The present study was to investigate the association of aldosterone excess and apnea-hypopnea index (AHI) in patients with resistant hypertension. Patients with resistant hypertension were enrolled and baseline characteristics including plasma aldosterone concentration (PAC) and 24 h-urine aldosterone levels were collected and compared between groups with different degrees of AHI as assessed by polysomnography. Association of key variables and AHI was then evaluated by univariate and multiple linear regression analysis. A total of 534 patients with resistant hypertension were enrolled and mean age was 57 ± 11 years. Overall, mean number of AHI was 21.7 ± 9.6 and nearly 92.3% of resistant hypertensive patients had obstructive sleep apnea (OSA). Mean PAC and 24 h-urine aldosterone level was 12.4 ± 6.3 ng/dL and 13.1 ± 6.8 ug, respectively. Compared with other groups, participants in the severe OSA group (AHI ≥ 30) had significantly higher PAC and 24 h-urine aldosterone level. Multiple linear regression analysis showed that PAC and 24 h-urine aldosterone levels were positively associated with AHI, while spironolactone was negatively associated with AHI, independent of age, gender, body mass index, smoking, plasma renin activity and diuretics. OSA is highly prevalent in patients with resistant hypertension and both PAC and 24 h-urine aldosterone level are significantly associated with AHI. Essential hypertension is a major public health problem around the world and lowering blood pressure (BP) is beneficial for reducing the incidence of cardiovascular and kidney diseases12Previously, a substantial number of observational researches have shown that patients with hypertension and OSA were more difficult to have their BP control than hypertensive patients without OSA69We therefore conducted a cross-sectional research to investigate the above clinically relevant issues. Our preliminary data show that OSA is highly prevalent in patients with resistant hypertension and both PAC and 24 h-urine aldosterone level are independently associated with OSA severity as indexed by the AHI. The application of aldosterone antagonist in our daily clinical practice is still extremely low, and in the future we should make concerted efforts to narrow the gap in order to improve BP control in these high-risk populations.2 using the Modification of Diet in Renal Disease formulaThe present research was approved by the clinical research ethical committee of Shenzhen Sun Yat-sen Cardiovascular Hospital. All the performances were in accordance to the Declaration of Helsinki. Informed consent was obtained from all participants. Included criteria were as follows: 45–75 years-old hypertensive patients; clinic BP ≥ 140/90 mm Hg despite treating with 3 anti-hypertensive medications including one diuretic at optimal doses for at least 4 weeks+), sodium (Na+), albumin (ALB), creatinine (Cr), blood urine nitrogen (BUN), plasma aldosterone concentration (PAC) and plasma renin activity (PRA). Aldosterone/renin ratio (ARR) was then calculated by the standard formula of PAC divided by PRA+, 24 h-urine Na+ and 24 h-urine Cr levels by mass spectrometryClinical data were collected using constructed questionnaire which included information about the demographic, anthropometric and medical history of all participants. Briefly, fasting venous blood were used to measure serum levels of fasting plasma glucose (FPG), total cholesterol (TC), potassium (K2) was also continuously monitored by a pulse oximeter and the mean and lowest SaO2 during sleep were recorded. Those with central sleep apnea were excluded and only those with OSA were included into final analysis. According to the current AASM guideline2 for more than 10 seconds would register as apnea or hypopnea events, and the AHI was calculated by the total number of apnea and hypopnea events per sleep hour, with AHI of 5–14 were defined as mild, 15–29 moderate, and 30 or more severe OSA, respectivelyOvernight PSG was performed in all participants using Philips Respironics Alice PDx. Thoraco-abdominal movements were monitored, and oxyhemoglobin saturation . All statistical tests were two-sided and considered statistically significant when P < 0.05.2 and proportion of obesity  and OSA was independently associated with resistant hypertension. Notably, diagnostic criterion of OSA was based on the AHI ≥ 10Similar to previous findings68et al. enrolled 109 resistant hypertensive patients, and they found that OSA severity was significantly associated with PAC. Similarly, we also observed that there was a trend, that is, the more severe OSA, the higher PAC and 24 h-urine aldosterone levels as indicated in et al. did not evaluate whether the significant relationship between OSA severity and PAC was independent of other potential confounding factorsAlthough the relationship between OSA and resistant hypertension has been extensively evaluated, the associated mechanisms were still far from clear. Previously, some studies have revealed the relationship of PAC with OSA severity and BP level. For example, in a cross-sectional studyet al. conducted a study to investigate the trend of antihypertensive medication use among US patients with resistant hypertension from 2008 to 2014Aldosterone antagonist such as spironolactone has been recognized as the preferred add-on therapy for BP-lowering in resistant hypertension since the publication of the PATHYWAY-2 clinical trialNotably, in the multiple linear regression analysis, after adjusted for potential confounding factors, we observed that only spironolactone was negatively associated with the AHI, and the underlying mechanisms might be multiple folds. On the one hand, it was noted that fluid retention was one of the major mechanisms of resistant hypertension, and during sleep time, rostral shift from lower extremity could lead to peri-pharyngeal fluid accumulation which in turn caused upper airway narrowing and OSA development232423There were several limitations of our current study. First, the inherent limitation of cross-sectional design could not allow us to draw causal relationship between increased PAC and the AHI, although a positive association was observed in a multiple linear regression analysis. Second, a small proportion of patients were treating with spironolactone when PAC and 24 h-urine aldosterone level were measured which might influence the relationship between PAC and the AHI. However, in the multiple linear regression analysis, we observed that both PAC and 24 h-urine aldosterone level were significantly associated with the AHI, which was independent of spironolactone usage. Moreover, regarding the ethical issues, it might be inappropriate for us to discontinue anti-hypertensive medications. Finally, participants in our current study were relatively healthy with respect to without existing overt cardiovascular or kidney disease and low prevalence of obesity and diabetes. Therefore, the data should not be extrapolated to other more morbid populations.In conclusion, our current study showed that OSA is highly prevalent in patients with resistant hypertension, and both PAC and 24 h-urine aldosterone level are significantly associated with the AHI. The application of aldosterone antagonist is still extremely low and clinical trials evaluating the impact of adding spironolactone on top of ACEI/ARB, CCB and diuretic therapy may represent important future research steps toward improving BP control rate in patients with resistant hypertension.How to cite this article: Ke, X. et al. Association of aldosterone excess and apnea-hypopnea index in patients with resistant hypertension. Sci. Rep.7, 45241; doi: 10.1038/srep45241 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Although previous investigators have established an association between blood transfusion and adverse outcomes, the relative frequency of different morbid events and the association with transfusion dose are not well understood.The purpose of the study is to characterize the relationship between blood transfusion and different types of morbidity after posterior spine fusion.We retrospectively analyzed electronic medical records for 963 patients who underwent posterior spinal fusion surgery at a single institution, of which 603 (62.6%) received an allogeneic blood transfusion. Then, we assessed patient and surgical characteristics in a risk-adjusted fashion to identify various morbid event rates and independent predictors in these adverse outcomes.P < 0.0001), thrombotic events , and hospital-acquired infections . Renal, respiratory, and ischemic morbidity occurred less frequently and were not more common in transfused patients. Risk-adjusted analysis revealed a dose-response effect, whereby for each unit of allogeneic blood transfused, the risks of any morbid event , thrombotic complication , and infectious complication  were increased.Compared to the non-transfused patients, transfused patients had a higher incidence of any morbid event  contains supplementary material, which is available to authorized users. Spinal fusion is among the top 10 surgical procedures associated with blood transfusion , and theAlthough the relationship between transfusion and infection after spine surgery has been established, the association of transfusion with other complications is unclear , 25, 32.A better understanding of the risk-benefit balance between anemia, transfusion, and clinical outcomes after spinal fusion is necessary to optimize clinical outcomes and reduce healthcare costs . Such a After receiving approval from the institutional review board at our institution, we acquired electronic medical record data from a web-based intelligence portal , our hospital billing database (Datamart), and the anesthesia information management system  for patients who were discharged from our institution between January 2009 and January 2015. Current Procedural Terminology (CPT) codes were queried to identify consecutive patients who underwent posterior spinal fusion surgery. CPT codes included were 22612, 22630, 22633, 22800, 22802, and 22804 , pulmonary embolism (PE), and disseminated intravascular coagulation (DIC). Postoperative infection includes a postoperative urinary tract infection, a surgical site infection, pneumonia, or other infectious complications occurring in the postoperative period. A thrombotic event was defined as one or more of the following: DIC, DVT, or PE. A hospital-acquired infection was defined as one or more of the following: postoperative infection, sepsis, drug-resistant infection, or C. difficile infection. An ischemic event was defined as one or more of the following: TIA, CVA, or MI. These groupings were not mutually exclusive, for instance, a patient could have both a TIA and an MI but that would only count as one ischemic event.In-hospital morbid events were determined by ICD-9 codes upon discharge, as we have described previously , 30. Outt test was used to analyze continuous variables. The Wilcoxon rank sum test was used to analyze data that were not normally distributed. Normality was tested with the Shapiro-Wilk test. Risk for transfusion and perioperative morbidity were analyzed in both an unadjusted and risk-adjusted fashion by univariable and multivariable logistic regressions, respectively. Variables entered into the logistic regression model include those clinical factors that have been shown in previous studies to be associated with adverse outcomes, and those factors that were associated with morbidity upon univariate testing in the current study. Estimated blood loss was entered as quartiles since as a continuous variable the interaction between RBCs transfused and estimated blood loss rendered the model unstable. Continuous variables that were normally distributed are presented as mean ± SD, whereas other variables are presented as median (interquartile range). P < 0.05 (by two-tailed tests) was used to define significance. Non-adjusted and risk-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) are reported. Analyses were generated with JMP version 12 .Chi-squared and Fisher’s exact tests were used to compare dichotomous variables, and Student’s N = 553, 57.4%) than men, and the average age was 56 ± 16 years , increased Charlson score (P < 0.0001), female sex (P < 0.0001), increased estimated blood loss (P < 0.0001), and increased surgical time (P < 0.0001)  received a blood transfusion, with 419 (43.5%) receiving blood intraoperatively, 499 (51.8%) receiving blood postoperatively, and 311 (32.3%) receiving blood during both time periods. Of the 963 patients included in the analysis, 505 (52.4%) were on the orthopedic surgery service and 458 (47.6%) were on the neurosurgery service. In the univariate analysis, significant predictors of transfusion were increased age (.6% receiP < 0.0001), thrombotic events , and hospital-acquired infections  .Compared with the non-transfused patients, transfused patients had a higher incidence of any morbid event  was assessed by univariable and multivariable analyses Table . UnivariC. difficile. Renal complications occurred with an overall frequency of 1.4%, and ischemic and respiratory morbid events occurred with an overall frequency of less than 1%. Ischemic, respiratory, and renal morbid events, despite being less likely, tended to increase with increasing dose of RBC transfused, demonstrating a possible dose-response relationship , and increased odds of a thrombotic event .In a risk-adjusted multivariable analysis controlling for age, sex, race, Charlson score, body mass index, levels fused, intraoperative blood loss, and surgical duration, RBC transfusion dose (per unit) was independently associated with an increased odds of any infection  receptor-positive helper cells, increased CD8 suppresser cells, decreased natural killer cells, increased numbers of B cells, decreased IL-2 production, and increased prostaglandin E2 production , 17. TraIn general, restrictive transfusion practices are supported by multiple randomized trials, , 23, 31 To our knowledge, this study represents the largest series to date to examine the association between blood transfusion and noninfectious outcomes after spine fusion. Our findings offer new insights into the risk-benefit balance between anemia, transfusion, and outcomes, and may help inform clinical decision-making. By identifying transfusion as a risk factor for thrombosis and infections, our results may serve to heighten clinician awareness to optimize prevention, diagnosis, and treatment of these complications and thereby improve outcomes after spinal fusion.ESM 1(PDF 1224 kb)ESM 2(PDF 1224 kb)ESM 3(PDF 1224 kb)ESM 4(PDF 1224 kb)ESM 5(PDF 1224 kb)ESM 6(PDF 1224 kb)Below is the link to the electronic supplementary material.


