Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anat...

Pathophysiology of Sleep Apnea

ContextObstructive sleep apnea (OSA) has been increasingly implicated in the
initiation and progression of cardiovascular diseases.ObjectiveTo systematically review the interactions of OSA with cardiovascular
pathophysiology and diseases.Data Sources and Study SelectionThe MEDLINE database from January 1966 to March 2003 was searched using
the Medical Subject Headings sleep, sleep apnea, obesity, hypertension, heart failure, cardiac
arrhythmia, coronary artery disease, stroke, sympathetic activity, endothelium, inflammation, and continuous positive airway pressure (CPAP) to identify peer-reviewed studies of OSA. Priority was given
to large prospective cohort studies and to randomized controlled trials.Data ExtractionWe identified 154 original investigations and reviews of sleep-related
breathing disorders. Data from these studies were examined for relevance and
extracted by one of the authors.Data SynthesisApproximately 1 in 5 adults has at least mild OSA (apnea-hypopnea index
[ie, the number of apneic and hypopneic events per hour], 5-15), and 1 in
15 adults has at least moderate OSA (apnea-hypopnea index, 15-30). Repetitive
apneic events disrupt the normal physiologic interactions between sleep and
the cardiovascular system. Such sleep fragmentation, as well as abnormalities
evident in patients with OSA (eg, increased sympathetic activation, vascular
endothelial dysfunction, increased oxidative stress, inflammation, increased
platelet aggregability, metabolic dysregulation), may be implicated in the
initiation and progression of cardiac and vascular disease. Persuasive data
implicate OSA in the development of hypertension, and OSA also may contribute
to cardiac ischemia, congestive heart failure, cardiac arrhythmias, and perhaps
also to cerebrovascular disease and stroke.ConclusionsObstructive sleep apnea is common, readily diagnosed, and usually treatable.
It frequently coexists undiagnosed in patients with cardiovascular disease,
activates disease mechanisms known to elicit cardiac and vascular damage,
and may be implicated in progression of cardiovascular disease and resistance
to conventional therapeutic strategies. In the absence of definitive evidence
from large-scale trials and a better understanding of potential cost-effectiveness,
the likely benefits of diagnosis and treatment of OSA are presently best appraised
on an individualized patient basis.

https://jamanetwork.com/journals/jama/articlepdf/197410/jcc30007.pdf

Obstructive sleep apnea: implications for cardiac and vascular disease.

Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality. Free radicals and adhesion molecules were implicated in the pathogenesis of atherosclerosis leading to cardiovascular disorders. Therefore, we investigated the link between CD15, CD11c, CD11b, and CD64 expression on leukocytes and their ability to generate reactive oxygen species (ROS) in patients with OSA and control volunteers. We also studied the effects of hypoxia in vitro on monocytes from control subjects and the ability of monocytes from both groups to adhere to human endothelial cells in culture. The effect of nasal continuous positive airway pressure (nCPAP) treatment was studied as well. We found that OSA was associated with increased expression of adhesion molecules CD15 and CD11c on monocytes, increased adherence of monocytes in culture to human endothelial cells, increased intracellular ROS production in some monocyte and granulocyte subpopulations, and upregulation of CD15 expression due to hypoxia in vitro in monocytes of control subjects. Furthermore, nCPAP treatment was associated with downregulation of CD15 and CD11c monocyte expression and decreased basal ROS production in CD11c+ monocytes. Monocyte adherence to endothelial cells decreased as well. Our findings provide one of the possible mechanisms for explaining the high rate of cardiovascular morbidity in patients with sleep apnea.

Increased Adhesion Molecules Expression and Production of Reactive Oxygen Species in Leukocytes of Sleep Apnea Patients

It has been known for more than 60 years, and suspected for over 100, that alveolar hypoxia causes pulmonary vasoconstriction by means of mechanisms local to the lung. For the last 20 years, it has been clear that the essential sensor, transduction, and effector mechanisms responsible for hypoxic pulmonary vasoconstriction (HPV) reside in the pulmonary arterial smooth muscle cell. The main focus of this review is the cellular and molecular work performed to clarify these intrinsic mechanisms and to determine how they are facilitated and inhibited by the extrinsic influences of other cells. Because the interaction of intrinsic and extrinsic mechanisms is likely to shape expression of HPV in vivo, we relate results obtained in cells to HPV in more intact preparations, such as intact and isolated lungs and isolated pulmonary vessels. Finally, we evaluate evidence regarding the contribution of HPV to the physiological and pathophysiological processes involved in the transition from fetal to neonatal life, pulmonary gas exchange, high-altitude pulmonary edema, and pulmonary hypertension. Although understanding of HPV has advanced significantly, major areas of ignorance and uncertainty await resolution.

