Intermittent Versus Sustained Hypoxemia from Sleep-disordered Breathing: Outcomes in Patients with Chronic Lung Disease and High Altitude.

In a variety of physiologic and pathologic states, people may experience both chronic sustained hypoxemia and intermittent hypoxemia ("combined" or "overlap" hypoxemia). In general, hypoxemia in such instances predicts a variety of maladaptive outcomes, including excess cardiovascular disease or mortality. However, hypoxemia may be one of the myriad phenotypic effects in such states, making it difficult to ascertain whether adverse outcomes are primarily driven by hypoxemia, and if so, whether these effects are due to intermittent versus sustained hypoxemia.

Mild Hypoxia Accelerates Cerebral Cavernous Malformation Disease Through CX3CR1-CX3CL1 Signaling.

Background: Heterogeneity in the severity of cerebral cavernous malformations (CCMs) disease, including brain bleedings and thrombosis that cause neurological disabilities in patients, suggests that environmental, genetic, or biological factors act as disease modifiers. Still, the underlying mechanisms are not entirely understood. Here, we report that mild hypoxia accelerates CCM disease by promoting angiogenesis, neuroinflammation, and vascular thrombosis in the brains of CCM mouse models.

Duration of intermittent hypoxia impacts metabolic outcomes and severity of murine NAFLD.

Rationale: Obstructive sleep apnea (OSA) is associated with metabolic dysfunction, including progression of nonalcoholic fatty liver disease (NAFLD). Chronic intermittent hypoxia (IH) as a model of OSA worsens hepatic steatosis and fibrosis in rodents with diet induced obesity. However, IH also causes weight loss, thus complicating attempts to co-model OSA and NAFLD.

Inflammation biomarkers in OSA, chronic obstructive pulmonary disease, and chronic obstructive pulmonary disease/OSA overlap syndrome.

Study Objectives: The coexistence of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) in a single individual, also known as overlap syndrome (OVS), is associated with higher cardiovascular risk and mortality than either OSA or COPD alone. However, the underlying mechanisms remain unclear. We hypothesized that patients with OVS have elevated systemic inflammatory biomarkers relative to patients with either disease alone, which could explain greater cardiovascular risk observed in OVS.

Neuroinflammation Plays a Critical Role in Cerebral Cavernous Malformation Disease.

Background: Cerebral cavernous malformations (CCMs) are neurovascular lesions caused by loss of function mutations in 1 of 3 genes, including ), , and ). CCMs affect ≈1 out of 200 children and adults, and no pharmacologic therapy is available. CCM lesion count, size, and aggressiveness vary widely among patients of similar ages with the same mutation or even within members of the same family.

Isovolemic hemodilution in chronic mountain sickness acutely worsens nocturnal oxygenation and sleep apnea severity.

Study Objectives: Chronic mountain sickness (CMS) is commonly observed among Andean and other highland populations. Sleep-disordered breathing (SDB) is highly prevalent at high altitude, and SDB and nocturnal hypoxemia have been observed in CMS. Phlebotomy is commonly performed to treat CMS, but it is unknown whether reducing hematocrit improves SDB.

The Cardiovascular and Metabolic Effects of Chronic Hypoxia in Animal Models: A Mini-Review.

Animal models are useful to understand the myriad physiological effects of hypoxia. Such models attempt to recapitulate the hypoxemia of human disease in various ways. In this mini-review, we consider the various animal models which have been deployed to understand the effects of chronic hypoxia on pulmonary and systemic blood pressure, glucose and lipid metabolism, atherosclerosis, and stroke.

Combined intermittent and sustained hypoxia is a novel and deleterious cardio-metabolic phenotype.

Study Objectives: Chronic obstructive pulmonary disease and obstructive sleep apnea overlap syndrome is associated with excess mortality, and outcomes are related to the degree of hypoxemia. People at high altitudes are susceptible to periodic breathing, and hypoxia at altitude is associated with cardio-metabolic dysfunction. Hypoxemia in these scenarios may be described as superimposed sustained hypoxia (SH) plus intermittent hypoxia (IH), or overlap hypoxia (OH), the effects of which have not been investigated.

Hepatocyte HIF-1 and Intermittent Hypoxia Independently Impact Liver Fibrosis in Murine Nonalcoholic Fatty Liver Disease.

Obstructive sleep apnea is associated with insulin resistance, lipid dysregulation, and hepatic steatosis and fibrosis in nonalcoholic fatty liver disease (NAFLD). We have previously shown that hepatocyte HIF-1 (hypoxia-inducible factor-1) mediates the development of liver fibrosis in a mouse model of NAFLD. We hypothesized that intermittent hypoxia (IH) modeling obstructive sleep apnea would worsen hepatic steatosis and fibrosis in murine NAFLD, via HIF-1.

Endotypes and phenotypes in obstructive sleep apnea.

Purpose Of Review: The purpose of this review is to describe the variability of obstructive sleep apnea (OSA), both from a standpoint of underlying mechanisms and in terms of clinical manifestations.