The aim of the present study was to investigate the metabolic benefits deriving from administration of a non-selective α-adrenoceptor antagonist from the group of pyrrolidin-2-one derivatives. The aim of the present study was to investigate the potential metabolic benefits deriving from chronic administration of a non-selective α-adrenoceptor antagonist, from the group of pyrrolidin-2-one derivatives.Previous studies have shown that several components of the metabolic syndrome, such as hypertension, obesity or imbalanced lipid and carbohydrate homeostasis, are associated with the sympathetic nervous system overactivity. Therefore, the inhibition of the adrenergic nervous system seems to be a reasonable and appropriate therapeutic approach for the treatment of metabolic disturbances. It has been suggested that non-selective adrenoceptor antagonists could be particularly beneficial, since α1- and α2-adrenoreceptor affinities of the tested compound—1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one had been investigated previously by means of the radioligand binding assay. In the present study, we extended the pharmacological profile characteristics of the selected molecule by additional intrinistic activity assays. Next, we investigated the influence of the tested compound on body weight, hyperglycemia, hypertriglyceridemia, blood pressure in the animal model of obesity induced by a high-fat diet, and additionally we measured the spontaneous activity and body temperature.The α1B and α2A-adrenoceptors. After the chronic administration of the tested compound, we observed reduced level of triglycerides and glucose in the rat plasma. Interestingly, the tested did not reduce the body weight and did not influence the blood pressure in normotensive animals. Additionally, the administration of the tested compound did not change the animals’ spontaneous activity and body temperature.The intrinistic activity studies revealed that the tested compound is a potent, non-selective antagonist of α2A-adrenoceptor antagonist drugs available in clinical use with the ability to modulate hyperglycemia that would not affect blood pressure.Non-selective α-adrenoceptor antagonist seems to carry potential benefits in the improvement of the reduction of elevated glucose and triglyceride level. The lack of influence on blood pressure suggests that compounds with such a pharmacological profile may be particulary beneficial for the patients with disturbed lipid and carbohydrate profile, who do not suffer from hypertension. These results are particulary valuable, since currently there are no safe α The metabolic syndrome has been defined as a simultaneous occurrence of at least three out of five symptoms, such as impaired fasting glycaemia, abdominal obesity, elevated blood pressure, hypertriglyceridemia, and low levels of high density lipoprotein (HDL) . The metPrevious studies have revealed that several components of the metabolic syndrome are associated with an increased activation of the sympathetic nervous system. For instance, the adrenergic nervous system plays a key role in the induction and progression of high blood pressure, alteration of the cardiac output, peripheral vascular resistance as well as controlling the triglyceride and glucose metabolism . It has 1-adrenoceptors causes vasodilatation and results in the reduction of blood pressure . The results are shown in Fig. The test compound administered at doses of 5 or 2 mg/kg b.w. intraperitoneally to rats fed on a high-fat feed did not cause a decrease in body weight gain compared to the obese rats (obesity control group = hight-fat feed + vechicle) . The results are shown in Fig. In groups receiving the test compound, the amount of adipose tissue pads was lower than that in obese rats, but the difference was not statistically significant. There was also no difference between the amount of adipose tissue in the treated and the control group . The level of triglycerides was significantly lower in the group treated with the test compound compared to the level determined in the plasma of the obese control group . The results are presented in Fig. In animals treated with the test compound at a dose of 5 mg/kg b.w., intraperitoneal, significantly lower blood glucose level was observed as compared to the group of obese animals treated with water . The test compound at a dose 2 mg/kg b.w., intraperitoneal, did not significantly affect blood pressure after a single administration . The results are shown in Fig. The tested compounds at a dose 5 mg/kg b.w., intraperitoneal, did not significantly affect blood pressure after a single administration . Results are shown in Fig. The test compound did not influence significantly the body temperature for 22 h after treatment in obese rats after one administration [two-way ANOVA; o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one (EP-47) was selected from the library of previously synthesized and described structures, considering its non-selective affinity for the adrenoceptors with a preference towards the α1-adrenoceptors [1B and α2A-adrenoceptors. While designing the present study, we considered the recent literature data regarding the ability of α2A-adrenoceptor antagonists to indirectly induce the weight loss in animal models of obesity [2-adrenoceptor antagonist, it is able to increase the release of noradrenaline, which stimulates the β-adrenoceptors located in adipocytes, and this could lead to increased lipolysis, thermogenesis and consequently to the weight loss. Therefore, we measured the influence on the body weight in the animal model of obesity induced by a high-fat diet, after the chronic administration of the tested compound. However, despite expected activity, the tested compound did not reduce the body weight in obese animals.Imbalanced lipid–carbohydrate homeostasis, the obesity, and the hypertension are the key components of the metabolic syndrome. Due to the vast distribution of the adrenoceptors in the body, and its impact on the blood pressure, metabolism of triglycerides and glucose, the α-adrenoceptor antagonists may be useful in the treatment of many types of disorders. In this paper, we investigated the effect of the pyrrolidin-2-one derivative on the body weight, hyperglycemia, hypertriglyceridemia and blood pressure in the animal model of obesity induced by a high-fat diet, measuring additionally the spontaneous activity and the temperature. The tested compound; 1-piperazin-1-yl)propyl)pyrrolidin-2-one effectively reduced the elevated glucose and triglyceride levels in the animal model of obesity induced by a high-fat diet. The tested compound only moderately reduced the amount of peritoneal body fat. It neither affected the body temperature nor caused any disturbance in the spontaneous activity and the blood pressure. The lack of influence on blood pressure is particulary significant, since currently there are no α2A-adrenolytic agents available in clinical use which would not impair blood pressure. Therefore, the search for novel molecules with a similar activity profile to the tested compound, seems to be a promising strategy regarding the potential treatment of hyperglycemia, hyperlipidemia induced by a high-fat diet. Maintaining stable euglycemia is one of the aims of an effective therapy of the metabolic syndrome as well as acute cardiac conditions, such as myocardial infarction, as it may significantly reduce the risk of cardiac complications in patients.The present study indicated that a non-selective α1B-/α2A-adrenoceptor antagonists might have a potential in the treatment of the metabolic syndrome, therefore 1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one requires further extended studies to explore its full pharmacological profile.We believe that non-selective α


We aimed to investigate in patients with type 2 diabetes whether aortic stiffness is: (i) associated with glycaemic control, (ii) associated with adverse outcomes and (iii) can be reversed on treatment with RAAS inhibition.Patients with type 2 diabetes (N = 94) and low vascular risk underwent assessment of cardiovascular risk and CMR assessment of ascending aortic distensibility (AAD), descending aortic distensibility (DAD) and aortic pulse wave velocity (PWV). Of these patients a subgroup with recent onset microalbuminuria (N = 25) were treated with renin–angiotensin–aldosterone system (RAAS) inhibition and imaging repeated after 1 year. All 94 patients were followed up for 2.4 years for major adverse cardiovascular disease (CVD) events including myocardial infarction detected on late gadolinium enhancement CMR.