Uncontrolled hypertension is a leading modifiable risk factor for cardiovascular disease morbidity and mortality. Data on adequacy of blood pressure control in Kenya is scarce. This study aimed at assessing the level of blood pressure control among hypertensive patients on follow-up in a regional referral hospital.Data regarding blood pressure, antihypertensive medication use, and comorbidities was abstracted from medical records of 452 hypertensive patients seen in Nyeri Provincial General Hospital between January and March 2013. Adequate blood pressure control was defined as a systolic pressure < 140 mmHg (< 130 mmHg for diabetic hypertensive patients) and a diastolic pressure < 90 mmHg (< 80 mmHg for diabetic hypertensive patients). Data was entered and analyzed using STATA 9 .Only 33.4% of patients had a blood pressure within the recommended limits. In multivariate analysis, using a calcium channel blocker was significantly associated with good blood pressure control . On the other hand, old age (≥ 60 years), being diabetic, and the use of three or more antihypertensive drugs were associated with reduced odds of good blood pressure control .Poorly controlled blood pressure is an important public health concern among hypertensive patients in this region. Elderly patients, those with diabetes, and those on multidrug regimens are at higher risk for poor blood pressure control and warrant closer attention. Hypertension is an important public health concern worldwide. According to the World Health Organization (WHO), the global prevalence of hypertension among adults aged 25 years and over was 40% in 2008 . The totLowering blood pressure in hypertensive patients reduces the risk for cardiovascular events , 5. ThusDespite the fact that central Kenya accounts for the highest proportion of hypertension-related outpatient clinic attendances , there iThe study was a cross sectional survey including 452 hypertensive patients who were seen at Nyeri Provincial General Hospital between January and March 2013. Nyeri hospital is a referral health-care facility serving a wide region within central Kenya  . The hosn=2/Z21-α/2)((N-1)+p)(1-p)(Np(1-p)/ and diastolic blood pressure (DBP) readings recorded at their clinic visits. Other data included demographics , current antihypertensive medication, and comorbidities. A trained medical records clerk performed the retrieval of patient files and data abstraction. The study underwent ethical review and clearance by the Kenya National Council for Science and Technology. Permission to access the patients’ medical records was sought from the management board of Nyeri Provincial General Hospital. All patient information was treated with utmost confidentiality, and no personal identifiers were included in the data abstraction forms.All data were analyzed using STATA 9 . The percentage of patients with well controlled blood pressure was determined according to guidelines provided in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) . For non2 test) was performed to examine the relationship between blood pressure control and sex, age, number of drugs in the antihypertensive regimen, class of medication , angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and beta blockers), and comorbidities. Secondly, a multiple binary logistic regression model was fitted using a forward selection approach, with variables significant at P < 0.05 being added to identify predictors of blood pressure control.To identify covariates significantly related to blood pressure control, a combined analysis of all patients was conducted, with good blood pressure control being defined as SBP < 140 mmHg and DBP < 90 mmHg. Firstly, a bivariate analysis . The mean age was 63 (+/- 12.4) years. Non-diabetic hypertensive patients accounted for 58.2% (263) of the study sample, with the remaining 41.8% (189) being hypertensive patients with diabetes. The other comorbid conditions documented in the patients’ medical records were as follows: cardiovascular disease (4%); asthma (3.3%); peptic ulcer disease (1.1%); hyperthyroidism (1.3%); and others (6.9%). Among the patients with cardiovascular disease (18/452), heart failure was the commonest comorbidity (2%), followed by stroke (1.3%) and ischemic heart disease (0.7%). Renal disease was not present in any of the patients reviewed.Of the 263 non-diabetic hypertensive patients, only 128 (48.7%) had a blood pressure < 140/90 mmHg. Among the diabetic hypertensive patients (n=189), only 23 (12.1%) had a blood pressure < 130/80 mmHg. Hence, the percentage of patients with good blood pressure control was 33.4% (151/452). In the combined analysis, involving both non diabetic and diabetic hypertensive patients (N=452), only 196 (43.4%) of the study subjects had a blood pressure < 140/90 mmHg. Of the remaining 256 patients with uncontrolled hypertension, 62.5% were at stage 1 and 37.5% were at stage 2. The prevalence of isolated uncontrolled SBP was more than twice that of isolated uncontrolled DBP (29.7% vs. 11.7%). Regarding antihypertensive medication use, 82.1% (161/196) required two or more drugs to have their blood pressure controlled. Diuretics were the most commonly prescribed drugs (78.1%), with the majority being thiazides. The antihypertensive medications prescribed are listed in 2; p< 0.05). The results of bivariate analysis between blood pressure control status and the other study variables are summarized in Bivariate analysis revealed that diabetes status and the number of prescribed antihypertensive drugs were significantly associated with BP control  in 2009 , which sIt is also worth noting that a substantial proportion of patients with uncontrolled blood pressure were at stage 2 (SBP ≥ 160 mmHg or DBP mmHg ≥ 100), indicating a higher long-term risk of cardiovascular disease . We noteMultivariate analysis revealed that old age, diabetes, and the use of three or more drugs were significant predictors of poor blood pressure control. Older age has been identified as an important risk factor for poor blood pressure control in a number of studies , 21, 22.For adequate blood pressure control, majority of the patients needed two or more drugs. This finding is in agreement with the existing evidence, that combination therapy is necessary for blood pressure control . HoweverBeing prescribed a CCB was significantly associated with good blood pressure control, and patients taking a CCB were twice as likely to have well-controlled blood pressure than those not taking a CCB. This finding is consistent with those of other studies, in which CCBs were more beneficial in achieving good blood pressure control, particularly in the elderly , 30.One important limitation needs to be taken into consideration when interpreting the findings of this study. The study involved patients being followed-up at a hospital; therefore, the findings may not reflect the picture in the general population. However, given the paucity of data in this area, the study provides an important entry point to understanding the burden and factors associated with hypertension in central Kenya and in other parts of the country.This study shows that a majority of hypertensive patients in central Kenya have poorly controlled blood pressure, and identifies the need for targeted interventions to address the problem. Elderly and diabetic patients, and those on multidrug regimens, are more likely to have poorly controlled blood pressure and require closer attention. Systolic blood pressure control should be emphasized, given that it was a particular problem in this study population. The use of calcium channel blockers should be considered as they appear to provide better blood pressure control. Further research is needed to identify barriers to effective blood pressure control and examine possible interventions to improve treatment outcomes.


Liberal and overaggressive use of vasopressors during the initial period of shock resuscitation may compromise organ perfusion and worsen outcome. When transiently applying the concept of permissive hypotension, it would be helpful to know at which arterial blood pressure terminal cardiovascular collapse occurs.In this retrospective cohort study, we aimed to identify the arterial blood pressure associated with terminal cardiovascular collapse in 140 patients who died in the intensive care unit while being invasively monitored. Demographic data, co-morbid conditions and clinical data at admission and during the 24 hours before and at the time of terminal cardiovascular collapse were collected. The systolic, mean and diastolic arterial blood pressures immediately before terminal cardiovascular collapse were documented. Terminal cardiovascular collapse was defined as an abrupt (<5 minutes) and exponential decrease in heart rate  followed by cardiac arrest.P = 0.04), left main stem stenosis  or acute right heart failure  had higher arterial blood pressures than patients without these risk factors. Patients with severe valvular aortic stenosis had the highest arterial blood pressures associated with terminal cardiovascular collapse , but this difference was not significant. Patients with sepsis and patients exposed to sedatives or opioids during the terminal phase exhibited lower arterial blood pressures than patients without sepsis or administration of such drugs.The mean ± standard deviation (SD) values of the systolic, mean and diastolic arterial blood pressures associated with terminal cardiovascular collapse were 47 ± 12 mmHg, 35 ± 11 mmHg and 29 ± 9 mmHg, respectively. Patients with congestive heart failure , drug exposure  and the type of acute illness .The online version of this article (doi:10.1186/s13054-014-0719-2) contains supplementary material, which is available to authorized users. This caerfusion . Even maerfusion . Becauseerfusion  or ongoierfusion . When imerfusion ,11.In this retrospective cohort study, we aimed to identify the arterial blood pressure associated with terminal cardiovascular collapse in 140 patients who died in the intensive care unit (ICU) while being invasively monitored.This study was designed as a retrospective cohort analysis. It included patients admitted to a 37-bed medical-surgical ICU of a tertiary university teaching hospital between July 2011 and April 2013. The study protocol was evaluated by the local ethics committee , which waived the requirement for written informed consent because of the retrospective study design.All critically ill patients who were invasively monitored and died in the ICU during the observation period were eligible for enrollment. The exclusion criteria were age younger than 18 years, pregnancy, organ donation following brain(stem) death, immediate death after withdrawal of ventricular assist device support and absence of continuous electrocardiographic or invasive arterial blood pressure measurements.All study variables were extracted from the institutional electronic patient data management system . This system prospectively collects demographic data and patient characteristics; hemodynamic and other vital parameters are collected at one minute intervals. The system uses median filtering at 1-minute intervals, which is an effective nonlinear, digital filtering process to eliminate artefacts due to a signal . Data reThe following study variables were extracted from the database: age, sex, body mass index, premorbid conditions (known at ICU admission and/or diagnosed at autopsy), admission diagnosis, Simplified Acute Physiology Score (SAPS) II  and SAPSThe arterial blood pressure associated with terminal cardiovascular collapse was defined as the systolic, mean and diastolic arterial blood pressures immediately within 1 minute) before terminal cardiovascular collapse occurred. Terminal cardiovascular collapse was defined as an abrupt (<5 minutes) and exponential decrease in heart rate  followed by cardiac arrest , acute right heart failure, sepsis and shock. In addition, we analyzed whether the arterial blood pressure at terminal cardiovascular collapse was correlated with any of the following simultaneously measured variables: age, SOFA score, hemoglobin, partial arterial carbon dioxide tension, plethysmographic oxygen saturation, body temperature and exposition to sedative drugs and/or opioids.t-test was used to compare these arterial blood pressure levels between subgroups. Bivariate correlations calculated by applying the Pearson correlation coefficient were used to evaluate the relationship between the arterial blood pressure associated with terminal cardiovascular collapse and predefined cofactors. P-values <0.05 were considered to indicate statistical significance. All parameters are presented as mean values ± SD, if not indicated otherwise.All statistical analyses were performed using the PASW Statistics 18 software package . Following plausibility testing of the dataset, the normality distribution was checked by using the Kolmogorov-Smirnov test and was approximately fulfilled by all variables. Descriptive methods were used to present patient characteristics and the arterial blood pressures associated with terminal cardiovascular collapse in the study population and subgroups. The unpaired Student’s Two hundred thirteen ICU patients died during the observation period. Of these, no one was aged <18 years or pregnant, but electrocardiographic or invasive blood pressure measurements were not recorded in 22 patients. Nine patients died after organ donation following brain(stem) death, and five died after withdrawal of venoarterial extracorporeal membrane oxygenation therapy. Of the remaining 177 patients, 27 had rhythmological pathologies in the terminal phase. In ten patients, the arterial blood pressure at terminal cardiovascular collapse could not be determined. Following exclusion of these patients, 140 patients were included in the final analysis  and acute right heart failure , as well as exposition to sedatives and/or opioids during the terminal phase , did not differ between patients with sepsis and those without sepsis. No differences in arterial blood pressure at terminal cardiovascular collapse between the remaining subgroups were observed  associated with terminal cardiovascular collapse were 47 ± 12 mmHg, 35 ± 11 mmHg and 29 ± 9 mmHg, respectively (Table P = 0.048) and mean arterial blood pressures  than patients without sedative and/or opioid administration. The correlation analysis revealed a significant indirect relationship . Also, in severe aortic stenosis, arterial blood pressure is a key determinant of coronary perfusion [Five subgroups presented with arterial blood pressures at terminal cardiovascular collapse that were different from those in the remaining population. The respective mean arterial blood pressure levels differed by approximately 5 mmHg between patients with and those without acute right heart failure. This finding is in line with clinical observations that patients with acute right heart failure require an adequate perfusion pressure to maintain right ventricular function ,19. Patierfusion ,23, whicAnother interesting finding of this analysis is that patients receiving sedatives and/or opioids during the terminal phase experienced terminal cardiovascular collapse at significantly lower arterial blood pressures than patients who were not exposed to such drugs. This observation may have important practical implications because terminal cardiovascular collapse in awake patients or patients not exposed to sedative agents or opioids may occur at relevantly higher arterial blood pressure levels (5 to 8 mmHg on average) than in sedated patients. Other investigators have postulated that sedative agents and opioids can reduce oxygen requirements and hence increase the body’s tolerance to hypoxia and arterial hypotension , as may When interpreting the results of this study, additional limitations need to be noted. This was a retrospective analysis and may thus contain methodological weaknesses such as missing values and heterogeneous datasets. A relevant selection bias may have been introduced into the analysis in that 20.9% of patients who originally met the inclusion criteria were excluded because their arterial blood pressure at terminal cardiovascular collapse could not be determined or because their terminal cardiovascular collapse was caused by rhythmologic pathologies. Although we failed to identify an arterial blood pressure at which rhythmologic pathologies occurred in patients excluded from this analysis (data not shown), it is possible that such terminal rhythm disturbances might have been the consequence of coronary hypoperfusion and that a delicate group of patients exclusively sensitive to low arterial blood pressure levels was excluded from our analysis.The arterial blood pressure associated with terminal cardiovascular collapse in critically ill patients was very low and varied with individual comorbid conditions , drug exposure  and the type of acute illness .The arterial blood pressure associated with terminal cardiovascular collapse in critically ill patients was very low at 47 ± 12 mmHg systolic, 35 ± 11 mmHg mean and 29 ± 9 mmHg diastolic arterial blood pressure.Relevant exceptions were patients with congestive heart failure, left main stem stenosis, severe valvular aortic stenosis or acute right heart failure.Sepsis patients and patients receiving sedatives and/or opioids exhibited even lower arterial blood pressures at terminal cardiovascular collapse.


To assess the association between plasma homocysteine (Hcy), blood pressure (BP) and poor outcome at hospital discharge among acute ischemic stroke patients, and if high Hcy increases the risk of poor outcome based on high BP status in a northern Chinese population.Between June 1, 2009 and May 31, 2013, a total of 3695 acute ischemic stroke patients were recruited from three hospitals in northern Chinese cities. Demographic characteristics, lifestyle risk factors, medical history, and other clinical characteristics were recorded for all subjects. Poor outcome was defined as a discharge modified Rankin Scale (mRS) score ≥3 or death. The association between homocysteine concentration, admission blood pressure, and risk of poor outcome following acute ischemic stroke was analyzed by using multivariate non-conditional logistic regression models.P<0.05). The dose-response relationship between Hcy concentration and risk of poor outcome was statistically significant . High BP was significantly associated with poor outcome following acute ischemic stroke . Compared with non-high BP with nhHcy, in a multivariate-adjusted model, the ORs (95% CI) of non-high BP with hHcy, high BP with nhHcy, and high BP with hHcy to poor outcome were 1.14 (0.85–1.53), 1.37 (1.03–1.84) and 1.70 (1.29–2.34), respectively.Compared with those in the lowest quartile of Hcy concentration in a multivariate-adjusted model, those in the highest quartile of Hcy concentration had increased risk of poor outcome after acute ischemic stroke, (OR = 1.33, The present study suggested that high plasma Hcy and blood pressure were independent risk factors for prognosis of acute ischemic stroke, and hHcy may further increase the risk of poor outcome among patients with high blood pressure. Additionally, the results indicate that high Hcy with high BP may cause increased susceptibility to poor outcome among acute ischemic stroke patients in a northern Chinese population. Stroke is the second most common cause of death and the leading cause of serious, long-term disability worldwide Homocysteine (Hcy), a sulphur-containing amino acid, was hypothesized to affect atherosclerotic processes as early as 1969 Epidemiological studies have documented that high blood pressure (BP) is the most important modifiable risk factor for the incidence of stroke Thus, we sought to assess the relationship between high plasma homocysteine, blood pressure and poor discharge outcome among acute ischemic stroke patients. We also examined if hHcy may increase the risk of poor outcome based on high BP status in a northern Chinese population.From June 1, 2009 to May 31, 2013, we recruited adult patients with a clinical diagnosis of acute ischemic stroke from three hospitals in northern cities in China . All participants were recruited within 7 days of symptom onset. Exclusion criteria were: (1) lack of plasma homocysteine concentration measurement; (2) lack of blood pressure data; (3) presence of illnesses including renal and kidney disease, malignancy, autoimmune disease, and hypothyroidism; and (4) inability to comply with a magnetic resonance examination.This study was approved by the Soochow University Ethics Committee. Written informed consent was obtained from all study participants.Demographic characteristics, lifestyle risk factors, medical history, clinical laboratory tests and imaging data (CT and MRI) were recorded within the first 24 h after admission to hospital by a face to face interview with patients or their family members (if patients were not able to communicate). All information was obtained using a standard questionnaire administered by trained staff. Cigarette smoking was defined as having smoked at least 1 cigarette per day for 1 year or more. The amount and type of alcohol consumed during the past year were collected. Alcohol consumption was defined as consuming one or more alcoholic drink per day during the last year. Blood pressure (BP) was measured in the first 72 h (one measurement every 8 h) after admission while the participants were in the supine position using a standard mercury sphygmomanometer according to a standard protocol. The first and fifth Korotkoff sounds were recorded as systolic (SBP) and diastolic BP (DBP), respectively. High admission BP was defined as SBP ≥140 mmHg and/or DBP ≥90 mmHg. History of hypertension was defined that patients have hypertension prior to admission to hospital, according to the question “have you received a diagnosis of hypertension from any doctor or hospital before this onset of stroke”, or use of antihypertensive medication, or SBP ≥140 mmHg and/or DBP ≥90 mmHg.Hcy, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides were analyzed on a Beckman Synchron CX5 Delta Clinical System  using commercial reagents Acute ischemic stroke was confirmed by imaging (CT scan or MRI) according to the acute ischemic stroke diagnosis and treatment guidelines in China. Study outcome was evaluated using the modified Rankin Scale (mRS) obtained at hospital discharge, and poor outcome was defined as a mRS score ≥3 or death. Scores on the modified Rankin Scale range from 0 to 6, with a score of 0 indicating no symptoms; a score of 5 indicating severe disability ; and a score of 6 indicating death Statistical analysis was conducted using SAS statistical software . Patients were divided into two groups according to study outcome: mRS <3 and mRS ≥3 or death. According to blood pressure and concentration level of Hcy, participants were divided into four groups: non-high BP with non-hHcy (nhHcy), non-high BP with hHcy, high BP with nhHcy, and high BP with hHcy. Baseline characteristics of continuous variables were compared in 2 or 4 subgroups using Student's t-test or ANOVA. Categorical variables were expressed as percentage and compared between groups using Chi-square test. Plasma Hcy concentration was divided into four quartiles . Univariate and multivariate non-conditional logistic regression models were used to assess the association between Hcy, blood pressure and discharge outcome among acute ischemic stroke patients. Odd ratios (ORs) and 95% confidence intervals (95% CIs) were