucr. Age and SBP were included in the model as they are well-established risk factors for kidney injury. There were no significant interactions between CrCl and suPAR, nor CrCl and PfHRP2, therefore these terms were not included in the models. To assess the relationship of the same independent variables with the indication for RRT, a logistic model with stepwise exclusion of non-significant covariates was used. Improved model fit with the inclusion of the interaction term was confirmed using the likelihood ratio test. A P value of less than 0.05 was considered significant. Statistical software used were STATA/IC 12.0 , and Prism 6 for Mac OS X .Differences between AKI groups  were compared by Student’s One-hundred and thirty-seven adults with severe falciparum malaria were included in this analysis Figure .Baseline characteristics and patient outcomes are shown in Table p = 0.003, 0.048 and 0.011, respectively). Direct and indirect bilirubin increased and all measures of acid–base status  worsened with increasing kidney injury severity (test-for-trend p <0.001).Increasing severity of AKI correlated with increasing age, and decreasing SBP and haematocrit  and increasing uNGAL/Ucr  . Admission plasma suPAR increased with increasing AKI severity  and uNGAL/Ucr   Figure A-B. PeriPfHRP2 ; the interaction term (suPAR × PfHRP2) also increased with both increasing creatinine , increasing uNGAL/Ucr  and AKI severity (test-for-trend p <0.0001). This was further evaluated using linear regression with uNGAL/Ucr as the dependent variable, representing acute tubular necrosis. In the univariate analysis suPAR, PfHRP2 and suPAR x PfHRP2 were significantly associated with a higher concentration of uNGAL/Ucr  versus 25.57 (23.27-28.10) ng/ml for suPAR (P = 0.12) and 1,685  versus 1,629  for PfHRP2 (P = 0.89). Plasma suPAR and PfHRP2 were significantly elevated in patients who were acidotic (base deficit >3.3 mmol/L) compared to those who were not: 29.63 (27.07-32.44) versus 20.67 (18.02-23.71) ng/ml for suPAR (P <0.001) and 2,025  versus 816  for PfHRP2 (P = 0.001). Standard base deficit was significantly elevated in patients who died compared to survivors; mean (SD), 11.8 (7.5) versus 6.5 (5.1) (P <0.001).Plasma suPAR and PfHRP2 were strongly and independently associated with AKI, and a later requirement for RRT. As suPAR is an indirect measure of mononuclear cell activation, and PfHRP2 a measure of sequestered parasite biomass, these results suggest that both mechanisms contribute to the pathogenesis of AKI. These findings are concordant with post-mortem renal histopathological findings in patients with falciparum malaria that shows both PRBC sequestration and mononuclear cell infiltration in glomerular and peritubular capillaries [In this study of adult patients with severe falciparum malaria, admission plasma suPAR and illaries .PfHRP2 independently correlated with uNGAL, and a requirement for RRT. Histopathology of falciparum malaria-associated AKI shows a significant increase in sequestration among patients with a creatinine >3 mg/dL, which defines AKI according to WHO malaria treatment guidelines [PfHRP2 concentrations [PfHRP2 was significantly elevated in patients who were acidotic. Peripheral parasitaemia does not reflect the pathogenic-sequestered parasite burden that causes impaired microvascular flow, and the correlation between parasitaemia and total parasite burden is variable. This might explain why the presented results contrast with other studies, in that an association between hyperparasitaemia and AKI severity was not found [PfHRP2, representing the total parasite biomass including the sequestered parasites, strongly correlated with AKI defined by either WHO or CrCl classification. The correlation between PfHRP2 and creatinine was also stronger than the correlation between peripheral parasitaemia and creatinine. Sequestered PRBCs occluding the renal microcirculation may explain why increasing the overall renal blood flow in severe malaria does not result in a change in renal oxygen consumption [Multivariate regression analysis showed that plasma idelines . Overalltrations -12,26. Pot found ,28. Howesumption ; as onlyPlasma suPAR increased with deteriorating renal function defined by CrCl classification and WHO criteria, urine NGAL and independently predicted RRT requirement. Plasma suPAR is positively correlated with creatinine in patients with Hantavirus and critically ill patients, and inversely correlated with estimated glomerular filtration rate (GFR) in chronic kidney disease -33. HistIn this study there was no association between suPAR and mortality, which contrasts with a study of African children with malaria where increased suPAR concentrations were associated with poor clinical outcomes . This maPfHRP2 did not reveal a significant contribution, and the association between suPAR and indication for RRT was also found in patients presenting without AKI on admission. It has been shown that plasma HRP2 half life is not correlated with biochemical evidence of kidney dysfunction [There are limitations to this study. Both suPAR and HRP2 measured in the plasma are not organ specific markers of monocyte activation and sequestration, respectively. However, kidney specific markers of these phenomena currently do not exist. The justification of the analyses of plasma suPAR and HRP2 is based on the histopathology that has shown sequestration of PRBCs and mononuclear cell infiltration in the kidney. Since suPAR was measured in plasma, the concentrations measured likely represent production by activated host immune cells, in particular mononuclear cells, however endothelial sources could also contribute. As suPAR has renal clearance, elevated plasma levels can be a consequence of reduced GFR ,33. Howefunction . Urine Nfunction . Howeverfunction . Using rThis study suggests that parasite sequestration and immune activation contribute to the pathogenesis of AKI in severe falciparum malaria. Early diagnosis of falciparum malaria and treatment with artemisinin-based anti-malarials will rapidly eliminate ring-staged parasites, preventing their microvascular sequestration in vital organs, including the kidney. Deeper understanding of the immunopathological mechanisms underlying AKI in severe malaria might reveal novel, targeted, treatment options to further prevent this common and life-threatening complication.Plasmodium falciparum histidine rich protein 2; AKI: Acute kidney injury; RRT: Renal replacement therapy; uNGAL: Urine neutrophil gelatinase-associated lipocalin; Ucr: Urine creatinine; uNGAL/Ucr: Urine neutrophil gelatinase-associated lipocalin corrected for urine creatinine; CrCl: Creatinine clearance; ATN: Acute tubular necrosis; SBP: Systolic blood pressure; PRBCs: Parasitized red blood cells; GFR: Glomerular filtration rate; WHO: World Health Organization.suPAR: Plasma soluble urokinase-type plasminogen activator receptor; PfHRP2: Plasma MJS is an advisor of Virogates A/S, Denmark. He has no financial interests in the company. All other authors declare that they have no competing interests.KP contributed to managing patients, sample collection, statistical analysis and manuscript preparation. AAR contributed to data analysis and manuscript preparation. JH contributed to patient management, sample collection and manuscript revision. MUH, SA and AG supervised the study and clinical care of the patients. RJM and PC contributed to patient management, data collection and entry and manuscript revision. PMS provided the suPAR measurements. SJL assisted with statistical analysis. GDHT assisted with data interpretation and critical manuscript revision. AMD and MSJ were the senior supervisors, conceived of and designed the study, assisted with statistical analysis and manuscript revision. All authors read and approved the final manuscript.


