Obstructive Sleep Apnea and Metabolic Syndrome: Where is the Chicken? Where is the Egg?

Objectives: Discuss the prevalence of obstructive sleep apnea and its outcomes Review clinical evidence on the relationships between obstructive sleep apnea and the metabolic syndrome Discuss potential mechanisms linking sleep apnea and the metabolic syndrome Overall Goals and Objectives: Following this activity, a participant should be able to: 1. Recognize recent advances and developments in Pulmonary Medicine & Critical Care and translate into clinical practice 2. Integrate perspectives of multiple disciplines into decision-making on behalf of patients through structured plans for patient care. 3. Develop areas for future research and discuss appropriate methods to address these needs. 4. Summarize and continually improve communications as a team, caring for Pulmonary/Critical Care patients. Note: Just PowerPoint slides, no audio

Obstructive Sleep Apnea A Cardiometabolic Risk in Obesity and the Metabolic Syndrome

Obstructive sleep apnea (OSA) is an underdiagnosed condition characterized by recurrent episodes of obstruction of the upper airway leading to sleep fragmentation and intermittent hypoxia during sleep. Obesity predisposes to OSA, and the prevalence of OSA is increasing worldwide because of the ongoing epidemic of obesity. Recent evidence has shown that surrogate markers of cardiovascular risk, including sympathetic activation, systemic inflammation, and endothelial dysfunction, are significantly increased in obese patients with OSA versus those without OSA, suggesting that OSA is not simply an epiphenomenon of obesity. Moreover, findings from animal models and patients with OSA show that intermittent hypoxia exacerbates the metabolic dysfunction of obesity, augmenting insulin resistance and nonalcoholic fatty liver disease. in patients with the metabolic syndrome, the prevalence of moderate to severe OSA is very high (similar to 60%). in this population, OSA is independently associated with increased glucose and triglyceride levels as well as markers of inflammation, arterial stiffness, and atherosclerosis. A recent randomized, controlled, crossover study showed that effective treatment of OSA with continuous positive airway pressure for 3 months significantly reduced several components of the metabolic syndrome, including blood pressure, triglyceride levels, and visceral fat. Finally, several cohort studies have consistently shown that OSA is associated with increased cardiovascular mortality, independent of obesity. Taken together, these results support the concept that OSA exacerbates the cardiometabolic risk attributed to obesity and the metabolic syndrome. Recognition and treatment of OSA may decrease the cardiovascular risk in obese patients. (C) 2013 by the American College of Cardiology FoundationUniv São Paulo, Sch Med, Heart Inst InCor, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psicobiol, Disciplina Med & Biol Sono, São Paulo, BrazilJohns Hopkins Univ, Sch Med, Dept Med, Div Pulm & Crit Care Med, Baltimore, MD 21205 USAUniversidade Federal de São Paulo, Dept Psicobiol, Disciplina Med & Biol Sono, São Paulo, BrazilWeb of Scienc

Vertical sleeve gastrectomy improves ventilatory drive through a leptin-dependent mechanism

Obesity hypoventilation syndrome (OHS) is a serious disorder characterized by daytime hypercapnia, disordered breathing, and a reduction in chemosensitivity. Vertical sleeve gastrectomy (VSG), a bariatric surgical procedure resulting in weight loss and weight-independent improvements in glucose metabolism, has been observed to substantially improve sleep-disordered breathing. However, it is unclear if the ventilatory effects of VSG are secondary to weight loss or the marked change in metabolic physiology. Using preclinical mouse models, we found that VSG leads to an improvement in the hypercapnic ventilatory response (HCVR) and reductions in circulating leptin levels independent of reductions in body mass, fat mass, and caloric intake. In the absence of leptin, VSG continues to improve body mass, fat mass, and glucose tolerance in ob/ob mice but no longer affects HCVR. However, the HCVR of ob/ob mice can be returned to wild-type levels with leptin treatment. These data demonstrate that VSG improves chemosensitivity and ventilatory drive via a leptin-dependent mechanism. Clinically, these data downgrade the relative contribution of physical, mechanical load in the pathogenesis of OHS, and instead point to physiological components of obesity, including alterations in leptin signaling, as key drivers in OHS

A Novel Non-invasive Approach for Measuring Upper Airway Collapsibility in Mice

Introduction: Invasive procedures were previously developed for measuring pharyngeal collapsibility in rodents during expiration, when declining neuromuscular activity makes the airway unstable. We developed a non-invasive approach for streamlining collapsibility measurements by characterizing responses in physiologic markers of dynamic expiratory airflow obstruction to negative nasal pressure challenges.Methods: Anesthetized mice were instrumented to monitor upper airway pressure-flow relationships with head-out plethysmography while nasal pressure was ramped down from ~ +5 to −20 cm H2O over several breaths. Inspiratory and expiratory flow, volume, and timing characteristics were assessed breath-wise. Pcrit was estimated at transitions in expiratory amplitude and timing parameters, and compared to gold standard PCRIT measurements when nasal and tracheal pressures diverged during expiration. Predictions equations were constructed in a development data set (n = 8) and applied prospectively to a validation data set (n = 16) to estimate gold standard PCRIT.Results: The development data demonstrated that abrupt reversals in expiratory duration and tidal volume during nasal pressure ramps predicted gold standard PCRIT measurements. After applying regression equations from the development to a validation dataset, we found that a combination of expiratory amplitude and timing parameters proved to be robust predictors of gold standard PCRIT with minimal bias and narrow confidence intervals.Conclusions: Markers of expiratory airflow obstruction can be used to model upper airway collapsibility, and can provide sensitive measures of changes in airway collapsibility in rodents. This approach streamlines repeated non-invasive PCRIT measurements, and facilitates studies examining the impact of genetic, environmental, and pharmacologic factors on upper airway control

