Shilpa Rahangdale

Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold

Recent insights into sleep apnoea pathogenesis reveal that a low respiratory arousal threshold (awaken easily) is important for many patients. As most patients experience stable breathing periods mediated by upper-airway dilator muscle activation via accumulation of respiratory stimuli, premature awakening may prevent respiratory stimuli build up as well as the resulting stabilization of sleep and breathing. The aim of the present physiological study was to determine the effects of a non-benzodiazepine sedative, eszopiclone, on the arousal threshold and the AHI (apnoea/hypopnoea index) in obstructive sleep apnoea patients. We hypothesized that eszopiclone would increase the arousal threshold and lower the AHI in patients with a low arousal threshold (0 to -15 cm H(2)O). Following a baseline overnight polysomnogram with an epiglottic pressure catheter to quantify the arousal threshold, 17 obstructive sleep apnoea patients, without major hypoxaemia [nadir SaO(2) (arterial blood oxygen saturation) >70%], returned on two additional nights and received 3 mg of eszopiclone or placebo immediately prior to each study. Compared with placebo, eszopiclone significantly increased the arousal threshold [-14.0 (-19.9 to -10.9) compared with -18.0 (-22.2 to -15.1) cm H(2)O; P<0.01], and sleep duration, improved sleep quality and lowered the AHI without respiratory event prolongation or worsening hypoxaemia. Among the eight patients identified as having a low arousal threshold, reductions in the AHI occurred invariably and were most pronounced (25±6 compared with 14±4 events/h of sleep; P<0.01). In conclusion, eszopiclone increases the arousal threshold and lowers the AHI in obstructive sleep apnoea patients that do not have marked overnight hypoxaemia. The greatest reductions in the AHI occurred in those with a low arousal threshold. The results of this single night physiological study suggest that certain sedatives may be of therapeutic benefit for a definable subgroup of patients. However, additional treatment strategies are probably required to achieve elimination of apnoea.

Effects of diabetes and obesity on vascular reactivity, inflammatory cytokines, and growth factors.

We examined the influences of obesity and diabetes on endothelium‐dependent and ‐independent vasodilation, inflammatory cytokines, and growth factors. We included 258 subjects, age 21–80 years in four groups matched for age and gender: 40 healthy nonobese (BMI <30 kg·m−2) nondiabetic subjects, 76 nonobese diabetic patients, 37 obese (BMI >30) nondiabetic subjects, and 105 obese (BMI >30) diabetic patients. The flow‐mediated dilation (FMD, endothelium‐dependent) and nitroglycerin‐induced dilation (NID, endothelium‐independent) in the brachial artery, the vascular reactivity at the forearm skin and serum growth factors and inflammatory cytokines were measured. FMD was reduced in the nonobese diabetic patients, obese nondiabetic controls, and obese diabetic patients (P < 0.0001). NID was different among all four groups, being highest in the obese nondiabetic subjects and lowest in the obese diabetic patients (P < 0.0001). The resting skin forearm blood flow was reduced in the obese nondiabetic subjects (P < 0.01). Vascular endothelial growth factor (VEGF) was higher in the obese nondiabetic subjects (P < 0.05), tumor necrosis factor–α was higher in the obese diabetic patients (P < 0.0001) and C‐reactive protein was higher in both the obese nondiabetic and diabetic subjects (P < 0.0001). Soluble intercellular adhesion molecule‐1 was elevated in the two diabetic groups and the obese nondiabetic subjects (P < 0.05). We conclude that diabetes and obesity affect equally the endothelial cell function but the smooth muscle cell function is affected only by diabetes. In addition, the above findings may be related to differences that were observed in the growth factors and inflammatory cytokines.

The effect of increased genioglossus activity and end-expiratory lung volume on pharyngeal collapse.

