Impairment of Endothelium-Dependent Vasodilation of Resistance Vessels in Patients With Obstructive Sleep Apnea Continuous positive airway pressure improves vascular function in obstructive sleep apnoea/hypopnoea syndrome: a randomised controlled trial Inflammation, Oxidative Stress, and Repair Capacity of the Vascular Endothelium in Obstructive Sleep Apnea Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Risk Stratification for Postoperative Cardiovascular Events via Noninvasive Assessment of Endothelial Function: A Prospective Study The Impact of CPAP on Cardiovascular Biomarkers in Minimally Symptomatic Patients with Obstructive Sleep Apnea: A Pilot Feasibility Randomized Crossover Trial Endothelial Dysfunction and Cardiovascular Risk Prediction in Peripheral Arterial Disease: Additive Value of Flow-Mediated Dilation to Ankle-Brachial Pressure Index Nasal continuous positive airway pressure improves myocardial perfusion reserve and endothelial-dependent vasodilation in patients with obstructive sleep apnea The sleep apnea cardiovascular endpoints (SAVE) trial: Rationale and start-up phase. Vascular endothelial function predicts mortality risk in patients with advanced ischaemic chronic heart failure. Endothelial function in obstructive sleep apnea and response to treatment. The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus. Microvascular endothelial function in obstructive sleep apnea: Impact of continuous positive airway pressure and mandibular advancement. CPAP improves endothelial function in patients with minimally symptomatic OSA: results from a subset study of the MOSAIC trial. Continuous Positive Airway Pressure Improves Daytime Baroreflex Sensitivity and Nitric Oxide Production in Patients with Moderate to Severe Obstructive Sleep Apnea Syndrome Effects of CPAP on oxidative stress and nitrate efficiency in sleep apnoea: a randomised trial Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. Effects of continuous positive airway pressure therapy withdrawal in patients with obstructive sleep apnea: a randomized controlled trial. Effects of continuous positive airway pressure on endothelial function and circulating progenitor cells in obstructive sleep apnoea: a randomised sham-controlled study. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials
Background — Patients with obstructive sleep apnea ( OSA ) experience repetitive episodic hypoxemia with consequent sympathetic activation and marked blood pressure surges , each of which may impair endothelial function . We tested the hypothesis that patients with OSA have impaired endothelium-dependent vasodilation , even in the absence of overt cardiovascular disease . Methods and Results —We studied 8 patients with OSA ( age 44±4 years ) and 9 obese control subjects ( age 48±3 years ) . Patients with OSA were newly diagnosed , never treated for OSA , on no medications , and free of any other known diseases . All obese control subjects underwent complete overnight polysomnographic studies to exclude occult OSA . Resistance-vessel function was tested by use of forearm blood flow responses to intra-arterial infusions of acetylcholine ( a vasodilator that stimulates endothelial release of nitric oxide ) , sodium nitroprusside ( an exogenous nitric oxide donor ) , and verapamil ( a calcium channel blocker ) . Conduit-vessel function was also evaluated by ultrasonography . Brachial artery diameter was measured under baseline conditions , during reactive hyperemia ( with flow increase causing endothelium-dependent dilatation ) , and after sublingual administration of nitroglycerin ( an endothelium-independent vasodilator ) . Patients with OSA had a blunted vasodilation in response to acetylcholine ( P < 0.007 ) , but responses to sodium nitroprusside and verapamil were not significantly different from those of control subjects . No significant difference in conduit-vessel dilation was evident between OSA patients and obese control subjects . Conclusions — Patients with OSA have an impairment of resistance-vessel endothelium-dependent vasodilation . This may be implicated in the pathogenesis of hypertension and heart failure in this condition Background : The obstructive sleep apnoea/hypopnoea syndrome ( OSAHS ) is associated with hypertension and increased cardiovascular risk , particularly when accompanied by marked nocturnal hypoxaemia . The mechanisms of these associations are unclear . We hypothesised that OSAHS combined with severe nocturnal hypoxaemia causes impaired vascular function that can be reversed by continuous positive airways pressure ( CPAP ) therapy . Methods : We compared vascular function in two groups of