Core Project #3

Models of Multi-Factor Disorders in Cardiorespiratory Control

Michael C.K. Khoo, Ph.D.

Project Leader

The overall goal of this project is to develop a better understanding and improved quantitative characterization of the complex dynamics that result from abnormal regulation of the respiratory, cardiovascular and metabolic control systems in important chronic diseases or clinical syndromes, such as hypertension, Type 2 diabetes, sickle cell disease, metabolic syndrome, and sleep-related breathing disorders (including sleep apnea). These problems are addressed by employing a combination of structured (“parametric”) modeling and minimal (“non-parametric”) modeling approaches that we have successfully applied in previous cycles of this grant. The current project builds on the work that has been accomplished in previous years, addressing several important issues that remain unresolved and extending our modeling efforts to more clinical applications. There are three major emphases in our current studies:

  1. The first pertains to developing models that can characterize the dynamics of the interactions among the participating physiological control systems (eg. respiratory, cardiovascular, metabolic and renal) as they are altered with time because of disease progression or therapy. Specifically, our structured, comprehensive model of sleep/cardiorespiratory/metabolic control (PNEUMA), is being expanded to incorporate the renal control of blood volume and arterial pressure, the renin-angiotensin-aldosterone system, the effects of obesity, and other interactions among the metabolic, cardiovascular and respiratory systems that have not been included to date. This would enable PNEUMA to predict the long-term pathophysiological changes that accompany the progression of disease from sympathetic overactivity and insulin resistance to hypertension and Type 2 diabetes.
  2. The second focus lends recognition to the fact that the vast majority of computational models of human physiology (and pathophysiology) have been designed with the adult forms of the disorder or disease under study. In the current phase of this project, we will devote significant effort to developing models that pertain more specifically to the pediatric manifestations of these multi-factor disorders. More specifically, we are developing a parallel version of PNEUMA with the relevant changes in model structure and parameter values, in order to make it applicable to the human infant – this would allow the model to simulate changes in cardiorespiratory dynamics that accompany natural development, with or without the presence of specific disorders or therapeutic intervention.
  3. A third focus is translate the computational methods and models that we have developed in this core project into clinical applications (“biophysical markers”) that can be used for early disease detection, noninvasive assessment of disease severity, and therapeutic decision-making. Two specific clinical applications addressed here include: (a) autonomic nervous system (ANS) correlates of pain and vaso-occlusive crisis in patients with sickle-cell disease; and (b) ANS predictors of long-term metabolic dysfunction in patients with obstructive sleep apnea and/or impaired fasting glucose. As well, we seek to characterize the diversity in phenotypic behavior observed in the respiratory variability patterns of sleep-related breathing disorders of overweight/obese pediatric subjects using model-based markers and information extracted from dynamic magnetic resonance imaging of the upper airway during sleep.

Selected Publications


Chalacheva P., Kato R.M., Sangkatumvong S., Detterich J., Bush A., Wood J.C., Meiselman H., Coates T.D., Khoo M.C. Autonomic responses to cold face stimulation in sickle cell disease: a time-varying model analysis. Physiological Reports 14;3(7):e12463, 2015. [PMC4552538]

Bhatia R., Lesser D.J., Oliveira F.G., Tran W.H., Keens T.G., Khoo M.C., Davidson Ward S.L. Body fat composition: A predictive factor for sleep related breathing disorder in obese children. Journal of Clinical Sleep Medicine 15;11(9):1039-45, 2015. [PMC4543248]

Davidson Ward S.L., Amin R., Arens R., Zhongping C., Davis S., Gutmark E., Superfine R., Wong B., Zdanski C., Khoo M.C. Pediatric sleep-related breathing disorders: advances in imaging and computational modeling. IEEE Pulse 5(5):33-39, 2014.[PubMed – In Process]

Wang, W., S.A. Redline and M.C.K. Khoo. Autonomic markers of impaired glucose metabolism: effects of sleep-disordered breathing. Journal of Diabetes Science & Technology 6(5):1159-1171, 2012. [PDF] — [PMC3570851]

Lesser, D.J., W.H. Tran, M.C.K. Khoo, T.G. Keens, R. Ortega, M.I. Goran, S.D. Mittelman, and S.L. Davidson Ward. Sleep fragmentation and intermittent hypoxemia associated with decreased insulin sensitivity in obese adolescent Latino males. Pediatrics Research 72(3):293-298, 2012. [PMC3427473]

Cheng, L.M. and M.C.K. Khoo. Modeling the autonomic and metabolic effects of obstructive sleep apnea: a simulation study. Frontiers in Physiology 2(111):1-20, 2012.[PMC3250672]

Hoppenbrouwers, T., F. Oliveira, S. Sandarupa, M.C.K. Khoo, M. Neuman and R. Rangasamy. The development of the circadian heart rhythm (CHR) in Asian infants. Early Human Development 88(7):555-561, 2012. [PDF]

Khoo, M.C.K., W. Wang and P. Chalacheva. Monitoring ultradian changes in cardiorespiratory activity in obstructive sleep apnea syndrome. Conference Proceedings, IEEE Engineering in Medicine and Biology Society 1:1487-1490, 2011. [PMC3398741]

Sangkatumvong, S., M.C.K. Khoo, R. Kato, J.A. Detterich, A. Bush, T.G. Keens, . . . T.D. Coates. Peripheral Vasoconstriction and Abnormal Parasympathetic Response to Sighs and Transient Hypoxia in Sickle Cell Disease. American Journal of Respiratory and Critical Care Medicine 184(4):474-481, 2011. [PDF] — [PMC3175540]

