endothelial dysfunction...

 

J Clin Sleep Med. 2007 June 15; 3(4): 409–415.
Copyright © 2007 American Academy of Sleep Medicine
Endothelial Dysfunction in Obstructive Sleep Apnea
Rohit Budhiraja, M.D., Sairam Parthasarathy, M.D., and Stuart F. Quan, M.D.

Abstract: Obstructive sleep apnea (OSA) is a common disorder and is associated with adverse cardiovascular consequences, including hypertension and coronary artery disease. While the mechanisms responsible for increased risk of cardiovascular events in OSA have not yet been fully elucidated, hypoxia, inflammation, obesity, metabolic dysregulation, and sympathetic activation, may contribute to these consequences. Endothelial dysfunction may be another link between OSA and cardiovascular disease. Dysfunctional endothelium is characterized by an imbalance in production of vasoactive hormones, increased adherence of inflammatory mediators to endothelial cells and hypercoagulability, and is a known risk factor for cardiovascular events. Studies have directly measured vascular endothelial function in patients with OSA and found a muted response compared to controls. Other studies have evaluated biochemical markers of endothelial function including circulating levels of vasoactive and thrombosis mediators and provide further proof of endothelial dysfunction in this disorder. A better appreciation of the role of the dysfunctional endothelium in OSA will help shed light on the pathogenesis of cardiovascular disease in this disorder and may lead to development of novel therapies aimed at preventing untoward outcomes.

 

Cardiovascular Diabetology 2006, 5:4doi:10.1186/1475-2840-5-4
Endothelial dysfunction: a comprehensive appraisal
Ricardo J Esper1, Roberto A Nordaby, Jorge O Vilariño, Antonio Paragano, José L Cacharrónand Rogelio A Machado

The electronic version of this article is the complete one and can be found online at: http://www.cardiab.com/content/5/1/4

© 2006 Esper et al; licensee BioMed Central Ltd.

Abstract

The endothelium is a thin monocelular layer that covers all the inner surface of the blood vessels, separating the circulating blood from the tissues. It is not an inactive organ, quite the opposite. It works as a receptor-efector organ and responds to each physical or chemical stimulus with the release of the correct substance with which it may maintain vasomotor balance and vascular-tissue homeostasis. It has the property of producing, independently, both agonistic and antagonistic substances that help to keep homeostasis and its function is not only autocrine, but also paracrine and endocrine. In this way it modulates the vascular smooth muscle cells producing relaxation or contraction, and therefore vasodilatation or vasoconstriction. The endothelium regulating homeostasis by controlling the production of prothrombotic and antithrombotic components, and fibrynolitics and antifibrynolitics. Also intervenes in cell proliferation and migration, in leukocyte adhesion and activation and in immunological and inflammatory processes. Cardiovascular risk factors cause oxidative stress that alters the endothelial cells capacity and leads to the so called endothelial "dysfunction" reducing its capacity to maintain homeostasis and leads to the development of pathological inflammatory processes and vascular disease.

There are different techniques to evaluate the endothelium functional capacity, that depend on the amount of NO produced and the vasodilatation effect. The percentage of vasodilatation with respect to the basal value represents the endothelial functional capacity. Taking into account that shear stress is one of the most important stimulants for the synthesis and release of NO, the non-invasive technique most often used is the transient flow-modulate "endothelium-dependent" post-ischemic vasodilatation, performed on conductance arteries such as the brachial, radial or femoral arteries. This vasodilatation is compared with the vasodilatation produced by drugs that are NO donors, such as nitroglycerine, called "endothelium independent". The vasodilatation is quantified by measuring the arterial diameter with high resolution ultrasonography. Laser-Doppler techniques are now starting to be used that also consider tissue perfusion.

There is so much proof about endothelial dysfunction that it is reasonable to believe that there is diagnostic and prognostic value in its evaluation for the late outcome. There is no doubt that endothelial dysfunction contributes to the initiation and progression of atherosclerotic disease and could be considered an independent vascular risk factor. Although prolonged randomized clinical trials are needed for unequivocal evidence, the data already obtained allows the methods of evaluation of endothelial dysfunction to be considered useful in clinical practice and have overcome the experimental step, being non-invasive increases its value making it use full for follow-up of the progression of the disease and the effects of different treatments.

American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 348-353, (2004)
© 2004 American Thoracic Society
Endothelial Function in Obstructive Sleep Apnea and Response to Treatment
Mary S. M. Ip, Hung-Fat Tse, Bing Lam, Kenneth W. T. Tsang and Wah-Kit Lam

Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Correspondence and requests for reprints should be addressed to Mary S. M. Ip, M.D., Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong SAR, China. E-mail: msmip@hkucc.hku.hk