−3 mmHg−1, P = 0.007.Ascending aortic distensibility, DAD and PWV all had a significant association with age and 24 h systolic blood pressure but only AAD had a significant association with glycaemic control, measured as HbA1c . The association between HbA1c and AAD persisted even after correction for age and hypertension. CVD events occurred in 19/94 patients. AAD, but not DAD or PWV, was associated with CVD events . On treatment with RAAS inhibition, AAD, but not DAD or PWV, showed significant improvement from 1.51 ± 1.15 to 1.97 ± 1.07 10Ascending aortic distensibility measured by CMR is independently associated with poor glycaemic control and adverse cardiovascular events. Furthermore it may be reversible on treatment with RAAS inhibition. AAD is a promising marker of cardiovascular risk in asymptomatic patients with type 2 diabetes and has potential use as a surrogate cardiovascular endpoint in studies of novel hypoglycaemic agents.Clinical trials registrationhttps://clinicaltrials.gov/ct2/show/NCT01970319 With aging there is progressive stiffening of the aorta that appears to be accelerated by the presence of additional risk factors such as hypertension and diabetes . Aortic Increased aortic stiffness can be detected in patients with type 2 diabetes with and without established cardiovascular disease by CMR –6 and apPatients with diabetes and microalbuminuria have even further elevated cardiovascular risk , 14. DatWe aimed to investigate in patients with type 2 diabetes whether aortic stiffness is: (i) associated with glycaemic control, (ii) associated with adverse outcomes and (iii) can be reversed on treatment with RAAS inhibition. We also aimed to compare three CMR measures of aortic stiffness including ascending aortic distensibility (AAD), descending aortic distensibility (DAD) and aortic pulse wave velocity (PWV).2), uncontrolled hypertension, treatment with insulin or angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB). All patients underwent 24 h blood pressure (BP) monitoring with a Welch-Allyn 6100 ambulatory blood pressure monitor. All HbA1c measurements since diagnosis were recorded from review of records.We measured aortic stiffness by CMR in 94 asymptomatic patients with type 2 diabetes from a cohort of 100 patients with type 2 diabetes studied to investigate the relationship between microalbuminuria, cardiac remodelling and fibrosis  who were due to be started on an ACE inhibitor by their primary care team following the baseline investigations . ACE inhThe study was approved by the National Research Ethics Service (13/YH/0098) and conducted in accordance with the declaration of Helsinki. All subjects gave informed written consent.® technology.Patients and controls underwent CMR using an identical protocol on a dedicated cardiovascular 3 Tesla Philips Achieva system equipped with a 32 channel coil and MultiTransmitFor aortic distensibility, brachial artery blood pressure was recorded by Dinamap  immediately prior to high temporal resolution multi-phase SSFP cine imaging   performed in 10–12 short axis slices with further slices acquired in the vertical and horizontal long axis orientations, phase-swapped or imaged in systole, if indicated based on LGE imaging obtained or wall-motion abnormality.Late gadolinium enhancement (LGE) imaging of the heart was carried out more than 6 min after contrast injection  using inversion recovery-prepared T1-weighted echo. The optimal inversion time to null signal from normal myocardium was determined using a Look-Locker approach  was calculated using the equation:Cardiovascular magnetic resonance data were assessed quantitatively using commercially available software  blinded to glycaemic status. To derive the aortic distensibility of the ascending and descending thoracic aorta, cross sectional measurements were made by manual planimetry of the endovascular-blood pool interface for each phase to determine the maximal and minimal aortic dimensions. Aortic distensibility (mmHghttps://github.com/plaresmedima/PMI-0.4-Runtime-CMRLeeds) based on IDL 6.4  [Aortic PWV (m/s) was calculated by dividing the distance separating two locations and the transit time needed to cover this distance . Analysier, USA) . The diser, USA) .The presence of silent MI was identified by two physicians experienced (5 and 15 years) in CMR interpretation based upon typical subendocardial distribution of LGE present.Cholesterol, hsCRP and microalbumin were measured on Siemens Advia  with typical coefficient of variability (CV) 0.94, 3.7 and 2.2%, respectively. HbA1c was measured on Tosoh G8  with typical CV 1.4%. Serum aldosterone was measured in the SAS Steroid Centre  with an in-house radio-immunoassay with typical CV 11% at 218 pmol/L.Patients were followed up by review of electronic and clinical records for CVD events including cardiovascular death, myocardial infarction , stroke, heart failure or arrhythmia.® Statistics 22.0 . Continuous variables were expressed as mean ± SD. Categorical variables were expressed as N (%). Logistic regression was performed to identify clinical and aortic parameters associated with CVD events over follow up. Univariable linear regression was performed to identify associations between clinical parameters and AAD, DAD and PWV. Only factors with a significant association on univariable regression (P < 0.05) were included in multivariable linear regression. In those who underwent treatment with RAAS inhibition paired t tests were used to compare parameters before and after treatment. When normally distributed, data are presented as mean ± SD. P < 0.05 was considered statistically significant.Statistical analysis was performed using IBM SPSSNinety-four patients had a CMR protocol that included aortic imaging and were included in this study. Patients had a mean age of 61 ± 11 years (range 32–86), Table −3 mmHg−1, DAD was 2.11 ± 1.05 10−3 mmHg−1 and PWV was 8.00 ± 2.87 m/s. In healthy controls AAD was 2.78 ± 1.67 10−3 mmHg−1, DAD was 3.47 ± 1.54 10−3 mmHg−1 and PWV was 7.58 ± 2.11 m/s. AAD and DAD were significantly lower in patients with diabetes than matched controls (P = 0.002 and 0.0002 respectively). The difference in PWV was not significant (P = 0.74).Baseline AAD was 1.81 ± 1.16 10Ascending aortic distensibility had significant associations with age , current HbA1c , maximum HbA1c since diagnosis , sulphonylurea use  and 24 h systolic blood pressure , Table DAD had significant associations with age  and 24 h systolic BP  but no indices related to diabetes. PWV had significant associations with age  and 24 h systolic BP  but no indices related to diabetes.Patients were followed up for 882 ± 146 days. 19 patients (20%) had a CVD event including silent MI on baseline scan 15 (16%), stroke 3 (3%), cardiovascular death 2 (2%), ST elevation MI 2 (2%), silent MI on follow up scan 1 (1%), percutaneous coronary intervention 2 (2%), heart failure 1 (1%) and arrhythmia 1 (1%). 9/19 subjects with CVD events were asymptomatic and were only detected on CMR. 1 patient died from non-cardiovascular causes .−3 mmHg−1, P = 0.0.8; DAD 1.76 ± 1.13 vs 2.18 ± 1.03 10−3 mmHg−1 P = 0.12; PWV 8.31 ± 2.14 vs 7.94 ± 3.00 m/s).The differences in aortic stiffness between those with silent MI on baseline scan (N = 15) and without silent MI did not reach statistical significance  0.49, 95% confidence interval (CI) 0.25–0.95, P = 0.01, Table −3 mmHg−1 but no significant change in DAD or PWV (P = 0.92 and 0.42 respectively). After treatment with RAAS inhibition AAD was increased but was still significantly lower than in healthy controls   or HbA1c . Treatment with RAAS inhibition was associated with a significant increase in AAD of 0.47 ± 1.04 10We have demonstrated increased aortic stiffness by CMR in asymptomatic patients with type 2 diabetes compared to healthy controls. We have also shown that AAD, DAD and PWV are significantly influenced by age and 24 h systolic BP. However only AAD had an association with HbA1c, which remained significant after correction for age and BP. AAD had a significant association with CVD events over 2.4 years follow up. Furthermore, no other traditional cardiovascular risk factors or marker of glycaemic control had an association with CVD events. Finally, we have shown with RAAS inhibition that AAD improves towards that of healthy controls.The findings that AAD is associated with glycaemic control, adverse CVD events and that it is improved on treatment suggest that AAD has a potential role as an imaging marker of cardiovascular risk in asymptomatic patients with type 2 diabetes, although the cost and availability of CMR may be prohibitive for routine clinical use.In the present study AAD was the only parameter of aortic stiffness to have a significant association with glycaemic control, independent of blood pressure. Previous studies have shown an association between dysglycaemia and PWV , 26 but In the present study decreasing AAD appeared to be a marker of cardiovascular disease events, independently of conventional risk factors. The association between AAD and outcome in patients with diabetes are in agreement with previous studies demonstrating the prognostic importance of AAD measured by CMR in asymptomatic cohorts of patients of varied cardiovascular risk (including a minority with diabetes). AAD was measured in 3675 subjects from the Multi-Ethnic Study of Atherosclerosis study who were followed up for 8.5 years . In thisThe prognostic importance of aortic PWV has been extensively studied by applanation tonometry with clear evidence of an incremental benefit over traditional risk factors for the prediction of cardiovascular events . This teA subgroup of 25 patients in the present study were treated with RAAS inhibition for newly diagnosed microalbuminuria. In these patients RAAS inhibition was associated with a significant increase in AAD (but not DAD or PWV). It is well recognised that patients with albuminuria have markedly elevated cardiovascular risk , 14 whicRecent trials of hypoglycaemic agents in type 2 diabetes have included patients with established CVD  or at riThis was an observational non-randomised study and the interventional component needs to be repeated in a larger randomised study, although it can be argued that this is a strength as patient selection was limited and they were studied under real life, and not randomised controlled trial, conditions. 9/19 patients with CVD events were asymptomatic with MI being detected on LGE CMR. However in patients with diabetes the mortality associated with unrecognised MI is significant and is comparable to those with clinically recognised MI , 34. TheAscending aortic distensibility measured by CMR is independently associated with poor glycaemic control and adverse cardiovascular events. Furthermore, it appears to be reversible on treatment with RAAS inhibition. AAD is a promising marker of cardiovascular risk in asymptomatic patients with type 2 diabetes and has potential use as a surrogate cardiovascular endpoint in studies of novel hypoglycaemic agents.