Monocyte chemoattractant protein-1 (MCP-1), which is up regulated in kidney diseases, is considered a marker of kidney inflammation. We examined the value of urine MCP-1 in predicting the outcome in idiopathic glomerulonephritis.Between 1993 and 2004, 165 patients  diagnosed with idiopathic proteinuric glomerulopathy and with serum creatinine <150 µmol/L at diagnosis were selected for the study. Urine concentrations of MCP-1 were analyzed by ELISA in early morning spot urine samples collected on the day of the diagnostic kidney biopsy. The patients were followed until 2009. The progression rate to end-stage kidney disease was calculated using Kaplan–Meier survival analysis. End-stage kidney disease (ESKD) was defined as the start of kidney replacement therapy during the study follow-up time.Patients with proliferative glomerulonephritis had significantly higher urinary MCP-1 excretion levels than those with non-proliferative glomerulonephritis (p<0.001). The percentage of patients whose kidney function deteriorated significantly was 39.0% in the high MCP-1 excretion group and 29.9% in the low MCP-1 excretion group. However, after adjustment for confounding variables such as glomerular filtration rate (GFR) and proteinuria, there was no significant association between urine MCP-1 concentration and progression to ESKD, .Our findings indicate that progression to end-stage kidney disease in patients with idiopathic glomerulopathies is not associated with urine MCP-1 concentrations at the time of diagnosis. Glomerular diseases, including idiopathic glomerulonephritis, are major causes of end-stage kidney disease (ESKD). Clinically, they are manifested with haematuria, proteinuria and declining kidney function. Histopathologically, they are associated with inflammation and proliferation of the glomerular tissue and enhanced glomerular and interstitial production of inflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1) Inflammatory cytokines, including MCP-1, play an important role in glomerular inflammation. MCP-1 is produced by macrophages, vascular endothelial cells, monocytes and fibroblasts. It triggers migration and retention of monocytes and transformation of fibroblasts in the glomeruli The urinary concentration of MCP-1 increases with increased activity of glomerular diseases (GN) The patients were enrolled in the large glomerular disease investigation program that was conducted at the Nephrology Department, Lund University Hospital, Sweden. The cohort and the controls  have been described in detail Of the patients investigated between August 1993 and February 2004, 189 patients  had initial serum creatinine <150 µmol/L at the time of kidney biopsy. Of these, urine samples were available from 165 patients  for MCP-1 analysis. The study was approved by the regional ethical committee of Lund (LU 47-02), and all patients gave informed written consent.n = 28), membranous glomerulonephritis (n = 15), minimal change nephropathy , focal segmental glomerulosclerosis , and nephrosclerosis (n = 23). We excluded patients with severe kindey failure on admission (serum creatinine >150 µmol/L), diabetic nephropathy, crescentic glomerulonephritis, and other secondary causes such as SLE, and small vessel vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA).Examination of the biopsies showed or confirmed the following diagnoses: mesangial proliferative glomerulonephritis (n = 64), IgA nephropathy  was calculated by adding one third of the pulse pressure to the diastolic blood pressure. The kidney biopsies were evaluated for the percentage of global glomerulosclerosis (GGS) and the extent of tubulo-interstitial damage. Interstitial fibrosis was scored semi quantitatively as 0 (absent), 1  or 2 (diffuse). All patients were followed regularly at the nephrology outpatient clinic of Lund University Hospital and were on a normal protein diet. Clinical data, including measures of serum creatinine, were collected during the scheduled clinic visits. The patients were followed until the last planned follow-up visit in 2009. The primary end point was end-stage kidney disease (ESKD) defined as the start of kidney replacement therapy.Blood samples and the first voided urine specimens were obtained in the morning of the day of the kidney biopsy. The patients had no signs of urinary tract infection in urinalysis examination performed at admission. The urinary albumin-to-creatinine ratio (ACR), measured in a spot morning urine sample, was used as a reliable estimate of the degree of proteinuria 4.62−0.0112*pCr−0.0124*age+0.339*ln(age)−0.2226 .Serum and urine creatinine were determined enzymatically using a Kodak Ektachem 700 XR-C system. Serum and urine albumin, IgG, and urine protein HC  were determined by immunoturbidimetry using a Cobas Mira S system (Roche Inc.) and monospecific rabbit antisera obtained from Dako  P<0.05 was selected as level of significance. The P-values were adjusted for multiple comparisons using Bonferroni-Holm adjustment method. Patients were divided into low and high MCP-1 groups according to the median urine concentration of MCP-1 at 0.05 mg/mmol creatinine . eatinine  and 2.vs. 0.039 (IQ 0.027–0.085) mg/mmol creatinine, p = 0.049 with Bonferroni-Holm correction; (p<0.001 with Bonferroni-Holm correction (p = 0.002). However, there was no statistical difference in the kidney function (p = 0.58) or IgG-uria (p = 0.33) between proliferative and non-proliferative glomerulonephritis.Urinary MCP-1 levels were significantly higher in patients with proliferative glomerulonephritis (IgA and mesangioproliferative) than in those with non-proliferative forms of glomerulonephritis , (0.061 (IQ 0.032–0.133) mg/mmol creatinine rection; , and botrrection . The albvs 83.3%, p = 0.18; p = 0.008; During the study, 126 patients were treated with angiotensin converting enzyme inhibitors or angiotensin II receptor antagonist; 51 patients were treated with immunosuppressive drugs . There ip = 0.01), but not to the degree of interstitial fibrosis . Patients with severe glomerulosclerosis  had lower urine MCP-1 concentrations than those with a lesser degree of glomerulosclerosis (0.037: IQ 0.026–0.069) vs. 0.06: IQ 0.033–0.142, p = 0.003).Urine MCP-1 was correlated to the degree of IgG-uria, HC-uria and ACR . Likewise, there was no difference in percentage of patients with deteriorated in kidney function between patients with low or high HC-uria , or between patients with low or high ACR . On the other hand, during the study follow-up time kidney function deteriorated significantly more frequently (p = 0.001) in patients with high IgG-uria (45.5%) than in patients with low IgG-uria (19.4%), data not shown.The kidney function of 32.8% of the patients deteriorated significantly (>3 ml/min/year) during the follow-up time. However, the percentages in the high and the low MCP-1 groups were not significantly different: they were 39% in the high MCP-1 group and 29.9% in the low MCP-1 group (p = 0.27). Only eGFR and IgG-uria remained as significant predictors for the outcome of ESKD  reached ESKD, 14  died of cardiovascular events, and 4  were lost from follow up . Univari of ESKD .Mounting evidence shows that urine MCP-1 is a potential diagnostic and prognostic marker in a variety of kidney diseases. Our results confirmed the previous reports of increased urine MCP-1 excretion in patients with glomerulonephritis and its correlation with on-going glomerular inflammation Contrary to our expectation, urine MCP-1 was not an independent predictor of long-term outcome in this cohort of patients with idiopathic chronic glomerulonephritis, while IgG-uria was Proteinuria, including the IgG-uria, is associated with induction of chemokines, accumulation of fibroblasts, and progressive glomerular and interstitial injuries, which ultimately lead to ESKD Furthermore, patients with active glomerulonephritis are more likely to receive immune-suppressive therapy. These drugs, as well as the antiproteinuric medications, such as angiotensin converting enzyme inhibitors, block the effect of the inflammatory chemokines and thereby alter the course of glomerulonephritis, diminishing the association between urine MCP-1 level and progression of kidney disease In our study we measured urine MCP-1 only once, which might have caused misclassification of patients who remitted rapidly and those with repeated flare-ups of glomerulonephritis. However, the cohort was large enough to allow the study of the predictive value of urine biomarkers at the time of diagnosis. Further studies should examine the value of repeated measurement of MCP-1 in idiopathic chronic glomerulonephritis patients, especially for monitoring the treatment response.In summary, although urine MCP-1 concentration is increased, we found that urine MCP-1 at the time of diagnosis is not a powerful predictor of long-term kidney disease outcome in patients with idiopathic glomerulonephritis. Future studies are needed to investigate the utility of repeated measurement of urine MCP-1 in patients with idiopathic chronic glomerulonephritis.


