Obstructive Sleep Apnea and Atherosclerosis

https://doi.org/10.1016/j.pcad.2008.03.001Get rights and content

Obstructive sleep apnea (OSA) is associated with significant cardiovascular morbidity and excess in mortality. Atherosclerosis has been shown to occur in OSA patients free of any other significant risk factors. In particular, intima media thickness, an early marker of atherosclerosis, may be increased at the carotid level in OSA. Thus, early atherosclerosis could be one of the intermediary mechanisms supporting the link between OSA and cardiovascular morbidity. The current concept is that the development of atherosclerotic lesions results from a dynamic interplay between the native cells of the vasculature and different proinflammatory leukocytes issued from the general circulation. Immunoinflammatory cells dominate early atherosclerotic processes, with the secretion of several proinflammatory molecules aggravating lesion progression. There is now substantial evidence that intermittent hypoxia in rodents, as a partial model of sleep apnea, triggers atherogenesis. Blood pressure alterations and hemodynamic strains on the vascular wall, impairment in vascular reactivity, lipid metabolism dysregulation, and activation of proinflammatory transcription factors at the vascular wall level are among the key factors promoting atherosclerosis. Specifically, increases in leukocyte rolling and adhesion molecule expression at the endothelial cell level have been shown to occur in the first 2 weeks after intermittent hypoxia exposure initiation. Early changes at the vascular wall level have been shown in OSA patients and its reversibility under continuous positive airway pressure has also been suggested. Several biological markers potentially linked with early atherosclerosis development are under study in OSA patients. Further studies are needed to identify at-risk subjects prone to develop vascular changes because OSA treatment may either be initiated earlier or combined with specific drug treatments.

Section snippets

General Mechanisms of Atherosclerosis

Coronary heart disease and stroke, both resulting from atherosclerosis (fatty deposits), account for 80% of deaths from cardiovascular diseases. Age-specific incidence rates for cardiovascular disease have fallen by half for the past 30 years in the economically advanced European nations, as a result of better prevention and treatments based on growing knowledge of vascular biology. Although these measures are becoming widely disseminated, an additional dramatic effect on cardiovascular disease

Atherosclerosis in Animal Models of Intermittent Hypoxia

Sleep apnea syndrome is a multicomponent disease including intermittent hypoxia (IH), respiratory efforts, and sleep fragmentation. Intermittent hypoxia has been proposed in rodents to mimic one of the major consequences of sleep apnea. As a partial model of sleep apnea, IH allows to test the specific role of IH on atherogenesis and to assess both plasma and tissue alterations that may contribute to atherosclerosis development and progression.

Atherosclerotic remodeling as evidenced by plaques

Clinical and Biological Findings in OSA

There have been significant efforts in this field of clinical research in reducing the number of confounding factors and comorbid conditions. In 2005, 3 reports were published nearly at the same time evidencing that sleep apnea may lead to early atherosclerosis as reflected at the carotid level by increase in IMT and occurrence of plaques, in the absence of any significant comorbidity.7, 8, 74 In our series of patients, severity of oxygen desaturation and BP status were the best predictors for

Conclusions

Sleep apnea and IH are associated with early vascular changes. There are both animal and clinical data supporting a specific role for IH in promoting cellular changes at the vascular wall level thus triggering atherosclerosis. These early changes as evidenced by subclinical markers in OSA patients are also seen in rodents exposed to IH for only several weeks. Lesions seem to be partly reversible as far as the inflammatory component is concerned. In OSA, CPAP impact needs certainly to be studied

References (96)

  • A.N. Vgontzas et al.

    Sleep apnea is a manifestation of the metabolic syndrome

    Sleep Med Rev

    (2005)
  • H. Greenberg et al.

    Chronic intermittent hypoxia activates nuclear factor-kappaB in cardiovascular tissues in vivo

    Biochem Biophys Res Commun

    (2006)
  • L. Lavie et al.

    Sleep-apnea–related intermittent hypoxia and atherogenesis: adhesion molecules and monocytes/endothelial cells interactions

    Atherosclerosis

    (2005)
  • V. Hoffstein et al.

    Hematocrit levels in sleep apnea

    Chest

    (1994)
  • M. McGuire et al.

