In adults, OSA most commonly is caused by decreased muscle tone (required for patency) in the soft tissues of the upper airway.7 Although the definitions of apnea and hypopnea can vary, they generally do not deviate significantly from those given in the previous sentence. OSA is graded on a scale termed the apnea-hypopnea index (AHI), which consists of the mean number of apneas and hypopneas per hour of sleep. An AHI of 5 to 15 is considered mild, 16 to 30 is considered moderate, and >30 is considered severe.1 Of note, AHI in severe OSA can exceed 100. A fall in O2 saturation of 10% to 15% is common during an OSA event; however, oxygen saturation can fall by ≥50% in extreme cases.1 Importantly, a decrease in the O2 saturation of hemoglobin by only 4% during OSA is associated with an increased incidence of cardiovascular disease independent of confounding covariates.8The result of excessive airway collapse is apnea, a cessation of airflow for >10 seconds, or hypopnea, a reduction of airflow to <50% of normal, or both.12 OSA almost certainly will become an even greater health problem in the future because 2 of the prominent risk factors for OSA, obesity and older age, are on the rise.15 Of further significance to the public health dilemma are the facts that (1) ≍85% of people with clinically significant OSA go undiagnosed, and (2) OSA can continue for years without the individual being aware of it.1Estimates of the incidence of OSA vary from <5% to up to 25% of the adult population in the Western world.16 Unfortunately, 30% of all patients with OSA do not tolerate CPAP or do not comply because of the discomfort of the CPAP mask, which is strapped over the nose or over both the nose and mouth by a headband. In asymptomatic or minimally symptomatic patients, lack of compliance is even greater.16 This lack of compliance is compounded by the estimate that 93% of women and 82% of men with moderate to severe sleep apnea syndrome have not been clinically diagnosed.17 Other therapies, such as mandibular devices, weight reduction, and surgery, have limited effectiveness in milder forms of OSA but generally are not effective in more severe OSA.16 Pharmacological therapies have been disappointing, even though several dozen drugs have been evaluated for the treatment of OSA.16The major treatment for OSA involves continuous positive airway pressure (CPAP), a therapy that holds the airway open by using pressures delivered by a mask. Variations that use positive pressure currently are being used, but all maintain positive pressure during inhalation. Although the use of CPAP seems to be beneficial in some studies, more randomized, prospective studies are needed to fully clarify the effectiveness of CPAP.18 Patients presenting with stroke or transient ischemic attack were 3 to 4 times more likely to have OSA than were matched control subjects.20 Regardless of sex, between 60% and 80% of patients with stroke and transient ischemic attack had an AHI >10.22 Furthermore, the incidence of obstructive apnea was ≍7-fold greater than the incidence of apneas that were predominantly central in nature.22 Palomaki23 compared 177 consecutive male patients with brain infarctions to age-matched controls. The odds ratio for snoring and brain infarction was 2.13 . (Odds ratio is defined as the odds of an event occurring in one group divided by the odds of the same event occurring in another group.) If sleep apnea (reported by subject or partner), daytime sleepiness, and obesity were also present, the odds ratio increased to 8.0 . Palomaki concluded that snoring could be a risk factor for ischemic stroke, likely because of the higher prevalence of OSA among snorers. Although the aforementioned studies are revealing and provocative, they did not determine definitively whether OSA was present before stroke or was the result of stroke.The incidence of OSA in patients who have had a stroke or transient ischemic attack is greater than that of the general population.18 Redline et al24 monitored 5422 participants from the Sleep Heart Health Study over a median of 8.7 years. Participants were excluded if they had a history of stroke at the baseline examination (1995–1998) or if they had been treated for OSA. A significant positive association between AHI and ischemic stroke in men (P=0.016) was observed. For men in the highest quartile (AHI >19), the hazard ratio was 2.86  after age, body mass index, smoking status, systolic blood pressure, use of antihypertensive medications, diabetes mellitus, and race were incorporated into the model.  The stroke risk was estimated to increase by 6% for each 1-unit increase in AHI between 5 and 25. In contrast to men, the incidence for stroke was not significantly associated with AHI quartiles in women. Still, an increased risk was observed in women when AHI was >25. Redline et al pointed out that modest to moderate associations between AHI and stroke in women could have been overlooked in the existing data set.Cross-sectional and longitudinal studies involving stroke and OSA confirm and amplify the findings of the previously discussed studies.25 examined 6424 individuals from the Sleep Heart Health Study (age ≥40 years). When the upper AHI quartile was compared to the lower AHI quartile, the adjusted relative odds ratio for stroke was 1.58  after accounting for age, race, sex, smoking status, self-reported diabetes mellitus, total cholesterol, and high-density lipoprotein cholesterol (P=0.03). However, when a model was used that added the number of cigarettes smoked per day, self-reported hypertension, systolic blood pressure, use of antihypertensive medications, and body mass index as additional covariates, the model approached but did not reach significance . Central apneas were relatively infrequent in the Sleep Heart Health Study, and removal of subjects whose apneic events were central in nature did not alter the findings.Shahar et al29 However, central and obstructive apneas were not always separated, and composite endpoints (cardiovascular events and stroke28 or stroke and death28) were used. Capampangan and colleagues30 used the data available in the study by Yaggi et al28 to separate the composite endpoints and calculated a relative risk of 5.16 for the association of OSA with the endpoint (stroke and transient ischemia attack).Similar results were reported in other cross-sectional and longitudinal studies.31 were frequent in patients with sleep apnea.34 Silent brain infarction occurred in 25% of patients with moderate to severe OSA (AHI=45) but occurred in only 6.7% and 7.7% of control subjects (AHI=3) or patients with mild OSA (AHI=11), respectively.33 Harbison et al35 reported that white matter disease severity correlated with AHI in patients with stroke. Because of the methods of assessing apneas, neither Harbison et al35 nor Eguchi et al32 were able separate obstructive apnea from central apnea. Others found that small-vessel cerebrovascular disease either was not associated with OSA36 or was best correlated with central sleep apnea.37Studies involving OSA and small-vessel cerebrovascular disease, including white matter lesions and lacunar infarcts, are limited. Silent brain infarcts, which lack stroke-like symptoms and predominantly involve small-vessel cerebrovascular disease,42 Thus, any relationship between OSA and small-vessel cerebrovascular disease could be indirect, through the aforementioned risk factors.Any relationship between OSA (or sleep-disordered breathing) and small-vessel cerebrovascular disease is complicated by the fact that the risk factors for small-vessel cerebrovascular disease  are associated with OSA.35 The best evidence that OSA is an underlying cause of stroke has been derived from cross-sectional and longitudinal studies of the general population. The studies are complicated by confounding comorbidities that might be both the result of OSA on one hand and a risk factor for stroke on the other.39 However, even after adjustment for these and other confounding comorbidities, OSA was often independently associated with stroke.29 When the literature is considered as a whole, the evidence is compelling that OSA is an independent risk factor for stroke.In summary, determining if OSA is an underlying cause of stroke and other cerebrovascular disorders has been a formidable challenge. In studies conducted after the occurrence of stroke, it can be determined only that OSA is more prevalent after stroke but not whether OSA preceded the stroke or was responsible for the stroke. Nevertheless, arguments can be made that preexisting cerebrovascular disease in patients with OSA or snoring (an indicator of OSA) preceded the stroke.46 OSA in patients with stroke increased the length of hospital stay and the likelihood of death after 6 months, with the most predictive measure for death being the length of apnea.47 Sahlin et al48 monitored 132 stroke patients over 10 years. Patients with an AHI <15 served as controls; 17% were classified as having OSA; and 21% were classified as having central sleep apnea. Two patients with mixed OSA and central sleep apnea were not included in the analysis. OSA was a significant risk factor for death  independent of age, sex, body mass index, current smoking status, hypertension, diabetes mellitus, atrial fibrillation, cognitive impairment, or dependency on caregivers. Interestingly, central sleep apnea was not related to increased rate of death, although AHIs for central and obstructive apnea were similar . In addition to contributing to a worse outcome after stroke, sleep apnea (predominantly OSA) was reported to be an independent risk factor for the recurrence of stroke.43OSA not only is a risk factor for stroke but also exacerbates the damage produced by a stroke once it has occurred and increases the risk for a subsequent stroke.49 If this observation in rodents can be translated to humans, then preconditioning resulting from repeated hypoxias accompanying OSA could limit the damage of stroke. However, even if preconditioning occurs in the human brain, the existing evidence suggests that the detrimental effects of OSA outweigh any protection from hypoxic preconditioning.Although it is clear that OSA exacerbates the damage produced by a stroke once it has occurred, it is possible that “preconditioning” resulting from repeated episodes of hypoxia prevents the insult from being even worse. Repeated episodes of systemic hypoxia protect the