Recent Findings: Recent data suggest that not all patients with sleep apnea get their disease for the same reason. As such, no one variable is effective at defining which patients do or do not have sleep apnea.

Obstructive sleep apnea and pulmonary hypertension: a bidirectional relationship.

Mesarwi O, Malhotra A. Obstructive sleep apnea and pulmonary hypertension: a bidirectional relationship. .

Obstructive Sleep Apnea, Hypoxia, and Nonalcoholic Fatty Liver Disease.

Recent studies have demonstrated that obstructive sleep apnea (OSA) is associated with the development and evolution of nonalcoholic fatty liver disease (NAFLD), independent of obesity or other shared risk factors. Like OSA, NAFLD is a prevalent disorder associated with major adverse health outcomes: Patients with NAFLD may develop cirrhosis, liver failure, and hepatocellular carcinoma. One major finding that has emerged from these studies is that the OSA-NAFLD association is related to the degree of nocturnal hypoxemia in OSA.

Sleep apnea, metabolic disease, and the cutting edge of therapy.

Obstructive sleep apnea (OSA) is common, and many cross-sectional and longitudinal studies have established OSA as an independent risk factor for the development of a variety of adverse metabolic disease states, including hypertension, insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, dyslipidemia, and atherosclerosis. Nasal continuous positive airway pressure (CPAP) has long been the mainstay of therapy for OSA, but definitive studies demonstrating the efficacy of CPAP in improving metabolic outcomes, or in reducing incident disease burden, are lacking; moreover, CPAP has variable rates of adherence. Therefore, the future of OSA management, particularly with respect to limiting OSA-related metabolic dysfunction, likely lies in a coming wave of alternative approaches to endophenotyping OSA patients, personalized care, and defining and targeting mechanisms of OSA-induced adverse health outcomes.

Hepatocyte Hypoxia Inducible Factor-1 Mediates the Development of Liver Fibrosis in a Mouse Model of Nonalcoholic Fatty Liver Disease.

Background: Obstructive sleep apnea (OSA) is associated with the progression of non-alcoholic fatty liver disease (NAFLD) to steatohepatitis and fibrosis. This progression correlates with the severity of OSA-associated hypoxia. In mice with diet induced obesity, hepatic steatosis leads to liver tissue hypoxia, which worsens with exposure to intermittent hypoxia.

Metabolic dysfunction in obstructive sleep apnea: A critical examination of underlying mechanisms.

It has recently become clear that obstructive sleep apnea (OSA) is an independent risk factor for the development of metabolic syndrome, a disorder of defective energy storage and use. Several mechanisms have been proposed to explain this finding, drawing upon the characteristics that define OSA. In particular, intermittent hypoxia, sleep fragmentation, elevated sympathetic tone, and oxidative stress - all consequences of OSA - have been implicated in the progression of poor metabolic outcomes in OSA.

Lysyl Oxidase as a Serum Biomarker of Liver Fibrosis in Patients with Severe Obesity and Obstructive Sleep Apnea.

Study Objectives: Obstructive sleep apnea (OSA) is associated with the progression of nonalcoholic fatty liver disease (NAFLD). We hypothesized that the hypoxia of OSA increases hepatic production of lysyl oxidase (LOX), an enzyme that cross-links collagen, and that LOX may serve as a biomarker of hepatic fibrosis.

Design: Thirty-five patients with severe obesity underwent liver biopsy, polysomnography, and serum LOX testing.

Intermittent hypoxia-induced glucose intolerance is abolished by α-adrenergic blockade or adrenal medullectomy.

Obstructive sleep apnea causes intermittent hypoxia (IH) during sleep and is associated with dysregulation of glucose metabolism. We developed a novel model of clinically realistic IH in mice to test the hypothesis that IH causes hyperglycemia, glucose intolerance, and insulin resistance via activation of the sympathetic nervous system. Mice were exposed to acute hypoxia of graded severity (21, 14, 10, and 7% O2) or to IH of graded frequency [oxygen desaturation index (ODI) of 0, 15, 30, or 60, SpO2 nadir 80%] for 30 min to measure levels of glucose fatty acids, glycerol, insulin, and lactate.

Carotid body denervation prevents fasting hyperglycemia during chronic intermittent hypoxia.

Obstructive sleep apnea causes chronic intermittent hypoxia (IH) and is associated with impaired glucose metabolism, but mechanisms are unknown. Carotid bodies orchestrate physiological responses to hypoxemia by activating the sympathetic nervous system. Therefore, we hypothesized that carotid body denervation would abolish glucose intolerance and insulin resistance induced by chronic IH.

Sleep disorders and the development of insulin resistance and obesity.

Normal sleep is characterized both by reduced glucose turnover by the brain and other metabolically active tissues, and by changes in glucose tolerance. Sleep duration has decreased over the last several decades; data suggest a link between short sleep duration and type 2 diabetes. Obstructive sleep apnea (OSA) results in intermittent hypoxia and sleep fragmentation, and also is associated with impaired glucose tolerance.