The Impact of Obstructive Sleep Apnea on Metabolic and Inflammatory Markers in Consecutive Patients with Metabolic Syndrome

Background: Obstructive Sleep Apnea (OSA) is tightly linked to some components of Metabolic Syndrome (MetS). However, most of the evidence evaluated individual components of the MetS or patients with a diagnosis of OSA that were referred for sleep studies due to sleep complaints. Therefore, it is not clear whether OSA exacerbates the metabolic abnormalities in a representative sample of patients with MetS. Methodology/Principal Findings: We studied 152 consecutive patients (age 48 +/- 9 years, body mass index 32.3 +/- 3.4 Kg/m(2)) newly diagnosed with MetS (Adult Treatment Panel III). All participants underwent standard polysomnography irrespective of sleep complaints, and laboratory measurements (glucose, lipid profile, uric acid and C-reactive protein). The prevalence of OSA (apnea-hypopnea index >= 15 events per hour of sleep) was 60.5%. Patients with OSA exhibited significantly higher levels of blood pressure, glucose, triglycerides, cholesterol, LDL, cholesterol/HDL ratio, triglycerides/HDL ratio, uric acid and C-reactive protein than patients without OSA. OSA was independently associated with 2 MetS criteria: triglycerides: OR: 3.26 (1.47-7.21) and glucose: OR: 2.31 (1.12-4.80). OSA was also independently associated with increased cholesterol/HDL ratio: OR: 2.38 (1.08-5.24), uric acid: OR: 4.19 (1.70-10.35) and C-reactive protein: OR: 6.10 (2.64-14.11). Indices of sleep apnea severity, apnea-hypopnea index and minimum oxygen saturation, were independently associated with increased levels of triglycerides, glucose as well as cholesterol/HDL ratio, uric acid and C-reactive protein. Excessive daytime sleepiness had no effect on the metabolic and inflammatory parameters. Conclusions/Significance: Unrecognized OSA is common in consecutive patients with MetS. OSA may contribute to metabolic dysregulation and systemic inflammation in patients with MetS, regardless of symptoms of daytime sleepiness.Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)[200032/2009-7]Fundacao Zerbini, BrazilNational Sleep Foundation/American Lung Association Pickwick[SF-78568 N]National Institutes of Health (NIH)[HL07534]National Institutes of Health (NIH)[R01 HL80105]National Institutes of Health (NIH)[5P50HL084945]American Heart Association[0765293U](BSF) United States Israel Binational Science Foundation[2005265

Disruption of Nrf2, a Key Inducer of Antioxidant Defenses, Attenuates ApoE-Mediated Atherosclerosis in Mice

Background: Oxidative stress and inflammation are two critical factors that drive the formation of plaques in atherosclerosis. Nrf2 is a redox-sensitive transcription factor that upregulates a battery of antioxidative genes and cytoprotective enzymes that constitute the cellular response to oxidative stress. Our previous studies have shown that disruption of Nrf2 in mice (Nrf2-/-) causes increased susceptibility to pulmonary emphysema, asthma and sepsis due to increased oxidative stress and inflammation. Here we have tested the hypothesis that disruption of Nrf2 in mice causes increased atherosclerosis. Principal Findings: To investigate the role of Nrf2 in the development of atherosclerosis, we crossed Nrf2-/- mice with apoliporotein E-deficient (ApoE-/- mice. ApoE-/- and ApoE-/- Nrf2-/- mice were fed an atherogenic diet for 20 weeks, and plaque area was assessed in the aortas. Surprisingly, ApoE-/- Nrf2-/- mice exhibited significantly smaller plaque area than ApoE-/- controls (11.5% vs 29.5%). This decrease in plaque area observed in ApoE-/- Nrf2-/- mice was associated with a significant decrease in uptake of modified low density lipoproteins (AcLDL) by isolated macrophages from ApoE-/- Nrf2-/- mice. Furthermore, atherosclerotic plaques and isolated macrophages from ApoE-/- Nrf2-/- mice exhibited decreased expression of the scavenger receptor CD36. Conclusions: Nrf2 is pro-atherogenic in mice, despite its antioxidative function. The net pro-atherogenic effect of Nrf2 may be mediated via positive regulation of CD36. Our data demonstrates that the potential effects of Nrf2-targeted therapies on cardiovascular disease need to be investigated.9 page(s

Leptin and Leptin Resistance in the Pathogenesis of Obstructive Sleep Apnea: A Possible Link to Oxidative Stress and Cardiovascular Complications

Obesity-related sleep breathing disorders such as obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS) cause intermittent hypoxia (IH) during sleep, a powerful trigger of oxidative stress. Obesity also leads to dramatic increases in circulating levels of leptin, a hormone produced in adipose tissue. Leptin acts in the hypothalamus to suppress food intake and increase metabolic rate. However, obese individuals are resistant to metabolic effects of leptin. Leptin also activates the sympathetic nervous system without any evidence of resistance, possibly because these effects occur peripherally without a need to penetrate the blood-brain barrier. IH is a potent stimulator of leptin expression and release from adipose tissue. Hyperleptinemia and leptin resistance may upregulate generation of reactive oxygen species, increasing oxidative stress and promoting inflammation. The current review summarizes recent data on a possible link between leptin and oxidative stress in the pathogenesis of sleep breathing disorders