used to evaluate the risk of poor outcome after adjusting for important confounding factors. Multivariable interaction models were used to evaluate the interaction of Hcy and blood pressure with poor outcome among acute ischemic stroke patients. All P values were 2-tailed, and a significance level of 0.05 was used.A total of 3695 patients  were included in this study. The mean age of the participants was 62.40±11.45 years. P<0.05). After adjustment for age, gender, days hospitalized, onset to hospital admission time, smoking, drinking, history of hypertension, history of hyperglycemia, history of coronary heart disease, history of atrial fibrillation, high BP, hyperglycemia, and dyslipidemia, those in the highest quartile still had an increased risk of poor outcome . The dose-response relationship between Hcy concentration and risk of poor outcome remained significant after adjustment for other covariates .As shown in We also analyzed the independent effect of admission blood pressure on poor outcome after acute ischemic stroke. The multivariable-adjusted OR (95% CI) of poor outcome was 1.44 (1.19–1.74). P = 0.68).As shown in In this study, we found that there was a positive and significant association between plasma Hcy concentration and poor discharge outcome among acute ischemic stroke patients. Additionally, the results indicated that blood pressure was an independent risk factor for poor outcome among acute ischemic stroke in this study. Meanwhile, those with high BP and nhHcy or with high BP and hHcy were at a significantly higher risk of poor outcome compared to those with non-high BP and nhHcy. Participants with high BP and hHcy were at the highest risk in this population. To the best of our knowledge, this is the first multi-center study conducted to assess the cumulative effect of high admission BP and Hcy concentration on poor discharge outcome following acute ischemia stroke in three northern cities of China. Compared with previous studies in which Hcy and blood pressure were each shown separately to predict prognosis of stroke Several epidemiological studies indicated that elevated Hcy concentration is an important risk factor for short-term and long-term poor outcome following acute ischemia stroke P = 0.045) Some experimental studies indicate that Hcy may cause vascular inflammation and oxidative stress, damage endothelial cells, inhibit endothelium dependent relaxation, and enhance thrombogenicity Increased BP in the acute stage of ischemic stroke may be associated with poor functional outcome because there is augmentation of cerebral edema, hemorrhagic transformation, or stroke recurrence In the present study, the mean age of the participants was 62.40±11.45 years, which is lower than that in western countries The potential limitations of this paper merit consideration. Firstly, blood pressure and plasma Hcy concentration were recorded only once at baseline, and we have no data on possible changes in blood pressure and Hcy concentration during the follow-up. Future studies should examine the association between blood pressure and Hcy concentration changes and prognosis of acute ischemic stroke. Secondly, all participants were recruited upon hospital admission and within 7 days of symptom onset, and due to this possible delay of up to 7 days since symptom onset, some patients' Hcy concentration and blood pressure at admission may not accurately reflect the levels of Hcy and blood pressure at stroke onset. In addition, the follow-up period of our study is relatively short, which prevented an evaluation of the long-term effects of plasma Hcy on acute ischemic stroke outcomes.In conclusion, our study suggested that high Hcy and blood pressure were independent risk factors for prognosis of acute ischemic stroke, and high Hcy may further increase the risk of poor outcome among patients with high blood pressure. Additionally, the results indicated that high Hcy with high BP may cause increased susceptibility to poor outcome among acute ischemic stroke patients in a northern Chinese population.


Background and Aims. It is widely accepted that obstructive sleep apnea (OSA) is independently associated with atherosclerosis. Similar to OSA, hypertension (HTN) is a condition associated with atherosclerosis. However, to date, the impact of the simultaneous presence of OSA and HTN on the risk of atherosclerosis has not been extensively studied. The aim of this study was to evaluate the consequences of the coexistence of OSA and HTN on carotid intima-media thickness (IMT) and on inflammatory markers of atherosclerosis (such as interleukin- [IL-] 6 and pentraxin- [PTX-] 3). Methods. The study design allowed us to define 4 groups: (1) controls (n = 30); (2) OSA patients without HTN (n = 30); (3) HTN patients without OSA (n = 30); (4) patients with OSA and HTN (n = 30). In the morning after portable monitoring (between 7 am and 8 am), blood samples were collected, and carotid IMT was measured. Results. Carotid IMT, IL-6, and PTX-3 in OSA normotensive patients and in non-OSA HTN subjects were significantly higher compared to control subjects; in addition, in OSA hypertensive patients they were significantly increased compared to OSA normotensive, non-OSA HTN, or control subjects. Conclusions. OSA and HTN have an additive role in the progression of carotid atherosclerosis and in blood levels of inflammatory markers for atherosclerosis, such as interleukin-6 and pentraxin-3. Obstructive sleep apnea (OSA) is a disorder characterized by recurrent episodes of upper airway obstruction during sleep , resultiThe aim of this study was to evaluate the consequences of the coexistence of OSA and HTN on a marker of carotid atherosclerosis (such as IMT) and on inflammatory markers of atherosclerosis (such as IL-6 and PTX-3).n = 30); (2) OSA patients without HTN (n = 30); (3) HTN patients without OSA (n = 30); (4) patients with OSA and HTN (n = 30). Groups were matched for age (±5 years) and body mass index . Exclusion criteria were as follows: chronic obstructive pulmonary disease (COPD), history of smoking, congestive heart failure (CHF), previous myocardial infarction, unstable angina, prior coronary intervention, arrhythmias, use of cardioactive drugs, chronic renal disease, diabetes mellitus, morbid obesity (BMI > 40 kg/m2), any chronic inflammatory disease, and systemic infections at the time of the study or within two weeks before the study. HTN patients were outpatients from the Section of Cardiovascular Disease, and HTN was previously diagnosed according to current guidelines [During a period of eighteen months, we recruited patients who were referred to our Sleep Laboratory with suspected OSA. Moreover, we selected healthy subjects and patients with a diagnosis of HTN at low risk for OSA  to undeidelines . The cutidelines . Blood pidelines –27.The study was approved by the Institutional Review Board of Bari University General Hospital and carried out in accordance with the principles of the Helsinki Declaration. All patients gave prior written informed consent to take part in the study.All subjects underwent overnight in-laboratory portable monitoring with the Somtè Compumedics Inc., Abbotsford, VIC, Australia. Two sleep medicine physicians interpreted PM recordings , 28. TheAll patients underwent two-dimensional echo-color Doppler of the carotid arteries, adopting a high definition vascular echograph Philips Sonos 5500 Bothell, Washington, USA, and a 10–3 MHz linear electronic probe. All subjects were examined by the same investigator. IMT is defined as a double-line pattern visualised ecographically on both walls of the common carotid artery in a longitudinal view. Two parallel lines  form it: lumen-intima and media-adventitia interfaces , 31. As Samples of peripheral venous blood were collected between 7 a.m. and 8 a.m. Samples were stored at −80°C until the time of assay. Quantitative sandwich enzyme immunoassay kits (R&D Systems) were used to measure IL-6 and PTX-3 concentrations in plasma.p < 0.05 was considered statistically significant. The analyses were made using STATISTICA 6.1 software .Data are presented as mean ± SD unless otherwise indicated. Differences between four groups were analyzed by analysis of variance with Bonferroni correction. Multiple regression analysis was performed to identify variables that were independently associated with carotid IMT, IL-6, and PTX-3. A value of 2 nadir are shown in 2 nadir was significantly lower in OSA and OSA + HTN than in controls and HTN groups. In the hypertension and the OSA-plus-hypertension groups, the percentage of patients who were receiving diuretics, β-blockers, calcium-channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor antagonists was similar (data not shown).Characteristics of study population including age, sex, body mass index, neck circumference, systolic/diastolic blood pressure, heart rate, apnea-hypopnea index, total sleep time with oxyhemoglobin saturation below 90% (TST90), and SaOp < 0.01). In addition, carotid IMT in OSA hypertensive patients (0.99 ± 0.09 mm) was significantly increased compared to OSA normotensive subjects (p < 0.05), non-OSA HTN subjects (p < 0.01), or control subjects (p < 0.01).Carotid IMT values are shown in p < 0.01; 1.44 ± 0.43 ng/mL, p < 0.01, resp.). Moreover, levels of IL-6 and PTX-3 in OSA + HTN patients  were significantly elevated compared to OSA normotensive subjects (p < 0.01 for both markers), non-OSA HTN subjects (p < 0.01 for both markers), or control subjects (p < 0.01 for both markers).Plasma levels of interleukin-6 and pentraxin-3 are shown in Figures 2 nadir. Carotid IMT was positively related to AHI and systolic blood pressure (p < 0.05). The only variable independently associated with IL-6 was AHI (p < 0.01). The two variables independently associated with PTX-3 were AHI and systolic blood pressure (p < 0.01).In the multivariate analysis performed on the whole study sample, carotid IMT, PTX-3, and IL-6 were used as dependent variables, and their relationship with the following independent variables was evaluated: age, BMI, neck circumference, systolic/diastolic blood pressure, heart rate, AHI, TST90, and SaOThe present study demonstrated that carotid IMT, interleukin-6, and pentraxin-3 have a similar increase among OSA normotensive and non-OSA HTN patients, compared to normotensive non-OSA subjects. In addition, a further increase of the three above-mentioned atherosclerotic markers in OSA HTN patients was found. Further indicating the role of both OSA and HTN it was observed that AHI and systolic blood pressure were independently associated with carotid IMT and inflammatory markers. These results lead to considering a possible additive role of OSA and HTN on the progression of endothelial dysfunction.To date, in the literature two important works are reported, in which the role of OSA + HTN on the progression of atherosclerosis has been evaluated. Drager et al.  studied Pathophysiologically, it is widely accepted that the role of both OSA and HTN on the progression of endothelial damage is mediated by inflammation –36. IndeSome important limitations need to be considered. First, although OSA patients were not receiving treatment, all the HTN subjects were in treatment (though their mean systolic/diastolic blood pressure was significantly higher than in normotensive subjects). On the other hand, it is well known that HTN patients have increased endothelial impairment compared to normotensive patients, despite optimal treatment . This coIn conclusion, OSA and HTN have an important pathogenic role in vascular pathology. Moreover, these two conditions have an additive role in the progression of carotid atherosclerosis and in blood levels of inflammatory markers for atherosclerosis, such as interleukin-6 and pentraxin-3.


Epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), the AA and BB isoforms of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) are involved in the pathogenesis of airway inflammation in asthma. In the present study, the associations between asthmatic phenotypes and the expression levels of these mediators in induced sputum and serum were investigated. A total of 62 asthmatic patients were divided into eosinophilic or neutrophilic phenotypes by cytological classification of the induced sputum. In addition, patients were classified according to lung function (FEV1/FVC >70% or FEV1/FVC <70%) and asthma severity . The concentrations of EGF, bFGF, PDGF-AA, PDGF-BB and VEGF in the serum and induced sputum were measured using sandwich enzyme immunoassays. VEGF levels in the serum and induced sputum were higher in patients with an eosinophilic phenotype compared with those with a neutrophilic phenotype. In addition, VEGF expression was higher in patients with an FEV1/FVC value of <70% as compared with patients with an FEV1/FVC value of >70%. Furthermore, the levels of VEGF were higher in patients with severe asthma compared with the patients with mild and moderate asthma. There were no statistically significant differences observed with regard to EGF, bFGF, PDGF-AA and PDGF-BB levels among the various phenotypes. Therefore, the observations of the present study indicated that increased VEGF expression in the serum and induced sputum of patients may be associated with eosinophilic airway inflammation, severe airflow limitation and the severity of asthma. Asthma is a type of heterogeneous, chronic airway disease with a variety of phenotypes. The disease is characterized by reversible airway obstruction and airway hyperreactivity (AHR) . PhenotyGrowth factors have an important role in airway inflammation and remodeling in asthma. Epidermal growth factor (EGF) and its receptor are highly expressed in bronchial epithelial cells –6. Not oEGF, bFGF, PDGF and VEGF have important roles in airway inflammation, airway obstruction and AHR during the pathogenesis of asthma. Thus, clinical indicators that are easily obtained, practical, operable, repeatable and meaningful are required in clinical practice to aid the assessment of airway inflammation and the severity of asthma, thereby guiding the selection of targeted therapies and evaluating the prognosis for the patients. Few systematic studies investigating correlations among levels of EGF, bFGF, PDGF and VEGF in the serum and induced sputum with different clinical phenotypes of asthmatic patients have been performed. Thus, in the present study, outpatients and inpatients with asthma were recruited from the Beijing Shijitan Hospital  between 2010 and 2011, and the levels of EGF, bFGF, PDGF and VEGF in the serum and induced sputum were detected. Correlations between growth factors and the phenotypes of asthmatic patients were then analyzed with the aim of producing results that may be useful for the prevention and treatment of severe asthma.A total of 62 outpatients and inpatients from the Beijing Shijitan Hospital, diagnosed with an acute attack of bronchial asthma, were recruited between 2010 and 2011. All patients complied with the diagnostic criteria in the Prevention and Treatment Guidelines of Bronchial Asthma prepared by the Asthma Study Group under the Respiratory Disease Branch of the Chinese Medical Association in 2008 . All patSputum induction was performed as recommended by the Respiratory Disease Institute of the Chinese Medical Association . The patConcentrations of the growth factors were determined in the serum and sputum samples at the same time. EGF, bFGF, VEGF, PDGF-AA and PDGF-BB levels were measured in duplicate using sandwich enzyme immunoassays , in accordance with the manufacturer’s instructions.All subjects underwent a spirometric assessment  to measure the forced expiratory volume in 1 sec (FEV1) and the forced vital capacity (FVC). The results were compared with reference values.2 test was used for the comparison of classification data. P<0.05 was considered to indicate a statistically significant difference.SPSS 17.0 software  was used for statistical analysis and data are expressed as the mean ± standard deviation. One-factor analysis of variance was used for the comparison of means among multiple groups, while the χClinical characteristics of the patients are presented in In 62 separate samples of serum and induced sputum, the levels of EGF, PDGF-AA and VEGF in the induced sputum were significantly higher compared with that in the serum. By contrast, the levels of bFGF and PDGF-BB in the serum were higher compared with that in the induced sputum .Concentrations of VEGF in the serum and induced sputum of patients with asthma of an eosinophil phenotype were higher compared those of a neutrophil phenotype. In addition, VEGF levels were higher in patients with an FEV1/FVC value of <70% as compared with those with an FEV1/FVC value of >70%. Furthermore, VEGF levels were higher in patients with severe asthma when compared with those with moderate and mild asthma. However, no statistically significant differences were observed between EGF, bFGF, PDGF-AA and PDGF-BB in the serum and induced sputum of patients with asthma  and IV.A total of nine cases were followed-up, and the levels of growth factors in the serum and sputum were analyzed following one month of treatment; however, no statistically significant differences were observed among the levels of growth factors, despite the clinical symptoms of the patients improving  and VI.Growth factors play an important role in airway inflammation and remodeling in asthma. In the present study, associations between the levels of growth factors in the serum and induced sputum with clinical phenotypes of asthma were investigated. The results from the present study demonstrated that EGF, bFGF, PDGF-AA, PDGF-BB and VEGF were all detected in the serum and induced sputum of asthmatic patients. Concentrations of VEGF in the serum and induced sputum of asthmatic patients with an eosinophil phenotype were higher compared with those with a neutrophil phenotype. In addition, patients with an FEV1/FVC value of <70% had higher levels of VEGF compared with patients with an FEV1/FVC value of >70%, and patients in the severe group had higher levels of VEGF compared with those in the moderate and mild groups. However, no statistically significant differences were observed with regard to EGF, bFGF, PDGF-AA and PDGF-BB levels in the serum and induced sputum of asthmatic patients. These observations indicate that the levels of VEGF may be associated with an eosinophil phenotype, airway flow limitation and the severity of asthma.The main sources of VEGF are peripheral blood eosinophils ,15, eosiThe National Heart Lung and Blood Institute American Working Group  proposedA previous study identified that inhaled corticosteroids reduced the expression of growth factors in asthma, with the level of VEGF in the induced sputum of asthmatic patients shown to decrease significantly after one year of corticosteroid treatment . In addiIn conclusion, the results of the present study demonstrated that the concentrations of VEGF in the serum and induced sputum of asthmatic patients with an eosinophil phenotype were higher compared with those with a neutrophil phenotype. In addition, the concentration of VEGF was higher in patients with an FEV1/FVC value of <70% compared with those with an FEV1/FVC value of >70%. The levels of VEGF in the severe group were also higher compared with those in the moderate and mild groups. These observations indicate that VEGF levels may be associated with an eosinophil phenotype, airway flow limitation and the severity of asthma. Thus, the results of the present study are significant for the future prevention and treatment of severe asthma.