In women treated with nifedipine+VD, the minimum number of dosages needed to control hypertension was also lower. With regard to adverse effects, no statistical difference was observed between the two treatment groups. Moreover, treatment with VD increased IL-10 and reduced TNF-α serum levels. VD possesses the potential of serving as a safe and effective adjuvant to oral nifedipine in treating women with preeclampsia against hypertension, possibly through the upregulation of IL-10 and the downregulation of TNF-α.Vitamin D (VD) has exhibited immunomodulatory role in the pathogenesis of preeclampsia. We hypothesize VD potentiate nifedipine treatment for preeclampsia by shortened the time to control blood pressure and prolong time before subsequent hypertensive crisis. We conduct a randomized trial of 683 primigravid women with preeclampsia, who were assigned to different treatment groups, either nifedipine+placebo or nifedipine+VD orally, by random after screening. Primary endpoints include time to control hypertension and time before another hypertensive crisis. Maternal adverse effects including nausea, vomiting, chest pain, mild headache, dizziness, maternal tachycardia, hypotension or shortness of breath, and neonatal parameters including birth weight and Apgar scores, as well as the minimum number of dosages needed to control hypertension were defined as secondary endpoints. Serum levels of cytokines tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were also examined. There was a marked reduction of the time required to control hypertension and a significant lengthening ( Preeclampsia, which uniquely manifests during pregnancy after 20 weeks post-gestation, is a severe disorder affecting various systems . As a le2+ channels  in the pathogenesis of pregnancy-related hypertension and/or preeclampsia as a potential risk factor . For exaRecently, the inflammatory process was implicated in the pathophysiology of preeclampsia . In addiThis is a double-blinded, placebo-controlled, randomized clinical trial of women with preeclampsia. The present clinical trial was designed in conformity with the guidelines of Declaration of Helsinki. All experimental protocols were approved by the Ethical Committee of Cangzhou Central Hospital. All participants provided oral and written consent. This study was registered in Chinese Clinical Trial Registry Center (registration number: ChiCTR-IPR-17013313).During January 2011 and December 2016, women with singleton pregnancy who were diagnosed of preeclampsia in Cangzhou Central Hospital participated in the present trial. Inclusion criteria were: (1) primigravid women; (2) Gestation age between 20 and 30 weeks ; (3) hypertensive disorders (≥150 mmHg systolic and/or ≥100 mmHg diastolic); (4) proteinuria (≥0.3 g protein/24 h). All patients were later excluded based on the following criteria: (1) history of heart failure during the course of the pregnancy; (2) history of smoking and/or diabetes, both of which could contribute to hypertension; (3) use of anti-hypertensive drugs and/or VD supplementation; (4) HELLP syndrome or chronic hypertension.n = 298), given one capsule containing nifedipine (10 mg per capsule) and VD (200 IU per capsule) every 15 min orally, up to four doses, until blood pressure was equal to or below 150/100 mmHg; (2) nifedipine+placebo group (n = 304), given one capsule containing nifedipine (10 mg per capsule) plus glucose (20 mg per capsule) as placebo every 15 min orally, up to four doses, until blood pressure was equal to or below 150/100 mmHg. The therapy was discontinued once blood pressure reached the set level, or after four doses, whichever comes earlier. Capsules containing VD or placebo were prepared by researchers unaware of the group assignment, and appeared identical to mask the content to the patients.Eligible patients were divided into two groups using stratified permuted-block randomization method with diastolic blood pressure as a factor: (1) nifedipine+VD group (Primary endpoints included: (1) time needed to lower blood pressure of the patients to 150/100 mmHg; (2) time before another hypertensive crisis (blood pressure > 150/100 mmHg). Secondary endpoints included: (1) the number of dosages needed to lower blood pressure to 150/100 mmHg; (2) maternal adverse effects including nausea, vomiting, chest pain, mild headache, dizziness, maternal tachycardia, hypotension, or shortness of breath; (3) neonatal parameters including birth weight and Apgar scores; (4) parameters such as placenta weight, delivery modus, and incidences of intensive care unit visits of mother or newborn; (5) serum levels of TNF-α and IL-10. All measurements were carried out double-blindly.2. Measurement of blood pressure was preformed using a digital blood pressure monitor with 0.1 mmHg accuracy.Body weight was measured on a digital scale with 0.1 kg accuracy and body height was measured on a stadiometer with accuracy of 0.1 cm while patients stood straight bare-footed in light clothing. Body mass index (BMI) was then calculated as body weight/(body height)All patients were surveyed at the end of the trial on symptoms that might have occurred during the trial: nausea, vomiting, chest pain, mild headache, dizziness, maternal tachycardia, hypotension, or shortness of breath. Heart rates of the mother and the fetus were continually monitored throughout the therapy.10 mL of blood samples were collected from each patient after blood pressure was equal to or below 150/100 mmHg, or after four doses, whichever comes earlier. Whole blood was immediately centrifugated at 3,000 rpm for 10 min to separate the serum, which was stored at -70°C for further analysis. Serum levels of TNF-α and IL-10 were examined using ELISA kits specific for human TNF-α and IL-10  according to the manufacturer’s protocol.t-test or Pearson chi-square test, whichever was appropriate. p-Values less than 0.05 were considered significant. All analysis was performed using SPSS 18.0 .Sample size of treatment groups was determined using established statistical power analysis . DiffereFigure 1). 298 patients received nifedipine+VD orally, and 304 patients received oral nifedipine+placebo, a single dosage every 15 min until their blood pressure were equal to or lower than 150/100 mmHg. Anthropometrical parameters, such as maternal age, gestational age at term, heart rate, BMI, and systolic and diastolic blood pressures, are presented in Table 1. The difference between patients from two treatment groups was not statistically significant.From January 2011 to December 2016, 683 primigravid women (age 31–37) with preeclampsia and singleton pregnancy were enrolled in the current trial, among which 81 participants were later excluded. The remaining 602 eligible participants were assigned to two treatment groups in a random manner . Further, group the time before another hypertensive crisis after blood pressure was controlled in the nifedipine+VD group was 8.1 ± 2.2 h, statistically longer than 4.8 ± 2.6 h in the nifedipine+placebo (p = 0.017).Figure 2 . Further, both maternal and neonatal adverse effects, were evaluated at the end of the trial as summarized in Table 3. No statistical difference with regard to maternal adverse effects was observed between the two treatment groups, including vomiting, dizziness, nausea, mild headache, chest pain, maternal tachycardia, hypotension, or shortness of breath. Neither was there any difference in terms of neonatal parameters, such as birth weight and newborn Apgar scores. Moreover, delivery parameters, including placenta weight, mode of delivery, incidences of intensive care unit stay of mother or newborn were also analyzed (Table 4) and yielded no significant difference between the two treatments. No neonatal death was observed in the study.Secondary endpoints following both treatments were also assessed. The number of dosages needed to effectively control blood pressure was greatly lower in patients who received nifedipine+VD compared to nifedipine+placebo group, as demonstrated in Figure 3, in nifedipine+VD group, serum level of TNF-α was significantly reduced , whereas that of IL-10 was significantly elevated .Serum levels of TNF-α and IL-10 were examined in all patients from both the treatment groups. As shown in Based on the reported function of VD against hypertension, we included VD in our clinical trial among women with preeclampsia, to examine whether VD could synergize with oral nifedipine to alleviate hypertension in preeclampsia. Our findings demonstrated that use of oral nifedipine and VD combined greatly improved the primary as well as the secondary endpoints, compared to nifedipine and placebo. Specifically, in the nifedipine+VD group, the time to control hypertension was reduced, time before another hypertensive crisis was delayed, and number of dosages needed to control hypertension was lower. Furthermore, we did not observe any serious adverse effects, either maternal or neonatal, following conjunctional use of VD, demonstrating the clinical safety of VD in pregnant patients.Controlling severe range blood pressure in the management of preeclampsia is essential for reducing both maternal and fetal complications . CurrentDespite of the fact that drugs for alleviating hypertension are widely available, patients with preeclampsia are often faced with the dilemma that effective anti-hypertensive compounds may not be safe for pregnant individuals, particularly for oral medications. Therefore, an oral agent with proved safety and efficacy to assist oral nifedipine therapy will definitely benefit the treatment of severe preeclampsia. VD is a commonly taken as dietary supplement, and reportedly helpful in a number of pregnancy-related complications such as gestational diabetes mellitus .Moreover, the mechanism accountable for the therapeutic actions of VD in preeclampsia remains largely unclear. A recent study has proposed that, in preeclampsia affected pregnancy, deficiencies in VD and long chain polyunsaturated fatty acid metabolism might disturb the one carbon cycle, leading to altered feto-placental growth and development in preeclampsia . On the Nevertheless, this study has some limitations. First, the data of adverse maternal effects was based on patient recall rather than objective measures, which limited the significance and accuracy of this data. Second, dose effect of VD on hypertension and cytokine regulation was not adequately investigated in the current study, which also limited the understanding of VD action on the inflammatory process. Third, the expectant management of preeclampsia patients with severe features beyond 34 weeks is may not be the standard of care in all institutions, which limited the generalizability of the data. Last, the study population was entirely comprised of primips without preexisting hypertension or diabetes mellitus, who were treated at an atypical blood pressure threshold of severe hypertension, which poses another potential issue in the generalizability of the study.In summary, our data from the current randomized, double blinded and placebo-controlled clinical trial is the first report on the potency and safety of VD serving as a potential adjuvant to oral nifedipine to enhance the efficacy of therapies against hypertension in women with preeclampsia. Importantly, this beneficial action of VD is likely mediated by downregulating TNF-α and upregulating IL-10. Future study is warranted to investigate the molecular mechanism of VD action on downregulating TNF-α and upregulating IL-10 during preeclampsia.Did the experiments and analyzed the data: D-DS, YW, J-JG, and LZ. Wrote the manuscript and designed the study: NW.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