The incidence of hypertension is high in the elderly and is present in 2/3 of the patients older than 65 years. Prevalence can reach 90% in patients older than 80 years. The presence of isolated systolic hypertension (ISH) is characteristic of this population. However, the prevalence of hypertension by ambulatory blood pressure monitoring (ABPM) is not well known. In this study, we analyzed the special characteristics of hypertension in this population, giving special emphasis on ABPM readings. The incidence of hypertension is high in the elderly, and it is present in 2/3 of the patients older than 65 years . PrevaleAgeing results in a decline in the cardiac output and cardiac frequency (beta-receptors-mediated response), as well as a trend towards ventricular hypertrophy, reduction of the left ventricular filling, renal plasma flux and renin plasma, and an increase in renal and peripheral resistances.compliance, and an increase in the pulse pressure; this, together with an increase in peripheral resistances, leads to ISH. Several systems are involved in the increase of peripheral resistances, such as reduction of beta-2 receptors involved in vasodilation, or reduction in sodium ions, potassium and calcium ions, renin-angiotensin system, sympathetic nervous system, hormones, natriuretic factors, and endothelial factors. All this can explain the frequency of ISH, blood pressure (BP) variability, and the episodes of associated orthostatic hypotension. Old subjects present more frequently essential hypertension (except for renovascular secondary hypertension) and more severe target organ damage than the younger population. Hypertension affects subjects with a higher prevalence of ischemic heart disease, myocardial infarction, diastolic dysfunction, a tendency to arrhythmia and in general cerebral arteriosclerosis and peripheral arterial disease. There are also present other factors such as diabetes, and other concomitant diseases like pulmonary disease, depression, neoplasia, and so forht that should be considered when making diagnosis and treatment decisions.Ageing also produces an increase in arterial stiffness, a reduction of the Normality values of ABPM are based on several studies  Table 1Table 1 oTherefore, normality values must be carefully studied in patients older than 80 years. It is not known yet the benefit of reducing clinical BP in this population group. Previous studies like HYVET, demonstrated a reduction in the mortality rate in 3.845 patients with SBP >160 mm Hg, with the aim of reaching values of SBP <150 mm Hg, but this study included patients with good physical and mental conditions, without previous cardiovascular disease, and only 7% of them were diabetics.Bejan-Angoulvant et al.  carried Evidences of reducing BP under 140/90 mm Hg in old subjects has been recently discussed; however, any active treatment trial versus placebo therapy has been able to reduce SBP under 140 mm Hg . TherefoABPM data of patients with ISH are mainly reported in the SYST-EUR study , in patiClinical SBP of 160 mm Hg was correlated with a 24-h SBP monitoring of 142 mm Hg, 145 mm Hg for daytime BP, and 132 mm Hg for nighttime BP. Differences of the SBP between clinical and ambulatory BP measurement were higher in old subjects . A study  carried Today, the US and European consensus for ABPM agrees that ABPM measures are important in children and old people, since CBP does not reflect accurately real BP values in these population groups . This isBoth conditions are more frequently found altered in older ages. It is well known that pulse pressure (PP) is an independent cardiovascular risk factor especially present in old subjects , 16 as aIn the placebo group, 24-h and nighttime PP was predictive of total and cardiovascular mortality, stroke, and cardiac events. Daytime PP was a predictor of cardiovascular mortality, all cardiovascular events, and stroke. The hazard rates for 10 mm Hg rise was from 1.25 to 1.68; however, conventional measurement of pulse pressure was 1.35. No significant differences were found in the active treatment group.Staessen et al.  reportedIn the PIUMA study , ABPM vaHowever, Masahiro et al., in a study carried out in 1542 Ohasama residents, found that the ambulatory arterial stiffness index (AASI) and PP were reliable to measure arterial stiffness and to predict vascular mortality, although PP when adjusted for age and gender was less efficient in the prognostic value of vascular events of the ABMP or AASI .Arterial distensibility can be measured indirectly by pulse wave velocity, which is altered with age. Asmar et al.  found a P < 0.001).Nighttime SBP is becoming more and more important, as reported in the SYST-EUR study  or HOPE Orthostatic hypotension can occur at any age; however, it is more frequent in the elderly. It is defined as a decrease in the SBP of at least 20 mm Hg or a decrease in the DBP of 10 mm Hg in the orthostatic position 3 minutes after BP measurement in the supine position . It is gPostprandial hypotension is more frequently found in old subjects  and is dThe white-coat effect occurs when CBP is temporary elevated in the clinical setting but not at home. This phenomenon was described by Scipione Riva-Rocci in 1897, but it was really studied in the clinical setting after the introduction of ABPM. Its prognostic significance is not yet clear. In some studies –32 mortaMasked hypertension is defined as a normal blood pressure (BP) in the clinic or office <140/90 mm Hg), but an elevated BP out of the clinic (ambulatory daytime BP or home BP >135/85 mm Hg) . Its pre/90 mm Hgdipper (a decrease of BP at night >10%), nondipper (BP decrease <10%), extreme dipper (BP decrease >20%), and riser pattern (an elevation of BP at night). There are increasing evidences that nondipper pattern is associated with a poorer cardiovascular prognosis [ABPM allows knowing BP absolute values and gives information about circadian BP rhythm. According to these patterns, patients are classified as rognosis , 49, whirognosis  in old prognosis .Patients with a lower decrease of BP at night due to insomnia do not seem to present a poorer vascular prognosis, or, if so, it is not related to the nondipping pattern but probably due to a higher value of nocturnal BP . Sleep qA prevalence of 25–35% of the nondipping pattern was observed in the general population. A Spanish study  carried The morning elevation of BP is also important , 56. KarFurther studies are needed in order to determine whether morning elevation of BP is especially relevant in the old population.Diurnal and nocturnal BP variability (defined by quantification of SD of mean BP) is associated with an increased cardiovascular risk, left ventricular mass, and progression of carotid intima-media thickness , 59. MedAlthough several studies have reported the relationship between ABPM and cardiovascular risk in the elderly , few stuDementia from all causes has a prevalence of about 8% of the population over 65 years. Between 15 and 30% of these cases are vascular. In the elderly, subcortical small vessel disease is known to be associated with vascular dementia. Mild cognitive impairment (MCI) is described as a transition phase between healthy cognitive aging and dementia.This concept facilitated case identification in early stage, and its progression may be preventable through modification of vascular risk factors as hypertension.The SYST-EUR study  showed tABPM has been shown to provide a better predictive value for cardiovascular events than clinic BP. Recent studies have shown that ambulatory BP variation is associated with cognitive function. High nocturnal SBP level , NondippIn conclusion, there are many reasons to recommend ABPM in hypertensive old patients, such as ISBP, differences between clinical and ambulatory BP, PP, magnitude of the white-coat effect, assessment of orthostatic hypotension values and its relationship with the patient medication, nighttime hypertension, mild cognitive impairment and BP variability. These important variables demonstrate that just the fact of being an aged patient is a sufficient reason to perform ABPM. We support that the diagnosis of hypertension by ABPM may have substantial clinical and epidemiological implications.Even so, further studies are needed to demonstrate the importance of ABPM values in the study of the morbidity and mortality in these patients.