rodent brain from subsequent ischemic damage.50 CPAP therapy might be particularly important during the acute stages after stroke in patients with OSA. As a result of stroke, brain regions with compromised rates of blood flow can be affected negatively by ongoing OSA. First, regions with compromised blood flow are further jeopardized by the hypoxia that occurs during OSA. Second, cerebral vessels in healthy tissues more effectively dilate during hypercapnia than do vessels within the compromised regions. During an episode of OSA when hypercapnia occurs, healthy tissue can “steal” blood from regions with inadequate cerebrovascular reserve. This phenomenon is called the “Reversed Robin Hood Syndrome.”53 Thus, CPAP therapy in OSA patients could be especially important during the acute phase after stroke by reducing or preventing apneas and possibly preventing further damage to brain regions at risk because of compromised blood flow.55Although some encouraging studies indicate beneficial effects of CPAP treatment in patients with stroke and OSA, the results have not been consistent, and more studies will be required to determine any benefits conclusively.56 studied the effects of CPAP therapy in OSA patients after ischemic stroke. Two months after the acute stroke, patients were assessed for the presence of sleep apnea. Only patients with AHI ≥20 were enrolled, and CPAP therapy was prescribed for all patients. The patients were divided into 1 of 2 groups: those who tolerated CPAP therapy for the duration of the study (15 patients) and those who could not tolerate and discontinued CPAP therapy after 1 month (36 patients). The incidence of new cerebrovascular or ischemic coronary events was determined during the subsequent 18 months. The incidence of new vascular events was 5-fold greater in patients who discontinued CPAP than in CPAP users after adjustment for other vascular risk factors and neurological indexes (57 reported an improved sense of well-being and decreased blood pressure after 10 days in stroke patients (n=74) who adhered to CPAP therapy compared to those who did not (n=36). Ryan et al57a randomized stroke patients with OSA (AHI ≥15) to a CPAP (n=22) group or control (n=22) group. CPAP treatment for 4 weeks improved functional and motor outcomes but not neurocognitive outcomes. The authors concluded that CPAP treatment provided a “significant, although modest, beneficial effect” on stroke-related outcomes in patients with OSA. However, another study found no beneficial effects of 8 weeks or 6 months of CPAP therapy in stroke patients with AHI ≥30.58 However, in that study, patients in the treatment group had limited compliance with CPAP, with the average use being only 1.4 hours per night. Depending on the study, compliance with CPAP therapy among patients who had a stroke was similar to or lower than compliance in patients who did not have a stroke.61Martinez-Garcia et al indexes . Martine63 with the severity of the dementia being related to the severity of the sleep-disordered breathing.65 In one study, Yaffe et al66 monitored 298 women without dementia (mean of 82 years of age) for ≍5 years. Women with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia even after adjustment for other risk factors. The vast majority of the dementia and cognitive impairment in individuals >80 years of age is mixed, as opposed to pure Alzheimer's disease or vascular in nature.67 Given that OSA might be an underlying cause of stroke and that strokes can be a major component in brain atrophy and confusion in older patients,68 it stands to reason that OSA, though not necessarily the underlying cause of the dementia, is certainly a factor that would exacerbate the dementia.67Published studies have reported an association between OSA and dementia in the elderly,69 assessed cognitive function in younger (25 to 44 years) and older (45 to 59 years) subjects with and without OSA. Older subjects with OSA showed cognitive decline when compared to older subjects without OSA, younger subjects with OSA, or younger subjects without OSA. Thus, cognitive decline, which normally occurs with aging, can be accelerated in individuals with OSA.Ayalon et al70 CPAP treatment for 13 months showed positive benefits in mood, sleep quality, and cognition compared to a group of patients not using CPAP treatment.71 Although definitive conclusions are hampered by the limited sample sizes, the findings are still provocative and should motivate future studies. As such, CPAP therapy might provide lasting improvements, or at least stabilization, in the quality of life of individuals with dementia.Studies indicate that patients with OSA and Alzheimer's disease could have positive benefits from CPAP therapy. Modest but statistically significant cognitive improvements were reported after 3 weeks of CPAP therapy in one study.66 although not all studies found a significant association between OSA and cognitive function in the elderly.73 That the incidence of OSA increase with age14 adds to the seriousness of the clinical situation in the elderly.If the studies are taken as a whole, a convincing argument can be made that OSA accelerates cognitive decline and the onset and severity of dementia,2 demand by the brain requires an uninterrupted supply of O2 by the blood. Disruptions in O2 delivery for relatively short periods of time are accompanied by significant pathological consequences. In this review, we will discuss only a few aspects of the cerebral circulation as they pertain to OSA. For in-depth discussion of the cerebral circulation, see the referenced reviews.78The cerebrovascular system must accommodate the distinct anatomic structure and physiological function of the brain. As a consequence, it is different in many respects from the peripheral vascular system. These differences present unique challenges and vulnerabilities for the cerebrovascular system in maintaining a homeostatic environment in which the brain can operate. The O81 Although TCD has its limitations, it is a powerful and noninvasive tool that has been used in humans to provide meaningful insight into changes in CBF during OSA.Transcranial Doppler ultrasonography (TCD) measurements of blood velocity in cerebral arteries have been an important tool in assessing cerebral blood flow (CBF) in humans. TCD, which measures the velocity of red blood cells in vessels , does not provide a quantitative measure of CBF. Instead, it provides an index that is directly proportional to the rate of blood flow, provided the diameter of the vessel remains constant throughout the time of measurement. Several studies indicate that CBF velocity (CBFV) in the middle cerebral artery can provide a reasonable index of CBF with different conditions.84 On termination of apnea, CBFV often, but not always, decreases below baseline before recovering after ≍1 minute.84CBFV has been reported to increase steadily in the middle cerebral artery during an episode of OSA. The magnitude of the CBFV increase varies greatly but can exceed 200% of the baseline velocity .5,82–84 Po2 and pH decrease, and Pco2 increases.7 Blood gasses and pH changes in these directions act in concert to dilate cerebral arteries and arterioles.86 The increase in arterial Pco2 (hypercapnia) during an episode of OSA has been more of a focus on CBF regulation than the concomitant hypoxia.88Several known, and likely some unknown, vasoactive influences impinge on the cerebral circulation during OSA. During an episode of OSA, arterial 83 If autoregulation is compromised (see later) or the changes in blood pressure are sufficiently rapid that autoregulation, even if intact, does not have time to adapt, then all or a portion of the changes in TCD velocity could be related to the changes in blood pressure.5 Indeed, Balfors and Franklin82 reported a linear correlation between percent change in mean arterial blood pressure and percent change in CBFV during and after an episode of apnea. It must be noted that during an episode of OSA, blood pressure mostly increases, Po2 and pH decrease, and Pco2 increases. Therefore, it is not surprising that changes in the CBFV also correlate with arterial Pco2.88Arterial blood pressure has been reported to increase progressively during the apnea and to fall below baseline after the apnea.2 saturation data during a single or multiple OSA event(s).89 The timing of maximal O2 desaturations often occurred after breathing had resumed. For example, Balfors and Franklin82 noted that maximum O2 desaturation (as assessed by pulse oximetry) occurred ≍20 seconds after termination of the apnea. Although the delay was noted in the previously discussed studies, no explanations were provided for the unexpected timing of the O2 desaturations. We suggest that the timing of the O2 desaturations shown in these publications represents a delay in the output of the measuring devices. The delay time for pulse oximetry, which depends on manufacturer, sampling interval, and probe placement, can be ≥30 seconds.91Several publications in the literature present CBFV and O92 reported that CBFV decreased during 76% of obstructive hypopneas and 80% of obstructive apneas observed. The reason for this disparity in the literature is not known. However, blood pressure was not measured in the study by Netzer et al.92 As discussed previously, changes in arterial blood pressure can be an important consideration in CBF changes during an episode of OSA.Contrary to the majority of studies that show an increase in CBFV during OSA, Netzer et al94 In addition, the sensory, sympathetic, or parasympathetic nervous system innervates cerebral arteries95 and could influence CBF during an episode of OSA. In general, however, activation of the sympathetic nervous system has little effect on the cerebral circulation except during some pathological states.96 Although none of the systems that innervate cerebral vessels has been investigated in OSA, they must be considered, given the complexity and the number of systems involved with the response to OSA.Other changes that potentially could affect CBF during an episode of OSA include vasoactive substances in blood or stimulation of vasoactive central neurons.Pco2 and to a lesser extent by changes in arterial pressure.87 Although these studies in healthy subjects could provide insight into CBF during OSA, it must be pointed out that the mechanisms in healthy subjects might not totally reflect the mechanisms