Increasing either genioglossus muscle activity (GG) or end-expiratory lung volume (EELV) improves airway patency but not sufficiently for adequate treatment of obstructive sleep apnea (OSA) in most patients. The mechanisms by which these variables alter airway collapsibility likely differ, with increased GG causing airway dilation, whereas increased EELV may stiffen the airway walls through caudal traction. We sought to determine whether the airway stabilizing effect of GG activation is enhanced when EELV is increased. To investigate this aim, 15 continuous positive airway pressure (CPAP)-treated OSA patients were instrumented with an epiglottic catheter, intramuscular GG-EMG electrodes, magnetometers, and a nasal mask/pneumotachograph. Subjects slept supine in a sealed, head-out plastic chamber in which the extra-thoracic pressure could be lowered (to raise EELV) while on nasal CPAP with a variable deadspace to allow CO(2) stimulation (and GG activation). The pharyngeal critical closing pressure (P(CRIT)) was measured by sudden reduction of CPAP for three to five breaths each minute during non-rapid eye movement (NREM) sleep in 4 conditions: a) baseline, b) 500 ml increased EELV, c) 50% increased GG, and d) conditions b and c combined. P(CRIT) was found to be reduced from 2.2 + or - 0.7 cmH(2)O at baseline to -1.0 + or - 0.5 with increased EELV, 0.6 + or - 0.7 with increased GG and -1.6 + or - 0.7 when both variables were raised (P < 0.001). The slope of the P(CRIT) curves remained unchanged in all conditions (P = 0.05). However, the CPAP level at which flow limitation developed was lower in both increased EELV conditions (P = 0.001). These findings indicate that while both increased GG and EELV improve airway collapsibility, the combination of both variables has little additional effect over increasing EELV alone.

Vascular Dysfunction in Obstructive Sleep Apnea and Type 2 Diabetes Mellitus

Despite the high prevalence of obstructive sleep apnea (OSA) in type 2 diabetes mellitus (DM), the attributable vascular risk from each condition is unknown. We hypothesize that OSA may have a similar effect on vascular function as type 2 diabetes does. Healthy normal‐weight subjects, healthy obese subjects, subjects with type 2 diabetes, and obese subjects with OSA were enrolled. Vascular function was assessed with brachial artery ultrasound for flow‐mediated dilatation (FMD) and in skin microcirculation by laser Doppler flowmetry. One hundred fifty‐three subjects were studied: healthy normal‐weight controls (NCs) (n = 14), healthy obese controls (OCs) (n = 33), subjects with DM (n = 68), and obese subjects with OSA (n = 38). The DM group did not undergo sleep study and thus may have had subclinical OSA. The OSA and type 2 diabetes groups had impaired FMD as compared to both the normal‐weight and OC groups (5.8 ± 3.8%, 5.4 ± 1.6% vs. 9.1 ± 2.5%, 8.3 ± 5.1%, respectively, P < 0.001, post hoc Fischer test). When referenced to the NC group, a multiple linear regression model adjusting for covariates found that baseline brachial artery diameter (β = −3.75, P < 0.001), OSA (β = −2.45, P = 0.02) and type 2 diabetes status (β = −2.31, P = 0.02), negatively predicted % FMD. OSA status did not seem to affect nitroglycerin‐induced vasodilation (endothelium‐independent) of the brachial artery or vascular function in the skin microcirculation. OSA impairs endothelial function in the brachial artery to a similar degree as type 2 diabetes does. OSA, however, does not appear to affect brachial endothelium‐independent vasodilation or skin microcirculatory function. Treatment of OSA in patients with concomitant type 2 diabetes, therefore, may be a potential therapeutic option to improve macro‐, but not microvascular outcomes.

Effect of mild, asymptomatic obstructive sleep apnea on daytime heart rate variability and impedance cardiography measurements.

Dysregulation of autonomic nervous system dynamics is important in the pathophysiology of cardiovascular risk in obstructive sleep apnea (OSA). Heart rate variability (HRV) and impedance cardiography measures can estimate autonomic activity but have not gained traction clinically. The hypothesis of this study was that even in a cohort of patients with mild, asymptomatic OSA without overt cardiovascular disease, daytime HRV metrics and impedance cardiography measurements of preejection period would demonstrate increased sympathetic and decreased parasympathetic modulation compared to matched controls. Obese subjects (body mass index ≥30 kg/m(2)) without any known cardiovascular or inflammatory co-morbidities were recruited from the community. Subjects underwent standard in-laboratory polysomnography followed by simultaneous electrocardiographic and impedance cardiographic recordings while supine, supine with paced breathing, and after standing. Seventy-four subjects were studied, and 59% had OSA (apnea-hypopnea index ≥10 events/hour), with a median apnea-hypopnea index of 25.8 events/hour. Subjects with OSA had significantly decreased daytime time- and frequency-domain HRV indexes, but not significantly different preejection periods, compared to controls. Apnea-hypopnea index was a significant independent predictor of time-domain HRV measures in all awake conditions, after controlling for age, gender, blood pressure, fasting cholesterol levels and glycosylated hemoglobin. In conclusion, these results demonstrate reductions in cardiac vagal modulation, as measured by multiple daytime time-domain markers of HRV, in patients with asymptomatic OSA compared to controls. Further prospective outcomes-based studies are needed to evaluate the applicability of these metrics for noninvasive screening of obese patients with asymptomatic OSA, before the onset of overt cardiovascular disease.