Supplemental Digital Content is available in the text. 2. In donors compared with controls, there were significant increases in left ventricular mass  and mass:volume ratio , whereas aortic distensibility  and global circumferential strain decreased . Donors had greater risks of developing detectable highly sensitive troponin T  and microalbuminuria . Serum uric acid, parathyroid hormone, fibroblast growth factor-23, and high-sensitivity C-reactive protein all increased significantly. There were no changes in ambulatory blood pressure. Change in GFR was independently associated with change in left ventricular mass . These findings suggest that reduced GFR should be regarded as an independent causative cardiovascular risk factor.There is a robust inverse graded association between glomerular filtration rate (GFR) and cardiovascular risk, but proof of causality is lacking. Emerging data suggest living kidney donation may be associated with increased cardiovascular mortality although the mechanisms are unclear. We hypothesized that the reduction in GFR in living kidney donors is associated with increased left ventricular mass, impaired left ventricular function, and increased aortic stiffness. This was a multicenter, parallel group, blinded end point study of living kidney donors and healthy controls (n=124), conducted from March 2011 to August 2014. The primary outcome was a change in left ventricular mass assessed by magnetic resonance imaging (baseline to 12 months). At 12 months, the decrease in isotopic GFR in donors was −30±12 mL/min/1.73mhttp://www.clinicaltrials.gov. Unique identifier: NCT01028703.URL:  The Chronic Renal Impairment in Birmingham (CRIB)–Donor study was designed to test the hypothesis that the reduction in renal function in living kidney donors is associated with adverse structural and functional cardiovascular effects.Kidney donors are ideal subjects to study the effects of a reduction in kidney function on the cardiovascular system. After donation, there is an immediate 50% reduction in GFR followed by a gradual improvement to 60% to 70% of baseline as a result of hypertrophy and hyperfiltration in the remaining kidney.12 The study had a prospective, longitudinal, parallel group, blinded end point design comparing living kidney donors with similarly healthy controls and was conducted between March 2011 and August 2014 . Donor-related family members and subjects attending blood donation and community healthcare facilities who fulfilled medical fitness criteria for living kidney donation were also invited to participate as controls .A flow chart of the study protocol is available in Figure S1. Investigations were performed in each participant at baseline (within 6 weeks before nephrectomy in donors), with subsequent follow-up studies performed at 6 and 12 months. Kidney donors underwent routine follow-up by their local medical and surgical team with no alteration to normal care.The primary end point was the change in LV mass at 12 months, as measured by cardiac magnetic resonance imaging (MRI). Secondary end points comprised changes in GFR by isotopic and creatinine-based methods; LV mass:volume ratio by cardiac MRI; office and ambulatory blood pressure; aortic distensibility by MRI; LV strain indices by cardiac MRI feature tracking; urinary albumin:creatinine ratio; high-sensitivity C-reactive protein (hsCRP); serum N-terminal pro-B-type natriuretic peptide (NTpro-BNP), and highly sensitive troponin T. Potential mediators of increased LV mass were also measured; these comprised renin, aldosterone, uric acid, parathyroid hormone (PTH), and fibroblast growth factor-23.15All studies were performed on a 1.5-T scanner . LV size, function, and mass were assessed using serial contiguous short-axis cine images piloted from the vertical long-axis and horizontal long-axis images of the left and right ventricles  in accordance with previously validated methodology.15 Mass was calculated as end-diastolic epicardial−endocardial volume×1.05. LV mass was indexed to body surface area using the Mosteller formula. The mass:volume ratio calculated as LV mass/LV end-diastolic volume was used as an index of concentric LV remodeling.16All LV measurements were made off-line in a Core laboratory by a single observer (W.E.M.) blinded to subject group and temporal sequence . Manual planimetry of the short-axis epicardial and endocardial contours in end-diastole and end-systole was performed using standardized methods.17 Longitudinal atrioventricular plane displacement was measured in the septum and lateral wall as the distance travelled by the respective annulus from end-diastole to end-systole.15 The biplane area–length method was used to measure left atrial volume.18Systolic and diastolic function was assessed using cardiac MRI feature tracking .20 The measurement of aortic cross-sectional area in systole and diastole was made off-line using automated software .21Distensibility of the proximal ascending aorta was assessed at the level of the pulmonary artery using the formula: aortic distensibility=Δaortic area/(minimum aortic area×pulse pressure).Resting blood pressure was measured in triplicate in the nondominant arm using a validated oscillometric sphygmomanometer  after 15 minutes of supine rest. The mean of the last 2 brachial blood pressure measurements was used in analysis. Subjects also underwent 24-hour ambulatory blood pressure monitoring .22 Common carotid intima-media thickness was measured as the distance between lumen-intima and media-adventitia interfaces using automated wall tracking software . The mean of the right and left carotid measurements was used for analysis.Right and left common carotid arteries were imaged using high-resolution ultrasound  1 cm proximal to the carotid bifurcation in accordance with published guidelines.23 The CKD-EPI (Epidemiology Collaboration) equation was used to determine eGFRcr with serum creatinine recalibrated to be traceable to an isotope-derived mass spectroscopy method.24 Urinary albumin:creatinine ratio was determined from a spot morning urine sample.25 Moderately increased albuminuria  was defined by an albumin:creatinine ratio of 30 to 300 mg/g.26 The methods used for biomarker assessment are available in the online-only Data Supplement.Isotopic GFR (iGFR) was performed at baseline and 12 months in donors and controls using the renal clearance of 51Cr-EDTA.To assess intraobserver report variability of LV mass measurement, 10 baseline studies were reanalyzed by the same observer (W.E.M) 4 weeks later, blinded to the original data. A random subset of participants (n=10) also underwent repeat imaging within 7 days to determine interstudy reproducibility; both scans were analyzed by the same observer (W.E.M) blinded to temporal sequence and patient identity. Reliability was assessed using the intraclass correlation coefficient with a model of absolute agreement.27 a sample size of 55 subjects per group provided 90% power to detect a change in LV mass of 7.5 g with a α=0.05. Therefore, we aimed to recruit 70 patients per group to allow for potential loss to follow-up.Sample size calculation was based on the primary outcome of change in LV mass. Assuming an SD of change in LV mass of 12 g based on our own data from a previous intervention study in CKD,t or Fisher exact tests. The primary analysis tested differences between groups >12 months using repeated-measures ANOVA. A further quantitative analysis was performed using a last observation carried forward principle. Generalized estimating equations were used to compare donors with controls for the likelihood of developing detectable serum and urinary biomarkers >12 months. Independent predictors of changes in LV mass were determined using multivariable logistic regression. To allow for multiple comparisons, P values were adjusted using the Holm–Bonferroni method. A 2-tailed P<0.05 was considered statistically significant.Data are expressed as mean±SD, median (interquartile range), or frequency (%), unless otherwise stated. The normality of distribution for continuous variables was determined using the Kolmogorov–Smirnov test. Variables not normally distributed were log-transformed. Baseline data were analyzed using independent samples Student A total of 124 subjects were enrolled (68 donors and 56 controls). The first participant entered the study in March 2011 and recruitment continued until August 2013 with the last follow-up visit in August 2014. Because of resource constraints, recruitment was terminated before reaching our prespecified target (140) but after attaining adequate numbers with 12-month follow-up data to provide >85% power to detect the specified change in LV mass. Baseline characteristics of the 2 study groups are shown in Table Eleven donors did not complete follow-up to 12 months . At 12 months, over one third of donors (35%) had an iGFR <60 mL/min/1.73m2, whereas more than one half (53%) had an eGFR <60 mL/min/1.73m2. When compared with controls, donors had significant increases in uric acid , iPTH , fibroblast growth factor-23 , and hsCRP . Detectable highly sensitive troponin T  and microalbuminuria  became significantly more common in donors than in controls. There were no significant changes in levels of renin or aldosterone.The changes in biochemical indices and cardiovascular disease biomarkers are presented in Table P<0.001; Figure 2; P<0.001) and LV mass:volume ratio . Nephrectomy did not affect LV volumes or ejection fraction but was associated with a reduction in long-axis function determined by septal AV plane displacement compared with controls . LV systolic function as measured by global circumferential strain was reduced with directionally similar but nonsignificant changes in global longitudinal strain. There was no difference in mean left atrial volume.The effects of nephrectomy on cardiac structure and function are presented in Table –3 versus +0.28±0.79×10–3 mm Hg−1; P=0.03). There were no significant differences between donors and controls in any office or ambulatory measures of blood pressure . There was also an association between the increase in LV mass and the decrease in iGFR . This relationship remained significant after adjustment for age, sex, baseline LV mass, and 12-month changes in blood pressure, uric acid, iPTH, and fibroblast growth factor-23 .Univariate analysis showed that there was an association between the baseline LV mass and the iGFR .This study has demonstrated that unilateral nephrectomy in healthy subjects is associated with structural and functional cardiovascular abnormalities within 1 year. There was an increase in LV mass, which had a graded independent association with the reduction in GFR after adjustment for demographic and hemodynamic factors. In addition, there was reduced LV myocardial deformation and increased aortic stiffness. There was no effect on atherosclerosis progression as measured by carotid intima-media thickness. The prevalence of microalbuminuria and detectable cardiac troponin increased after donation, and there was a significant rise in hsCRP. These findings provide insight into the pathophysiological effects of CKD on the cardiovascular system, suggesting that they are not primarily atherosclerotic but instead mediated via myocardial hypertrophy and increased large artery stiffness.1 clear proof of causation has been lacking. The debate has been heightened by an increasing body of opinion, suggesting that early stage CKD is benign and that age-related nephron loss should not be medicalized.28 Distinguishing causality from association in CKD is made difficult by the numerous concomitant diseases that accompany reduced GFR including hypertension, diabetes mellitus, anemia, and dyslipidemia. By studying kidney donors, we were able to examine prospectively the effect of a reduction in kidney function on the cardiovascular system, free from such confounding disease processes. The results suggest that reduced GFR is an independent graded risk factor for adverse LV remodeling independent of blood pressure. Because the prevalence of early stage CKD is high (1 in 7 people in the United States),29 it may be a major cause of increased LV mass in the community, a potent risk factor for cardiovascular death and adverse events.30 Further investigation is required to identify the mediators of renal cardiovascular disease. We have found no evidence to support effects mediated by blood pressure or activation of the renin–angiotensin system. Uric acid, PTH, and fibroblast growth factor-23 all require further investigation as mediators of both increased ventricular mass and arterial stiffening.32Despite robust epidemiological evidence of an association between reduced eGFR and increased cardiovascular risk,33 and in patients with CKD.34 Although no subject in the current study reached criteria for LV hypertrophy, both LV mass and mass:volume ratio have continuous rather than dichotomous relationships with risk.35 Indeed, LV mass is second only to age in its ability to predict cardiovascular events, cardiovascular death, and total mortality.36 Detectable troponin also independently predicts both total and cardiovascular mortality in healthy adults,38 and adverse cardiovascular events in subjects with CKD.39 Furthermore, there is a strong independent association between hsCRP and mortality in healthy subjects, as well as in the nondialysis CKD population.41 The lack of an increase in circulating NTpro-BNP  is perhaps unexpected given the degree of adverse LV remodeling, but may be the result of a compensatory increase in wall thickness normalizing wall stress.42 When considering the clinical implications of our findings, it should be noted that few donors reached an eGFR <45 mL/min/1.73m2, a level at which excess cardiovascular risk rises sharply.43Our findings may have clinical implications as all of the variables examined are of prognostic importance. Both LV mass and aortic stiffness have been consistently associated with increased mortality in both the general population44 Although observational studies of kidney donors have been reassuring with adverse event rates lower than those of the general population,46 studies using highly selected healthy control groups suggest that there may be a small increase in the risk of cardiovascular events and in the risk of developing end-stage CKD, particularly in non-white ethnic groups.48 Our results provide insight into the potential mechanisms by which adverse cardiovascular effects of kidney donation may be mediated and extend those which have been presented in the only other prospective, controlled pathophysiological study of kidney donors to date.49 Kasiske et al49 also found no effect of kidney donation on peripheral blood pressure, but recorded similar biochemical effects including an increase in PTH and uric acid. Both these factors have been associated with adverse cardiovascular outcomes and may themselves have direct adverse effects on LV geometry.51 The lack of change in hsCRP in donors reported by Kasiske et al49 is in contrast to our findings.47 Our own donor cohort had a higher mean age (47±12 versus 43±12 years) and included twice the proportion of non-white subjects (10% versus 5%), which could explain this discrepancy.The practice of living kidney donation is expanding rapidly; to date >135 000 such procedures have been performed in the United States alone.The strengths of our study include its prospective blinded end point design, the selection of similar donors and controls, and the high recruitment rate, but there are some limitations. First, the study was not randomized, which may have introduced bias although randomized trials of donation would never be possible for ethical reasons. Second, although over one half of all subjects approached (57%) took part in the study, we cannot exclude the potential for selection bias. Third, the use of nonsurgical controls means that we cannot exclude the possibility that other factors related to surgery may have exerted adverse cardiovascular effects. Fourth, most donors included were white (90%) and whether similar adverse changes in LV structure and function occur in non-white donors requires further assessment. Finally, our study was not large enough, or of sufficient duration to provide data on the risk of adverse outcomes.Compared with healthy controls, kidney donors exhibited adverse changes in LV mass and systolic function, aortic stiffness, and cardiovascular disease biomarker profile at 12 months after donation. The increase in LV mass was independently related to changes in kidney function but independent of blood pressure. These findings suggest that reduced renal function should be regarded as an independent causative cardiovascular risk factor.This article has been prepared on behalf of the Chronic Renal Impairment in Birmingham (CRIB)-Donor study investigators. We are grateful to the following nurses for help with participant visits: Theresa Brady, Donna Begg, Kathryn Adams, and Elizabeth Dwenger. We are grateful to Dr Daniel Zehnder for facilitating access to subjects undergoing transplant at University Hospital Coventry and Warwickshire. We are also indebted to the Oxford CMR group  for help in setting up the automated analysis of aortic distensibility. Finally, we wish to thank James Hodson and Peter Nightingale for help with the statistical analysis.W.E. Moody was supported by a British Heart Foundation Clinical Research Fellowship (FS/11/17/28700). The study was performed in the National Institute for Health Research/Wellcome Clinical Research Facility and was also supported by a Queen Elizabeth Hospital Birmingham Charity Grant.None.