in individuals with OSA. The increase in CBFV during voluntary apnea was reduced in patients with OSA compared to control subjects. Significantly, the response to the voluntary apnea returned to normal after 1 day or 1 month of CPAP therapy.98In healthy awake subjects, the CBFV increases observed during voluntary apnea and the CBFV decreases observed after the apnea were driven largely by arterial 2 desaturations were >10% during OSA, brain adenosine triphosphate decreased, and inorganic phosphate increased.99 With different protocols, comparable or even greater levels of hypoxia did not significantly alter the energy state in normal subjects or in animal models.102 During nonpathological conditions, an increase in CBF can accommodate the O2 requirement for adenosine triphosphate production through the respiratory chain. Rae et al99 concluded that “transient hypoxia experienced during sleep may impair brain function more than previously thought.”Impaired cerebrovascular control in individuals with OSA can affect the energy state of the brain during an episode of apnea. When O104 reported that CBF in patients with OSA was decreased during both sleep and wakefulness compared to volunteers without OSA. These studies, using stable xenon and xenon-133 computerized tomography, are significant in that they are the only studies, to our knowledge, in which rates for CBF (mL / 100 g per minute) have been actually quantified in patients with OSA. CBF was decreased in the hemispheric, brainstem, and cerebellar gray regions of patients with OSA during wakefulness.104 Additionally, during sleep, patients with OSA exhibited significant reductions in flow to the frontal and occipital cortex, pons, and the cerebellum.103 These decreases occurred even though end-tidal CO2 was significantly greater in patients with OSA during wakefulness (2 mm Hg) and sleep (4 mm Hg) than in control subjects.103Although they are limited, studies indicate that resting CBF is chronically altered in individuals with OSA. Meyer and colleagues105 This decrease in CBFV persisted in wakefulness, non–rapid eye movement sleep, and rapid eye movement sleep in patients with OSA, despite their having end-tidal CO2 values greater than those of control subjects for all states.106 Hajak et al107 extended these findings by measuring CBFV during the 4 different stages of non–rapid eye movement sleep. CBFV was decreased in patients with OSA during sleep stages 1 to 3 after falling asleep compared to control subjects. However, during all stages of rapid eye movement sleep and in most sleep stage twos after the first occurrence, CBFV was greater in patients with OSA than in controls. Overall, patients with OSA and control subjects exhibited similar patterns of fluctuations in nocturnal brain perfusion; however, the amplitude of these changes was greater in control subjects during non–rapid eye movement sleep and was greater for patients with OSA during rapid eye movement transitions.107TCD studies support the idea that resting CBF is decreased in individuals with OSA.111 Consistent with this idea is a recent study that shows disruption of neurovascular coupling in the sensory cortex in mice after intermittent hypoxia, a model of sleep apnea.112When the data are taken as a whole, it can be concluded that CBF is decreased in the resting state with OSA. Although there are some variations between studies, particularly during sleep, existing studies consistently report alterations in resting CBF. The resting state reflects the background upon which CBF is regulated, and deviations from the resting state of healthy individuals are indicative of cerebrovascular dysfunction. Of note, moderate decreases in CBF can have significant adverse consequences, including deficits in memory, spatial learning, and attention, which are described commonly in patients with severe OSA.96 Unlike many peripheral tissues in which the major resistance to flow resides in the arterioles, the resistance in the cerebrovascular system occurs along the entire vascular tree, including not only the smaller arteries and arterioles but also the larger cerebral arteries.114 The vascular tree in a healthy brain, in which large arteries contribute significantly to the resistance, not only serves to regulate CBF but also protects arterioles and capillaries from excessive pressures.Autoregulation helps to maintain a homeostatic environment in which the brain can operate by maintaining a constant CBF in the face of changes in arterial blood pressures over a range between 60 and 160 mm Hg.105 exposed control subjects and patients with OSA (average AHI=78) to an orthostatic hypotension challenge by having each subject stand from a squatting position. The recovery of CBFV in the middle cerebral artery after a transient decrease in mean arterial blood pressure was used to assess the autoregulatory response. The resistance to flow in the middle cerebral artery  was greater in patients with OSA after standing than in control subjects (115 studied the autoregulation in awake patients with moderate OSA (average AHI=23) and matched controls by computing an autoregulatory index consisting of a moving correlation coefficient between mean CBFV and mean arterial blood pressure. Not only was autoregulation impaired in awake patients with OSA, but also the severity of the impairment strongly correlated with OSA severity.115 Finally, a recent study showed that the mechanism for myogenic tone, the intrinsic property of arteries to constrict when pressurized, was altered in ex vivo middle cerebral arteries from rats after they had been subjected to intermittent hypoxia.116 An impairment of cerebral autoregulation likely contributes to the increased incidence of stroke, as well as the poor outcome after stroke, in patients with OSA.Urbano et alsubjects . The incsubjects . Nasr et117 and 36%118 in patients with severe OSA as compared to controls. The CBFV response to hypoxia correlated with the AHI and nocturnal O2 desaturation.117 Interestingly, significant improvements in the CBFV response to hypoxia occurred after 4 to 6 weeks117 or 12 weeks118 of CPAP treatment. Finally, the dilator response to hypoxia in isolated pressurized middle cerebral arteries from rats after 2 weeks of intermittent hypoxia was completely abolished.119Repeated exposures to hypoxia in individuals with OSA could lead to hypoxic/ischemic brain injury, especially if cerebrovascular control is impaired. The increase in CBFV in the middle cerebral artery during hypoxic challenges was attenuated significantly by 42%120 exposed patients with severe OSA to repetitive hypercapnic conditions while measuring CBFV by TCD. Both studies reported no difference in the hypercapnic response as compared to control patients. Reichmuth et al118 reported that the increase in CBFV when end-tidal CO2 was increased by 5 and 10 mm Hg was attenuated by 22% in individuals with OSA compared to controls. Similarly, Morgan et al121 reported that the cerebrovascular response to hypercapnia was blunted in individuals with OSA, with the severity of the response positively correlating with the degree of oxygen desaturation during OSA. Using methods to quantitatively measure CBF, Meyer et al104 reported that the increase in CBF with the addition of 5% CO2 to the ventilator gas was blunted in patients with OSA during sleep and wakefulness compared to control subjects. Given the limited number of studies and the conflicting results, any conclusion about the cerebrovascular response to hypercapnia is premature. Unlike the autoregulatory response and the cerebrovascular responses to hypoxia, the effects of OSA on the response to hypercapnia must await further investigations.Studies investigating the cerebrovascular response to hypercapnia in patients with OSA have yielded conflicting results. Studies performed by Urbano et al and Foster et al83 At the end of an episode of OSA, blood pressure was reported to sharply increase by ≍35 mm Hg on average; however, in some individuals, the systolic pressure surge exceeds 100 mm Hg.122 These surges in blood pressure can be sufficiently rapid that autoregulation, even if it were intact, might not have time to fully accommodate.5 Pressure surges will expose smaller arteries, arterioles, and capillaries to damaging pressures, resulting in endothelial damage and disruption of the blood–brain barrier. At the end of an episode in which the blood pressure sharply increased, intracranial pressure was reported to often exceed 50 mm Hg.123 In a similar manner, the sharp decreases in blood pressure on termination of OSA83 can leave the brain vulnerable to ischemia, especially in regions with poor cerebrovascular reserve.39 This would be especially true for areas without good collateral circulation, including border zone areas and terminal arterial territories. Consistent with this idea is the fact that OSA has been associated with lacunar infarcts, small-vessel disease, and leukoaraiosis.124Several events take place during an episode of apnea, in addition to hypoxia/reoxygenation, that have detrimental effects on the cerebral circulation. There are repeated swings in blood pressure with each episode of apnea, consisting not only of increased blood pressure during the episode but also a period of hypotension after the episode.109 Vibrations in the carotid arteries from snoring, common in patients with OSA, can produce endothelial damage and atherosclerosis.126 Vascular dysfunction in the carotid artery will put more stress on the vascular system in the brain, rendering it more vulnerable to other pathological consequences of OSA.Although the carotid artery is outside the cranial vault, the carotid artery must be included when CBF is considered because the majority of blood flow to the brain is via the carotid arteries. The carotid arteries are a primary site for development of atherosclerosis (carotid artery disease), a risk factor for stroke.131), it is tempting to extrapolate these findings directly to the cerebrovascular circulation. However, extrapolation must be conducted with caution because (1) the distinct anatomic structures and physiological function of the brain are uniquely affected by disease processes and (2) the cerebrovascular circulation can be more sensitive to the pathological processes.109There is a paucity of studies involving pathological mechanisms in the cerebral circulation in OSA. Given the more extensive literature