The mechanisms of intradialytic increases in blood pressure are not well defined. The present study was undertaken to assess the role of autonomic nervous system activation during intradialytic hypertensive episodes.increased (n = 45) or decreased (n = 17) heart rate. The maximal blood pressure was similar in both groups. In patients with increased heart rate the increase in blood pressure was associated with marked increases in SBP and IBI variability, with suppressed BRS indices and enhanced sympatho-vagal balance. In contrast, in those with decreased heart rate, there were no significant changes in the above parameters. End-of- dialysis blood pressure in all sessions associated with hypertensive episode was significantly higher than in those without such episodes. In logistic regression analysis, predialysis BRS in the low frequency range was found to be the main predictor of intradialytic hypertension.Continuous interbeat intervals (IBI) and systolic blood pressure (SBP) were monitored during hemodialysis in 108 chronic patients. Intradialytic hypertensive episodes defined as a period of at least 10 mmHg increase in SBP between the beginning and the end of a dialysis session or hypertension resistant to ultrafiltration occurring during or immediately after the dialysis procedure, were detected in 62 out of 113 hemodialysis sessions. SBP variability, IBI variability and baroreceptor sensitivity (BRS) in the low (LF) and high (HF) frequency ranges were assessed using the complex demodulation technique (CDM). Intradialytic hypertensive episodes were associated with an Our data point to sympathetic overactivity with feed-forward blood pressure enhancement as an important mechanism of intradialytic hypertension in a significant proportion of patients. The triggers of increased sympathetic activity during hemodialysis remain to be determined. Intradialytic hypertensive episodes are associated with higher end-of- dialysis blood pressure, suggesting that intradialytic hypertension may play a role in generation of interdialytic hypertension. During hemodialysis treatment, blood pressure usually decreases with ultrafiltration and weight loss. In a significant proportion of patients, however, the blood pressure increases during or immediately after hemodialysis. Intradialytic hypertension has been recognized for many years, and it is believed to occur in at least 8–15% of patients Several mechanisms are believed to lead to intradialytic increases in blood pressure. A positive sodium balance, resulting in extracellular fluid overload and hypertension in dialysis patients, is thought by many investigators to be the main cause of intradialytic increases in blood pressure Sympathetic overactivity, believed to be generated by neuro-hormonal mechanisms arising within the diseased kidneys, is considered an important mechanism of hypertension in patients with chronic renal insufficiency Sympathetic activity is best detected using microneurography  and regional norepinephrine spillover technique Since direct methods are not available or applicable in complex patients, sympathetic activity is assessed in many studies by non-invasive techniques. Heart rate variability (HRV), blood pressure variability (BPV) and baroreflex function  are the most frequently used methods to assess autonomic nervous system function and cardiovascular variability, a measure of the integrated control mechanisms of circulation Complex demodulation is a newer method for assessing time dependent changes in signals around a specific frequency. The technique of complex demodulation (CDM) reveals instantaneous dynamic changes in heart rate and blood pressure that are not revealed by the standard spectral methods The present study was undertaken: 1. to detect increases in blood pressure during hemodialysis, and, 2. to assess the role of autonomic nervous system function during intradialytic hypertensive episodes. This is the first report of cardiovascular variability indices determined before and during intradialytic hypertensive episodes using the CDM methodology.Continuous beat to beat blood pressure recordings were obtained during 113 routine midweek dialysis sessions in 108 chronic patients on maintenance hemodialysis. Patients with chronic atrial fibrillation or frequent ventricular premature beats, with debilitating illness and frequent hospital admissions, with permanent pacemakers or with severely decreased radial pulses following multiple vascular access surgical interventions were excluded from the study. Antihypertensive drugs were stopped 12–14 hr before the dialysis session. The study was approved by Hadassah Medical Organization Ethics Committee for Clinical Research. The patients signed an informed consent form before taking part in the study.Demographic, clinical and laboratory data of all patients are shown in The ultrafiltration rate during dialysis sessions never exceeded 1 liter/hour and was adjusted according to the presumed dry weight. The temperature of the dialysate was kept constant at 36°C.All patients were treated with recombinant erythropoietin and phosphate binders  as needed.Blood pressure and inter-beat intervals were measured noninvasively by Finometer 1.10 . Continuous beat to beat recording of the finger arterial pressure waveform was performed as previously described hypertensive episodes were defined as: 1. a period of at least 10 mmHg increase in the systolic blood pressure (SBP) between the start and the end of a dialysis session, or, 2. hypertension occurring after significant ultrafiltration was achieved, i.e. during the second to the fourth hour of dialysis or immediately after the dialysis procedure episodes with decreased IBI, when the increase of at SBP was associated with a parallel increase in heart rate (n = 45) and, b) episodes with increased IBI, when the SBP increase was accompanied a decrease in heart rate (n = 17). Representative tracings of hypertensive episode associated with increased or decreased rate are depicted in The data from Finometer were downloaded into a PC and analyzed by the BeatScope Software  and our specifically designed programs. The BeatScope software performs beat to beat analysis of the finger arterial pressure and uses filtering and level correction to calculate reconstructed brachial pressures from finger pressures. The resulted data files containing beat to beat values of hemodynamic variables such as inter-beat intervals (IBI), systolic (SBP), diastolic (DBP) and mean blood pressures (MBP), were used for further processing. Data files included beat to beat values for the whole duration of hemodialysis. SBP and IBI signals were resampled at 1 Hz to obtain equidistant time series Complex demodulation is a nonlinear time domain method of time series analysis. It is suited to the investigation of nonstationary oscillations and reveals instantaneous dynamic changes that are not revealed by the power spectrum methods. The analysis used in the present study was based on technique of Hayano et al 0) were 0.09 Hz for the low frequency (LF) and 0.30 Hz for the high frequency (HF) band. The result was then filtered by a low-pass 16th degree Butterworth filter with cut-off frequencies of 0.05 Hz and 0.16 Hz for the low and high frequencies range respectively. The signals were then smoothed by a 201 point least-square moving polynomial. Complex demodulation baroreflex (BRS) time series was computed as the ratio of the IBI and SBP time series instantaneous values in the two frequency ranges.Complex demodulation of SBP and IBI signals was performed at two frequency bands. The central frequencies  and high (around center frequency of 0.30 Hz) frequency ranges were followed during the whole dialysis session. Five minute averages of the LF and HF SBP, LF and HF IBI, LF IBI/HF IBI ratio  and BRS indices were calculated the following manually detected periods: 1) the first 20 minutes (beginning), 2) the last 20 minutes (end) of dialysis, 3) 20 minutes before, and, 4) during hypertensive episodes.chi-square test. Age and laboratory data (mean and standard deviation) were compared using Student's t test. Blood pressure, inter-beat interval and baroreceptor variables are given as medians and inter-quartile ranges.Demographic and clinical categorical variables were compared by Wilcoxon signed-ranks test was used to compare paired differences at the beginning and the end of dialysis and to assess differences between the periods before and during hypertensive episodes. Mann-Whitney U-test was used to compare between sessions without and with hypertension, and between hypertensive episodes with increased and decreased heart rate.Correlations of intradialytic changes in SBP with CDM indices and between different CDM variables were performed by Pearson correlation and linear regression analysis.Logistic regression analysis  was performed to