Ex vivo incubation of whole blood with levosimendan decreased MPO release after PMN-stimulation (8.2 ± 1.4-fold increase at baseline vs. 6.0 ± 1.1-fold increase with levosimendan). MPO levels also significantly correlated with diastolic blood pressure over the time course. In a multivariate linear model, the main contributor to systolic, diastolic and mean blood pressure was level of PMN elastase. MPO contributed only in heparin-treated patients, suggesting a more significant role for endothelial-bound MPO than for circulating MPO or elastase with respect to blood pressure regulation. We here provide the first evidence that levosimendan treatment inhibits MPO release by PMNs in decompensated heart failure patients. This mechanism may regulate endothelial function and vascular tone in heart failure patients.Treatment of decompensated heart failure often includes administration of levosimendan. Myeloperoxidase (MPO) is released during polymorphonuclear neutrophil (PMN) degranulation, and mediates dysregulation of vascular tone in heart failure. We evaluated the effects of levosimendan-treatment on MPO in patients with acute decompensation of chronic heart failure over a one week course. Plasma MPO levels were significantly decreased after levosimendan treatment .  Heart failure (HF) is a significant cause of morbidity in Western society, affecting approximately 1–2% of the adult population. The prevalence is considered to be 8.4% for patients older than 75 years, whereas the risk of developing new onset heart failure is 0.2/1000 person-years in those aged 45–55 years, and increases up to 12.4/1000 person-years for those over age 85. Five year mortality is high, ranging from 45% in women up to 59% in men, and accounting for 55,000 annual deaths in the US alone12de novo symptoms. Published data provide evidence for polymorphonuclear neutrophils (PMN) activation and myeloperoxidase (MPO)-release in patients with severe HF4578101314The majority of patients hospitalized for acute heart failure have worsening chronic heart failure, rather than +-channels, but also has complex pleiotropic effectsFor patients showing clinical signs of acute peripheral hypoperfusion due to HF, the current European Society of Cardiology guidelines suggest levosimendan as a viable treatment option to help reverse the negative inotropic effects of pre-existing oral beta-blocker treatment. Levosimendan, is a calcium sensitizer and opens KThe present study assessed the effects of levosimendan on PMN function and activation by analysis of MPO and elastase levels as indicators of neutrophil degranulation in patients with acute heart failure. Further, we analyzed the correlation of PMN activation with blood pressure regulation and vascular tone in these patients.Twenty-five consecutive acute heart failure patients admitted to the Department of General and Interventional Cardiology at the University Heart Center Hamburg were enrolled. Patients referred to the unit with signs of acute heart failure were evaluated for cardiac function and signs of acute peripheral hypoperfusion as well as for co-morbidities and other potential causes for acute decompensation. All patients underwent transthoracic echocardiography to verify low cardiac output, defined as left ventricular ejection fraction below 30% (Simpson method). Patient inclusion criteria consisted of: age >17 years, heart failure NYHA class III and IV, or ACC/AHA class D, acute worsening of heart failure with signs of peripheral hypoperfusion, clinical indication for treatment with levosimendan (not determined by an study investigator), left ventricular ejection fraction below 30% determined by echocardiography or cardiac MRI). Exclusion criteria comprised: severe impairment of renal function (creatinine clearance <30 ml/min), severe hepatic dysfunction (bilirubin >2.0 mg/dl), systemic inflammatory disorders, overt infection, malignancy, autoimmune disorders, and concomitant treatment with intravenous vasoactive agents, such as inotropes or catecholamines.Mean arterial pressure was calculated as diastolic blood pressure plus 1/3 of pulse pressure (the difference between systolic and diastolic blood pressure). Right heart catheterization was performed if indicated per standard-of-care (to verify diagnosis or plan further treatment) within 24 hours before levosimendan treatment (twelve out of twenty-five patients).The study was performed in accordance with the Declaration of Helsinki and approved by the Board of Physicians Ethics Committee Hamburg. All patients provided informed consent.Levosimendan solution (0.025 mg/ml) was prepared using a 5 ml vial containing 12.5 mg of levosimendan concentrate  diluted in 500 ml sterile 5% glucose . Administration was performed via a central venous line at a constant rate of 21 ml/hour over 24 hours with no loading dose. If during administration a clinically relevant decrease in blood pressure occurred, as judged by the treating physician, the infusion was temporarily halted for a maximum of 1 hour, and then re-started at a 50% decreased rate.Blood was collected at baseline (immediately before levosimendan administration) and at 1, 6, 24, and 48 hours, as well as 1 week after treatment initiation. Blood samples were processed immediately, and 2 ml of separated plasma were pelleted and stored at −80°C pending further processing.MPO was quantitated using the CardioMPO kit (Cleveland Heart Lab) according to manufacturer's instructions. Elastase immunoassay was performed using a PMN-Elastase ELISA kit . Plasma nitrite was analyzed using a Nitrate/Nitrite Fluorometric Assay Kit  without performing nitrate reduction.Additionally, the following biomarkers were measured in plasma: C-reactive protein , N-terminal prohormone of brain natriuretic peptide  and interleukin-6 . The following data were recorded from clinical routine laboratory tests performed at the clinical central laboratory, University Hospital Hamburg: differential blood count, CRP, AST, ALT, GGT, bilirubin and creatinine.EDTA-blood was collected from healthy human subjects and incubated with levosimendan for 6 hours (500 ng/ml) at room temperature. Samples were subsequently stimulated with 20 μl of HBSS +0.25% BSA (control), or 20 μl of 100 nM PMA (phorbol 12-myristate 13-acetate), or 1 μM fMLP (N-formyl-Met-Leu-Phe). Stimulation was performed for 45 minutes at room temperature. Plasma was collected through centrifugation  and stored at −80°C until further analysis.All calculations were made with SPSS 17.0  and GraphPad Prism 6.01. Normal distribution tested by Kolmogorov-Smirnov-Test led to pairwise testing with Students unpaired t-test. Otherwise the Mann-Whitney rank sum test was performed. Linear mixed-model regression was used for multiple comparisons, and post-hoc Fisher's Least Significant Difference (LSD) tests were performed. Differences between timepoints of levosimendan administration  were calculated using a linear mixed model with inclusion of intersubject effects and timepoint as repeated measurements, the specific plasma marker as dependent variable, and post-hoc LSD testing.Correlations were calculated using a Pearson product-moment correlation coefficient if variables were interval-scaled and normally distributed. Otherwise, rank correlation using a Spearman's coefficient was performed.Multivariable testing was performed using a general linear model including systolic and diastolic blood pressure as dependent variables, and all markers of inflammation that were significantly correlated with blood pressure as factors or co-variates . Inter-subject effects were calculated via partial eta squared.A p value of <0.05 was considered statistically significant. Data are presented as mean ± SEM or median ± interquartile range if data were not normally distributed or not interval scaled.Levosimendan treatment led to significantly decreased MPO levels at 6 hours  as well as inflammation  in our patients . Plasma with (n = 9) or without (n = 16) heparin therapy during levosimendan-administration  strongly contributing to nitrotyrosine formationFurther, in a placebo-controlled study in patients with severe heart failure, Parissis and colleaguesMost intriguingly, we identified a significant increase in MPO levels at 7 days after levosimendan. This augmentation in MPO-concentration occurred without a coincident increase in elastase levels, indicating an underlying mechanism separate from PMN degranulation. Several other explanations may apply. Former studies have shown that a release of MPO from the endothelial glycocalyx is possible, allowing the vessel wall to achieve higher NO-availability and improved flow-mediated dilationIncreased nitrite plasma levels can also be a marker of macrophage activationIn porcine endothelial cells, levosimendan causes an increase in NO-concentration by activation of eNOS via MAP-kinases like p38, AKT and ERKAdamopoulos et al. showed anti-inflammatory effects of levosimendan on day 3 after levosimendan in heart failure patients with regard to TNF-alpha, interleukin-6, soluble Fas and soluble Fas-ligandWe additionally evaluated parameters of PMN activation and inflammation that were associated with blood pressure in a multivariate regression model. While our analysis does not provide causal insights, we utilized systolic, diastolic and mean blood pressure as an indirect estimate of endothelium-dependent vasoconstriction, as blood pressure correlates with endothelial function333436ex vivo, and after 24 hours in vivo, inhibition of PMN function through levosimendan might contribute to better endothelial-dependent vascular function with more NO bioavailability and lower blood pressure. A direct effect on PMNs would imply less MPO deposition on the endothelial layerSince we found that endothelial-bound MPO and PMN activation are significantly correlated with blood pressure regulation in HF patients treated with levosimendan, this implies a direct influence of blood pressure regulation on leukocyte and especially PMN activation and endothelial MPO deposition. On the other hand, given the inhibitory effect of levosimendan on MPO-release in whole blood We acknowledge that our work has certain limitations. The implementation of a randomized control group (randomization of levosimendan application vs. no levosimendan application) raised ethical concerns. Therefore we do not have a sufficient untreated control group, and can only compare changes over the time course of levosimendan application, but not to patients that have improved without levosimendan treatment. Further, the correlation and regression analyses we performed do not necessitate causal connection, and in general show moderate strength.Nevertheless, our data suggest that levosimendan has inhibitory effects on MPO release which might be beneficial for vascular endothelial function, contributing to blood pressure regulation in heart failure patients. Given the general state of neurohormonal activation which accompanies acute heart failure decompensation, the direct effects of levosimendan on MPO release and PMN activation have likely been under-recognised.M.A. designed the study, collected patient data, performed experiments, wrote and edited the manuscript. S.M. designed the study, collected patient data and edited the manuscript. H.K. collected patient data and performed experiments. A.K. designed the study, performed experiments and edited the manuscript. U.K.R. collected patient data. J.M.S. reviewed and edited the manuscript. T.K.R., V.R., P.S.T. and A.C.J. reviewed and edited the manuscript and provided supervision. S.B. designed the study, reviewed and edited the manuscript and provided supervision.