involving vascular effects outside of the brain , although the full extent of endothelial dysfunction is much more involved.9 Notably, dysfunction of cerebrovascular endothelium occurs sooner and to a greater extent in the progression of cardiovascular diseases than that of endothelium in the periphery.109OSA initiates a pathological cascade through multiple and often redundant pathways affecting the cardiovascular system .1 This c7 In addition to the acute activation during a single episode, chronic intermittent hypoxia or OSA alters the sensitivity of the chemoreceptors and baroreceptors, as well as altering their central integration by nuclei in the brainstem and hypothalamus.136 The carotid chemoreceptors increase baseline activity and become more sensitive to hypoxia through alterations in neurotransmitter systems, including endothelin-1 (ET-1) and angiotensin II.139 The mechanism for altered chemoreceptor function involves reactive oxygen species (ROS), resulting from transcriptional genes that upregulate hypoxia-inducible factor-1 and downregulate hypoxia-inducible factor-2.135The sympathetic nervous system is activated acutely during OSA as a result of (1) chemoreceptor discharges with changes in blood gasses and pH, (2) arousals from sleep, and (3) sleep deprivation.142 Through stimulation of angiotensin I receptors on the endothelium, angiotensin II enhances the production of superoxide by activating NADPH oxidase.143 Although angiotensin II has similar effects in all endothelial cells, cerebral vessels have greater NADPH oxidase activity than do peripheral vessels and are particularly sensitive to the effects of the superoxide generated.146 The pathway described in this paragraph is shown in 109 In addition to NADPH oxidase being a major source, superoxide also can be generated in the vascular system by mitochondria, cyclooxygenase, lipoxygenases, hydroxylases, and xanthine oxidase.One consequence of increased sympathetic activity on the kidney is stimulation of the renin–angiotensin system and the subsequent increase in angiotensin II. Angiotensin II can enhance oxidative stress, produce inflammation, disrupt blood–brain barrier integrity, initiate vessel remodeling, and impair increases in nutritive blood flow.2 becomes the terminal electron acceptor in the oxidation-reduction reaction to create superoxide in place of the normal end product, NO.109 The net result of an increased oxidative state includes reduced NO bioavailability, damage to lipid membranes, and alterations in protein structure and function. In addition to the increased production of ROS, reduced glutathione, a component of the antioxidant system for protecting the brain, was reported to be significantly reduced with reoccurring obstructive apneas over 1 hour, whereas reduced glutathione in the periphery was not affected.147Superoxide is involved in the generation of other ROS and reactive nitrogen species. One of these reactive nitrogen species, peroxynitrite, is produced when superoxide reacts with NO. Peroxynitrite uncouples endothelial NO synthase, whereby O119 After only 2 weeks of intermittent hypoxia in rats, dilations to acetylcholine in isolated middle cerebral arteries were attenuated by ≍90%.119 Activation of cholinergic receptors on the endothelium stimulate the synthesis of NO by endothelial NO synthase. Once generated in the endothelium, NO diffuses to the vascular smooth muscle and activates guanylyl cyclase, the initial step in a dilatory pathway. Phillips et al119 demonstrated that intermittent hypoxia did not alter the dilations when guanylyl cyclase was activated directly by sodium nitroprusside. Thus, attenuated dilations after intermittent hypoxia were the result of reduced NO  because the vascular smooth muscle still had the ability to dilate.Although studies of endothelial dysfunction in cerebral arteries are limited, intermittent hypoxia, a model for sleep apnea, produced endothelial dysfunction in rodents.112 amplified and extended the studies by Phillips et al.119 Increases in cortical blood flow in response to dilators requiring intact endothelium were attenuated by ≍40% after 14 and 35 days of intermittent hypoxia in mice. However, dilations in response to adenosine, which acts directly on the vascular smooth muscle, were not affected by intermittent hypoxia. ROS was enhanced significantly in both cerebral arterioles and neurons after intermittent hypoxia, as compared to tissues from control mice.112 Significantly, an acute application of a superoxide dismutase mimetic to decrease the oxidative stress completely restored the blood flow response to acetylcholine.112 The source of the ROS after the intermittent hypoxia was predominantly, if not exclusively, from superoxide generated by NADPH oxidase, because an inhibitor of NADPH oxidase or mice lacking functional NADPH oxidase-2 showed neither endothelial dysfunction nor enhanced tissue ROS after 35 days of intermittent hypoxia. The studies by Capone et al112 complement previous studies demonstrating a crucial role for brain NADPH oxidase in hypersomnolence and the decline in cognitive function after intermittent hypoxia or sleep fragmentation.150 Thus, intermittent hypoxia produces oxidative stress and decreases the bioavailability of endothelium-derived NO through superoxide derived from NADPH oxidase-2.In a recent study, Capone et al151 developed a model of OSA in rats in which apnea was elicited in unanesthetized freely ranging rats by remotely inflating a balloon implanted in the trachea. The balloon was inflated for 10 seconds 30 times per hour during 8 hours of the sleep cycle every day for 28 days. Dilations in isolated pressurized middle cerebral arteries, elicited by stimulating endothelial P2Y2 receptors by adenosine triphosphate, were attenuated by ≍40% compared to a control group that was surgically prepared but did not undergo apnea. Although the dilation in response to adenosine triphosphate was the result of multiple endothelial-dependent mechanisms of dilation,155 the attenuated response was due to suppression of the NO component.151 Thus, there is continuity with the findings from different animal models for OSA, intermittent hypoxia, and apnea.Crossland et al157; however, during pathological states, the vascular smooth muscle also can synthesize ET-1.157 Stimulation of endothelin receptor type B on the endothelium produces dilation of vessels through generation of NO, whereas stimulation of primarily endothelin receptor type A, but sometimes endothelin receptor type B, on the vascular smooth muscle produces potent and sustained constrictions.158 During normal physiological states, NO inhibits transcription and release of ET-1, reduces the interaction of ET-1 with endothelin receptors on smooth muscle, and interferes with second messenger signaling in the endothelin signaling pathway.160 However, during pathological states such as OSA, reduced NO bioavailability, as a result of the oxidative stress, allows the endothelin pathway to upregulate. The endothelin system further adds to the oxidative stress by enhancing the pathological cascade that generates ROS.164ET-1 is a potent vasoconstrictor that is involved with pathological processes, including OSA. The primary, but not exclusive, source for ET-1 in the vascular system is endothelial cells168 Intermittent hypoxia increased ET-1 in cerebral vessels of mice by ≍2 orders of magnitude and increased mRNA for endothelin-converting enzyme-1 and endothelin receptor type A but not mRNA for endothelin receptor type B.112 Furthermore, the increase in ET-1 expression occurred in both the endothelium and vascular smooth muscle. The attenuated cerebrovascular responses to acetylcholine with intermittent hypoxia were restored after acutely blocking endothelin type A receptors.112 Administration of the endothelin type A blocker also reduced ROS in cerebral vessels and neurons after intermittent hypoxia to the levels in control mice.112 It is interesting to note that either inhibiting NADPH oxidase-2 or blocking endothelin type A receptors reduced ROS and restored the cerebrovascular responses to endothelial-mediated dilations. Upregulation of NADPH oxidase often is associated with angiotensin II; however, with intermittent hypoxia, it seems that ET-1 replaces the role of angiotensin II in regulating NADPH oxidase. This alternative pathway is shown in 169 However, at this time, we do not know if inhibition of NADPH oxidase or scavenging ROS prevents upregulation of the endothelin system in the context of intermittent hypoxia. Answers to these and other significant questions are needed for a clear understanding of the relationships among NADPH oxidase, ROS, and the endothelin system.The endothelin system is upregulated in animal models of OSA and likely is upregulated with OSA in humans, although plasma ET-1 levels might not be increased.112 also demonstrated that the increases in cerebral perfusion resulting from sensory input  were attenuated after intermittent hypoxia. As with dilations involving stimulation of endothelial receptors, neurovascular coupling could be restored by inhibition of NADPH oxidase signaling  OSA is an independent risk factor for stroke, (2) OSA exacerbates damage produced by a stroke, (3) OSA increases the risk for a subsequent stroke, and (4) OSA contributes to brain atrophy and dementia in the elderly. OSA interferes with the basic control mechanisms for regulating CBF by decreasing resting CBF, impairing autoregulation, and reducing cerebrovascular reserve. These alterations to normal cerebrovascular control interfere with brain function and render the brain more vulnerable to ischemic events. Although we only have begun to understand the molecular and cellular mechanisms involved with cerebrovascular dysfunction in OSA, endothelial dysfunction, oxidative stress, and the endothelin system seem to have major roles. Given that OSA can continue for years without recognition and that most individuals with OSA go undiagnosed, it is logical that the damage to the cerebral circulation occurs over a long period of time, creating an environment that predisposes an individual to stroke, transient ischemia attacks, and dementia. Because our population is aging and becoming more obese (risk factors for OSA), the incidence of cerebrovascular disease associated with OSA should be expected to increase, and cerebrovascular disease should occur at an earlier age.