select determinants of intradialytic hypertension. Age, gender, hemodialysis vintage (years), the presence of diabetes mellitus, history of hypertension, hyperlipidemia , ischemic heart disease and of intradialytic hypotensive episodes, administration of antihypertensive drugs, hypertensive medication, biochemical data and predialysis SBP, IBI and CDM measurements  were all included in the analysis.Ischemic heart disease was defined by: documentation of prior myocardial infarction or of coronary interventions, the presence of significantly abnormal Q waves on a 12-lead electrocardiogram, symptomatic angina pectoris or a thallium perfusion scan suggestive of myocardial ischemia. Left ventricular systolic dysfunction was defined as decreased left ventricular ejection fraction (LVEF) to less than 40% on echocardiography. Doppler interrogation of the mitral valve, pulmonary vein and mitral annulus was used to assess diastolic function. Severe diastolic dysfunction was defined as :a) pseudo-normalization of E (early filling wave) to A (late filling wave) ratio, suggesting an elevated left ventricular diastolic pressure, or, b) a restrictive pattern, suggesting reduced compliance, i.e. grade 2–4 diastolic dysfunction by echocardiographic criteria st, 22 in the 2nd and 24 in the 3rd hour, and 6 towards the end of hemodialysis session. The duration (mean ± SD) of the hypertensive episodes was 27±16 min (range 5–80 min). While many patients with intradialytic increases in blood pressure episodes complained of dizziness, palpitations or weakness, none developed syncope or loss of consciousness.One hundred and eight patients were examined during 113 hemodialysis sessions. Hypertensive episodes (n = 62) were detected in 57 patients. The timing of the occurrence of the hypertensive episode was different for each patient. Ten episodes occurred in the 1+ was similar in both groups, post dialysis K+ level was lower in patients with hypertensive episodes  episodes in 16 patients .The timing of occurrence of hypertension during dialysis was similar in the two types of episodes. Five episodes were detected on repeated examinations; one patient was examined 3 times, and the remaining 3 patients were examined twice. Intradialytic hypertensive episodes with increased heart rate were detected during repeated examinations in 3 patients; in one remaining patient intradialytic increase in blood pressure with decreased heart rate was detected during two separate sessions.Forty-five (72.5%) intradialytic hypertensive episodes (mean duration 24±14 min) in 41 patients were associated with an increased heart rate (p<0.001 vs. before) and 159 (25), 73 (17) and 102 (19) mm Hg in patients with decreased heart rate (p<0.001 vs. before). SBP, IBI and their variability before and during hypertensive episodes are depicted in increased heart rate (decreased IBI) , but did not significantly change in those in whom heart rate decreased  and enhanced LF/HF ratio ] were 158 (30), 80 (24) and 104 (19) mm Hg in patients with HF ratio . In decrincreased heart rate (Significant correlations between changes in heart rate variability with changes in blood pressure variability in both LF (r = 0.526) and HF (r = 0.405) bands (p<0.001) were found during hypertensive episodes, but only in those with art rate . We founincreased or decreased heart rate showed that age, medical history and comorbidities, the number of years in dialysis, dialysis prescription and the biochemical profile were similar for the two subgroups (not shown). A higher proportion of women, 9 of 16, was noted, however, in the subgroup of patients with decreased heart rate as compared with 11 of 41 in patients with increased heart rate during hypertensive episodes (p = 0.036). In addition, in the former subgroup, 8 (50%) patients were treated with an angiotensin converting enzyme inhibitor as compared with 6 (14.6%) patients in the latter (p = 0.005). Pre-and post-dialysis SBP, DBP, IBI and CDM measurements were similar in patients with increased or decreased heart rate during intradialytic hypertension episodes.Comparisons of patients experiencing intradialytic hypertension with st and 2nd models, Odds Ratio 1.455 and 1.650, p = 0.004 and 0.001, respectively). Because of the strong correlation of baroreflex sensitivity with heart rate variability and the inverse correlation with blood pressure variability rd model). In this model, a higher predialysis LF IBI  and a lower LF SBP  were found to be significant predictors of hypertensive episodes.Logistic regression analysis  was performed to define independent predictors of intradialytic hypertension. Three different models were constructed including clinical, dialysis and laboratory data and CDM measurements see Methods.nd and 3rd models, p = 0.020 and 0.037) and age .Other significant predictors were lower serum albumin level , interbeat interval variability (LF IBI), decreased baroreceptor sensitivity (LF BRS and HF BRS) and enhanced sympatho-vagal balance  and 3.ThSympathetic overactivity associated with chronic hypertension was detected by MSNA in patients with early or advanced chronic kidney disease and on maintenance hemodialysis We have previously shown that in chronic dialysis patients, LF SBP was increased, while LF IBI and the baroreceptor sensitivity indices were markedly decreased as compared to normal individuals In the present study, the alterations noted during 45 (72.5%) of 62 intradialytic hypertensive episodes  and 3 arThe mechanisms of acute intradialytic activation of the sympathetic nervous system are not well defined. Activation of RAS was suggested as a potential mechanism of both sympathetic stimulation and intradialytic hypertension. A recent study, however, did not show increases in plasma renin and aldosterone levels during hemodialysis in patients with intradialytic increases in blood pressure Another proposed mechanism extensively investigated in chronic kidney disease links between renal ischemia and hypoxia, activation of mechano- and chemo-receptors, secretion of adenosine and sympathetic activation Tonic arterial chemoreceptor activation was also shown to be involved in sympathetic activation in patients with advanced renal failure Other possible, non-mutually exclusive mechanism of intradialytic sympathetic activation may be related to a reduced vascular and hypothalamic availability of nitric oxide (NO) associated with alterations in sympathetic outflow and in vascular endothelial function Insufficient sodium removal during hemodialysis and volume excess were proposed and are still believed by many investigators to be the main causes of intradialytic and interdialytic hypertension initial BRS and LF IBI may suggest the presence of a more robust autonomic nervous system in patients with intradialytic hypertension and may be interpreted as resulting from the synergistic effect of enhanced sympathetic tone coupled with reflex vagal activation On logistic regression analysis, a higher predialysis BRS in the low frequency band (LF BRS) was found to be the main predictor of intradialytic hypertension . Indeed,Comparisons of patients with and without hypertensive episodes  shows a Other predictors of intradialytic hypertension in the present study were lower plasma albumin and age. These factors may be suggestive of the link between autonomic imbalance and chronic inflammation in elderly individuals and in patients with end stage renal disease on maintenance hemodialysis The second important finding of this study is the markedly increased end-of-dialysis blood pressure in patients with intradialytic hypertensive episode  as compaOne main shortcoming of our study is the use of noninvasive methodology of assessment of autonomic nervous function, since more direct techniques as MNSA or pharmacological challenge were not applicable to our patient population. The study patient population included many elderly individuals with multiple comorbidities. These patients however, are most characteristic of the present day general hemodialysis population. Likewise, because of the methodology limitations, patients with arrhythmia or pacemakers were excluded from the study. Furthermore, blood volume and hemodynamic parameters were not assessed in parallel with the CMD determinations.Our findings support the hypothesis that increased sympathetic activity mediates intradialytic hypertension. Intradialytic hypertensive episodes with elevated post-dialysis blood pressure may contribute to interdialytic hypertension. This association deserves further studies using hemodynamic monitoring, different dialysis protocols and pharmacological approaches. The prognostic impact of intradialytic sympathetic activation and hypertension on overall survival and cardiovascular morbidity of these patients remain to be further clarified.Methods S1(DOC)Click here for additional data file.