These findings were robust in various statistical analyses. The associations between comorbidities and risk factors were in accordance with previous findings, thereby underlining the validity of our data. In conclusion, hyperlipidemia was associated with less hyperinflation and airway obstruction in patients with COPD. This surprising result might be due to different COPD phenotypes in these patients or related to effects of medication.Although hyperlipidemia is common in COPD, its relationship to comorbidities, risk factors and lung function in COPD has not been studied in detail. Using the baseline data of the COSYCONET cohort we addressed this question. Data from 1746 COPD patients  were evaluated, focusing on the comorbidities hyperlipidemia, diabetes and cardiovascular complex . Risk factors comprised age, gender, BMI, and packyears of smoking. The results of linear and logistic regression analyses were implemented into a path analysis model describing the multiple relationships between parameters. Hyperlipidemia  was associated with lower intrathoracic gas volume (ITGV) and higher forced expiratory volume in 1 second (FEV Hyperlipidemia is a major risk factor for cardiovascular diseases which are common comorbidities in patients with chronic obstructive pulmonary disease (COPD) , but thein vitro they led to accumulation of erythrocytes in the pulmonary capillary bed [In subjects with metabolic syndrome and hyperlipidemia but no obvious lung disease a restrictive spirometric lung function pattern was observed –8, but tlary bed . Thus itlary bed –13.WhethBased on these considerations the aim of our study was to analyze the relationship of hyperlipidemia to lung function, risk factors and comorbidities linked to hyperlipidemia in patients with COPD. For this purpose we used data from the German COSYCONET (“COPD and SYstemic consequences-COmorbidities NETwork”) COPD cohort .1), intrathoracic gas volume (ITGV) and transfer coefficient for carbon monoxide (KCO), as well as on age, gender, packyears of smoking, body-mass index (BMI) and the comorbidities hyperlipidemia, diabetes, and cardiovascular complex (see below) were included. This resulted in a study population of n = 1746 out of 2741 patients recruited into COSYCONET [The analysis was based on the baseline data set (visit 1) of COSYCONET which is a multi-center study focusing on the role of comorbidities in COPD . Only paOSYCONET . The stuAll assessments were approved by the central (Marburg (Ethikkommission FB Medizin Marburg) and local ; Berlin (Ethikkommission Ärztekammer Berlin); Bochum (Ethikkommission Medizinische Fakultät der RUB); Borstel (Ethikkommission Universität Lübeck); Coswig (Ethikkommission TU Dresden); Donaustauf (Ethikkommission Universitätsklinikum Regensburg); Essen (Ethikkommission Medizinische Fakultät Duisburg-Essen); Gießen (Ethikkommission Fachbereich Medizin); Greifswald ; Großhansdorf (Ethikkommission Ärztekammer Schleswig-Holstein); Hamburg (Ethikkommission Ärztekammer Hamburg); MHH Hannover / Coppenbrügge (MHH Ethikkommission); Heidelberg Thorax/Uniklinik (Ethikkommission Universität Heidelberg); Homburg (Ethikkommission Saarbrücken); Immenhausen (Ethikkommission Landesärztekammer Hessen); Kiel (Ethikkommission Christian-Albrechts-Universität zu Kiel); Leipzig (Ethikkommission Universität Leipzig); Löwenstein (Ethikkommission Landesärztekammer Baden-Württemberg); Mainz ; München LMU/Gauting (Ethikkommission Klinikum Universität München); Nürnberg (Ethikkommission Friedrich-Alexander-Universität Erlangen Nürnberg); Rostock (Ethikkommission Universität Rostock); Berchtesgadener Land ; Schmallenberg ; Solingen (Ethikkommission Universität Witten-Herdecke); Ulm (Ethikkommission Universität Ulm); Würzburg(Ethikkommission Universität Würzburg)) ethical committees and written informed consent was obtained from all patients. The study was conducted from September 2011 to December 2013 within the COSYCONET framework  . The appProtocol and methods have been described previously . To faci1, ITGV and KCO, for the description of the population the forced vital capacity (FVC), the ratio FEV1/FVC and transfer factor for CO (TLCO) were chosen, each as percent of predicted. For the path analysis FEV1, ITGV and KCO were taken as representatives of the domains obstruction, hyperinflation and gas exchange limitation. Predicted values of FEV1, FEV1/FVC, FVC were taken from GLI [Lung function comprised spirometry, body plethysmography and carbon monoxide (CO) diffusing capacity . In addifrom GLI , of ITGVfrom GLI , and of from GLI . As majoData are presented as mean values and standard deviations (SD). Comparisons between the two groups with and without hyperlipidemia were performed with the unpaired t-test irrespective of potential small deviations from normality (Kolmogorov-Smirnov-test) which commonly have no major impact on the test result. However, to be on the safe side and to check whether these deviations affected the result we additionally employed the Mann-Whitney-U-test and explicitly give the results for both types of tests. Categorical variables were compared between groups using cross-tabulation and the chi-square-test statistics.Next the association between variables was evaluated by standard multivariate linear and binary logistic regression analyses comprising one dependent and multiple independent variables. These types of analyses are however limited to describe complex relationships in networks that can be represented by only two types of variables: dependent and independent. A potential relationship between dependent variables as well as the possibility that the same variable is both dependent and independent can be modeled by path analysis . All ana1/FVC and TLC%pred there were significant differences between the two groups, in both parametric and non-parametric testing. For comparison the values for the total COSYCONET study population  are given in 1/FVC and TLC%pred. For selected lung function parameters the differences between hyperlipidemia groups remained significant after adjustment for risk factors and are illustrated in 1%pred, KCO%pred).We first performed standard multivariate linear and logistic regression analyses , hyperinflation (ITGV%pred) and gas exchange (KCO%pred). Among the comorbidities a combined entity “cardiovascular complex” was defined comprising arterial hypertension, cardiac failure and ischemic heart disease. The comorbidities depended on age, BMI and partially on gender  improved the results and (b) did not introduce artefacts compared to the reported diagnoses.Among the comorbidities of COPD known to be linked to hyperlipidemia, diabetes and cardiovascular diseases are the most prevalent ones . We therAs risk factors we considered age and gender, as well as packyears and BMI, which were either independent of the individual behaviour, or linked to lifestyle. All of them are known to be correlated with comorbidities and lung function, and indeed their association with cardiovascular diseases was consistent with previous findings . The sam1 . Error terms of dependent variables have been omitted for the sake of clarity. There were no significant correlations between the independent variables.(TIF)Click here for additional data file.S2 FigPreliminary path analysis model comprising two layers, on the top risk factors and as bottom layer lung function parameters. All of the relationships shown were statistically significant (p<0.05 each). Error terms of dependent variables have been omitted for the sake of clarity. There were no significant correlations between the independent variables.(TIF)Click here for additional data file.S1 TableThe table shows mean values and standard deviations or absolute numbers. Lung function parameters are given in terms of %predicted, except for alveolar volume, VA, which is given in liters. Column 4 shows the results of comparisons between the hyperlipidemia group (extended definition) and the complementary group of non-hyperlipidemia patients. The comparisons between groups were performed by unpaired t-tests, either for equal or unequal variances depending on the data, or by chi-square-tests in the case of categorical variables. The results of t-tests were checked by the Mann-Whitney-U-test to accommodate for deviations from normality; the results of both approaches were qualitatively equivalent. Significant (p<0.05) differences are marked with (*).(DOCX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.


These results tend to confirm the hypothesized benefits of MM training for this population, and indicate that autonomic function may be important in the etiology and treatment of their symptoms. No adverse effects were reported. This trial is registered at ClinicalTrials.gov , and is supported by a grant from the Flight Attendant Medical Research Institute (FAMRI).This single-arm non-randomized pilot study explores an intervention to improve the health of flight attendants (FA) exposed to second-hand cigarette smoke prior to the smoking ban on commercial airlines. This group exhibits an unusual pattern of long-term pulmonary dysfunction. We report on Phase I of a two-phase clinical trial; the second Phase will be a randomized controlled trial testing digital delivery of the intervention. Subjects were recruited in the Northeastern US; testing and intervention were administered in 4 major cities. The intervention involved 12 h of training in Meditative Movement practices. Based on recent research on the effects of nicotine on fear learning, and the influence of the autonomic nervous system on immune function, our hypothesis was that this training would improve autonomic function and thus benefit a range of health measures. Primary outcomes were the 6-min walk test and blood levels of C-reactive protein. Pulmonary, cardiovascular, autonomic, and affective measures were also taken. Fourteen participants completed the training and post-testing. There was a 53% decrease in high sensitivity C-Reactive Protein ( Flight attendants (FA) who flew before the ban on smoking in commercial aircraft (implemented progressively from 1988 to 2000) present with many of the co-morbidities of chronic obstructive pulmonary disease (COPD) but their pulmonary dysfunction differs from the standard definition of this disorder. At the time that they were hired, they were required to be in good health. They were exposed to second-hand cigarette smoke (SHCS) in the course of their often vigorous work activities, as well as to a wide range of other stressors  to Forced Vital Capacity (FVC) ratio  activation in this population of first responders, whose job is “to perform vital crewmember functions onboard air carrier aircraft, including emergency functions for aircraft evacuations, firefighting, first aid, and response to security threats” , and an earlier paper describing the proposed protocol has been published . Additionally, this study is registered at ClinicalTrials.gov: (Flight attendants (FA) were recruited from the Northeastern region of the US, in particular from areas where travel to the testing and training centers in Burlington VT, Woburn MA and New York NY was possible. Primary outreach was through existing flight attendant organizations and networks, social media and flight attendant events, as well as in collaboration with the Harvard School of Public Health Flight Attendant Health Study. Social media and audio-visual support were provided by the Department of Health Behavior at the Roswell Park Cancer Institute in Buffalo, NY.This was a pilot study designed, in part, to select the most useful exercises, and a control group was not warranted. There was a baseline set of measurements for each subject before any MM intervention, and each participant acted as his/her own control so that data collected before the intervention could be compared to data collected after the MM training.All participants were required to be non-smoking former or current (FA), who, in the course of their occupation, had been exposed to SHCS for at least 5 years. In addition, participants were required to attend at least 12 h of in-person training sessions and focus group feedback sessions provided in central locations over a 4-month period. They were also required to have devices on which to listen to audio and watch video instruction, and be willing to do so. Pregnancy or planned pregnancy, as well as cognitive impairment, severe emotional problems, or physical inability to perform the exercises, were grounds for exclusion. Participants were asked not to modify their lifestyle significantly during the study period apart from the practice required by the study. Since each participant acted as his/her own control, we did not exclude on the basis of medication use.Figure Training was commenced in three locations on three different dates: Burlington VT, New York NY, and Woburn MA. The content of the training shifted over time in response to participant compliance and feedback. All participants were asked to complete 12 mandatory hours of class time over a period of 4–5 months. Classes were offered at approximately 1 month intervals at convenient locations. There were between 2 and 7 participants at each class; at a given location classes were usually offered on two consecutive days to accommodate participants' schedules. There was an initial focus on exercises to be practiced at specific times, but in response to participant feedback the emphasis shifted to practices that could be integrated with daily life, such as standing, walking, and sitting. The practices involved static postures or slow and gentle movement, with encouragement to attend to kinesthetic and interoceptive experience and to focus on specific mental images. Figure During class time participants were encouraged to provide feedback on their experience and practice of the exercises; all feedback was recorded in writing at the time. Participants were also asked to maintain a log of their experiences during the training. They were provided with printed sheets for recording their practice sessions as well as an online Survey Monkey page  immediately if they experienced any of the following: dizziness, rapid or irregular heart-beat, sudden or excessive dyspnea, chest pain, significant pain anywhere in the body, pressure in the head, headache. During the classes the instructor carefully monitored the participants for signs of distress including facial paleness or redness, rapid breathing, sweating, or jerky movement.Outcome measures were selected to monitor a wide range of health measures. Further technical details about these measures are available in a previously published protocol paper , was conducted on an indoor level surface free of