Most patients are readily liberated from mechanical ventilation (MV) support, however, 10% - 15% of patients experience failure to wean (FTW). FTW patients account for approximately 40% of all MV days and have significantly worse clinical outcomes. MV induced inspiratory muscle weakness has been implicated as a contributor to FTW and recent work has documented inspiratory muscle weakness in humans supported with MV.We conducted a single center, single-blind, randomized controlled trial to test whether inspiratory muscle strength training (IMST) would improve weaning outcome in FTW patients. Of 129 patients evaluated for participation, 69 were enrolled and studied. 35 subjects were randomly assigned to the IMST condition and 34 to the SHAM treatment. IMST was performed with a threshold inspiratory device, set at the highest pressure tolerated and progressed daily. SHAM training provided a constant, low inspiratory pressure load. Subjects completed 4 sets of 6-10 training breaths, 5 days per week. Subjects also performed progressively longer breathing trials daily per protocol. The weaning criterion was 72 consecutive hours without MV support. Subjects were blinded to group assignment, and were treated until weaned or 28 days.P = 0.36. The IMST and SHAM groups participated in 9.7 ± 4.0 and 11.0 ± 4.8 training sessions, respectively, P = 0.09. The SHAM group's pre to post-training maximal inspiratory pressure (MIP) change was not significant , while the IMST group's MIP increased . There were no adverse events observed during IMST or SHAM treatments. Twenty-five of 35 IMST subjects weaned  = 55% to 84%), while 16 of 34  SHAM subjects weaned, P = .039. The number of patients needed to be treated for effect was 4 (95% CI = 2 to 80).Groups were comparable on demographic and clinical variables at baseline. The IMST and SHAM groups respectively received 41.9 ± 25.5 vs. 47.3 ± 33.0 days of MV support prior to starting intervention, An IMST program can lead to increased MIP and improved weaning outcome in FTW patients compared to SHAM treatment.NCT00419458ClinicalTrials.gov:  Failure to wean (FTW) from mechanical ventilation (MV) is a significant clinical and economic problem. In 2003, approximately 300,00 patients required MV support for more than 96 hours in the USA and the estimated cost of these episodes was $16 billion [br/Pimax) has been implicated as a major contributor to this problem [The etiology of FTW is often complex, but an imbalance in the demand placed on the inspiratory muscles used to generate inspiratory pressure during tidal breathing and their maximal pressure generating capability , written informed consent was obtained from the patients or their legally designated surrogates. The trial was registered on Clinical Trials number NCT00419458. Patients were recruited from the adult medical, general surgical and burn ICUs of Shands Hospital at the University of Florida. Censuses of patients who were supported with MV were regularly queried and patients who had FTW with usual care were identified. Subjects were considered a FTW case when the patient failed to wean with usual care. Entry and exclusion criteria are shown in Table Subjects were studied from February 2004 until February 2009. The protocol was a single-blinded design with SHAM treatment. Subjects were blinded to their group assignment. Randomization was performed with a computerized random number generator and group assignments were sealed in opaque envelopes. Subjects were not randomized until they failed the initial BT.Maximal inspiratory pressure (MIP) was measured on the first day of participation, every Monday and on days when the subjects attempted a 12-hour aerosol tracheotomy collar (ATC) trial. MIP was measured using the method of Caruso et al. . Briefly2O. The Threshold PEP device is marketed as an expiratory positive pressure device, but can provide an inspiratory threshold load if one inspires through the exhalation port. An inspiratory threshold training device is commercially available , but we found that many patients were unable to open the poppet valve at the lowest pressure setting (8 cmH2O) on the Threshold IMT device. When performing IMST, the subjects were disconnected from the MV and the IMST device was attached to their tracheostomy tube with the cuff inflated. Subjects breathed room air during IMST. Subjects performed four sets of 6 to 10 breaths per day, with two minutes of rest with MV support between each set. The training device was set to the highest pressure setting that the subject could consistently open during inspiration, and was progressed daily as tolerated. Subjects were instructed to inhale and exhale as forcefully as possible during the IMST breaths. The IMST training program was based on clinical experience obtained prior to initiating this trial. Respiratory pressures at the tracheostomy tube were monitored during IMST and SHAM training with CO2SMO Plus respiratory monitors with Analysis Plus software  interfaced to a laptop computer.IMST was performed five days per week (Monday to Friday) with a threshold inspiratory muscle trainer , which provided a threshold inspiratory pressure load between -4 and -20 cmHThe SHAM group used a resistive inspiratory muscle training device  set on the largest opening. The Pflex device had a 3 mm hole drilled into the body, which further reduced the pressure required to generate airflow. Subjects performed SHAM training by being removed from the ventilator circuit and the training device was attached to the tracheostomy tube. Subjects breathed room air during SHAM treatment. Subjects performed four sets of 6 to 10 breaths, five days per week, and were instructed to breathe with long, slow inspiratory and expiratory efforts during training. SHAM subjects were given two minutes of rest with MV support between each set. IMST and SHAM treatments were normally conducted between 07.30 am and 09.00 am, Monday through Friday.PO2) below 90% for five minutes, respiratory rate above 35 breaths/min for five minutes, serious dysrhythmias, if the patient requested to be returned to MV support or there was clinical evidence of respiratory distress .All subjects participated in progressively lengthening BTs with reduced or no MV support. Three types of BT were used: ATC, continuous positive airway pressure (CPAP) and reduced pressure support trials. Trials were conducted seven days per week, usually commencing around 09.00 am and only one trial per day was attempted. The initial BT was an ATC trial, and patients were allowed to breathe without MV support as long as tolerated. Subjects who tolerated this initial ATC trial for 72 hours were considered weaned and were not studied. Criteria for terminating BT included: 30 beats/min or more increase in heart rate, systolic blood pressure above 180 mmHg or below 90 mmHg, oxygen-hemoglobin saturation ). If successful, the reduced pressure support trial duration was increased by one hour per day until reaching three hours whereupon they then began the CPAP and ATC trial progressions as detailed above.2SMO Plus respiratory monitor with Analysis Plus software  interfaced to a laptop computer. Prior to commencing the first and final BT, dynamic compliance and inspired and expired airway resistance were measured with the CO2SMO Plus respiratory monitors while the patients received their baseline level of MV support.Patients received usual nursing care during BT, but rehabilitation activities were withheld during BT until the patients could tolerate a six-hour ATC BT. Once patients could tolerate a six-hour BT, rehabilitation activity during BT was begun but reduced to approximately 50% of the normal duration and intensity until weaning. Breathing data during BT were monitored with ICU clinical bedside monitors and with a COP< 0.05.Categorical variables were analyzed with Chi-square tests. Between groups tests on continuous variables were analyzed with independent samples Student t tests. Within-group variables were analyzed with t tests for paired measures. Repeated measures analysis of variance (ANOVA) tests were used for variables with group, time factors, and group × times interactions. Cell means contrasts were used to explore differences when significant interactions were present in ANOVA. Statistical significance was set at The flow of subjects from evaluation to participation is shown in the CONSORT diagram Figure . The ranSix subjects did not fail during the initial ATC trial and were weaned without further intervention. These subjects were not randomized to treatment groups and were not included in the analysis. Three IMST subjects died during the 28-day treatment period, one withdrew from the study and two patients were transferred to other facilities before completing 28 days of treatment. These six subjects were classified as weaning failures. Three subjects in the SHAM group died during the 28-day treatment period and three subjects were transferred to other facilities before completing 28 days. These six subjects were also classified as weaning failures.P = 0.23).Excluding the initial BT, the IMST group performed 330 trials and the SHAM group performed 382 trials. The IMST and SHAM groups successfully completed 77.0% and 73.0% of the BT, respectively (P = 0.09). The mean training pressure setting on the IMST device was 7.2 ± 2.6 vs. 12.8 ± 3.6 cmH2O for the initial and final training bouts, respectively . Corresponding training pressure values for the SHAM group were -3.10 ± 1.54 and -3.36 ± 2.08 cmH2O (P = 0.86). The treatment × group interaction for pressure developed during training was significant (P< 0.0001). The SHAM group's pre to post-training MIP change was not significant , while the IMST group's MIP increased . There were no adverse events observed during IMST or SHAM treatments.The IMST and SHAM groups participated in 9.7 ± 4.0 and 11.0 ± 4.8 strength and SHAM training sessions, respectively (P = 0.039). The number of patients needed to be treated for effect was 4 (95% CI = 2 to 80).Twenty-five of 35 IMST subjects weaned  = 55% to 84%), while 16 of 34  SHAM subjects weaned  and failure (n = 28) groups were respectively; -44.0 ± 20.2 and -53.5 ± 20.7 cmH2O versus -43.9 ± 14.8 and -43.9 ± 15.0 cmH2O. A repeated measures ANOVA revealed a significant outcome × time interaction and the change in MIP for the successfully weaned group was significantly greater than the failure to wean group (P< 0.0001).In order to further explore the role of MIP changes in weaning outcome, we performed a Our primary findings were that the IMST rehabilitation program rapidly improved MIP and improved weaning outcome compared with the SHAM condition. The weaning rate (47%) achieved by the SHAM group was comparable with usual care conditions as reported in observational studies examining comparable FTW patients -26.br/Pimax ratio of successfully weaned patients was lower than FTW patients. Carlucci et al. [br/Pimax ratio, while those who FTW did not. Our findings also support a role for increased MIP in improved weaning outcomes.Other workers have shown that MIP is a poor predictor of extubation success -31. Sevei et al.  have recWe propose that respiratory muscle weakness is a greater contributor to failed weaning than fatigue. During failed BTs in FTW patients, respiratory distress is often clinically described as "fatigue". However, several authors have reported heightened respiratory muscle activity during failed BTs compared with stable respiratory muscle activity among patients who successfully completed BTs. For example, Teixeira et al.  measuredAlternatively, we hypothesize that inspiratory muscle weakness initiates a high proportional ventilatory drive requirement during unassisted BT, when weakened inspiratory muscles must generate increased muscle tension in order to adequately ventilate the lungs. During MV support, a relatively low motor drive elicits large, ventilator-assisted tidal volume breaths. When an unsupported BT begins, a discrepancy between the elevated respiratory drive and afferent lung volume feedback can lead to an increased awareness of respiratory effort . PerceivOngoing efferent-afferent feedback errors propel a positive feedback loop, resulting in the progressively higher levels of respiratory drive, inspiratory esophageal pressure, and work of breathing reported by others, and it may lead to clinical respiratory distress ,36. If tStrengthening the inspiratory muscles theoretically could correct the feedback discrepancy between respiratory drive and lung/chest expansion and may result in a lower perception of breathing effort. The perception of breathing effort has been experimentally altered by manipulations of inspiratory muscle strength. Campbell et al.  studied Whenever severely debilitated patients undergo muscle strength training, the possibility of exercise-induced muscle damage must be considered. Human ,43 studiOur results are encouraging, but limitations must be acknowledged. The weaning results were significant, but this was a single site study with a relatively small sample size. Our IMST method is not suitable for all FTW patients. Patients must be sufficiently alert to cooperate with IMST, and patients whose FTW etiology is not the result of treatable inspiratory muscle weakness are unlikely to benefit from IMST. Our subjects were recruited primarily from surgical ICUs, with approximately 22% of the subjects treated in the medical ICU.In conclusion, we found an improved MIP and weaning outcome with IMST compared with SHAM training in medically complex, long-term FTW patients. IMST is a clinically practical and safe method to improve weaning outcome in selected FTW patients.• IMST can rapidly increase MIP in medically complex, long-term FTW patients.• IMST, in conjunction with BT, can increase the number of FTW patients weaned versus SHAM training plus BT.br/Pimax: ratio of inspiratory tidal breathing pressure to maximal inspiratory pressure; SpO2: oxygen-hemoglobin saturation.ANOVA: analysis of variance; ATC: aerosol tracheotomy collar; BT: breathing trials; CI: confidence interval; CPAP: continuous positive airway pressure; FTW: failure to wean; IMST: inspiratory muscle strength training; MIP: maximal inspiratory pressure; MV: mechanical ventilation; PEEP: positive end expiratory pressure; PiThe University of Florida and Drs Martin, Gabrielli and Banner have applied for a patent to modify clinical mechanical ventilators to provide threshold inspiratory muscle training to patients receiving mechanical ventilation support.ADM had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. ADM, Gabrielli, MBanner, LJC, PD, EH and RJG contributed to study concept and design. ADM, BKS, TH and HD contributed to acquisition of data. ADM, AG, PD, MBanner, EH, MBaz, RJG and BKS contributed to analysis and interpretation of data. ADM, BKS, MBanner, RJG and AJL contributed to drafting of the manuscript. AG, PD, MBanner, EH, MB, HD, TH, RJG and AJL contributed to critical revision of the manuscript for important intellectual content. ADM, BKS, HD and TH contributed to statistical analysis. ADM obtained funding. This project was supported by NIH R01HD42705 to ADM. AJL, MBanner, LJC and MBaz contributed to administrative, technical, or material support. ADM, AG, LJC, EH, AJL, MBaz and RJG contributed to study supervision.