The effect of commonly used oral contraceptives (OCs) on blood pressure is still unclear. The aim of this study was to examine the relationship between OCs use and blood pressure and the prevalence of hypertension in a population-based sample of Korean women.A cross-sectional study was conducted using data from 3356 participants aged 35–55 years collected in the 2007–2009 Korea National Health and Nutrition Examination Surveys. OC use and demographic characteristics were obtained from participants using a questionnaire, and blood pressure was measured with a mercury sphygmomanometer.Longer duration of OC use was positively associated with increasing levels of systolic blood pressure and diastolic blood pressure (p for trend <0.001). After adjusting for covariates, the odds ratio (OR) of hypertension was significantly increased in longer-term (>24 months) OC users  1.03–3.73) compared with those who had never used OCs. Additionally, use of OCs >24 months was associated with increased odds of prehypertension  and hypertension or prehypertension .This study found a statistically significant association between OC use and blood pressure or hypertension among Korean women. Hypertension is one of the most prevalent and etiologically significant risk factors for cardiovascular disease . AlthougOCs are an important and widely accepted contraceptive modality worldwide . In KoreUntil now, several epidemiological studies have indicated that exposure to OCs may have an effect on blood pressure. OCs has been reported to cause alterations in systolic blood pressure (SBP), diastolic blood pressure (DBP), and the prevalence of hypertension in various study designs with short- and long-term administration ,11,12. HAlteration of blood pressure profiles may represent an important and potentially etiological component in the pathogenesis of many disorders, including cardiovascular disease, stroke, and renal disease ; thus, in = 272) or were pregnant (n = 13). Thus, the final analysis included 3356 subjects.This study was based on data from the 2007–2009 KNHANES, provided by the Korea Centers for Disease Control and Prevention. The sample for KNHANES was selected using a stratified, multistage, cluster-sampling design with proportional allocation based on the National Census Registry. Detailed information on survey design and sampling procedures has been reported elsewhere . In totaKNHANES included well-established questions to determine demographic and socioeconomic characteristics of the subjects. These included questions on age, gender, education level, income, physical exercise, smoking habits, and alcohol consumption. Height and weight were measured with the participants wearing light clothing and no shoes. Body mass index (BMI) was then calculated as weight (in kg) divided by the square of height (in m). Then, subjects were categorized as underweight (BMI < 18.5), normal (18.5 ≤ BMI < 23.0), overweight (23.0 ≤ BMI < 25.0), or obese (BMI ≥ 25.0), according to the World Health Organization (WHO) definitions for Asian populations . InformaThe study protocol was approved by the Korean Ministry of Health and Welfare and was conducted in accordance with the Ethical Principles for Medical Research Involving Human Subjects, as defined by the Helsinki Declaration. All study participants provided written informed consent.Hypertensive status was sorted into three categories: normotensive, prehypertensive, and hypertensive. Normotension was defined as not taking an antihypertensive medication and having a SBP of <120 mmHg and DBP of <80 mmHg. Prehypertension was defined as not taking antihypertensive medication and having a SBP of 120–139 mmHg and/or DBP of 80–89 mmHg. Hypertension was defined as SBP ≥140 mmHg and/or DBP ≥90 mmHg or taking medication for hypertension . As a coThe frequency and percentage or mean and standard error (SE), as appropriate, were calculated for demographic characteristics to describe the sample population according to categories of duration of OC use. Logistic regression models were used to estimate the odds ratio (OR) and 95% confidence intervals (CIs) for prehypertension (vs. normotension) and hypertension status (vs. normotension) among participants who consumed OCs compared with the reference group (those who never used OCs). The presence of a linear trend was evaluated by defining a linear contrast in each of the linear and logistic regression models. All statistical analyses were conducted using SAS software . Statistical analyses accounted for the survey design, and appropriate procedures in SAS such as surveymeans, surveyfreq, and surveylogistic were used with weighted data.This study included 3356 women aged 35–55 years; their demographic characteristics are shown in Table The overall mean SBP and DBP of the study population were 111.7 and 74.2 mmHg, respectively, and the trends for the weighted mean SBP and DBP were significantly related to increased OC use Table . The weiTable OCs containing estrogen and progestin constitute a widely used means of contraception. Currently used third-generation OCs were designed to minimize adverse effects, including unfavorable effects on the cardiovascular system . Since tIn the present nationwide cross-sectional study among Korean women aged 35–55 years, the duration of OC use was positively associated with SBP and DBP levels. SBP and DBP among those who had used OCs >24 months were higher than among those who had never used them by 5.8 and 3.6 mmHg, respectively. Similar to the results of this study, most studies have reported a steady increase in SBP and DBP among users of third-generation OCs containing estrogen and progestin. However, the magnitude of the increase varies among populations and also with the duration of OC use. Case–control studies using 24-h ambulatory BP monitoring indicated a higher SBP and DBP in OC users than in non-users of about 7.6–8.6/1.8–5.8 mmHg ,22. AlsoIn this study, hypertension, prehypertension, or prehypertension + hypertension were about twofold more common in women taking OCs for more than 2 years than in women not taking OCs. However, no significant increase was observed among women who had used OC use for less than 2 years in the odds of hypertension, prehypertension, or prehypertension + hypertension. Although the cumulative time of OC use shown to produce an increased odds of hypertension varies by study, long-term effects of OC use on hypertension have been confirmed in many studies ,11,12. PAlthough the detailed biological mechanism of the hypertensive risk due to exogenous estrogen and/or progestin remains to be determined, estrogen and progesterone are known to regulate many intracellular signal transduction and cellular functions ,31. EstrThe present study has several limitations. As a result of the cross-sectional design, the results only demonstrated associations and could not be used to determine causality. Additionally, self-reporting of drinking and smoking patterns and of OC use may lead to misclassification and measurement error . AlthougIn this population-based study of Korean women aged 35–55 years, long-term use of OCs was associated with increased SBP and DBP. Additionally, odds of hypertension or prehypertension was significantly increased among women using OCs for more than 2 years compared with non-users. Although controlled studies to investigate causal relationships between OC use and blood pressure are needed, the present results suggest significant associations between long-term use of OCs and increased hypertension.All authors declare that they have no competing of interests.Dr HP contributed to data analysis and interpretation, statistical analysis, and drafting the manuscript. Dr KK contributed to design of the study, critical revision of the manuscript, and supervision of the study. Both authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6874/13/39/prepub