obstructions according to the guidelines established by the American Thoracic Society (ATS). Research assistants were on hand to assist participants with any difficulties. Maximum distances walked in 6 min were recorded , a marker for systemic inflammation   questionnaire  has few reported side effects  using a chi-squared test to determine the significance of the change from pre- to post-testing.Results are shown in Table There was a highly significant improvement in the 6MWT comparing pre- to post-intervention distances, as well as a significant reduction in hs-CRP levels, systolic blood pressure and resting heart rate, as well as in the Zung Self-rating Anxiety Scale and the COMPASS 31 (indicating improved autonomic function). There was also a significant increase in the MAIA score, indicating improved interoceptive awareness. Non-significant trends were observed of decreased pulse pressure, reduced diastolic blood pressure, reduced blood oxygen saturation, reduced (improved) COPD Assessment Test score, and increased peak expiratory flow (PEF), as well as a substantial, although not significant, increase in the percent change in heart rate after the 6MWT. We note that there was a 22% reduction in the number of participants with a diastolic pressure above the clinical threshold of 90 mmHg and a 36% reduction in the number with a systolic pressure above 140, although only the figure for systolic blood pressure reached significance. Vitamin D levels did not change.Figures Our results indicate improved autonomic function, improved exercise tolerance and cardio-pulmonary function, and reduced systemic inflammation. Autonomic dysfunction, reduced functional ability, and increased systemic inflammation are all co-morbidities of COPD. These results are in line with other studies of the effects of Qigong, specifically on respiratory disease  reduced substantially, 3 to below the clinical threshold. These results are likely of clinical relevance. In a cohort of women, average age 68, systemic inflammation would be expected to increase with advancing age, and is a risk factor for the development of many diseases of the elderly, including cardiovascular disease, COPD, diabetes, and cancer , spirometry, Borg Dyspnea Inventory, the COMPASS 31, the Zung Inventories of Anxiety and Depression, the Multidimensional Assessment of Interoceptive Awareness (MAIA), and Vitamin D.Cardiovascular measures improved substantially. There was a significant decrease of 7% in average resting systolic blood pressure. 11 out of 14 participants showed reduced systolic blood pressure, and the numbers of subjects above the clinical threshold of 140 mgHg reduced from 4 to 1. There was also an almost significant 12% drop in average pulse pressure. Although the decrease in diastolic pressure did not reach significance, in all three blood pressure-related measures , the number of participants above accepted clinical range diminished substantially, a result which may be meaningful in clinical terms. Also, resting heart rate decreased significantly by 6%. Since the intervention did not include any forms of conventional physical exercise known to decrease blood pressure or resting heart rate, we speculate that improved autonomic cardiovascular control may be responsible. This hypothesis is supported by the fact that there was a substantial (42%) increase in the change of heart rate after the 6MWT. Although this change did not quite reach significance, it is evidence of a more dynamic cardiovascular autonomic control.In comparing the graphs of the changes in the 6MWT, hs-CRP and systolic blood pressure, we note that in the measures having a clinical threshold, the change was toward a normal clinical level rather than an across-the-board change. In systolic blood pressure and hs-CRP, values in the normal range showed relatively little change whereas values outside clinical range moved into normal range, with the amount of change approximately proportional to the prior deviation from normal. However, the 6MWT by contrast showed a fairly uniform amount of change regardless of baseline value. Qigong practice claims to normalize physiological variables rather than simply to reduce or increase them in a linear fashion Cohen, ; these rIn addition to objective measures, we included questionnaires to evaluate self-reported autonomic symptoms, affective state and bodily awareness. These are important for evaluating quality of life and changes in cognitive and affective functioning.p ≤ 0.05), and supports the hypothesis of improved autonomic function as a result of the intervention.The COMPASS 31, a questionnaire evaluating general autonomic function, dropped from 15 to 11.5. This 24% change was significant (p ≤ 0.05), a significant 8% drop. Since anxiety is associated with autonomic imbalance (increased sympathetic and reduced parasympathetic activity), this result too is compatible with improved autonomic function, as well as being important for better health and quality of life.The Zung Anxiety score dropped from 29.4 to 26.9 , whether inhaled directly or second-hand, is known to be a principle cause of COPD and its comorbidities as well as other respiratory system disorders , using an attention/health education control group, which will provide a well-controlled validation of the effects of the selected MM exercises. It is however possible that positive results from the testing in Phase I, followed by negative results from Phase II, might reflect the ineffectiveness of digital delivery rather than the ineffectiveness of the intervention. In this case an RCT testing in-person delivery would be indicated.The 6MWT is known to be influenced by motivation . doi: McNeely, 10.7910/DVN/KDUJXH  through grants CIA 130052, CIA 130051, and CIA 13050.PP and MC in part receive compensation from teaching and consulting relating to Meditative Movement and MC from consulting on flight attendant health concerns; DZ is financially compensated by the lab that provides the biomarker analysis for the study. SF and JL declare no conflict of interest.


The aim of this study is to investigate factors associated with poor blood pressure (BP) control in older hypertensive patients living in Iran. Poorly controlled hypertension was defined as blood pressure greater than or equal to 140/90 mmHg. Multiple logistic regressions were performed to identify factors associated with poor BP control.p = .003), being widowed or divorced , having a waist circumference ≥ 90 cm  for cardiovascular specialists and other health care practitioners is needed for elderly patients at risk for poor BP control.More than half of the patients (55.1%) had poor control of hypertension. Multivariate logistic regression analysis showed that being over 60 years of age  contains supplementary material, which is available to authorized users. Hypertension is a common risk factor for cardiovascular disease and is a major health problem around the world. In addition, it is the most important single contributor to premature mortality –3. It haPoor control of blood pressure could augment cardiovascular risks, stroke, and myocardial infarction, which can be catastrophic to individuals and results in increasing costs for health care systems . The rolBecause the need to control and to manage hypertension is well recognized, primary health care systems are on the front lines. They can provide screening programs for early detection, manage regular contacts with patients, apply preventive measures, and deliver consistent and persistent care for patients with hypertension . HoweverIt is therefore important to identify factors that could affect BP control among older hypertensive patients. The aim of this study is to investigate factors that may influence poor BP control in older hypertensive patients and to identify patients’ characteristics associated with poor control of BP in order to improve the management and care of these patients.This cross-sectional study was conducted in Takab, West Azerbaijan province, Iran. A total of 750 patients with a diagnosis of hypertension in primary health care centers were randomly recruited from August 2016 to February 2017. The inclusion criteria were: (1) having been diagnosed with hypertension in the previous 6 months, (2) being 50 years old or above, and (3) having a household health record in one of the Takab health care centers. Subjects who have diabetes and a cognitive disorder were not eligible.Patients who had been referred to health care centers were randomly selected and contacted by telephone for eligibility. During the phone interview, eligible patients who were interested in participating in the study were asked to come to the health centers for a clinical assessment by a trained health care researcher. The response rate was 83.3% (750/900).Data were collected by administering a questionnaire. The questions related to the participants’ sociodemographic characteristics, treatment for hypertension, medical history, and current cigarette smoking habits followed the guidelines provided by the American college of cardiology . FurtherConsistent with , uncontr2 or Student’s t tests. A series of t tests and multiple logistic regressions were performed to compute odds ratios (ORs) and their confidence intervals. In the univariate analyses, demographic and anthropometric factors were entered separately. p values below .05 were considered to be significant.Statistical analyses were conducted using the STATA release 14.0 software . Data were presented using frequencies (percentages) for categorical variables and means for numeric variables. Descriptive statistics were calculated to compare the characteristics of patients with controlled and uncontrolled hypertension. Between-group differences were calculated using χn = 413) of the patients had uncontrolled hypertension. There were significant marital status differences between patients with controlled and uncontrolled BP. Significant differences between patients with controlled and uncontrolled hypertension were found for BMI, weight, WC, years living with hypertension and comorbidities in hypertension .The sociodemographic and clinical characteristics of the hypertensive patients are shown in Table Table p = .003), being widowed or divorced , smoking , BMI > 25 kg/m2 (OR 1.51 95% CI 1.05–2.78), having a waist circumference of 90 cm or more , using CCBs , and using ACEIs .The results of the multivariate analyses of factors predicting poor BP control are shown in Table The study presents an analysis of factors that may be associated with poor BP control in hypertensive patients in Takab, West Azerbaijan province, Iran. The findings from this study revealed that only 44.9% of the patients had adequate BP control . A similResults from the multivariate logistic regression analysis revealed that being older than 60 years, being widowed or divorced, smoking, having a waist circumference of 90 cm or more, the use of CCBs, and the use of ACEIs contribute to poor control of hypertension. The finding that being 60 years old or above is associated with higher odds of uncontrolled BP is consistent with previous studies . One majIn this study, we found a significant association between poor BP control and being widowed or divorced, which is consistent with other studies , 23. ThiAnother factor that affected poor BP control is smoking. This result confirms that smoking acutely increases blood pressure due to an increase in both cardiac output and total peripheral vascular resistance . AlternaThe relationship between waist circumference and hypertension has been clearly established . In the All of the patients had been treated with antihypertensive drugs for an average of 8.04 years prior to study enrollment. Our findings suggest that poor control of blood pressure is also significantly associated with the use of CCBs and ACEIs, which is consistent with the findings of a study by Xu et al. . HoweverHypertension surveillance could be used more frequently in daily practice in primary care to identify at-risk individuals. As such, it is important to make hypertensive patients and their families aware of the risk factors of uncontrolled BP. The results of the present study indicate the need for greater efforts at safe, effective strategies in order to achieve controlled BP among the oldest patients with hypertension. BP control may be related to factors beyond medication adherence, including lifestyle factors, social support, and the ability to navigate the health care system effectively, though this requires further study. In addition, the failure of antihypertensive medication to adequately control BP is determined by both the patients’ characteristics and factors related to the medication. The findings of this study indicate that treating elderly hypertensive patients will reduce the risk of cardiovascular events. There is evidence that hypertension treatment reduces the incidence of cognitive impairment and dementia in the elderly .This study was cross-sectional, and could not determine causality. Another limitation was potential measurement error for the medication use. There wasn’t any information on actual adherence to high blood pressure medication use and treatment.