patients with OSAHS : 27 with more than 20 4 % desaturations/h ( desaturator group ) and 19 with no 4 % and less than five 3 % desaturations/h ( non-desaturator group ) . In a r and omised , double blind , placebo controlled , crossover trial , the effect of 6 weeks of CPAP therapy on vascular function was determined in the desaturator group . In all studies , vascular function was assessed invasively by forearm venous occlusion plethysmography during intra-arterial infusion of endothelium dependent ( acetylcholine 5–20 μg/min and substance P 2–8 pmol/min ) and independent ( sodium nitroprusside 2–8 μg/min ) vasodilators . Results : Compared with the non-desaturator group , patients with OSAHS and desaturations had reduced vasodilatation to all agonists ( p = 0.007 for all ) . The apnoea/hypopnoea index and desaturation frequency were inversely related to peak vasodilatation with acetylcholine ( r = −0.44 , p = 0.002 and r = −0.43 , p = 0.003 ) and sodium nitroprusside ( r = −0.42 , p = 0.009 and r = −0.37 , p = 0.02 ) . In comparison with placebo , CPAP  therapy improved forearm blood flow to all vasodilators ( p = 0.01 ) . Conclusions : Patients with OSAHS and frequent nocturnal desaturations have impaired endothelial dependent and endothelial independent vasodilatation that is proportional to hypoxaemia and is improved by CPAP therapy . Impaired vascular function establishes an underlying mechanism for the adverse cardiovascular consequences of OSAHS Background — Indirect evidence implicates endothelial dysfunction in the pathogenesis of vascular diseases associated with obstructive sleep apnea ( OSA ) . We investigated directly whether dysfunction and inflammation occur in vivo in the vascular endothelium of patients with OSA . The effects of continuous positive airway pressure ( CPAP ) therapy on endothelial function and repair capacity were assessed . Methods and Results — Thirty-two patients with newly diagnosed OSA and 15 control subjects were studied . Proteins that regulate basal endothelial nitric oxide ( NO ) production ( endothelial NO synthase [ eNOS ] and phosphorylated eNOS ) and inflammation ( cyclooxygenase-2 and inducible NOS ) and markers of oxidative stress ( nitrotyrosine ) were quantified by immunofluorescence in freshly harvested venous endothelial cells before and after 4 weeks of CPAP therapy . Vascular reactivity was measured by flow-mediated dilation . Circulating endothelial progenitor cell levels were quantified to assess endothelial repair capacity . Baseline endothelial expression of eNOS and phosphorylated eNOS was reduced by 59 % and 94 % , respectively , in patients with OSA compared with control subjects . Expression of both nitrotyrosine and cyclooxygenase-2 was 5-fold greater in patients with OSA than in control subjects , whereas inducible NOS expression was 56 % greater . Expression of eNOS and phosphorylated eNOS significantly increased , whereas expression of nitrotyrosine , cyclooxygenase-2 , and inducible NOS significantly decreased in patients who adhered to CPAP ≥4 hours daily . Baseline flow-mediated dilation and endothelial progenitor cell levels were lower in patients than in control subjects , and both significantly increased in patients who adhered to CPAP ≥4 hours daily . Conclusions — OSA directly affects the vascular endothelium by promoting inflammation and oxidative stress while decreasing NO availability and repair capacity . Effective CPAP therapy is associated with the reversal of these alterations BACKGROUND Endothelial vasodilator dysfunction is a characteristic feature of patients at risk for coronary atherosclerosis . Therefore , we prospect ively investigated whether coronary endothelial dysfunction predicts disease progression and cardiovascular event rates . METHODS AND RESULTS Coronary vasoreactivity was assessed in 147 patients using the endothelium-dependent dilator acetylcholine , sympathetic activation by cold pressor testing , dilator responses to increased blood flow , and dilation in response to nitroglycerin .  Cardiovascular events ( cardiovascular death , unstable angina , myocardial infa rct ion , percutaneous transluminal coronary angioplasty , coronary bypass grafting , ischemic stroke , or peripheral artery revascularization ) served as outcome variables over a median follow-up period of 7.7 years . Patients suffering from cardiovascular events during follow-up ( n=16 ) had significantly increased vasoconstrictor responses to acetylcholine infusion ( P=0 . 