Effects of sleep apnea on nocturnal free fatty acids in subjects with heart failure

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Sleep (Impact Factor: 4.59). 05/2011; 34(9):1207-13. DOI: 10.5665/SLEEP.1240
Source: PubMed


Sleep apnea is common in patients with congestive heart failure, and may contribute to the progression of underlying heart disease. Cardiovascular and metabolic complications of sleep apnea have been attributed to intermittent hypoxia. Elevated free fatty acids (FFA) are also associated with the progression of metabolic, vascular, and cardiac dysfunction. The objective of this study was to determine the effect of intermittent hypoxia on FFA levels during sleep in patients with heart failure.
During sleep, frequent blood samples were examined for FFA in patients with stable heart failure (ejection fraction < 40%). In patients with severe sleep apnea (apnea-hypopnea index = 65.5 ± 9.1 events/h; average low SpO₂ = 88.9%), FFA levels were compared to controls with milder sleep apnea (apnea-hypopnea index = 15.4 ± 3.7 events/h; average low SpO₂ = 93.6%). In patients with severe sleep apnea, supplemental oxygen at 2-4 liters/min was administered on a subsequent night to eliminate hypoxemia.
Prior to sleep onset, controls and patients with severe apnea exhibited a similar FFA level. After sleep onset, patients with severe sleep apnea exhibited a marked and rapid increase in FFA relative to control subjects. This increase persisted throughout NREM and REM sleep exceeding serum FFA levels in control subjects by 0.134 mmol/L (P = 0.0038). Supplemental oxygen normalized the FFA profile without affecting sleep architecture or respiratory arousal frequency.
In patients with heart failure, severe sleep apnea causes surges in nocturnal FFA that may contribute to the accelerated progression of underlying heart disease. Supplemental oxygen prevents the FFA elevation.

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Available from: Jonathan C Jun, Jan 02, 2014
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    • "Barceló et al. showed that OSA patients have elevated levels of FFA, which can lead to increased cardiovascular and metabolic risk [32]. Moreover, an increased amount of nocturnal FFA was shown to be associated with accelerated cardiac disease progression in patient with OSA and concomitant heart failure [33]. "
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    ABSTRACT: Obstructive sleep apnea and dyslipidemia are common medical disorders that independently increase vascular morbidity and mortality. Current animal and human data show that, indeed, obstructive sleep apnea may mediate pathological alterations in cholesterol and triglyceride metabolism. The mechanisms involved are increased lipolysis, decreased lipoprotein clearance, and enhanced lipid output from the liver. Human evidence shows that the treatment of obstructive sleep apnea with continuous positive airway pressure leads to an improvement of postprandial hyperlipidemia. However, more studies are needed, to clarify the pathophysiology of the interrelationship between obstructive sleep apnea and dyslipidemia and whether treatment of obstructive sleep apnea will lead to an improvement in the lipid profile and, more importantly, reduce hyperlipidemia-related vascular outcomes.
    01/2013; 2013(5). DOI:10.1155/2013/687069
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    • "Activation of the SNS during IH occurs through the hypoxic chemo-reflex in the carotid body and ablation of the carotid sinus nerve prevents IH-induced hypertension (Fletcher et al., 1992a,b; Fletcher, 2001; Prabhakar et al., 2007; Prabhakar and Kumar, 2010). We and others have recently shown that sleep apnea raises circulating FFA levels in proportion to the severity of hypoxia (Barcelo et al., 2011; Jun et al., 2011) suggesting that IH leads to exuberant lipolysis in adipose tissue. The FFA influx into the liver may induce insulin resistance and triglyceride biosynthesis leading to hepatic steatosis (Delarue and Magnan, 2007; Guilherme et al., 2008; Jocken and Blaak, 2008; Neuschwander-Tetri, 2010; Tilg and Moschen, 2010). "
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    ABSTRACT: Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH). OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD). NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohep-atitis (NASH), liver fibrosis, and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1) IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA) flux into the liver; (2) IH up-regulates lipid biosynthetic pathways in the liver; (3) IH induces oxidative stress in the liver; (4) IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done.
    Frontiers in Neurology 10/2012; 3. DOI:10.3389/fneur.2012.00149
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    ABSTRACT: Obesity causes insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD), but the relative contribution of sleep apnea is debatable. The main aim of this study is to evaluate the effects of chronic intermittent hypoxia (CIH), a hallmark of sleep apnea, on IR and NAFLD in lean mice and mice with diet-induced obesity (DIO). Mice (C57BL/6J), 6-8 weeks of age were fed a high fat (n = 18) or regular (n = 16) diet for 12 weeks and then exposed to CIH or control conditions (room air) for 4 weeks. At the end of the exposure, fasting (5 h) blood glucose, insulin, homeostasis model assessment (HOMA) index, liver enzymes, and intraperitoneal glucose tolerance test (1 g/kg) were measured. In DIO mice, body weight remained stable during CIH and did not differ from control conditions. Lean mice under CIH were significantly lighter than control mice by day 28 (P = 0.002). Compared to lean mice, DIO mice had higher fasting levels of blood glucose, plasma insulin, the HOMA index, and had glucose intolerance and hepatic steatosis at baseline. In lean mice, CIH slightly increased HOMA index (from 1.79 ± 0.13 in control to 2.41 ± 0.26 in CIH; P = 0.05), whereas glucose tolerance was not affected. In contrast, in DIO mice, CIH doubled HOMA index (from 10.1 ± 2.1 in control to 22.5 ± 3.6 in CIH; P < 0.01), and induced severe glucose intolerance. In DIO mice, CIH induced NAFLD, inflammation, and oxidative stress, which was not observed in lean mice. In conclusion, CIH exacerbates IR and induces steatohepatitis in DIO mice, suggesting that CIH may account for metabolic dysfunction in obesity.
    Obesity 07/2011; 19(11):2167-74. DOI:10.1038/oby.2011.240 · 3.73 Impact Factor
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