Crataegus oxyacantha) is a widely used Chinese herb for treatment of gastrointestinal ailments and heart problems and consumed as food. In North America, the role of treatment for heart problems dates back to 1800. Currently, evidence is accumulating from various in vivo and in vitro studies that hawthorn extracts exert a wide range of cardiovascular pharmacological properties, including antioxidant activity, positive inotropic effect, anti-inflammatory effect, anticardiac remodeling effect, antiplatelet aggregation effect, vasodilating effect, endothelial protective effect, reduction of smooth muscle cell migration and proliferation, protective effect against ischemia/reperfusion injury, antiarrhythmic effect, lipid-lowering effect and decrease of arterial blood pressure effect. On the other hand, reviews of placebo-controlled trials have reported both subjective and objective improvement in patients with mild forms of heart failure (NYHA I–III), hypertension, and hyperlipidemia. This paper discussed the underlying pharmacology mechanisms in potential cardioprotective effects and elucidated the clinical applications of Crataegus and its various extracts.Hawthorn ( Crataegus oxyacantha), also known as haw, maybush, or whitehorn, is part of a genus of spiny shrubs and trees native to temperate regions in the Northern Hemisphere in Europe, Asia, and North America i by interferring with sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) and the inositol 1,4,5-trisphosphate (IP3) pathway without inducing store-operated calcium entry (SOCE) [Crataegus prevented aging-related endothelial dysfunction by reducing the prostanoid-mediated contractile responses, most likely by improving the increased oxidative stress and the over expression of COX-1 and COX-2 [Endothelial hyperpermeability, that is, a compromised endothelial barrier function, and the subsequent formation of edema are hallmarks of many severe disorders, such as atherosclerosis, asthma, sepsis, or heart failure –60. One y (SOCE) . Past annd COX-2 .β kinase activity and decreased PDGFR-β activation and extracellular signal-regulated kinase (ERK) activation in VSMCs [There have been few studies on the migration and proliferation effects of herbal medications such as hawthorn. Hawthorn appears to exhibit some cardioprotective effects due to reduction of smooth muscle cell migration and proliferation properties. Currently, up to 50% of patients undergo conventional balloon angioplasty recurrent stenosis . After vin VSMCs .Ischemia and reperfusion (I/R) exerts multiple injuries in microcirculation, frequently accompanied by endothelial cell injury, enhanced adhesion of leukocytes, macromolecular efflux, production of oxygen free radicals, and mast cell degranulation . Thus, mCrataegus extract prolongs action potential duration and delays recovery of Vmax [Crataegus extract [Crataegus resulted in a significant decrease in the total number of ventricular ectopic beats, mainly by reduction of beats occurring as ventricular tachycardia. Also it reduced the total number of ventricular ectopic beats but this reduction was due to the decrease of single extrasystoles [Hawthorn extract may produce some antiarrhythmic effects in the rat heart, but the mechanism underlying the effect remains elusive. One result shows that f Vmax . On the  extract . Anothersystoles .125I-LDL to the liver plasma membranes in vitro. This may be related to enhancement of the LDL-receptor activity. TCR was also shown to increase bile acid excretion and to depress hepatic cholesterol synthesis in atherogenic diet fed rats by upregulating hepatic LDL-receptors resulting in greater influx of plasma cholesterol into the liver [α, PPARγ, SREBP 1c, aP2, and adiponectin in vitro [γ-dependent mechanism directed towards identification of the components [As we know, oxidation of the low-density lipoprotein (LDL) cholesterol plays an important role in atherosclerosis . This ache liver . Treatmehe liver . The flain vitro . As we kmponents . TCR premponents . One resmponents .Crataegus, especially the hyperoside fraction, prevented L-NAME-induced hypertension in rats and had beneficial effects on the cardiovascular system [Crataegus administered at escalating doses produced a dose-time-dependent decrease in heart rate (HR) and mean arterial pressure (MAP). Higher doses produced the most significant reduction in both HR and MAP and induced sinus node suppression and progressive atrio-ventricular blockade. The underlying mechanism appeared to be related to the direct stimulation of the muscarinic receptor M2 and possible blockade of beta-receptors, while the hypotension was caused by enhanced nitric oxide release [It was observed that r system . Crataeg release .  in five major electronic databases, including CNKI, CBMdisc, VIP, PubMed, and the Cochrane Library, to retrieve any potential randomized controlled trials (RCTs). A number of keywords were used for data searching including Crataegus and cardiovascular disease clinical trial, Crataegus hypertension and hyperlipidemia, Crataegus arrhythmias platelet aggregation, and clinical trial. Finally, there were 15 trials included in the review, of which 8 trials were therapies of heart failure, 4 trials were therapies of hypotension, and 3 trials of hyperlipidemia  . Role ofgression . This paCrataegus extract is an adjunct to conventional treatment in patients with HF (New York Heart Association classes I–III) due to its positive inotropic, antiarrhythmic, and vasodilating properties. The hawthorn extract may provide additional benefit in symptoms control  and frequency of nocturnal urinations and exercise tolerance  [Crataegus on congestive heart failure. The majority of hawthorn clinical trials have been performed with WS 1442, a dry extract from hawthorn leaves with flowers (4–6.6 : 1), extraction solvent ethanol 45% (w/w).Contemporary therapies of heart failure such as ACE inhibitors, beta-blockers, spironolactone, implantable cardioverter defibrillators, and biventricular pacemakers have produced remarkable reductions in morbidity and mortality. However, quality of life (QOL) for patients with heart failure remains impaired and improved treatment regimens are still needed. fatigue) . A numben = 110) or ACE inhibitorydiuretics (n = 102) for 8 weeks. The trial using Crataegus preparation Cralonin among NYHA class II. Patients demonstrated that the Cralonin is noninferior to usual ACE inhibitorydiuretics treatment for mild cardiac insufficiency on all parameters except BP reduction [In a 3-year open cohort study, 372 patients  of stage NYHA II taking 900 mg/day WS 1442 in addition to their standard medication were followed for three years by their treating office-based physicians. Outcome parameters demonstrated that maximal workload (MWL), left ventricular ejection fraction (LVEF) and pressure-heart rate product increase (PHRPI) at 50 W ergometric exercise improved more in active treatment than in placebo patients. In addition improvement of typical symptoms like reduced exercise tolerance, exertional dyspnea, weakness, fatigue, and palpitations improved more with active treatment and in patients with more severe symptoms . Similarn = 69) or placebo (n = 74) for 8 weeks showed the efficacy and safety of a standardised extract of fresh berries of Crataegus oxyacantha L. and monogyna Jacq. (Crataegisan) in patients with cardiac failure NYHA class II. The result is confirmed that changes in blood pressure-heart rate product (BHP) at 50 watts and at comparable maximum load were in favour of Crataegus extract but the results are not statistically significant. What is more, an improvement in their heart failure condition may be achieved under long term therapy [n = 20) or placebo (n = 20), the difference between the groups was borderline statistically significant in the exercise tolerance and the double product (heart rate × systolic blood pressure × 10−2). It is demonstrated that WS 1442 was safe and well tolerated and was clinically effective in patients with congestive heart failure corresponding to NYHA class II [Another placebo-controlled, randomized, parallel group, multicentre trial recruiting 143 patients and treated with 3 times 30 drops of the extract ( therapy . Effecticlass II .Crataegus extract (n = 50) or with a placebo preparation (n = 50) for a period of 8 weeks, with a wash-out phase of one week. Outcomes of MWL, LVEF, PHRPI and typical symptoms were statistically significant with the LI 132 preparation compared to the patients treated with the placebo preparation. Apart from that, a significant reduction of the systolic blood pressure, of the heart rate and of the pressure/rate product was observed for the patients treated with the verum preparation. Besides, there were no severe side effects observed [One RCT studied effect of the extract LI 132 on chronic heart failure defined as NYHA functional class II. Patients were treated either with observed .However, controversy result showed that hawthorn provides no symptomatic or functional benefit when given with standard medical therapy to patients with heart failure. The research performed a