009 ) and cold pressor testing ( P=0.002 ) , as well as significantly blunted vasodilator responses to increased blood flow ( P<0.001 ) and the intracoronary injection of nitroglycerin ( P=0.001 ) . Impaired endothelial and endothelium-independent coronary vasoreactivity were associated with a significantly higher incidence of cardiovascular events by Kaplan-Meier analysis . By multivariate analysis , all tests of coronary vasoreactivity were significant , independent predictors of a poor prognosis , even after adjustment for traditional cardiovascular risk factors or the presence of atherosclerosis itself . CONCLUSIONS Coronary endothelial vasodilator dysfunction predicts long-term atherosclerotic disease progression and cardiovascular event rates . Thus , the assessment of coronary endothelial vasoreactivity can provide pivotal information as both a diagnostic and prognostic tool in patients at risk for coronary heart disease Background —Brachial artery endothelial function is impaired in individuals with atherosclerosis and coronary risk factors and improves with risk reduction therapy . However , the predictive value of brachial artery endothelial dysfunction for future cardiovascular events is unknown . Methods and Results —We preoperatively examined brachial artery vasodilation using ultrasound in 187 patients undergoing vascular surgery .  Patients were prospect ively followed for 30 days after surgery . Forty-five patients had a postoperative event , including cardiac death ( 3 ) , myocardial infa rct ion ( 12 ) , unstable angina/ischemic ventricular fibrillation ( 2 ) , stroke ( 3 ) , or elevated troponin I , reflecting myocardial necrosis ( 25 ) . Preoperative endothelium-dependent flow-mediated dilation was significantly lower in patients with an event ( 4.9±3.1 % ) than in those without an event ( 7.3±5%;P < 0.001 ) , whereas endothelium-independent vasodilation to nitroglycerin was similar in both groups . In a Cox proportional-hazards model , the independent predictors of events were age ( P = 0.001 ) , renal insufficiency ( P = 0.03 ) , noncarotid surgery ( P = 0.05 ) , and lower brachial artery flow-mediated dilation ( P = 0.007 ) . If troponin I elevation was not considered an event , low flow-mediated dilation remained an independent predictor of risk ( odds ratio 9.0 , 95 % CI 1.2 to 68;P = 0.03 ) . When a flow-mediated dilation cutpoint of 8.1 % was used , endothelial function had a sensitivity of 95 % , specificity of 37 % , and negative predictive value of 98 % for events . Conclusions —Impaired brachial artery endothelial function independently predicts postoperative cardiac events , which supports a role for endothelial dysfunction in the pathogenesis of cardiovascular disease . The strong negative predictive value of preserved endothelial function raises the possibility that assessment of brachial artery flow-mediated dilation will be useful in the management of patients undergoing vascular surgery Background Previous , largely uncontrolled studies demonstrated the substantial effects of continuous positive airway pressure ventilation ( CPAP ) on a variety of physiologic and biochemical markers known to be risk factors for cardiovascular disease in patients with obstructive sleep apnea ( OSA ) . In this pilot crossover study , we assessed ( 1 ) the feasibility of using CPAP in a group of minimally symptomatic patients with OSA , assessed through patient compliance and ( 2 ) CPAP therapy ’s effect on biomarkers in these patients . Methods We studied patients with minimal daytime sleepiness who were referred to the University of British Columbia ’s Hospital Sleep Clinic with suspected OSA and an apnea-hypopnea index ( AHI ) > 15 events/h . Patients were r and omized to either CPAP or no therapy for 4 weeks followed by a washout of 4 weeks , and then a crossover to the other intervention . Fasting morning blood and urine , 24-h blood pressure ( BP ) measurements , and endothelial function ( peak flow-mediated dilation to nitroglycerin-mediated dilation ratio ) were assessed before and after each study intervention . Results Nine adult male and four female patients were studied . Mean ( SD ) age was 55 ( 7 ) years , mean AHI = 27.9/h , mean Epworth Sleepiness Score = 6.8 ( 11/13 had a score < 10 ) , and mean BMI = 31.1 kg/m2 .  