Therapeutic interventions and oxidative stress in diabetes.

Many therapeutic agents that are used in patients with diabetes mitigate oxidative stress. These agents are of particular interest because oxidative stress is elevated in diabetes and is thought to contribute to vascular dysfunction. Agents that merely quench already formed reactive oxygen species have demonstrated limited success in improving cardiovascular outcomes. Thus, although vitamin E, C, and alpha lipoic acid appeared promising in animal models and initial human studies, subsequent larger trials have failed to demonstrate improvement in cardiovascular outcomes. Drugs that limit the production of oxidative stress are more successful in improving vascular outcomes in patients with diabetes. Thus, although statins, ACE inhibitors, ARBs and thiazolinediones are used for varied clinical purposes, their increased efficacy in improving cardiovascular outcomes is likely related to their success in reducing the production of reactive oxygen species at an earlier part of the cascade, thereby more effectively decreasing the oxidative stress burden. In particular, statins and ACE inhibitors/ ARBs appear the most successful at reducing oxidative stress and vascular disease and have potential for synergistic effects.

Total serum bilirubin does not affect vascular reactivity in patients with diabetes

Abstract Bilirubin may have a major role in the prevention of cardiovascular disease based on recent data regarding its anti-oxidant properties. We determined the relationship between total serum bilirubin and vascular reactivity in a large cohort of individuals with diabetes, a disease associated with known oxidant stress. We studied 302 individuals: 52 controls, 37 with type 1 diabetes, 213 with type 2 diabetes. High-resolution ultrasound was used to measure flow-mediated dilation (FMD; endothelium-dependent) and nitroglycerin-induced dilation (NID, endothelium-independent) of the brachial artery. Laser Doppler perfusion imaging was used to measure microvascular reactivity in the forearm skin before and after iontophoresis of acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent). Bilirubin levels were higher in the type 2 diabetes group (0.71 ± 0.34 mg/dl) compared to controls (0.56 ± 0.26 mg/dl, p < 0.0001). A weak inverse correlation was observed between bilirubin and FMD (r = –0.125, p = 0.032) and skin endothelium-dependent vasodilation (r = –0.157, p = 0.019). In multivariate analyses, however, these correlations were not statistically significant. There is no association between bilirubin levels and vascular reactivity in the macro- and microcirculation of individuals with diabetes. Bilirubin, therefore, does not correlate with predictors of cardiovascular risk in the diabetic population.

Metabolic Syndrome, Obstructive Sleep Apnea, and Continuous Positive Airway Pressure: A Weighty Issue