randomized, double-blind, placebo-controlled trial in 120 ambulatory patients with NYHA class II-III chronic heart failure. All patients were randomized to either hawthorn 450 mg twice daily or placebo for 6 months. But there were no significant differences between groups in the change in 6 min walk distance or on measures of QOL, functional capacity, neurohormones, oxidative stress, or inflammation .Crataegus in CHF therapy, meta-analyses are required to prove its efficacy.Two clinical trials used WS 1442 to investigate the efficacy and safety of an add-on treatment in patients with congestive heart failure. In one of this randomized, double-blind, placebo-controlled multicenter study, 2681 patients  were included. Results showed that WS 1442 reduced sudden cardiac death by 39.7%, so that it was safe to be used in patients receiving optimal medication for heart failure . Anothern = 39) or placebo (n = 40) for 16 weeks, taking prescribed drugs. Results demonstrated that there was a significant group difference in mean diastolic blood pressure reductions: the hawthorn group showed greater reductions than the placebo group. What is more, this is the first randomized controlled trial to demonstrate a hypotensive effect of hawthorn in patients with diabetes taking medication [Hypertension is an increasingly important medical and public health issue, which could lead to severe complications . It is adication .One pilot study was aimed at investigating the hypotensive potential of hawthorn extract and magnesium dietary supplements individually and in combination, compared with a placebo. Volunteers were then randomly assigned to four groups: 600 mg hawthorn extract, 500 mg hawthorn extract, a combination of the previous two groups and placebo. Results showed that there was a decline in both systolic and diastolic blood pressure in all treatment groups or placebo, but hawthorn extract group showed a promising reduction in the resting diastolic blood pressure at week 10 in the 19 subjects, compared with the other groups. Furthermore, a trend towards a reduction in anxiety was also observed in those taking hawthorn compared with the other groups .Crataegus berry combination (CCC) on orthostatic hypotension, two similar, controlled, randomized studies were carried out in a balanced crossover design in 24 patients each with orthostatic dysregulation. Results showed that CCC drops decreased the orthostatic fall in blood pressure, especially affecting diastolic blood pressure after 1 minute of orthostasis in all dosages as compared to placebo. A statistically significant effect of the highest dose of 80 drops on diastolic blood pressure could be demonstrated after 1-, 3-, and 5-minute orthostasis [Similarly, in order to test the efficacy of a camphor-hostasis .Crataegus and its various preparations in hypertension have demonstrated somewhat contradictory results. One randomized, controlled cross-over designed trial was to investigate the relationship between hawthorn extract dose and brachial artery flow mediated dilation (FMD), an indirect measure of nitric oxide release. Randomly sequenced doses of hawthorn extract  and placebo were assigned to each participant. However, results showed that there was no evidence of a dose-response effect for our main outcome (FMD percent) or any of our secondary outcomes, such as absolute change in brachial artery diameter and blood pressure [Clinical investigations exploring the effects of pressure .C. laevigata group or a matching placebo. The main results were that C. laevigata decreased NE and showed a trend to lower LDL-C compared to placebo as add-on treatment for diabetic subjects with chronic CHD [Although the lipid-lowering property of the hawthorn extract has been shown in a number of animal studies by means of reducing in total cholesterol, low density lipoprotein, and ApoB synthesis, there are still few well-designed clinical trials. One study included 49 diabetic subjects with chronic CHD who were randomly assigned to either a micronized flower and leaf preparation of onic CHD . Two Chionic CHD . While conic CHD .Crataegus? How to use the hawthorn properly? Although modern drugs are effective in preventing cardiovascular disorders, their use is often limited because of their side effects [Then what is the adverse effect of  effects . Most of effects . Most efCrataegus and its various extracts were such NHPs. Currently, Crataegus products are currently marketed as an alternative treatment for hypertension, angina, arrhythmia, and the early stages of congestive heart failure by regulating whole body on multilevel and multitargets. What is the mechanism of Crataegus for cardiovascular diseases? The previous described animal studies have suggested that hawthorn extracts exert a wide range of cardiovascular pharmacological properties, including antioxidant activity, positive inotropic effect, anti-inflammatory effect, anticardiac remodeling effect, antiplatelet aggregation effect, vasodilating effect, endothelial protective effect, reduction of smooth muscle cell migration and proliferation, protective effect against ischemia/reperfusion injury, antiarrhythmic effect, lipid-lowering effect, and decrease of arterial blood pressure effect. Moreover, numerous clinical studies have demonstrated that hawthorn preparations are very effective in early stages of congestive heart failure. A few researches were reported on therapy of hypertension and hyperlipidemia.In the last 20 years, over 60% of new drugs for the treatment of cancer and 75% of new drugs used to treat infectious diseases were of natural health products . In NortCrataegus was first mentioned in “New Materia Medica.” The herb was used widely in traditional Chinese medicine, particularly in department of internal medicine, such as the food stagnation, nausea or vomiting, abdominal pain or diarrhea, hernia pain, hematocele in bosom, and postpartum lochia. Seldom narration was seen in ancient literature on Crataegus for treatment of cardiovascular diseases but many literature showed that Crataegus had the effect of “activating blood and dissolving stasis.” Since Crataegus has effect of eliminating food mass and removing blood stasis, it can be used for treatment of stomach disease and cardiovascular disease. In traditional Chinese medicine, there is a theory of “Treating heartache by regulating the spleen and stomach.” It comes from “gastric collaterals goes into heart” in the ancient literature of “The Miraculous Pivot.” The theory regarded that chest-bi had close association with dysfunction of spleen and stomach in physiological and pathological aspects, so it is important for treating heartache by regulating the spleen and stomach. In future, carrying out the research of traditional Chinese medical theory combined with modern pharmacological achievement is beneficial to the treatment of heart disease.In China, Crataegus on vasodilating effect and lipid-lowering effect were performed more frequently than those other effect of studies. Nevertheless there are only a few studies that have been published about the anticardiac remodeling effect and effect of reducting smooth muscle cell migration and proliferation. So, further systematic in vivo and in vitro researches are warranted to explore and verify the potential effect to provide precise guidance for clinical use and new drug discovery. Besides, with the studies published, the strength of the evidence, however, was often limited by lack of controls or placebos, nonrandomization, non-blinded design, or small numbers of patients. It is imperative to conduct multicentered, large-sized samples and randomized and arid controlled trials to reasonably evaluate the efficacy and safety of Chinese herb and formulas for CVDs. In addition, there are so many active ingredients in Crataegus, so that large quantity of active ingredients should be identified, extracted, and purified from the herb. What is more, some active ingredients are chemically unstable, which have limited the large-scale synthesis. All these pressing issues should be resolved in future researches.Nowadays, with the population of NHPs, finding the high efficiency and fewer adverse effects of cardiovascular-protective drugs from Chinese herb and formulas attracts great attention of researchers, and the study of target or mechanism of Chinese herb and formulas for hypertension is to be the hot topic of research and development of antihypertensive drugs. But there are still some problems we need to arise. On current, anminal research of