Mean compliance with CPAP therapy was 5.53 h/night . Compared to no therapy , potential improvements were observed with CPAP for urinary microalbumin , norepinephrine , and epinephrine to creatinine ratios ( decreased by 3.51 mg/mmol , 1.70 nmol/mmol , and 0.95 nmol/mmol , respectively ) ; 24-h BP ( systolic decreased by 3.60 mmHg , diastolic by 0.70 mmHg ) ; homeostasis model for insulin resistance score ( decreased by 1.11 ) ; and endothelial function ( increased by 7.4 % ) . However , none of the above differences was significant ( p > 0.10 ) . Conclusion In this pilot study there were potential improvements in a variety of cardiovascular biomarkers with CPAP . CPAP compliance was reasonably good even though patients were not particularly sleepy . Accordingly , larger r and omized controlled trials in this area appear feasible and warranted Background —Endothelial dysfunction plays a key role in atherogenesis . We prospect ively investigated the impact of noninvasive measurement of endothelial function on cardiovascular risk in peripheral arterial disease ( PAD ) . The study was specially aim ed at assessing whether brachial artery flow-mediated dilation ( FMD ) added to the predictive value of  ankle-brachial pressure index  ( ABPI ) . Methods and Results —Of 131 patients monitored for a mean of 23±10 months , 18 had a coronary event , 12 a cerebrovascular event , and 9 a peripheral event .  The median FMD was lower in patients with an event than in those without ( 5.8 % versus 7.6 % , P < 0.05 ) , whereas vasodilation to nitroglycerin was similar in the two groups . The cardiovascular event rate was higher in patients with FMD below the median versus those with FMD above the median ( P < 0.001 by log-rank test ) . In a Cox proportion hazard model , independent predictors of events were FMD below the median ( P < 0.01 ) , ABPI below the median ( P < 0.01 ) , and previous stroke ( P < 0.02 ) . Similar results were obtained when peripheral events were excluded from the analysis . Below-median ABPI and FMD combined was more accurate in predicting risk ( relative risk [ RR ] 13.0 ; 95 % CI , 3.0 to 56.2 ; P < 0.01 ) than ABPI ( RR , 6.4 ; 95 % CI , 1.4 to 29.1 ; P < 0.02 ) and FMD ( RR , 4.8 ; 95 % CI , 1.1 to 23.3 ; P < 0.05 ) alone . Conclusions —A low brachial artery FMD is an independent predictor of cardiovascular risk in patients with PAD and adds to the prognostic value of ABPI , which is currently the most powerful prognostic indicator in PAD Background Obstructive sleep apnea ( OSA ) has been associated with cardiovascular disease ( CVD ) , but whether OSA is an independent risk factor for CVD is controversial . The purpose of this study is to determine if patients with OSA have sub clinical cardiovascular disease that is detectable by multi-modality cardiovascular imaging and whether these abnormalities improve after nasal continuous positive airway pressure ( nCPAP ) . Results Of the 35 consecutive subjects with newly diagnosed moderate to severe OSA recruited from the Stanford Sleep Disorders Clinic , 20 patients were r and omized to active vs. sham nCPAP . Active nCPAP was titrated to pressures that would prevent sleep disordered breathing based on inpatient polysomnography . OSA patients had baseline vascular function abnormalities including decreased myocardial perfusion reserve ( MPR ) , brachial flow mediated dilation ( FMD ) and nitroglycerin-induced coronary vasodilation . Patients r and omized to active nCPAP had improvement of MPR ( 1.5 ± 0.5 vs. 3.0 ± 1.3 , p = 0.02 ) and brachial FMD ( 2.5 % ± 5.7 % vs. 9.0 % ± 6.5 % , p = 0.03 ) after treatment , but those r and omized to sham nCPAP showed no significant improvement . There were no significant changes seen in chamber sizes , systolic and diastolic function , valvular function and coronary vasodilation to nitroglycerin . Conclusions Patients with moderate to severe OSA had decreased MPR and brachial FMD that improved after 3 months of nCPAP . These findings suggest that relief of apnea in OSA may improve microvascular disease and endothelial dysfunction , which may prevent the development of overt cardiovascular disease . Further study in a larger patient population may be warranted THE SLEEP APNEA CARDIOVASCULAR ENDPOINTS ( SAVE ) STUDY ( CLINICAL TRIALS REGISTRATION NUMBER : NCT00738170 ) is an academic initiated and conducted , multinational , open , blinded endpoint , r and omised controlled trial design ed to determine whether treatment of obstructive sleep apnea ( OSA ) with continuous positive airways pressure ( CPAP ) can reduce the incidence of serious cardiovascular events in patients with established cardiovascular disease . The answer to this question is of major importance to population s undergoing ageing and lifestyle changes all over the world . The SAVE study brings together respiratory , sleep and cardiovascular clinician-scientists in a unique interdisciplinary collaborative effort with industry sponsors to conduct the largest and most ambitious clinical trial yet conducted in the field of sleep apnea , with a global recruitment target of 5000 patients . Following its launch in Australia and China in