    Chronic intermittent hypoxia increases haematocrit and causes right ventricular hypertrophy in the rat

    Respir Physiol

    (1999)
  • L. Lavie

    Obstructive sleep apnoea syndrome—an oxidative stress disorder

    Sleep Med Rev

    (2003)
  • G.E. Carpagnano et al.

    Increased 8-isoprostane and interleukin-6 in breath condensate of obstructive sleep apnea patients

    Chest

    (2002)
  • K.C. Tan et al.

    HDL dysfunction in obstructive sleep apnea

    Atherosclerosis

    (2006)
  • T. Young et al.

    Epidemiology of obstructive sleep apnea: a population health perspective

    Am J Respir Crit Care Med

    (2002)
  • T. Young et al.

    The occurrence of sleep-disordered breathing among middle-aged adults

    N Engl J Med

    (1993)
  • J. Teran-Santos et al.

    The association between sleep apnea and the risk of traffic accidents. Cooperative Group Burgos-Santander

    N Engl J Med

    (1999)
  • P. Levy et al.

    Should all sleep apnoea patients be treated? Yes

    Sleep Med Rev

    (2002)
  • L.F. Drager et al.

    Early signs of atherosclerosis in obstructive sleep apnea

    Am J Respir Crit Care Med

    (2005)
  • P. Lavie et al.

    Mortality in sleep apnea patients: a multivariate analysis of risk factors

    Sleep

    (1995)
  • P. Lavie et al.

    All-cause mortality in males with sleep apnoea syndrome: declining mortality rates with age

    Eur Respir J

    (2005)
  • H.K. Yaggi et al.

    Obstructive sleep apnea as a risk factor for stroke and death

    N Engl J Med

    (2005)
  • G.K. Hansson

    Inflammation, atherosclerosis, and coronary artery disease

    N Engl J Med

    (2005)
  • P. Libby

    Inflammation in atherosclerosis

    Nature

    (2002)
  • A.J. Lusis

    Atherosclerosis

    Nature

    (2000)
  • E. Ohga et al.

    Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1

    J Appl Physiol

    (2003)
  • A. Ursavas et al.

    Circulating ICAM-1 and VCAM-1 levels in patients with obstructive sleep apnea syndrome

    Respiration

    (2006)
  • E. Ohga et al.

    Increased levels of circulating ICAM-1, VCAM-1, and L-selectin in obstructive sleep apnea syndrome

    J Appl Physiol

    (1999)
  • V. Braunersreuther et al.

    Leukocyte recruitment in atherosclerosis: potential targets for therapeutic approaches

    Cell Mol Life Sci

    (2006)
  • P. Pignoli et al.

    Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging

    Circulation

    (1986)
  • P.J. Touboul et al.

    Mannheim carotid intima-media thickness consensus (2004-2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006

    Cerebrovasc Dis

    (2007)
  • J.T. Salonen et al.

    Ultrasonographically assessed carotid morphology and the risk of coronary heart disease

    Arterioscler Thromb

    (1991)
  • D.H. O'Leary et al.

    Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group

    N Engl J Med

    (1999)
  • G. Mancia et al.

    2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)

    J Hypertens

    (2007)
  • M.W. Lorenz et al.

    Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis

    Circulation

    (2007)
  • E. Lonn et al.

    Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE)

    Circulation

    (2001)
  • A. Zanchetti et al.

    Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial

    Circulation

    (2002)
  • D.M. Nathan et al.

    Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus

    N Engl J Med

    (2003)
  • S. Laurent et al.

    Expert consensus document on arterial stiffness: methodological issues and clinical applications

    Eur Heart J

    (2006)
  • M.H. Criqui et al.

    Noninvasively diagnosed peripheral arterial disease as a predictor of mortality: results from a prospective study

    Circulation

    (1985)
  • G.T. Kondos et al.

    Electron-beam tomography coronary artery calcium and cardiac events: a 37-month follow-up of 5635 initially asymptomatic low- to intermediate-risk adults

    Circulation

    (2003)
  • K. Wachtell et al.

    Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study

    Ann Intern Med

    (2003)
  • V. Savransky et al.

    Chronic intermittent hypoxia induces atherosclerosis

    Am J Respir Crit Care Med

    (2007)
  • K.J. Allahdadi et al.

    Augmented endothelin vasoconstriction in intermittent hypoxia-induced hypertension

    Hypertension

    (2005)
  • Cited by (112)

    View all citing articles on Scopus
    View full text