Impaired endothelium-dependent vascular relaxation is a prognostic marker of atherosclerosis and cardiovascular disease. We evaluated endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent nitroglycerin (NTG)–induced dilation of the brachial artery with Doppler ultrasound in 28 men with obstructive sleep apnea (OSA) and 12 men without OSA. Subjects with OSA (apnea–hypopnea index; mean ± SD, 46.0 ± 14.5) had lower FMD compared with subjects without OSA (5.3 ± 1.7% vs. 8.3 ± 1.0%, p < 0.001), and major determinants of FMD were the apnea–hypopnea index and age. There was no significant difference in NTG-induced dilation. Subjects with OSA were randomized to nasal continuous positive airway pressure (nCPAP) or observation for 4 weeks. Subjects on nCPAP had significant increase in FMD, whereas those on observation had no change (4.4% vs. -0.8%, difference of 5.2%, p < 0.001). Neither group showed significant change in NTG-induced vasodilation. Eight subjects who used nCPAP for over 3 months were reassessed on withdrawing treatment for 1 week. On nCPAP withdrawal, FMD became lower than during treatment (p = 0.02) and were similar to baseline values. Our findings demonstrated that men with moderate/severe OSA have endothelial dysfunction and treatment with nCPAP could reverse the dysfunction; the effect, however, was dependent on ongoing use.

American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 328-329, (2004)
© 2004 American Thoracic Society
Editorial
Vascular Dysfunction in Sleep Apnea
A Reversible Link to Cardiovascular Disease?
Virginia A. Imadojemu, M.D., Lawrence I. Sinoway, M.D. and Urs A. Leuenberger, M.D.

Pennsylvania State University College of Medicine Hershey, Pennsylvania

In the past decade, obstructive sleep apnea has been increasingly recognized as an important and independent risk factor for cardiovascular disease. In addition, large cross-sectional and prospective studies have demonstrated that sleep-disordered breathing predicts hypertension, a major risk factor for cardiovascular disease, in a dose-dependent fashion (1, 2). The precise mechanism underlying this association, however, is not fully understood. Moreover, the independent contribution of obesity, which frequently coexists in these patients, to cardiovascular complications of sleep apnea is not clear.

Two studies in this issue of the Journal add important insights regarding these questions. The investigators propose that sleep apnea is associated with endothelial dysfunction and that it may be reversible with nocturnal continuous positive airway pressure therapy (3, 4). These studies add further weight to the concept that sleep-disordered breathing has profound adverse consequences on cardiovascular health.

Nieto and colleagues (3) report findings on flow-mediated vasodilation measured via high-frequency ultrasound in a subset of the Sleep Heart Health/Cardiovascular Health Study cohort comprising 1,037 largely asymptomatic subjects with variable degrees of sleep-disordered breathing. All subjects were elderly (older than 68 years) and most were female. Thus, these subjects were somewhat different from the typical patient with sleep apnea: a middle-aged man. Flow-mediated vasodilation was measured as the change of brachial artery diameter following a 4-minute period of forearm ischemia produced by inflation of a pneumatic cuff at the lower arm to suprasystolic pressure. The reactive hyperemia that follows the cuff deflation is associated with a transient brachial artery dilation, which is dependent on the release of the endothelial-derived relaxing factor nitric oxide (5). Therefore, flow-mediated vasodilation is commonly assumed to be an index of endothelial function. In a number of clinical settings, flow-mediated vasodilation has been shown to be a predictor of cardiovascular disease (6). Nieto and coworkers (3) found that: the percent of flow-mediated vasodilation was correlated inversely with the degree of sleep-disordered breathing; resting brachial artery diameter was linked directly to indices of sleep-disordered breathing; and both relationships were weakened when corrections for body-mass-index were made, suggesting that obesity per se may have deleterious effects on vascular structure and function. Whether increased resting arterial diameter can be considered a manifestation of vascular remodeling due to the atherosclerotic process is not clear.

J Am Soc Nephrol 18: 2836-2842, 2007
© 2007 American Society of Nephrology
Frontiers in Nephrology: Early Atherosclerosis—A View Beyond the Lumen
Mario Gossl*, Lilach O. Lerman{dagger} and Amir Lerman*

* Divisions of Cardiovascular Diseases and {dagger} Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota

Correspondence to: Dr. Amir Lerman, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. Phone: 507-255-6670; Fax: 507-255-1824; E-mail: lerman.amir@mayo.edu

Endothelial dysfunction is an established clinical marker of early coronary artery disease and has been shown to be associated with increased cardiovascular morbidity and mortality. New concepts now extend the view of endothelial dysfunction beyond the traditional involvement of the coronary arterial endothelium alone. Recent research indicates that the coronary vessel wall, especially the vasa vasorum, as well as bone marrow–derived endothelial progenitor cells may be subject to proatherosclerotic changes, even before the development of angiographically evident endothelial dysfunction; therefore, "microvascular endothelial dysfunction," which is composed of dysfunction of the vasa vasorum's endothelium as well as "microcellular endothelial dysfunction," reflecting impaired mobilization and function of endothelial progenitor cells, may precede "macrovascular endothelial dysfunction." Vasa vasorum neovascularization, with endothelial leakage and dysfunction increasing influx of proinflammatory and proatherogenic cellular and noncellular substances into the vessel wall, is proposed as one feature of this new concept. In addition, the role of bone marrow–derived endothelial progenitor cells is discussed as are the potential impact of impaired progenitor cell mobilization, release from the marrow, and function in acute and stable coronary artery disease. Finally, potential future therapies are proposed, focusing on interventions that may prevent or diminish the development of the microvascular and microcellular endothelial dysfunction.