late 2008 , SAVE has now entered a phase of international expansion with new recruitment networks being established in New Zeal and , India and Latin America . This article describes the rationale for the SAVE study , the considerations behind its design , and progress thus far in establishing the recruitment network . The report emphasises the important role that Chinese sleep and cardiovascular investigators have played in the start-up phase of this l and mark international project AIMS Endothelial function is impaired in advanced chronic heart failure ( ACHF ) patients . We explored a possible association between endothelial function and subsequent mortality risk in ACHF . METHODS AND RESULTS We prospect ively assessed brachial flow-mediated dilation ( FMD ) in 82 consecutive New York Heart Association class IV ischaemic ACHF patients with a mean left ventricular ejection fraction ( LVEF ) of 22 + /- 3 % . Following overnight fasting and discontinuation of all medications for > or = 12 h ,  percent increase in FMD ( % FMD ) and nitroglycerin-mediated vasodilation were assessed using linear array ultrasound . All patients were followed for 14 + /- 2 months for adverse cardiovascular events , including death , hospitalization for CHF exacerbation , or myocardial infa rct ion . Patients were divided into two groups : those with an FMD lesser than or equal to the median % FMD of 4.6 % ( n = 41 ) and those with an FMD above the median ( n = 41 ) . Both groups were comparable regarding cardiovascular risk factors , LVEF , and concomitant medications . During follow-up , 22 ( 53.6 % ) patients with FMD lesser than or equal to the median had composite adverse cardiovascular events compared with only eight patients ( 19.5 % ) with FMD above the median ( P < 0.01 ) . Furthermore , fiver deaths ( 12.1 % ) occurred in patients with FMD lesser than or equal to the median , compared with no deaths in patients with FMD above the median ( P < 0.03 ) . Cox regression analyses revealed that FMD was an independent predictor for these events . CONCLUSION Flow-mediated dilation is associated with increased mortality risk in ischaemic ACHF patients Impaired endothelium-dependent vascular relaxation is a prognostic marker of atherosclerosis and cardiovascular disease . We evaluated endothelium-dependent flow-mediated dilation ( FMD ) and endothelium-independent nitroglycerin (NTG)-induced dilation of the brachial artery with Doppler ultrasound in 28 men with obstructive sleep apnea ( OSA ) and 12 men without OSA . Subjects with OSA ( apnea-hypopnea index ; mean + /- SD , 46.0 + /- 14.5 ) had lower FMD compared with subjects without OSA ( 5.3 + /- 1.7 % vs. 8.3 + /- 1.0 % , p < 0.001 ) , and major determinants of FMD were the apnea-hypopnea index and age . There was no significant difference in NTG-induced dilation .  Subjects with OSA were r and omized to nasal continuous positive airway pressure ( nCPAP ) or observation for 4 weeks . Subjects on nCPAP had significant increase in FMD , whereas those on observation had no change ( 4.4 % vs. -0.8 % , difference of 5.2 % , p < 0.001 ) . Neither group showed significant change in NTG-induced vasodilation . Eight subjects who used nCPAP for over 3 months were reassessed on withdrawing treatment for 1 week . On nCPAP withdrawal , FMD became lower than during treatment ( p = 0.02 ) and were similar to baseline values . Our findings demonstrated that men with moderate/severe OSA have endothelial dysfunction and treatment with nCPAP could reverse the dysfunction ; the effect , however , was dependent on ongoing use Most systematic review s rely substantially on the assessment of the method ological quality of the individual trials . The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of r and omized clinical trials ( RCTs ) . The invited participants were experts in the field of quality assessment of RCTs . The initial item pool contained all items from existing criteria lists . Subsequently , we reduced the number of items by using the Delphi consensus technique . Each Delphi round comprised a question naire , an analysis , and a feedback report . The feedback report included staff team decisions made on the basis of the analysis and their justification . A total of 33 international experts agreed to participate , of whom 21 completed all question naires . The initial item pool of 206 items was reduced to 9 items in three Delphi rounds . The final criteria list ( the Delphi list ) was satisfactory to all participants . It is a starting point on the way to a minimum reference st and ard for RCTs on many different research topics . This list is not intended to replace , but rather to be used alongside , existing criteria lists OBJECTIVES Endothelial dysfunction has been proposed as a potential mechanism implicated in the pathogenesis of cardiovascular complications of obstructive sleep apnea syndrome ( OSAS ) . This study aim ed to evaluate the microvascular endothelial function ( MVEV ) in OSAS and the impact on MVEF of 2 months of treatment with continuous positive airway pressure ( CPAP ) and m and ibular advancement device ( MAD ) . METHODS Microvascular reactivity was assessed using laser Doppler flowmetry combined with acetylcholine ( Ach ) and sodium nitroprusside ( SNP ) iontophoresis in 24 OSAS patients and 9 control patients . In 12 of the 24 OSAS patients , microvascular reactivity was reassessed after 2 months of CPAP and MAD using a r and omized cross-over design . RESULTS Ach-induced vasodilation was significantly lower in OSAS patients than in matched controls and correlated negatively with apnea hypopnea index ( r=-0.49 , p<0.025 ) and nocturnal oxygen desaturations ( r=-0.63 , p<0.002 ) . Ach-induced vasodilation increased significantly with both CPAP and MAD . The increase in Ach-induced vasodilation under OSAS treatment correlated with the decrease in nocturnal oxygen desaturations ( r=0.48 , p=0.016 ) . CONCLUSION Our study shows an impairment of MVEF in OSAS related to OSAS severity . Both CPAP and MAD treatments were associated with an improvement in MVEF that could contribute to improve cardiovascular outcome in OSAS patients BACKGROUND Minimally symptomatic OSA is a highly prevalent disorder , and the effects of CPAP on vascular function in these patients are unknown . This trial aim ed to investigate whether CPAP  improves vascular function in minimally symptomatic OSA . METHODS In two centers taking part in the MOSAIC ( Multicentre Obstructive Sleep Apnoea Interventional Cardiovascular ) trial , 253 patients with minimally symptomatic OSA were r and omized to 6 months of CPAP or st and ard care .  Two hundred eight patients attended their follow-up visit within the predefined time window and had complete measurements of arterial stiffness ( augmentation index [ AIx ] ) , and 64 patients had endothelial function measurements by brachial artery flow-mediated dilatation ( FMD ) . Multivariable analyses adjusting for baseline measurements and minimization factors were performed to assess the effect of CPAP treatment on FMD ( % dilatation ) and AIx ( % augmentation ) compared with st and ard care . RESULTS The mean ± SD baseline oxygen desaturation index and Epworth Sleepiness Score ( ESS ) of the 208 patients ( age 58 ± 7.3 years , 31 women ) were 13.7 ± 12.8 events/h and 8.3 ± 4.2 , respectively . There was no CPAP treatment effect on arterial stiffness ( AIx , -1.4 % ; 95 % CI , -3.6 to + 0.9 % ; P = .23 ) , but CPAP  improved endothelial function ( FMD , + 2.1 % ; 95 % CI , + 1.0 to + 3.2 % ; P < .0001 ) . CPAP  reduced daytime sleepiness ( ESS , -2.2 ; 95 % CI , -3.0 to -1.5 ; P < .0001 ) compared with st and ard care . There was a larger improvement in FMD in patients using CPAP for > 4 h/night than those who used it less ( P = .013 ) . CONCLUSIONS CPAP  improves endothelial function , but not arterial stiffness , in minimally symptomatic OSA . Thus , minimally symptomatic OSA may be a cardiovascular risk factor . TRIAL REGISTRY IS RCT N Register ; No. : IS RCT N 34164388 ; URL : http://is rct n.org Individuals with obstructive sleep apnea syndrome ( OSAS ) are at high risk for cardiovascular morbidity and mortality . The effects of OSAS severity and nocturnal continuous positive airway pressure ( CPAP ) on daytime baroreflex sensitivity ( BRS ) and nitric oxide ( NO ) production were investigated in OSAS patients . Fifty-one consecutive males with OSAS and 29 age-matched healthy men underwent the Valsalva test and st and ard polysomnography .  Patients with an apnea-hypopnea index ( AHI ) of ≥20 episodes per hour were r and omized to receive CPAP treatment for 3 months ( n=14 ) or no such treatment ( n=19 ) . The BRS index measured from the overshoot phase ( phase IV ) of the Valsalva maneuver and plasma NO concentration were significantly lower , whereas the AHI , oxygen desaturation time , arousal index , percentage of sleep stage 1 , and systolic blood pressure were significantly greater , in patients with an AHI of ≥20/h than in those with an AHI of < 20/h or in controls . The 24-h urinary excretion of norepinephrine was significantly reduced and the plasma NO concentration was significantly increased after one night of CPAP . The BRS index for phase IV and the Valsalva ratio were significantly increased in the CPAP group after the 3-month treatment period but remained unchanged in the non-CPAP group of OSAS patients . The daytime BRS index and NO production were thus inversely related to the severity of OSAS , and successful CPAP treatment improved these parameters in patients with moderate to severe OSAS .  