The consumption of beetroot juice on a low nitrate diet may lower blood pressure (BP) and therefore reduce the risk of cardiovascular events. However, it is unknown if its inclusion as part of a normal diet has a similar effect on BP. The aim of the study was to conduct a randomized controlled trial with free-living adults to investigate if consuming beetroot juice in addition to a normal diet produces a measureable reduction in BP.Fifteen women and fifteen men participated in a double-blind, randomized, placebo-controlled, crossover study. Volunteers were randomized to receive 500 g of beetroot and apple juice (BJ) or a placebo juice (PL). Volunteers had BP measured at baseline and at least hourly for 24-h following juice consumption using an ambulatory blood pressure monitor (ABPM). Volunteers remained at the clinic for 1-h before resuming normal non-strenuous daily activities. The identical procedure was repeated 2-wk later with the drink (BJ or PL) not consumed on the first visit.P=0.064) to lower systolic blood pressure (SBP) at 6-h after drinking BJ relative to PL. Analysis in men only (n=13) after adjustment for baseline differences demonstrated a significant (P<0.05) reduction in SBP of 4 – 5 mmHg at 6-h after drinking BJ.Overall, there was a trend (Beetroot juice will lower BP in men when consumed as part of a normal diet in free-living healthy adults.anzctr.org.au ACTRN12612000445875 The getables -16.3-[Beetroot is a rich source of dietary NO3- and a nu3-,17-20, wAlthough beetroot appears to be a promising means of lowering blood pressure, previous studies in free-living subjects have been small in size and routinely used a controlled diet in combination with administering the beetroot juice. It is not clear whether a blood pressure-lowering effect may be seen when beetroot juice is consumed on top of a normal diet. The present study examines the use of beetroot juice as a means of regulating blood pressure in free-living individuals whilst not imposing any dietary restrictions.The nitrate was administered as Sunraysia Beetroot and Apple Juice (72% beetroots and 28% apples) (BJ), containing 15 mmol nitrate/L . The placebo (PL) consisted of an apple juice concentrate base matched to the BJ for sweetness (sucrose) and colour (carmine red and rubini red). Both the BJ and PL were supplied by The Sunraysia Natural Beverage Company, Melbourne, VIC.A total of thirty healthy volunteers  were recruited for the trial from Melbourne, Australia. The primary inclusion criterion was a systolic blood pressure (SBP) of greater than 120 mmHg at the time of administering the first treatment. Subjects who were pregnant/lactating, on blood pressure medication or had been diagnosed with diabetes mellitus were excluded from participating. Written informed consent was obtained from all volunteers prior to participation in the study. The study was approved by the Alfred Research Human Ethics Committee (377/11) and took place in January 2012.The study was designed as a double-blind, randomized, crossover, intervention trial in which volunteers were asked to consume 500 g of either BJ or PL on a single occasion. No dietary restrictions were placed on the subjects prior to visits, in the 24 h period following consumption of the BJ or PL or during the 2-wk washout period.Subjects arrived at the clinic at approximately 0800 h on the day of treatment in a non-fasted state (light breakfast only), having performed no more than light physical activity on the study day. Subsequent to anthropometric measurements (height and body weight) and a rest period of 5-min, subjects were fitted with an ABPM  to measure SBP, diastolic blood pressure (DBP) and pulse rate. Three baseline blood pressure measurements were recorded by the ABPM at intervals of 2-min apart with the subject in a seated position. If the subject recorded an average baseline SBP of greater than 120 mmHg they were randomly assigned by computer software to receive the BJ or PL, which was then consumed immediately in unmarked glasses over the course of 5 to 10-min. Subjects remained in a seated and unfed state at the clinic for 1-h post-drink consumption, during which time three BP measurements were taken by the ABPM. Subjects then left the clinic and resumed normal daily tasks whilst continuing to wear the ABPM for a further 23-h. Subjects were instructed not to undertake any moderate or intense physical activity  during this time and to loosely hang their cuffed arm by their side during BP readings. ABPM measurements were automatically taken half-hourly during the active period (0700 h – 2300 h) and hourly during the remaining passive period. An activity log book was also given to volunteers to record actual awake and sleeping times and the times of any ‘unusual’ events that may have effected BP measurements . Subjects returned to the clinic 24-h following the treatment to have the ABPM removed. Subjects returned to the clinic 2-w later, and repeated the same methodology with the drink (BJ or PL) not consumed on the first visit.P<0.05).Power calculations were based on a previous similar study  where thP<0.05.The data from the BP monitors was transferred into Microsoft Excel  and then analyzed using statistical software . The ABPM provided all raw data as well as averages for active/ day time (0600 – 2259 h) or passive / night time (2300 to 0559 h) periods. Averages were calculated for baseline BP from the 3 measures taken, over 3 to 4-h, 6 to 7-h or 23 to 24-h after the drink. Depending on the number of successfully recorded measurements in each period, there may have been 1–3 values in each of these time periods. Repeated measures analysis of covariance was used with a covariate of the difference between baseline blood pressure on the two days (ANCOVA). A separate analysis with a post hoc removal of outliers (>3SD drop in blood pressure after ingestion of the juice) was also performed. Given the previous results showing men showed greater effects, a planned analysis in men only was performed. In all cases, differences were deemed significant at Satisfactory blood pressure recordings were reported by the 15 men and 15 women Table . The numOverall, there was no significant difference in treatments for any parameter except day time pulse pressure (difference between systolic and diastolic pressures) of 1 mmHg higher on the PL treatment Table . There wP=0.064), with men showing a difference of −4.7 mmHg, (P=0.1) and women a difference of −2.5 mmHg (P=0.5). In the planned ANCOVA in men only BJ treatment was significantly different from placebo (P=0.007) and a treatment covariate interaction was observed (P=0.024). In those subjects with little variation in baseline BP measures there was a clear effect of BJ. In those subjects with a large variation in baseline BP measures, SBP did not change with BJ and increased with PL, although the difference between the drinks was smaller.Individual BP changes from baseline after each treatment showed a drop of 4.6 mmHg with BJ and 3.4 mmHg with PL at 3-h, 6.2 mmHg and 2.2 mmHg respectively at 6-h and 4.5 mmHg and 2.3 mmHg respectively, at 24-h. Statistically the 6-h difference was a trend overall (n =2) were removed. In the remaining 13 men the 6-h difference between PL and BJ of 4.9 mmHg was statistically significant (P=0.042).In a post hoc analysis of outliers, those men with large drops in BP (≥ 20 mmHg SBP) at 6-h following drink consumption on either treatment  on BP, thus making interpretation of study results more straightforward. The drawback, however, is that beetroot juice as a nutritional intervention to regulate BP would likely be consumed as part of a normal diet, not as part of a low nitrate diet or in the absence of other dietary components  that may affect BP [It has been postulated that the inclusion of dietary nitrates in the form of beetroot-derived foods may be useful in the regulation of normal BP due their high inorganic NOffect BP -23. It wper se, or whether the older age of the women (48.9 ± 3.1 y) compared to the men (36.2 ± 2.9 y) may have influenced the variation seen. It is also notable that approximately half of the women (n=8) who participated in the study took prescription medication, whilst none of the men did. The crossover design of the study should have eliminated any individual variation in blood pressure due to any medication taken daily on the two 24 h periods that BP was measured. However, the possibility of the effect of medication or diet (e.g. sodium intake) on the outcomes of the trial cannot be discounted and ideally the experiment should be repeated in non-medicated individuals and the dietary intake recorded. Two of the studies in the literature investigating beetroot juice and BP that used both men and women did not report results by gender [3 (or KCl) in capsules in a double-blind crossover study in 8 males (baseline BP 126/73 mmHg) and 12 females (baseline BP 102/67 mmHg) and found that the KNO3 lowered systolic BP by 9.4 mmHg at 6-h and diastolic by 6 mmHg at 2.5-h (systolic lowering was 6 mmHg at this time point) [P<0.001) between men and women in that particular study as it was noted that decreases in BP were correlated with baseline BP (r= 0.66 to 0.7). In the present study, baseline BP readings were remarkably similar between men (132/80 ± 2.2/1.8 mmHg) and women (133/83 ± 2.3/1.7 mmHg). It is difficult to ascertain if there is in fact a gender-specific response to dietary nitrates.Unsurprisingly, there was a large degree of variation in the BP readings for a given individual both across the two measurement days and throughout each day. This may have been a result of the free-living nature of the study. Whilst there was no significant difference in baseline SBP or DBP between men and women, the trend of BJ lowering BP was stronger in men than in women and a planned separate analysis in men showed that BJ lowered SBP by 