Model-Based Studies of Autonomic and Metabolic Dysfunction in Sleep Apnea

  • Michael C.K. Khoo
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 669)


Obesity and insulin resistance are highly prevalent in subjects diagnosed with sleep apnea. One factor common to obesity, sleep and insulin resistance is autonomic nervous system dysfunction, in particular, sympathetic overactivity. Although the causal links among these factors are not well understood, it is likely that the vicious cycle of interplay among these factors predisposes to the emergence of “metabolic syndrome”, a convergence of obesity, hypertension, insulin resistance and dyslipidemia that is appearing in epidemic proportions in the United States and other countries. This chapter provides an overview of the ongoing experimental and modeling studies in my laboratory aimed at elucidating and quantifying the relationships among autonomic dysfunction, insulin resistance and severity of sleep apnea in overweight subjects. These studies employ a “minimal modeling” approach to extract information characterizing autonomic function from noninvasive cardiorespiratory measurements. We subsequently determine the relationship of these model parameters to the parameters estimated from the Bergman minimal insulin-glucose model using data obtained from the frequently sampled intravenous glucose tolerance test performed on the same individuals.


Insulin Resistance Heart Rate Variability Continuous Positive Airway Pressure Autonomic Function Intermittent Hypoxia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



I thank the following colleagues and students for contributing to the implementation of the experimental studies and the analysis of the data collected: Sally Ward, MD, Thomas Keens, MD, Steven Mittelman, MD, Michael Goran, PhD, Daniel Lesser, MD, Winston Tran, MS, Flavia Oliveira, MS, and Ricardo Ortega. This work was supported in part by NIH Grants HL090451, EB001978, M01 RR00047, and the USC Center for Transdisciplinary Research on Energetics and Cancer (TREC U54 CA 116848).


  1. Baselli, G., Cerutti, S., Civardi, S., Malliani, A., and Pagani, M. (1988) Cardiovascular variability signals: towards the identification of a closed-loop model of the neural control mechanisms. IEEE Trans. Biomed. Eng. 35, 1033–1045.CrossRefPubMedGoogle Scholar
  2. Belozeroff, V., Berry, R.B., Sassoon, C.S.H., and Khoo, M.C.K. (2002) Effects of CPAP therapy on cardiovascular variability in obstructive sleep apnea: a closed-loop analysis. Am. J. Physiol. 282, H110–H121.Google Scholar
  3. Belozeroff, V., Berry, R.B., and Khoo, M.C.K. (2003) Model-based assessment of autonomic control in obstructive sleep apnea syndrome. Sleep 26, 65–73.PubMedGoogle Scholar
  4. Bergman, R.N., Finegood, D.T., and Ader, M (1985) Assessment of insulin sensitivity in vivo. Endocr. Rev. 6, 45–86.CrossRefPubMedGoogle Scholar
  5. Brown, T.E., Beightol, L.A., Koh, J., and Eckberg, D.L. (1993) Important influence of respiration on human RR interval power spectra is largely ignored. J Appl. Physiol. 75, 2310–2317PubMedGoogle Scholar
  6. Chaicharn, J., Lin, Z., Chen, M.L., Ward, S.L.D., Keens, T.G., and Khoo, M.C.K. (2009) Model-based assessment of cardiovascular autonomic control in children with obstructive sleep apnea. Sleep 32, 927–938.PubMedGoogle Scholar
  7. Chasens, E.R., Weaver, T.E., and Umlauf, M.G. (2003) Insulin resistance and obstructive sleep apnea: is increased sympathetic stimulation the link? Biol. Res. Nurs. 5, 87–96.CrossRefPubMedGoogle Scholar
  8. Coughlin, S.R., Mawdsley, L., Mugarza, J.A., Calverley, P.M.A., and Wilding, J.P.H. (2004) Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur. Heart J. 25, 735–741.CrossRefPubMedGoogle Scholar
  9. Eckberg, D.L. (1997) Sympathovagal balance: A critical appraisal. Circulation 96, 3224–3232.PubMedGoogle Scholar
  10. Esler, M., and Eikelis, N. (2006) Is obstructive sleep apnea the cause of sympathetic nervous activation in human obesity? J. Appl. Physiol. 100, 11–12.CrossRefPubMedGoogle Scholar
  11. Fletcher, E.C.(2003) Sympathetic overactivity in the etiology of hypertension of obstructive sleep apnea. Sleep 26, 15–19.PubMedGoogle Scholar
  12. Harsch, I.A., Schahin, S.P., Radespiel-Troger, M., Weintz, O., Jahreiss, H., Fuchs, F.S., Wiest, G.H., Hahn, E.G., Lohmann, T., and Konturek, P.C. (2004) Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome. Am. J. Respir. Crit. Care Med. 169, 156–162.CrossRefPubMedGoogle Scholar
  13. Jo, J.A., Blasi, A., Valladares, E., Juarez, R., Baydur, A., and Khoo, M.C.K. (2003) Model-based assessment of autonomic control in obstructive sleep apnea syndrome during sleep. Am. J. Respir. Crit. Care Med. 167, 128–136.CrossRefPubMedGoogle Scholar
  14. Khoo, M.C.K., Kim, T.S. and Berry, R.B. (1999) Spectral indices of cardiac autonomic function in obstructive sleep apnea. Sleep 22, 443–451.PubMedGoogle Scholar
  15. Khoo, M.C.K. (2000) Physiological control systems: Analysis, simulation and estimation. New York: Wiley.Google Scholar
  16. Punjabi, N.M., and Polotsky, V.V. (2005) Disorders of glucose metabolism in sleep apnea. J. Appl. Physiol. 99, 1998–2007.CrossRefPubMedGoogle Scholar
  17. Somers, V.K. (1999) Debating sympathetic overactivity as a hallmark of human obesity: an opposing position. J. Hypertens. 17, 1061–1064.CrossRefPubMedGoogle Scholar
  18. Tasali, E., and Van Cauter, E. (2002) Sleep-disordered breathing and the current epidemic of obesity: consequence or contributing factor? Am. J. Respir. Crit. Care Med 165, 562–563.PubMedGoogle Scholar
  19. Task force of the european society of cardiology and the North American society of pacing and electrophysiology (1996) Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation 93, 1043–1065.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Biomedical Engineering DepartmentUniversity of Southern CaliforniaLos AngelesUSA

Personalised recommendations