CPAP may therefore reduce the risk of cardiovascular complications due to endothelial dysfunction or increased sympathetic activity Background : Previous studies have presented contradictory data concerning obstructive sleep apnoea syndrome ( OSAS ) , lipid oxidation and nitric oxide ( NO ) bioavailability . This study was undertaken to ( 1 ) compare the concentration of 8-isoprostane and total nitrate and nitrite ( NOx ) in plasma of middle-aged men with OSAS and no other known co-morbidity and healthy controls of the same age , gender and body mass index ; and ( 2 ) test the hypothesis that nasal continuous positive airway pressure ( CPAP ) therapy attenuates oxidative stress and nitrate deficiency . Methods : A prospect i ve , r and omised , placebo controlled , double-blind , crossover study was performed in 31 consecutive middle-aged men with newly diagnosed OSAS and 15 healthy control subjects . Patients with OSAS were r and omised to receive sham CPAP or effective CPAP for 12 weeks . Blood pressure , urinary catecholamine levels and plasma 8-isoprostane and NOx concentrations were obtained before and after both treatment modalities . Results : Patients with OSAS had significantly higher 8-isoprostane levels ( median ( IQR ) 42.5 ( 29.2–78.2 ) vs 20.0 ( 12.5–52.5 ) pg/ml , p = 0.041 , Mann-Whitney test ) and lower NOx levels ( 264 ( 165–650 ) vs 590 ( 251–1465 ) μmol/l , p = 0.022 ) than healthy subjects . Body mass index , blood pressure and urinary catecholamines were unchanged by CPAP therapy , but 8-isoprostane concentrations decreased ( 38.5 ( 24.2–58.7 ) pg/ml at baseline vs 22.5 ( 16.2–35.3 ) pg/ml on CPAP , p = 0.0001 ) and NOx levels increased ( 280 ( 177–707 ) vs 1373 ( 981–1517 ) μmol/l , p = 0.0001 ) after CPAP . Conclusions : OSAS is associated with an increase in oxidative stress and a decrease in NOx that is normalised by CPAP therapy OBJECTIVES The goal of this study was to prospect ively examine the long-term predictive value of brachial-artery endothelial dysfunction for future cardiovascular events . BACKGROUND Brachial-artery endothelial function is impaired in individuals with atherosclerosis and coronary risk factors . The prospect i ve relation between endothelial function determined by brachial-artery ultrasound and long-term cardiovascular risk is unknown . METHODS We examined brachial-artery endothelial function using ultrasound in 199 patients with peripheral arterial disease before elective vascular surgery .  Patients were prospect ively followed with an average follow-up of 1.2 years after surgery . RESULTS Thirty-five patients had an event during follow-up , including cardiac death ( 5 patients ) , myocardial infa rct ion ( 17 patients ) , unstable angina ( 10 patients ) , or stroke ( 3 patients ) . Preoperative endothelium-dependent flow-mediated dilation ( FMD ) was significantly lower in patients with an event ( 4.4 + /- 2.8 % ) compared with those without an event ( 7.0 + /- 4.9 % , p < 0.001 ) , whereas endothelium-independent vasodilation to nitroglycerin was similar in both groups . In a Cox proportional-hazards model , independent predictors of events included age ( p = 0.003 ) , more invasive surgery ( surgery other than carotid endarterectomy , p = 0.02 ) , and impaired brachial-artery endothelial function ( p = 0.002 ) . Risk was approximately nine-fold higher in patients with FMD < 8.1 % ( lower two tertiles ) compared with those in the upper tertile ( odds ratio 9.5 ; 95 % confidence interval 2.3 to 40 ) . CONCLUSIONS Impaired brachial-artery endothelial function independently predicts long-term cardiovascular events in patients with peripheral arterial disease . The findings suggest that noninvasive assessment of endothelial function using brachial-artery FMD may serve as a surrogate end point for cardiovascular risk RATIONALE To establish a new approach to investigate the physiological effects of obstructive sleep apnea ( OSA ) , and to evaluate novel treatments , during a period of continuous positive airway pressure ( CPAP ) withdrawal . OBJECTIVES To determine the effects of CPAP withdrawal . METHODS Forty-one patients with OSA and receiving CPAP were r and omized to either CPAP withdrawal ( subtherapeutic CPAP ) , or continued CPAP , for 2 weeks . Polysomnography , sleepiness , psychomotor performance , endothelial function , blood pressure ( BP ) , heart