To explore the potential relationship between optic disc haemorrhage, venous pulsation pressure (VPP), ocular perfusion pressures and visual field change in glaucomatous and glaucoma suspect eyes.This prospective observational study examined 155 open angle glaucoma or glaucoma suspect eyes from 78 patients over 5 years. Patients were followed with 3 monthly non-mydriatic disc photographs, 6 monthly standard automated perimetry and annual ophthalmodynamometry. The number of disc haemorrhages in each hemidisc was counted across the study period. Visual field rate of change was calculated using linear regression on the sensitivity of each location over time, then averaged for the matching hemifield. VPP and central retinal artery diastolic pressure (CRADP) were calculated from the measured ophthalmodynanometric forces (ODF). The difference between brachial artery diastolic pressure (DiastBP) and CRADP was calculated as an index of possible flow pathology along the carotid and ophthalmic arteries.Mean age of the cohort was 71.9 ± 7.3 Years. 76 out of 155 eyes (49%) followed for a mean period of 64.2 months had at least 1 disc haemorrhage. 62 (81.6%) of these 76 eyes had recurrent haemorrhages, with a mean of 5.94 recurrences over 64.2 months. Using univariate analysis, rate of visual field change (P<0.0001), VPP (P = 0.0069), alternative ocular perfusion pressure , carotid resistance index  and mean brachial blood pressure (P = 0.0203) were significantly associated with the number of disc haemorrhages. Using multivariate analysis, increased baseline visual field sensitivity  was significantly associated with disc haemorrhage, in conjunction with higher VPP , higher mean blood pressure , higher carotid resistance index , and rate of visual field loss .Higher VPP was associated with disc haemorrhage and implicates the involvement of venous pathology, but the effect size is small. Additionally, a greater carotid resistance index suggests that flow pathology in the ophthalmic or carotid arteries may be associated with disc haemorrhage. Optic disc haemorrhage is one of the most significant predictors of glaucoma progression . The visSpontaneous retinal vein pulsation is a phenomenon observed in most healthy eyes. In glaucomatous eyes this occurs much less frequently . In eyesWe hypothesized that if raised venous pressure is a cause of disc haemorrhage, then we may see an elevated VPP in these patients. We explored the relationship between two glaucoma progression predictors: disc haemorrhage and VPP, along with various ocular arterial perfusion parameters derived from ophthalmodynamometric central retinal artery diastolic pressure (CRADP) measurements. The CRADP measures arterial perfusion of the eye more directly than brachial artery blood pressure (BP), and was primarily used in the analysis.The research followed the tenets of the Declaration of Helsinki. Ethics approval was granted by the University of Western Australia Human Ethics Committee. Glaucoma patients at two practices were recruited between 2007 and 2009 for a 5 year study with written informed consent and opportunities for questions. Consecutive patients were invited to participate when they met the inclusion and exclusion criteria. There was no age, sex and ethnicity requirements. The subjects were required to have glaucoma in at least one eye, defined as a repeatable glaucomatous visual field defect  with a positive glaucoma hemifield test  and a matching, congruent optic disc defect  based on clinical opinion. The fellow eye must have had either glaucoma or be a glaucoma suspect, or with elevated intraocular pressure (IOP) more than 21 mmHg (ocular hypertension). Glaucoma suspect is defined as eye with disc rim thinning and/or excavation, but with no visual field changes as discussed above. The eyes were required to have clear ocular media for examination and photography. Subjects with both visual field mean deviations worse than -18 dB at baseline were excluded. Patients with diabetes, angle closure eyes and previous glaucoma filtration surgeries were excluded.Central corneal thickness was measured with the Pachymate  at baseline. Intraocular pressure was measured with Goldmann applanation tonometry every 3 months. Brachial artery BP was measured annually using automated sphygmomanometry, with the arm elevated and the cuff at eye level in order to more closely match carotid artery pressure at eye level . Use of The patients were given usual care consistent with National Health and Medical Research Council Glaucoma Guidelines . A step-All patients were seen every 3 months for IOP measurement and non-mydriatic optic disc photography . Visual field testing using the Humphrey 24–2 SITA test strategy and confocal laser scanning tomography  was performed every 6 months. Dilated examination with ophthalmodynamometry, VPP measurement and stereo-disc photography was performed annually.Disc haemorrhage data was collected using the series of non-mydriatic disc photographs. These photos were collated and aligned as layers using Adobe Photoshop . 3 masked experts  were instructed to review the photographs using a flicker chronoscopy technique . The phoHumphrey standard automated perimetry threshold sensitivity (dB) at each of the 54 points were recorded from each eye every 6 months. A 5-year progression slope and p-value for each point was calculated using linear regression of sensitivity versus time. Only points with progression P-value of < 0.05 were considered to have reliably changed. All other points with P-value of > 0.05 had recorded slopes of 0. Mean progression slopes for each hemi-field was calculated using the mean of all the 26 slopes, excluding the blind spot. We chose not to use regression on the mean hemifield sensitivity because of the likelihood that highly variable regions would mask the ability to detect change in other regions. If a patient was new to automated perimetry at the start of study, a learning session was provided and the result omitted. The baseline visual field was required to have less than 3 fixation losses, and less than 5% false positive and false negatives. The test was repeated if these conditions were not met. Follow up tests were used for progression analysis only  and did not have the above requirements.Ophthalmodynanometric force measurements were taken every 12 months for a total of 5 readings per eye. After pupil dilation and IOP measurement, the optic disc was observed with a 60 diopter condenser lens for spontaneous vein pulsation in the superior and inferior hemiveins. If present, ODF was recorded as 0 . If pulsOcular perfusion pressure, the difference between ocular arterial and venous pressure is difficult to measure. It is likely that CRADP, rather than brachial artery pressure, is closer to ophthalmic artery pressure and better reflects the true ocular arterial pressure . TraditiThe number of disc haemorrhages in the superior or inferior optic disc over the 5-year period was our response variable. The explanatory variables modelled were age, sex, diagnosis (glaucoma vs glaucoma suspect), antiplatelet/anticoagulant use, central corneal thickness, mean IOP, mean BP, mean baseline hemifield sensitivity (upper field matches lower disc and vice versa), hemifield sensitivity rate of change, VPP and CRADP. With this disc haemorrhage count data fitting a Poisson distribution, a linear mixed model with Poisson distribution was utilised for data analysis. Random effects were eye (left or right) nested within patient identity, to take into account potential correlation between upper and lower optic disc regions, as well as between right and left eyes. Univariate analysis was carried out for each explanatory variable. In the multivariate model, the least significant parameter was eliminated in a stepwise pattern, until all remaining parameters had a P-value of <0.05. The compound parameters of conventional OPP, alternative OPP and carotid resistance index were entered into separate multivariate analyses, to avoid collinearity with their individual components .An additional linear mixed model with same random effects was used to check correlation between VPP and visual field parameters. The response variable was VPP, explanatory variables were baseline hemifield mean sensitivity and hemifield sensitivity rate of change.https://www.R-project.org/). Parameters with P-value of <0.05 were considered significant.All analyses were performed using R (R Core Team (2017). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL A total of 155 eyes from 78 patients completed the study . Due to Mean number of detected disc haemorrhages was 2.46 per eye. 76 out of 155 eyes (49.0%) had at least one disc haemorrhage. Out of these, 62 (81.6%) had recurrent haemorrhages, with a mean of 5.94 haemorrhages over the 5-year period. This data was also presented in hemidisc format ; Fig 1, Univariate analysis of each parameter  revealedMultivariate linear mixed modelling using step-wise elimination of insignificant parameters revealed that VPP (P = 0.0029), carotid resistance index (P = 0.0172), mean BP (P = 0.0113) and rate of visual field change (P<0.0001) as significant predictors of disc haemorrhage . BaselinAn additional linear mixed effect analysis using VPP as the response variable and baseline field sensitivity as the explanatory variable showed strong association between the two (P = 0.0070).The validity of the final multivariate Poisson distribution model was tested. Pearson residuals were plotted against fitted values which showed no aberrant correlations. Dispersion statistics was calculated to be 1.1611, which complies with Poisson distribution model (dispersion should be close to 1).In this study with 155 glaucoma or glaucoma suspect eyes, 49% had at least one disc haemorrhage in the 5 year follow up. This is significantly higher than previously reported figures of 2–33% –33. ThisDisc haemorrhage has been established as one of the most significant predictors of glaucoma progression , 2. In oThere have been very few studies exploring the relationship between venous pulsation and disc haemorrhage. M. Kim et al found that spontaneous vein pulsation was not associated with disc haemorrhage (P = 0.626) . RecentlPrevious works consistently demonstrated the association between systemic hypertension and disc haemorrhage , 31, 41.Brachial arterial pressure measured with the armband at eye level is indicative of carotid and ophthalmic artery diastolic pressure based on earlier work . Thus anPrevious studies on the association between disc haemorrhage and the use of aspirin have had mixed results. Bojikian et al (post-phacoemulsification only)  and SoarThere are some limitations with our study. A major problem is clarifying whether an associated factor merely increases the size and hence visibility of the disc haemorrhage or is associated with its underlying cause. These data cannot resolve this problem for any of the explanatory variables. Elevated VPP probably reflects changes (increased resistance) in the larger hemi and central retinal veins  and probThis is the first systematic, prospective study that has taken annual VPP measures, which would reduce the effect of measurement variability . The retIn conclusion, higher VPP, carotid resistance index and rates of visual field progression were associated with optic disc haemorrhage in this study. Perfusion pressure has a complex relationship with haemorrhage. VPP is correlated with optic nerve haemorrhage but the low coefficient suggests that it requires very elevated VPP to be associated with increased number of optic disc haemorrhages. This does lend some support to the hypothesis that venous pathology is implicated in disc haemorrhage presence but the effect size is small.S1 File5 year clinical data used for statistical analysis.(CSV)Click here for additional data file.