Hypoxic pulmonary vasoconstriction.

Additional data from this article are available on the www.bmj.com/ Objective: To examine the research evidence for the health consequences of obstructive sleep apnoea and the effectiveness of continuous positive airways pressure. Design: A systematic review of published research, studies being identified by searching Medline (1966-96), Embase (1974-96), and CINAHL (Cumulative Index to Nursing and Allied Health Literature) (1982-95); scanning citations; and consulting experts. Studies in all languages were considered which either investigated the association between obstructive sleep apnoea in adults and key health outcomes or evaluated the effectiveness of treatment of obstructive sleep apnoea with continuous positive airways pressure in adults. Main outcome measures: Mortality, systematic hypertension, cardiac arrhythmias, ischaemic heart disease, left ventricular hypertrophy, pulmonary hypertension, stroke, vehicle accidents, measures of daytime sleepiness, and quality of life. Results: 54 epidemiological studies examined the association between sleep apnoea and health related outcomes. Most were poorly designed and only weak or contradictory evidence was found of an association with cardiac arrhythmias, ischaemic heart disease, cardiac failure, systemic or pulmonary hypertension, and stroke. Evidence of a link with sleepiness and road traffic accidents was stronger but inconclusive. Only one small randomised controlled trial evaluated continuous positive airways pressure. Five non-randomised controlled trials and 38 uncontrolled trials were identified. Small changes in objectively measured daytime sleepiness were consistently found, but improvements in morbidity, mortality, and quality of life indicators were not adequately assessed. Conclusions: The relevance of sleep apnoea to public health has been exaggerated. The effectiveness of continuous positive airways pressure in improving health outcomes has been poorly evaluated. There is enough evidence suggesting benefit in reducing daytime sleepiness in some patients to warrant large randomised placebo controlled trials of continuous positive airways pressure versus an effective weight reduction programme and other interventions. Key messages Obstructive sleep apnoea is claimed to be an important cause of premature death and disability There is increasing pressure to provide sleep services for the treatment of patients with sleep apnoea Epidemiological evidence suggests that sleep apnoea causes daytime sleepiness and possibly vehicle accidents Evidence for a causal association between sleep apnoea and other adverse health outcomes is weak There is a paucity of robust evidence for the clinical and cost effectiveness of continuous positive airways pressure in the treatment of most patients with sleep apnoea

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Health effects of obstructive sleep apnoea and the effectiveness of continuous positive airways pressure: a systematic review of the research evidence

Todetermine whether pulmonary hypertension (PH) can occur in obstructive sleep apnea syndrome (OSAS) in the absence of lung or primary cardiac disease, we studied 27 patients (26 males, mean age 49 ± 10 yr) with OSAS (respiratory disturbance index [RDI] > 10 events/h) in whom clinically significant lung or cardiac diseases were excluded. Pulsed Doppler measurements of pulmonary hemodynamics, pulmonary function tests, arterial blood gas analysis, and polysomnography were performed. A total of 11 OSAS pa­ tients (41%) were found to have pulmonary hypertension. The levels of PH were relatively mild (Ppa ~ 26 mm Hg). There were no differences between PH and non-PH patients in body mass index (BMI), smok­ ing history, or lung function. PH patients were more hypoxemic when awake than non-PHpatients (Pao, = 72.2 ± 7.6 versus 17.6 ± 7.3 mm Hg, respectively; p < 0.05) but did not differ in severity of sleep apnea (RDI = 51.9 ± 25.1 versus 56.8 ± 26.2 events/h, respectively; p = NS) or indices of sleep desaturation. The hypoxemia in PH patients could not be explained by impairment of lung function, greater body mass, or a higher prevalence of smoking, and Pao2 in the study population was significantly correlated with Ppa (r = -0.46, P < 0.02) but not with FEV, or BMI. We conclude that lung disease is not a prerequisite for PH in OSAS. We speculate that the development of PH in OSAS patients depends more on individual differ­ ences in the response of the pulmonary circulation to the episodic alveolar hypoxia and respiratory acido­ sis associated with sleep apneas than on differences in the frequency or severity of the apneas. Repetitive elevation of Ppa during sleep into the PH range may lead to pulmonary vascular remodeling in "responders" and thereby daytime PH and hypoxemia. Sajkov 0, Cowie RJ, Thornton AT, Espinoza HA, McEvoy RD. Pulmonary hypertension and hypoxemia in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1994; 149:416-22.

R. J. Cowie

Papers

Pulmonary hypertension and hypoxemia in obstructive sleep apnea syndrome