rate ( HR ) , urinary catecholamines , blood markers of systemic inflammation , and metabolism were assessed . MEASUREMENTS AND MAIN RESULTS CPAP withdrawal led to a recurrence of OSA within a few days and a return of subjective sleepiness , but was not associated with significant deterioration of psychomotor performance within 2 weeks . Endothelial function , assessed by flow-mediated dilatation , decreased significantly in the CPAP withdrawal group compared with therapeutic CPAP ( mean difference in change , -3.2 % ; 95 % confidence interval [ CI ] , -4.5 , -1.9 % ; P < 0.001 ) . Compared with continuing CPAP , 2 weeks of CPAP withdrawal was associated with a significant increase in morning systolic BP ( mean difference in change , + 8.5 mm Hg ; 95 % CI , + 1.7 , + 15.3 mm Hg ; P = 0.016 ) , morning diastolic BP ( mean difference in change , + 6.9 mm Hg ; 95 % CI , + 1.9 , + 11.9 mm Hg ; P = 0.008 ) , and morning HR ( mean difference in change , + 6.3 bpm , 95 % CI , + 0.4 , + 12.2 bpm ; P = 0.035 ) . CPAP withdrawal was associated with an increase in urinary catecholamines but did not lead to an increase in markers of systemic inflammation , insulin resistance , or blood lipids . CONCLUSIONS CPAP withdrawal usually leads to a rapid recurrence of OSA , a return of subjective sleepiness , and is associated with impaired endothelial function , increased urinary catecholamines , blood pressure , and heart rate . Thus the proposed study model appears to be suitable to evaluate physiological and therapeutic effects in OSA . Clinical trial registered with www.controlled-trials.com ( IS RCT N93153804 ) OBJECTIVE Obstructive sleep apnoea ( OSA ) is characterised by reoccurring apnoeas and hypopneas , causing repetitive hypoxia and reoxygenation , and is associated with endothelial dysfunction and reduced levels of circulating progenitor cells ( CPCs ) . The potential to improve endothelial function and CPC levels in people with OSA by preventing hypoxic episodes with Continuous Positive Airway Pressure ( CPAP ) was investigated in a sham-controlled CPAP study . METHODS Men with moderate-to-severe OSA ( mean ± SD : age=49 ± 12 y , apnoea hypopnea index (AHI)=37.6 ± 16.4 events/h , body mass index=31.5 ± 5.7 kg/m(2 ) ) who were CPAP naïve without diabetes mellitus were r and omised in a 12-week double-blind sham-controlled parallel group study to receive either active ( n=25 ) or sham ( n=21 ) CPAP .  CPCs , isolated from blood , were measured by flow cytometry and by co-staining cultured cells ( 7 days ) with acetylated low-density lipoprotein ( acLDL ) and lectin . Endothelial function was assessed by peripheral arterial tonometry ( PAT ) . RESULTS Compared to sham , CPAP significantly decreased AHI ( mean between-group difference -36.0 events/h ; 95%CI , -49.7 to -22.3 , p<0.0001 ) after 12 weeks . Despite this improvement in AHI , CPAP had no effect on change in CPC levels ( including CD34(+)/KDR(+ ) ( 565 cells/mL ; -977 to 2106 , p=0.45 ) , CD34(+)/KDR(+)/CD45(- ) ( 37.0 cells/mL ; -17.7 to 85.7 , p=0.13 ) , acLDL(+)/lectin(+ ) ( -43.1 cells/field , -247 to 161 , p=0.67 ) ) or change in endothelial function ( 0.27 ; -0.14 to 0.67 , p=0.19 ) compared to sham therapy . CONCLUSIONS Despite the improvement in OSA parameters and ablation of apnoeic events by CPAP , CPC counts and endothelial function in men with moderate-to-severe OSA were not significantly improved after 12 weeks of therapeutic CPAP when compared to sham control The CONSORT statement is used worldwide to improve the reporting of r and omised controlled trials . Kenneth Schulz and colleagues describe the latest version , CONSORT 2010 , which up date s the reporting guideline based on new method ological evidence and accumulating experience . To encourage dissemination of the CONSORT 2010 Statement , this article is freely accessible on bmj.com and will also be published in the Lancet , Obstetrics and Gynecology , PLoS Medicine , Annals of Internal Medicine , Open Medicine , Journal of Clinical Epidemiology , BMC Medicine , and Trials
Obstructive sleep apnoea ( OSA ) is a prevalent sleep-related breathing disorder associated with adverse cardiovascular outcome .
Endothelial dysfunction is one of the proposed mechanistic links between OSA and the increased cardiovascular risk .
Treatment with continuous positive airway pressure ( CPAP ) may reverse this detrimental pathophysiological consequence of OSA .
Most studies on the effect of CPAP on endothelial function in OSA are limited by their low sample size .
The objective of this systematic review was to assess the effect CPAP therapy on endothelial function in patients with OSA .