The effect of grape polyphenols on blood pressure remains unclear, which we aimed to address via a meta-analysis study.CRD42015019196).We conducted study trial searches in PubMed, Embase, and the Cochrane Library databases. Summary estimates of weighted mean differences and 95% confidence intervals were obtained by using fixed-effects models. Subgroup analyses were performed to identify the source of heterogeneity. The protocol details of our meta-analysis have been submitted to the international database of prospectively registered systematic reviews (registration number P = 0.03). Subgroup analyses indicated larger reduction was identified in the intake of low-dose of grape polyphenols  or patients with metabolic syndrome. Contrarily, diastolic blood pressure was not significantly decreased in the grape polyphenols group as compared to controls. No significant heterogeneity or publication bias was detected in the meta-analysis of either systolic or diastolic blood pressure.Ten studies were included in the present meta-analysis. Our results showed daily grape polyphenol intake could significantly reduce systolic blood pressure by 1.48 mmHg when compared to control subjects (12 comparisons; -1.48 [-2.79 to -0.16] mmHg; Daily grape polyphenol intake can significantly reduce the systolic blood pressure in humans, although the reduction is modest when compared with anti-hypertensive medications. Larger, better designed trials, that specifically include hypertensive subjects, are required to verify our results in the future. Blood pressure is a pivotal parameter of the cardiovascular system, and hypertension is an important risk factor for cardiovascular diseases . A previGrape products contain polyphenols, such as anthocyanins, flavanols and flavonols, as well as phenolic acids . ExperimFeringa et al. included 5 trials until 2010) and conducted a meta-analysis investigating the effect of grape polyphenols on blood pressure 10 and co,14,17,19http://www.crd.york.ac.uk/prospero/. Our registration number is CRD42015019196.The present meta-analysis was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines . The proAccording to PRISMA guidelines, we systematically searched PubMed , EMBASE , and the Cochrane Library for published reports by using the query “(grape) OR (polyphenol)” paired with “(blood pressure) OR (hypertension).” In addition, a manual search of references from reports of clinical trials or review articles was performed to identify relevant trials. When applicable, attempts were also made to contact investigators for clarification or additional unpublished data.Studies were selected for analysis if they met the following criteria: (i) the article was published in English; (ii) study was a randomized and controlled trial in humans; (iii) the subjects in the trial were exposed to the intervention for a minimum of 2 weeks; (iv) means of systolic blood pressure and diastolic blood pressure at the beginning and end of the intervention or the differences of systolic blood pressure and diastolic blood pressure between the beginning and end of the intervention were reported; (v) the dose of grape polyphenols was provided.According to the predefined inclusion criteria, two reviewers (Shao-Hua Li and Peng Zhao) independently completed the search, data extraction, and quality assessment. Any discrepancies between the two reviewers were resolved through discussion until a consensus was reached. The extracted data included the study characteristics , population information , the dose of grape polyphenols supplementation, the duration of the intervention, and the systolic and diastolic blood pressure at the start and end of the intervention. If alcoholized and de-alcoholized red wine were both used as the supplementation of grape polyphenols, only the de-alcoholized data were extracted because the alcohol may also affect the blood pressure ,23. MeanThe quality of the studies was judged by the following criteria: 1) randomization; 2) concealment of treatment allocation; 3) participant masking; 4) researcher masking; 5) reporting of withdrawals; 6) generation of random numbers; and 7) reporting of industry funding. Trials scored one point for each area addressed in the study design , with a possible score of between 0 and 5  (highestP < 0.1). The I2 statistic was also examined, and we considered an I2 value >50% to indicate significant heterogeneity between the trials , P = 0.52), but the grape polyphenols intake still resulted in a significant reduction of systolic blood pressure.Sensitivity analysis showed that the overall estimates of the changes in blood pressure were not altered after excluding the low-quality studies ,16. ExclP = 0.234) and diastolic blood pressure .The publication bias of trials was assessed by the statistical analyses of the Egger test and funnel plots . No publThe present meta-analysis showed that daily intake of grape polyphenols could significantly reduce systolic blood pressure by 1.48 mmHg when compared with control subjects. No significant heterogeneity publication bias could be detected in the meta-analysis of systolic blood pressure. Subgroup analysis indicated that larger reduction was identified in the intake of low-dose of grape polyphenols  or patients with metabolic syndrome. In contrast, diastolic blood pressure was not significantly decreased in the grape polyphenols intervention group as compared with controls, and no significant heterogeneity or publication bias was found in the meta-analysis of diastolic blood pressure. Therefore, the present study supported the hypothesis that daily grape polyphenol intake might affect systolic blood pressure, but not diastolic blood pressure.in vitro [In vivo animal studies have further demonstrated that grape polyphenols induce an endothelium-dependent relaxation in rabbits, [et al included 5 trials (until 2010) and conducted a meta-analysis investigating the effect of grape polyphenols on blood pressure [Significant increases of NO could be detected in human umbilical vein endothelial cells after being treated with grape polyphenol extract in vitro . In vivorabbits,  and redurabbits, , but thels until 10 and copressure ,14,17,19ls until 010 and cet al. found that the arterial blood pressure in hypertensive rats was significantly decreased after the supplementation of grape seed extract for 4 weeks [et al. further demonstrated that there was a negative association between the reduction of systolic blood pressure and the increased production of NO in patients with metabolic syndrome [et al. demonstrated that 1.0μmol/L grape seed extracts could induce the most significant relaxation of rabbit aortic rings in vitro, but no further prominent change of rabbit aortic rings could be found at higher concentrations (10μmol/L or 100μmol/L) of grape seed extracts [The precise mechanisms of grape polyphenols in reducing blood pressure are currently unknown. The majority of studies suggested that the stimulation and promotion of the release of NO, resulting in the vasorelaxation, might be the main cause of hypotensive effect of grape polyphenols. Peng  4 weeks . Barona syndrome . Our presyndrome  and prevsyndrome . Furtherextracts , which mextracts  and otheextracts , 45 showDespite the interesting results of the present meta-analysis, several potential limitations should be addressed. First, the sample sizes in the included trials, which varied from 10 to 50 subjects, were still small; therefore, larger and better designed trials are needed to verify our conclusions in the future. Secondly, hypertensive patients enrolled in the present meta-analysis was limited; only one trial  includedConclusively, our present meta-analysis indicates that daily intake of grape polyphenols can significantly reduce systolic blood pressure in humans, although the reduction is modest when compared with antihypertensive medications. Larger, better designed studies that also include hypertensive subjects are required to verify our present results.S1 TableThis is the detailed protocol of the present meta-analysis.(DOC)Click here for additional data file.S2 TableThis is the detailed checklist of the present meta-analysis according to the PRISMA guideline.(DOC)Click here for additional data file.S3 TableThe subgroup analyses were performed and showed as supporting information.(DOC)Click here for additional data file.