4–5 mmHg at 6-h after ingestion. It is uncertain whether these differences between the sexes was a result of gender y gender . The thie point) . Femaleset al. demonstrated that 500 ml of beetroot juice containing 45 mmol/L (or 2.79 g/L) of NO3- lowered BP by a maximum of 10/4.8 mmHg at approximately 3-h  and the effect persisted in SBP for 24-h [The drop of 4–5 mmHg observed in the study reported here at 6-h after consumption in men is smaller and with a later peak drop in BP than in other controlled studies with beetroot juice. In an open-label and unblinded study, Webb 3- relative to the control (water), and 22.2/18.3 mmHg with twice that dose of NO3-. Once again, subjects  were fasted for 12-h and the diet was restricted  in the 24-h prior to the test and were provided with a standard evening meal for the night before each visit and for the lunch and dinner of the study day. Subjects were also instructed not to take any dietary supplements, vitamins or minerals for 1-wk prior to the study or during the intervention period. Subjects were also required to meet a large number of inclusion criteria including not smoking, not exercising more than 3 times / wk (<20 min/session) and not consuming > 150 ml alcohol / wk. The highly controlled nature of this study may have been responsible for the particularly large decreases in BP observed.More recently, Hobbs and workers  conducteet al. tested 250 ml beetroot juice (5.5 mmol NO3-) relative to a water control [3- and NO2- were elevated for 3-h following beetroot juice ingestion. In another study, Vanhatalo et al. tested 8 volunteers  with 0.5 l beetroot juice daily, in two equal doses in the morning and evening, for 5 days against a placebo  in a randomized, crossover study with a 10-d washout period [Two other studies have also reported a reduction in BP from beetroot juice, but the number of study participants was small. In an open-label study in 9 volunteers (gender not stated) Kapil  control . A peak t period . On day t period , the exp3 levels before and after consumption of the BJ and PL in order to establish a causative relationship between the NO3 present in beetroot and the effect on plasma NO3 levels leading to a reduction in BP. This would assist in eliminating other possible causes of the effect seen, such as the diuretic property of beetroot.As a higher baseline BP has been correlated with a larger reduction in BP following BJ ingestion  it is poIn conclusion, it was demonstrated here that in free-living people consuming an unrestricted diet and a single dose of 500 g of beetroot and apple juice, a trend to lower blood pressure by 4–5 mmHg at 6-h was observed (significant only in men after adjustment for baseline variation). A reduction in SBP in the magnitude of 5 mmHg has been correlated to a cardiovascular mortality reduction of approximately 10% at the population level . AdditioABPM: Ambulatory blood pressure monitor; BJ: Beetroot and apple juice; BP: Blood pressure; DBP: Diastolic blood pressure; PL: Placebo; SBP: Systolic blood pressure.The authors declare that they have no competing interests. The Sunraysia Natural Beverage Company  funded this study but was not involved in its design or the collection, analysis or interpretation of data.PC designed the study, analysed the data and had primary responsibility for final content. LC conducted the study and drafted the report. Both authors read and approved the final manuscript.


Cardiovascular morbidity and mortality is high in patients with chronic obstructive pulmonary disease (COPD) and arterial stiffness is a potentially modifiable risk factor with added predictive value beyond that obtained from traditional risk factors. Arterial stiffness has been the target of pharmacologic and exercise interventions in patients with COPD, but the effects appear limited to those patients with more significant elevations in arterial stiffness. We aimed to identify predictors of increased arterial stiffness in a cohort with moderate to severe COPD.Aortic pulse wave velocity (aPWV) was measured in subjects with moderate to severe COPD enrolled in a multicenter randomized controlled trial. Subjects were categorized into quartiles based on aPWV values and factors affecting high arterial stiffness were assessed. Multivariate models were created to identify independent predictors of high aPWV, and cardiovascular disease (CVD).1 was 55.4 (SD 15.2) % predicted. Compared to the quartile with the lowest aPWV, subjects in the highest quartile were older, had higher systolic blood pressure (SBP), were more likely to be current smokers, and had greater burden of thoracic aortic calcification. On multivariate analyses, age  and SBP  were independent predictors of elevated aPWV. Body mass index, therapy with cholesterol lowering medications and coronary calcification were independent predictors of CVD.153 patients were included. Mean age was 63.2 (SD 8.2) years and mean FEVElevated arterial stiffness in patients with COPD can be predicted using age, blood pressure and thoracic aortic calcification. This will help identify subjects for enrollment in clinical trials using aPWV for assessing the impact of COPD therapies on CV outcomes.NCT00857766Clinicaltrials.gov  Cardiovascular morbidity and mortality is high in patients with chronic obstructive pulmonary disease (COPD) and this appears to be independent of established risks such as smoking, gender and age -3. A plaArterial stiffness is a potentially modifiable risk factor and has added predictive value beyond that obtained from traditional risk factors -13. Arte1)/forced vital capacity (FVC) ratio ≤ 0.70, and FEV1 <80% predicted. Patients had to be on stable doses of medications for diabetes mellitus, hyperlipidemia and cardiovascular disease for at least 3 months prior to enrolment. Baseline demographic and clinical characteristics were used for all analyses. Cardiovascular disease included a history of coronary artery disease , cerebrovascular disease (stroke and transient ischemic attacks), or peripheral arterial disease.Subjects with moderate to severe COPD enrolled in a multicenter, randomized controlled study (NCT00857766) were included. Written informed consent was obtained from all participants, and the study was approved by the Institutional Review Board at the University of Alabama (IRB No. W110208001). Details of the study design have been published previously . BrieflySerum was obtained for measurement of lipids, blood glucose, and inflammatory markers .Aortic pulse wave velocity (aPWV) was measured using the SphygmoCor™ system  by sequentially recording ECG-gated carotid and femoral artery waveforms by applanation tonometry. The distance between the site of measurement over the carotid and femoral arteries was divided by the wave transit time, averaged over ten cardiac cycles.> 130 HU). Coronary arterial calcification was first scored using the semi-automated calcium analysis software and then manually corrected by a technologist when mischaracterized by the software algorithm. A radiologist (HN or JW) then individually reviewed each case and additional corrections were made as needed. Thoracic aortic calcifications were scored separately using the same technique. Thoracic aorta was defined as the aorta, excluding brachiocephalic arteries, extending from aortic valve to the origin of the celiac axis.Multidetector computed tomography (CT) was used for quantitative estimation of emphysema. Scans were obtained at full inspiration . Percentage emphysema was calculated using the percentage of lung volume at total lung capacity with attenuation less than −950 Hounsfield Units (HU) using the Pulmonary Workstation 2.0 Software . Coronary artery calcification (CAC) and thoracic aortic calcification (TAC) were assessed using a post-imaging processing application  using the Food and Drug Administration-approved Calcium Analysis Tool. Coronary arterial calcification score was assessed by obtaining the sum of each CT slice’s area of calcification multiplied by a coefficient based on the peak CT number (Agatston score). Areas of calcification were defined by the standard scoring threshold  and chi square tests as appropriate. Variables significant on univariate analyses were entered into a multinomial regression model with the lowest aPWV quartile as reference to find independent predictors of the highest aPWV. Subjects with and without CVD were compared, and predictors of CVD were assessed using logistic regression by including variables significant on univariate analyses. All analyses were performed with SPSS software (version 20.0) and a p value <0.05 was used to define statistical significance.Of the 249 patients enrolled in the clinical trial, 153 patients with complete CT data were included in the current analysis , number of pack-years of smoking , systolic blood pressure , temperature , plasma glucose , logCAC , logTAC, and CVD . LDL-cholesterol  and treatment with lipid lowering medications  were not associated with aPWV. There was no association between aPWV and markers of inflammation, C-reactive protein  and fibrinogen , or with diabetes mellitus . There was also no association between %emphysema on CT scan and aPWV  though a relationship was observed when log %emphysema was used . On multivariate analyses, there was a significant association between aPWV and age, glucose, temperature and systolic blood pressure (Table Subjects were divided into four quartiles based on percentile aPWV Table . On compWe also assessed predictors of prevalent CVD and found that BMI, markers of dyslipidemia, cholesterol lowering medications, coronary calcification and aPWV were significantly associated with CVD on univariate analyses Table . On multWe have shown that in patients with moderate to severe COPD, arterial stiffness can be predicted by older age, higher systolic blood pressure and greater thoracic aortic