The current obstructive sleep apnea (OSA) literature regarding cardiovascular (CV) risk has been missing the “holy grail” of studies: the definitive multicenter randomized trial assessing hard CV outcomes and mortality. Until this trial can be achieved, we will always be asking if OSA, independent of obesity, contributes to increased CV morbidity and mortality despite compelling evidence from in vitro, animal, epidemiologic, cross-sectional, and observational studies.1,2 Focusing on certain populations with known increased risk of CV disease and assessing treatment of concomitant OSA may be an acceptable strategy for now. In this issue of CHEST (see page 686), Dorkova et al3 study the effect of continuous positive airway pressure (CPAP) on CV risk in a well-defined cohort of patients with metabolic syndrome. Although the predictive value of the various components of the metabolic syndrome has been called into question,4 many features of syndrome X have been associated with OSA (so-called syndrome Z).5 The results of the study by Dorkova et al,3 that treatment of OSA in patients with metabolic syndrome improves insulin sensitivity, reduces systemic inflammation, and decreases CV risk, are promising. The authors acknowledge, however, that this study has the same limitations that have plagued other OSA/CV studies: relying on surrogate measures of CV outcomes, and comparing adherent CPAP users to nonadherent CPAP users. One of the surrogate measures used in this study was a calculation of CV risk using a sex-specific multivariable risk factor algorithm derived from the Framingham Heart study.6 Reduction of the calculated risk score was observed in the OSA group adherent to CPAP but not in the nonadherent group. What does this mean? Can we assume that a reduction of risk in a treated group translates to a “real” risk reduction? For instance, previous research has shown that for a given BP, patients undergoing antihypertensive treatment have a higher CV risk than nontreated patients.7,8 The recent Framingham risk algorithm takes into account treated BPs vs non-treated BPs. However, the algorithm is not necessarily able to predict CV risk for those undergoing changes in risk factors from other types of medical treatment, eg, CPAP. The decreases in BP and cholesterol in the CPAP group reduced the calculated CV risk, but does this necessarily translate to reduced CV events? Despite this concern, the lowering of BP in the CPAP group was impressive in this study. Previous studies9 have shown only modest differences in BP in CPAP vs control. Many of these studies, however, were looking at differences in BP among normotensive participants. Dorkova et al3 observed almost 10 mm Hg reductions in both systolic and diastolic BPs in subjects with baseline hypertension. Similarly, the CPAP-induced improvement in insulin sensitivity (measured with the Homeostasis Model Assessment–Insulin Resistance) and cholesterol is also notable. To see differences before and after treatment with OSA, there may have to be an underlying abnormality. Even in the nonadherent CPAP group, the total cholesterol was within normal limits, and so one may not have expected a change in total cholesterol even if CPAP treatment were successful. However, the exclusion of known cardiovascular comorbidities in order to assess the independent effect of OSA on CV outcomes has become more common place. A “clean” cohort, however, may not in the end be able to detect the beneficial effects of CPAP seen in sicker patients. Although the results of this study are encouraging, the study design comparing CPAP adherent to CPAP nonadherent groups may be problematic. Prior studies10,11 have revealed that adherent patients have better outcomes than nonadherent ones (regardless of the intervention), presumably because adherence is a marker of a more educated, more motivated patient who may be more likely to follow diet, exercise, medication instructions. For example, minor dietary changes may underlie some of the improvements in lipids observed in the present study. Further, we can see that the CPAP-nonadherent group has a higher body mass index, which may play a role in the differences noted between the two groups. One also wonders if there is a difference the pathogenesis of OSA. Whether these underlying differences affected the outcomes is unclear. It is also discouraging to see that despite intensive counseling and monitoring by Dorkova et al3 that 50% of the participants were nonadherent to CPAP, despite their being motivated to participate in a clinical trial. We are reminded that despite having an effective treatment for OSA, CPAP is difficult to use for many patients and new therapeutic targets are needed. Some researchers are moving away from comparing CPAP-adherent vs CPAP-nonadherent groups and using placebos in the form of pills or sham CPAP. The ethical dilemma of not treating OSA, however, is not trivial especially in sleepy patients. Untreated OSA patients have increased risk of car accidents and work-place accidents.12,13 It does not seem right to withhold treatment in symptomatic OSA patients in order to study whether they may or may get heart disease, a process that takes years. Other researchers are working around this problem by randomizing nonsleepy OSA patients to CPAP (who may have poor adherence to therapy), or by doing research in countries that would otherwise not have any access to CPAP therapy. Whether these approaches are ethical or not is still debated, but there are not many other options. Even the use of sham CPAP controls have been criticized since “sham” can still provide partial treatment of OSA or cause sleep disruptions.14 Although these results are promising, the link between OSA and CV outcomes requires further study. What is a researcher to do? As long as we recognize potential limitations and understand the context of the outcomes reported, there is still valuable information to be gleaned. Targeting patients with OSA and metabolic syndrome and observing the benefits of CPAP therapy may alert physicians in other fields, such as endocrine, renal, or cardiology, to send their patients for sleep evaluations. At the end of the day, we all just want OSA to be recognized and treated whenever appropriate.