Background. Respiratory infections are a major cause of asthma exacerbations where neutrophilic inflammation dominates and is associated with steroid refractory asthma. Structural airway cells in asthma differ from nonasthmatics; however it is unknown if neutrophils differ. We investigated neutrophil immune responses in patients who have good (AGood) and suboptimal (ASubopt) asthma symptom control. Methods. Peripheral blood neutrophils from AGood , ASubopt , and healthy controls (HC) (n = 9) were stimulated with bacterial (LPS (1 μg/mL), fMLF (100 nM)), and viral (imiquimod (3 μg/mL), R848 (1.5 μg/mL), and poly I:C (10 μg/mL)) surrogates or live rhinovirus (RV) 16 (MOI1). Cell-free supernatant was collected after 1 h for neutrophil elastase (NE) and matrix metalloproteinase- (MMP-) 9 measurements or after 24 h for CXCL8 release. Results. Constitutive NE was enhanced in AGood neutrophils compared to HC. fMLF stimulated neutrophils from ASubopt but not AGood produced 50% of HC levels. fMLF induced MMP-9 was impaired in ASubopt and AGood compared to HC. fMLF stimulated CXCL8 but not MMP-9 was positively correlated with FEV1 and FEV1/FVC. ASubopt and AGood responded similarly to other stimuli. Conclusions. Circulating neutrophils are different in asthma; however, this is likely to be related to airflow limitation rather than asthma control. Howeverhe lungs ; howeverhe lungs , 5. Theshe lungs , 7.Asthma exacerbations may be triggered by a number of provokers of which the most common are respiratory infections. Viral infections have been extensively studied and rhinovirus (RV) is the most commonly detected virus in exacerbating adults . BacteriNeutrophils are the most abundant immune cell in the body; their main effector role is to control infections. CXCL8 is a potent neutrophil chemoattractant, neutrophil elastase (NE) has potent antimicrobial properties, and matrix metalloproteinase- (MMP-) 9 is important in activating antimicrobial peptides, all of which are released by neutrophils. Transient neutrophilia and neutrophilic inflammation are a normal phase of the immune response to pathogens ; howeverIt has been shown that structural cells, such as epithelial and smooth muscle cells, in the asthmatic airway are different compared to nonasthmatic cells in both morphology and function –24. It iNeutrophils are produced in the bone marrow and have a relatively short life span , 28. Giv1) and forced vital capacity (FVC). Participants with asthma were asked to withhold their short-acting β2 agonists for a minimum of 6 hours and 24 hours for long-acting β2 agonists and inhaled corticosteroids (ICS).The project was approved by the Human Research Ethics Committee, The University of Sydney, prior to commencement. Volunteers with doctor diagnosed asthma, stable disease, and no reported symptoms of respiratory infection were recruited into the study. Healthy control volunteers were also recruited. Participants were required to be over 18 years of age and be fluent in English. Exclusion criteria included if they were pregnant, were known to faint during venipuncture procedures, or had a blood borne infection or condition. All volunteers provided written informed consent and were asked to complete a standardised questionnaire regarding age, gender, asthma symptoms, asthma medication use, and smoking history. Patients also completed baseline spirometry for forced expiratory volume in 1 second  and were taking a minimum of GINA step 3 maintenance combination therapy. Patient information is provided in Tables Participants with asthma were stratified based on their asthma control questionnaire (ACQ) score . A cut pNeutrophils were isolated from peripheral blood collected from volunteers with and without asthma by a modified standard protocol , 31, 32.RV16 was generously donated by Professor Sebastian Johnston, Imperial College, London, UK. RV16 was grown in HeLa cells by standard procedures and infectivity titre determined by a titration assay as described .6 cells/mL. Cells were left unstimulated (negative control) or stimulated with EC50 concentrations of each TLR agonist based on dose-response curves generated for CXCL8 release (data not shown): 1 μg/mL LPS , 3 μg/mL imiquimod , 1.5 μg/mL R848 (Invivogen), and 10 μg/mL poly I:C (Sigma Aldrich), except fMLF (Sigma Aldrich) (100 nM) which was based on previous reports [2 for 1 hour for NE and MMP-9 measurements or 24 hours for CXCL8 measurements. Cell-free supernatant and neutrophils cell pellets were collected and stored at −80°C for analysis.Neutrophils were resuspended in 1% fetal bovine serum (FBS) , 1% 1 M HEPES (Gibco), and 1% penicillin/streptomycin RPMI 1640 (Gibco) at 1 × 10 reports . Neutrop reports , 35. CelCXCL8 production was measured using a sandwich ELISA in duplicate. Specific ELISA kits from R&D Systems  were used according to the manufacturer's instructions. Detection limit was 15.6 pg/mL.NE activity was measured in duplicate using a fluorescence assay from Cayman Chemicals  according to the manufacturer's instructions. Fluorescence readings from samples were compared to a standard curve of known concentrations of NE to determine the concentration. Detection limit was 3.1 ng/mL.2 activation buffer overnight before staining with Coomassie brilliant blue dye. Bands were determined to be pro-MMP-9 using size markers and MMP-9 standards. Densitometry was performed with Carestream Molecular Imaging Software on images taken on a Kodak Image Station from Integrated Sciences  to determine the relative fold change compared to media control.A bicinchoninic acid assay (Sigma Aldrich) was run for all samples according to the manufacturer's instructions to obtain the total protein concentration. Zymography was carried out according to previously published methods . Briefly10) before normality tests were conducted . They were deemed to have a normal distribution if they passed one of the three normality tests. A paired t-test or one-way analysis of variance (ANOVA) with Dunnett's posttest was performed if the data followed a normal distribution or a Wilcoxon matched t-test or Friedman test with Dunn's multiple comparison test if data were nonparametric. Two-way ANOVA with Tukey's posttest was performed for comparisons between healthy controls, well-controlled asthmatic, and suboptimally controlled asthmatic. For some data sets, correlation analysis was performed. Significant changes were identified where p < 0.05.For statistical analysis, data was normalised    with onlst (82%) . Howeverst (82%) . All par agonist  along wi agonist .All bacterial and viral mimetics including LPS, fMLF, imiquimod, R848, and poly I:C induced significant CXCL8 release from neutrophils isolated from healthy controls and well-controlled and suboptimally controlled asthmatics Figures . InteresfMLF was the only pathogen mimetic to induce NE from neutrophils in all three groups . InteresLPS, fMLF, and imiquimod induced MMP-9 release from neutrophils in all three groups Figures . Similar1% predicted and FEV1/FVC% ratio positively correlated with fMLF induced CXCL8 release  or MMP-9 . No correlations were found between pack year history and fMLF induced CXCL8  or basal CXCL8 . Similarly, no correlations were found between daily ICS dose and fMLF induced CXCL8  or basal CXCL8 . We also found no correlation between basal CXCL8 release and FEV1% predicted  or FEV1/FVC% ratio .To further investigate if the differences in fMLF induced CXCL8 and MMP-9 in controlled and uncontrolled asthmatics were related to airway obstruction, we performed correlation analysis. We found that FEV Figures  but not  Figures . There wIn this study we found that neutrophils from patients with asthma respond differently to fMLF compared to healthy controls. However, we did not see differences between neutrophils from patients with well- versus suboptimally controlled asthma. RV16 induced CXCL8 and R848 induced MMP-9 occurred in only neutrophils from well- and suboptimally controlled asthmatic groups but not in neutrophils from healthy controls. fMLF stimulation resulted in a deficient MMP-9 production in neutrophils from well-controlled asthmatics and a deficient CXCL8 and MMP-9 in suboptimally controlled asthmatics. In addition, NE was differentially regulated and was constitutively elevated in well-controlled asthmatics. This increased constitutive release most likely accounts for the difference observed in fMLF stimulated neutrophils from well-controlled asthmatics. We also found that fMLF induced CXCL8 and MMP-9 release correlated with lung function but not ACQ, smoking history, or ICS use. in vitro where they are deprived of altered signals in an asthmatic airway, we hypothesised that antimicrobial functions would similarly be dysfunctional in neutrophils from suboptimally controlled asthma. We hypothesised that there would be deficient immune responses in circulating neutrophils from people with suboptimally controlled asthma which potentially could lead to more severe or long lasting respiratory infections and ultimately an exacerbation. This study provides valuable and novel insights into circulating neutrophilic inflammatory responses.As airway epithelial cells and smooth muscle cells are fundamentally altered in asthma –24, evenIn this study we were interested in investigating if neutrophils are already dysfunctional prior to entering the airway tissue in patients with asthma which could be intensified with altered inflammatory signals. As such, we chose to use peripheral blood neutrophils which we believe to be appropriate for investigation of possible differences in these cells. Since neutrophils are released into the circulation from the bone marrow we believe this cell population best reflects neutrophil function that has not had further differentiation signals provided during extravasation and in the airway lumen.RV is a major precipitant of viral-induced exacerbations in asthma . Neutrop in vivo is likely to be much higher than we used in vitro ; thereffMLF, a bacterial derived protein and ligand for the fMLF receptor, stimulates neutrophils to migrate, produce inflammatory mediators, and release granules and reactive oxygen species . We obseNE and MMP-9 are both proteases and are found in neutrophil azurophil and gelatinase granules, respectively . Like alInterestingly, we found similar neutrophil responses between patients with suboptimally controlled asthma and well-controlled asthma, particularly with deficient fMLF induced CXCL8 and MMP-9 release. Neutrophil function is known to decline with age and these changes include decreased phagocytic ability , 49, red1 in asthmatic individuals [1 and FEV1/FVC. fMLF stimulates neutrophils via the FPR1 receptor. Interestingly annexin A1 also activates the fMLF receptor [Studies have reported CXCL8 levels in the airways inversely correlate with FEVividuals , 51, 52.receptor . As cortOur study has several limitations; the number of participants is small and the patients with suboptimal asthma control may have been quite heterogenous. Few participants had an ACQ > 1.5, which is the cut point used to be confident that asthma control is poor . As we dIn conclusion, no significant differences were seen in neutrophil function between patients with well- and suboptimally controlled asthma and therefore it is unlikely that neutrophil dysregulation drives asthma control. However, neutrophils from people with asthma appear to have different responses to pathogenic stimuli compared to healthy controls. This dysfunction may contribute to persistent or greater susceptibility to infection in asthmatics and is likely to be associated with airway obstruction.