Although mounting evidence supports the concept that growth hormone (GH) deficiency (GHD) affects cardiovascular function, no study has systematically investigated its prevalence and role in a large cohort of chronic heart failure (CHF) patients. Aim of this study is to assess the prevalence of GHD in mild-to-moderate CHF and to explore clinical and functional correlates of GHD.One-hundred thirty CHF patients underwent GH provocative test with GHRH+arginine and accordingly categorized into GH-deficiency  and GH-sufficiency  cohorts. Both groups received comprehensive cardiovascular examination and underwent Doppler echocardiography, cardiopulmonary exercise testing, and biochemical and hormonal assay.2  and increased ventilatory efficiency . After adjusting for clinical covariates , logistic multivariate analysis showed that peak VO2 , VE/VCO2 slope  and NT-proBNP , were significantly associated with GHD status. Finally, compared to GHS, GHD cohort showed higher all-cause mortality at median follow-up of 3.5 years , independent of age, sex, NT-proBNP, peak VO2 and LVEF.GHD was detected in roughly 30% of CHF patients. Compared to GHD, GHS patients showed smaller end-diastolic and end-systolic LV volumes , lower LV end-systolic wall stress , higher RV performance , lower estimated systolic pulmonary artery pressure , higher peak VOGH deficiency identifies a subgroup of CHF patients characterized by impaired functional capacity, LV remodeling and elevated NT-proBNP levels. GHD is also associated with increased all-cause mortality. Althpulation , and leapulation . Such evpulation , very lipulation , 7. The ClinicalTrials.gov with the code NCT00511927. Patients recruited during hospital stay were studied after a 3-month period of clinical stability. The inclusion criteria were as follows: patients of either sex affected by CHF New York Heart Association (NYHA) class I to III, secondary to ischemic or idiopathic dilated cardiomyopathy, age > 18 years, stable medications for at least three months, and LV ejection fraction 40% or less. Exclusion criteria were: active malignancy, unstable angina or recent myocardial infarction (within three months), severe liver disease, serum creatinine level > 2.5 mg/dl, and any relevant endocrine disease with the exception of diabetes. One hundred-thirty patients fullfilled the inclusion criteria and were evaluated with the following tests: Electrocardiogram (ECG), NYHA class, blood chemistry including N-terminal pro Brain Natriuretic Peptide (NT-proBNP), IGF-1, IGFBP-3, and GH stimulatory test. Patients diagnosed with GHD were subsequently studied with scan of the pituitary region. All patients underwent Doppler echocardiography and cardiopulmonary exercise stress testing. Using the Minnesota-Living with Heart Failure Questionnaire (MLHFQ) quality of life (QoL) was assessed. Anxiety and depression were assessed by a trained interviewer by using the State-Trait Anxiety Inventory [2 BMI and 4.1 μg/L for patients with BMI > 30 kg/m2). Patients who performed both GH provocative test and basal IGF-1 and IGFBP-3 measurement were sampled the same day. The study fully complied with the Declaration of Helsinki and all patients signed informed consent at the enrollment. The study protocol was approved by the Ethics Committee of the Federico II University of Naples.One hundred eighty-eight patients with CHF NYHA class I-III coming from 3 tertiary care centers were screened from December 2008 to December 2011 for this cross-sectional, observational trial which was registered on nventory , using a2 was recorded as the mean value of VO2 during the last 20 seconds of the test and expressed in millilitres per kilogram per minute. At the end of cardiopulmonary exercise test, patients were asked to identify the primary reason for stopping. Predicted peak VO2 was determined by use of a sex-, age-, height-, and weight-adjusted and protocol-specific formula outlined by Wassermann et al. [2 relationship was measured by plotting ventilation (VE) against carbon dioxide production (VCO2) obtained every 10 seconds of exercise (VE/VCO2 slope): both VE and VCO2 were measured in litres per minute. The VE/VCO2 slope was calculated as a linear regression function, excluding the non-linear part of the relationship after the onset of acidotic drive to ventilation.All patients underwent an incremental CPET on a bicycle ergometer. To stabilize gas measurements, patients were asked to remain still on the ergometer for at least 3 minutes before starting exercise. After a 1-minute warm-up period at 0 Watts workload, a ramp protocol of 10W/min was started and continued until exhaustion. The pedalling was kept constant at 55 to 65 revolutions/min. A 12-lead electrocardiogram (ECG) was monitored continuously during the test, and cuff blood pressure was manually recorded every 2 minutes. Respiratory gas exchange measurements were obtained breath-by-breath with use of a computerized metabolic cart . Peak VOn et al. . The venStandardized transthoracic echocardiography and Doppler examinations were performed with Aplio XG, Toshiba (Japan). Measurements were performed on- and off-line by one experienced investigator (M.A.) and confirmed by a second echocardiography expert in a blind fashion (A.C.). Both investigators were blinded to the patients’ group allocation. All measurements were made according to European Association of Cardiovascular Imaging/American Society of Echocardiography (ASE) guidelines : left veAll blood samples were collected by venipuncture and the sera were centrifuged within 3 h. After centrifugation, samples were frozen and stored at -80°C until used for assay. Serum GH for stimulatory test was assayed in local laboratories with an IRMA method . Serum N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentrations were measured by an electrochemiluminescence immunoassay (ECLIA by Roche diagnostics) using a Roche Elecsys analyzer. Serum concentration of total IGF-1 and IGFBP-3 were measured in an experienced core lab to assure consistency of measurements . An Enzyme-Labeled Chemiluminescent Immunometric Assays  was used. Assays employed were The IMMULITE® 2000 IGF-I, interassay variation = 5.7 CV% and Immulite 2000 IGFBP-3, interassay variation = 3.9 CV%. IGF-1/IGFBP-3 ratio, previously employed as an index of IGF-1 peripheral activity, was calculated as reported elsewhere . In malet-test with the assumption of unequal variance. Non-normally distributed variables were compared between two groups using the non-parametric Mann-Whitney U-test. Skewed variables were expressed as medians with lower and upper quartiles . Rates and proportions were compared between groups of interest using the chi-square test. Logistic mutivariate analysis was performed with GH status as dependent variable and age, gender, and tertiles of LV ejection fraction, IGF-1, peak VO2, VE/VCO2 slope, and NT-proBNP as covariates, chosen for their pathophysiological plausibility. Multivariable cox-regression analysis adjusted for age, sex, NT-proBNP, peak VO2 and LVEF was performed to determine the impact of GHD on mortality. Statistical analysis was performed using the SPSS version 16.0 package .Continuous variables are expressed as means ± standard error of the mean (SEM). Categorical variables were expressed as percentage. All variables were tested for normal distribution using the Kolmogorov-Smirnov test. Normally distributed variables were compared between two groups using the two-sided, unpaired Student's Clinical parameters, blood chemistry and hormonal evaluations of CHF patients according to GH status are shown in 2  and increased ventilatory efficiency . Moreover, GHD patients showed worse diastolic dysfunction as suggested by the higher E/E’ ratio , logistic multivariate analysis showed that peak VO2 , VE/VCO2 slope  and NT-proBNP , were significantly associated with GHD status. Finally, compared to GHS, GHD cohort showed higher all-cause mortality at median follow-up of 3.5 years   .2 and LVEF .Cox-regression analysis showed that GHD cohort showed higher risk of mortality compared to GHS cohort  independent of age, sex, NT-proBNP, peak VOand LVEF .2 was significantly lower in GHD patients, although similar values at anaerobic threshold were found  GHD is common in CHF, affecting about one-third of mild-to-moderate CHF patients of our study cohort; 2) GHD identifies a subgroup of CHF with a worse clinical status, QoL and depression scores, LV remodeling, and physical performance; 3) GHD status is associated with increased NT-proBNP levels and all-cause mortality. LV structure and biventricular function in CHF were more compromised by coexistence of GHD. In particular, CHF patients with GHD displayed larger LV volumes with elevated wall stress as well as higher filling pressures as estimated by E/E’ ratio compared to patients with normal GH pituitary secretion. Right ventricle hemodynamics was also impaired in CHF patients with GHD . Notablyre found . This ma, predominantly men, with mild-to-moderate systolic LV dysfunction may limit our conclusions. Thus, the results may not be applicable to elderly patients or to patients with more severe LV dysfunction. In addition, the cross-sectional design of the present study does not allow us to draw mechanistic relationships between GHD and cardiovascular performance. Finally, although a more exhaustive evaluation of all neurohormonal activation indexes  [ system)  are lack system) . DespiteGH deficiency identifies a subgroup of CHF patients characterized by impaired functional capacity, LV remodeling and neurohormonal activation. Future prospective trials, including the ongoing TOSCA registry , will heS1 File(SAV)Click here for additional data file.