calcification. These factors could be used to select patients for clinical trials aimed at modifying aPWV as a surrogate for CVD risk.A large proportion of patients with COPD die from cardiovascular causes rather than from respiratory failure, especially in mild to moderate disease, and this appears to be independent of traditional risk factors for CVD . EffortsWhile arterial calcification is a robust predictor of CVD, it is probably not modifiable. aPWV is the gold standard for measuring arterial stiffness and population based studies have shown that it is an independent risk factor for cardiovascular disease -27. MultThis study has some limitations. CT scans included in this study were not EKG-gated; however, a recent study showed that non-gated computed tomography is reliable for estimation of TAC and CAC . In addiIn summary, this study demonstrates that in patients with COPD elevated arterial stiffness can be predicted using age, blood pressure and thoracic aortic calcification. This will help identify subjects for enrollment in clinical trials using aPWV for assessing the impact of COPD therapies on CV outcomes. In addition, the findings suggest that aPWV may be an important predictor of CVD in subjects with COPD.S P B, A G C, J M W, H N, and J R W report no conflicts of interest. J R C received a research grant from GlaxoSmithKline to do this study. M T D reports consultant fees and speaker fees from GlaxoSmithKline and Boerhinger Ingelheim. The authors declare that they have no competing interests.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/14/1/prepub


According to the National Heart, Lung, and Blood Institute of the National Institute of Health, hypotension refers to an abnormally low blood pressure (BP). In childhood, hypotension can be determined according to two different definitions: BP below the 5th percentile or below two standard deviations (SDs) of the mean for age and gender . A graphWe used a computerized calculation method to develop high-resolution graphics containing curves with 5,841 points each, to depict the main percentiles associated with low BP for girls from 1 to 17 years old in the 50th percentile of height. Each point represents the calculation of the polynomial equation that includes the statistical processing of the last Report on Blood Pressure in 2004 . We alsoFive monotonic curves of systolic BP for girls representing the 50th, 25th, 10th, 5th, and 2.275th (-2SD) percentiles were built (Figure The correction of systolic BP for height is of little significance, and this updated graphic can be used to diagnose low systolic BP for girls. Clinical studies are necessary to determine the systolic BP percentile that better represents clinically significant hypotension.


Chronic renal failure is an important and common complication of diabetes mellitus; hence, renal transplantation is a frequent and the acceptable treatment in patients with diabetic nephropathy requiring renal replacement therapy. On the other hand, renal transplantation and its conventional treatment can lead to increased diabetes outbreak in normoglycemic recipients. Also, uncontrolled hyperglycemia may be increased and allograft lost thus decreasing patient survival.We aimed to assess the frequency of hyperglycemia in transplant patients and its risk factors.A large retrospective study was performed on 3342 adult kidney transplant recipients between 2008 and 2010. Demographic and laboratory data were gathered for each patient. All tests were done in a single laboratory and hyperglycemia was defined as a fasting plasma glucose of > 125 mg/dL. Univariate and multivariate logistic regression analyses were used to determine the risk factors of hyperglycemia following kidney transplantation.There were 2120 (63.4%) males and 1212 (36.3%) females. Prevalence of hyperglycemia was 22.5%. By univariate linear regression, hyperglycemia was significantly higher in patients with CMV infection (P = 0.001), elevated serum creatinine (P = 0.000), low HDL (P = 0.01), and increased blood levels of cyclosporine (P = 0.000). After adjusting for covariates by multivariate logistic regression, the hyperglycemia rate was significantly higher for patients with Cyclosporine trough level > 250 (P = 0.000), serum creatinine > 1.5 (P = 0.000) and HDL < 45 (P = 0.03).This study indicated that hyperglycemia is a common metabolic disorder in Iranian kidney transplant patients. Risk factors for hyperglycemia were higher Cyclosporine level, impaired renal function, and reduced HDL value. Diabetes mellitus (DM) is considered as one of the most costly diseases and important causes of end-stage renal disease (ESRD) throughout the world . HyperglAlthough some studies have shown that kidney transplant recipients with DM have an increased risk of allograft rejection , many stThere are limited data available regarding the prevalence of hyperglycemia after kidney transplantation among Iranian transplant recipients , 14-16. We carried out a retrospective analysis lab data of all adult patients (age > 18 years) who underwent renal transplantation at 8 academic hospitals of Tehran, Iran referred to Gholhak laboratory during 2008-2010. Living related and deceased kidney transplants were both included. We obtained 14986 lab data in 3342 renal transplant recipients within the period of the study. Ethics approval was supplied by the local ethics committee of Baqiyatallah university. We excluded patients who suffered from transient hyperglycemia due to steroid pulse, incomplete data and rejected allograft.Data recorded for all of the patients were age, sex, fasting plasma glucose level (FBS), serum creatinine concentration (Cr), low-density lipoprotein (LDL), high-density lipoprotein (HDL), uric acid, hemoglobin (Hb), trough level of cyclosporine (C0) and cytomegalovirus Ag (CMV Ag).We defined hyperglycemia as fasting plasma glucose of > 125 mg/dL, according to the world American diabetes association .The maintenance of immunosuppression in all patients was based on Cyclosporine neoral plus Mycophenolate mofetil or Azathioprine and Prednisolone. The amount of cyclosporine given to transplant patients was mostly based on drug levels in the blood. Monitoring of Cyclosporine using its trough levels was periodically performed at different times and dose was adjusted as necessary. In our treatment strategy, target therapeutic ranges for Cyclosporine levels were 200 to 300 ng/mL during the first 3 months, 100 to 250 ng/mL during 4 to 12 months and 100 to 150 ng/mL past 1 year from transplantation.CMV pp65 antigenemia was detected by Brite TM Turbu  and Cyclosporine levels were determined with Cobas Mira-Plus analyzer (Roche). Statistical analyses were performed using the SPSS software . All numeric data were presented as mean ± standard deviation. Differences between the quantitative variables were compared using the Chi square test or the Fisher exact test. The student t test was used for evaluating continuous quantitative variables. The univariate linear regression and multivariate logistic regression were performed for risk factors associated with hyperglycemia. A P value of less than 0.05 was considered statistically significant.There were 3342 renal transplant patients, 2120 males (63.4%) and 1212 females (36.3%), referred to a single laboratory from 8 academic transplant centers. The majority of the patients (93.4%) received a kidney from a living donor (85.2% unrelated and 8.2% related). The mean age of recipients was 37 ± 16 years . The majority of patients were followed up for more than one year (92.6%), while 3.5% of the recipients had 3-12 month follow ups and 3.9% had less than 3 months of follow ups. Patients with hyperglycemia were older compared to normoglycemic recipients . The preHyperglycemia patients had significantly higher rates of CMV infection, elevated plasma cyclosporine levels and increased plasma creatinine levels as compared to normoglycemic recipients By univariate linear regression, the prevalence of hyperglycemia was significantly higher in patient with CMV infection (P = 0.001), impaired renal allograft function (P = 0.000), low HDL (P = 0.01), and elevated plasma cyclosporine levels (P = 0.000). After adjusting for covariates by multivariate logistic regression, hyperglycemia rate was significantly higher for patients with plasma cyclosporine trough level > 250 , plasma Cr > 1.5 mg/dL  and HDL < 45 mg/dL .In the current study, hyperglycemia was a frequent problem among renal transplant recipients. Perez-Flores et al. showed that hyperglycemia was a common complication after kidney transplantation and it was present in 65% of their patients . The incHyperglycemia is a common and contributing factor for the outcome of kidney transplantation. Our study was able to confirm previous findings by showing an increased risk of renal allograft impairment associated with PTDM , 20, 21.Several risk factors for the development of hyperglycemia after transplantation have been previously described, which include advanced age, male donor, infections , obesity , immunosAlthough no significant correlation was seen between hyperglycemia and Hb concentration, hyperglycemic recipients were more likely to be anemic as compared to normoglycemic patients; also matching other research .The main limitation of the present study resides in its retrospective design. As a result, data about family history, BMI, metabolic syndrome, and BP were not accessible. However; we believe that this limitation exists in nearly all retrospective studies using secondary data collection. We could not consider all confounding factors in this study.In conclusion, this study indicated that hyperglycemia is a common metabolic disorder in Iranian kidney transplant patients. These results confirmed the importance of an appropriate control of cyclosporine levels among patients undergoing kidney transplantation.