Cheng, L., O. Ivanova, H.-H. Fan and M. C. K. Khoo. An integrative model of respiratory and cardiovascular control in sleep-disordered breathing. Respiratory Physiology & Neurobiology 174(1-2):4-28, 2010. [PDF][PMC2965826]

Khoo, M.C.K. Model-Based Studies of Autonomic and Metabolic Dysfunction in Sleep Apnea. New Frontiers in Respiratory Control 669:275-279, 2010. [PDF][PMC3137921]

Chaicharn, J., Z. Lin, M.L. Chen, . . . M.C.K. Khoo. Model-Based Assessment of Cardiovascular Autonomic Control in Children with Obstructive Sleep Apnea. Sleep 32(7):12, 2009.. [PDF][PMC2706908]

Chaicharn, J., M. Carrington, J. Trinder and M.C.K. Khoo. The effects on autonomic control of repetitive arousal from sleep. Sleep 31:93-103, 2008. [PDF][PMC2225561]

Jo, J., A. Blasi, E. Valladares, R. Juarez, A. Baydur and M.C.K. Khoo. A nonlinear model of cardiac autonomic control in obstructive sleep apnea syndrome. Annals of Biomedical Engineering 35(8):1425-1443, 2007. [PDF]

Asyali, M., R.B. Berry, M.C.K. Khoo and A. Altinok. Determining a continuous marker for sleep depth. Computers in Biology and Medicine 37(11):1600-1609, 2007. [PDF]

Blasi, A., J. Jo, E. Valladares, R. Juarez, A. Baydur and M.C.K. Khoo. Autonomic cardiovascular control following transient arousal from sleep: A time-varying closed-loop model. IEEE Transactions on Biomedical Engineering 53(1):74-82, 2006. [PDF]

Ivanova, O., L. Marcu and M.C.K. Khoo. A nonparametric method for analysis of fluorescence emission in combined time and wavelength dimensions. Annals of Biomedical Engineering 33(4):529-542, 2005. [PDF][PMC2672102]

Jo, J., A. Blasi, E. Valladares, R. Juarez, A. Baydur and M.C.K. Khoo. Determinants of heart rate variability in obstructive sleep apnea syndrome during wakefulness and sleep. American Journal of Physiology – Heart and Circulatory Physiology 288:H1103-H1112, 2005. [PDF]

Ivanova O.V., M.C.K. Khoo. Simulation of spontaneous cardiovascular variability using PNEUMA. Proc 26th Annual IEEE EMBS Conference p. 3901-3904, 2004.

Blasi, A., J. Jo, E. Valladares, B.J. Morgan, J.B. Skatrud, and M.C.K. Khoo. Cardiovascular variability after arousal from sleep: time-varying spectral analysis. Journal of  Applied Physiology 95:1394-1404, 2003.

Blasi A., J. Jo, E. Valladares, R. Juarez, A. Baydur and M.C.K. Khoo. Time-varying analysis of autonomic control during arousal from sleep in obstructive sleep apnea syndrome. Proc 25th Annual EMBS Conference p. 350-353, 2003.

Jo J., A. Blasi, A. Baydur, R. Juarez and M.C.K. Khoo. Nonlinear assessment of autonomic function in obstructive sleep apnea during long-term CPAP therapy. Proc 25th Annual EMBS Conference p. 346-349, 2003.

Ivanova O.V., L. Marcu and M.C.K. Khoo. Estimation of optical fluorescent impulse response kernel in combined time and wavelength spaces. Proceedings SPIE 4955:330-341, 2003.

Belozeroff, V., R.B. Berry, & M.C.K. Khoo. Model-based assessment of autonomic control obstructive sleep apnea syndrome. Sleep 26(1):1-9, 2003.

Belozeroff, V., R.B. Berry, C.S.H. Sassoon & M.C.K. Khoo. Effects of CPAP therapy on cardiovascular variability in obstructive sleep apnea: a closed-loop analysis. American Journal of Physiology – Heart and Circulatory Physiology 282:H110-H121, 2002. [PDF]

Blasi, A., J. Jo, A. Baydur, R. Juarez & M.C.K. Khoo. Effects of arousal from sleep on autonomic cardiovascular control in obstructive sleep apnea syndrome. Proc. 2nd Joint EMBS-BMES Conference  p. 1525-1526, 2002.

Fan H. & M.C.K. Khoo. PNEUMA: a comprehensive cardiorespiratory model. Proc 2nd Joint EMBS-BMES Conference p. 1533-1534, 2002.

Jo, J., M.C.K. Khoo, A. Blasi, A. Baydur & R. Juarez. Detection of autonomic abnormality in obstructive sleep apnea using a nonlinear model of heart rate variability. Proc. 2nd Joint EMBS-BMES Conference p. 1554-1555, 2002.

Fan H. & M.C.K. Khoo. Cardiorespiratory interactions in sleep-disordered breathing: an integrative model. American Journal of Respiratory and Critical Care Medicine  163(4):A630, 2001.

Garde, S., M.G. Regalado, V.L. Schechtman, & M.C.K. Khoo. Nonlinear dynamics of heart rate variability in cocaine-exposed neonates during sleep. American Journal of Physiology – Heart and Circulatory Physiology 280: H2920–H2928, 2001. [PDF]

Khoo, M.C.K., V. Belozeroff & R.B. Berry. Dynamics of heart rate control in obstructive sleep apnea: a minimal model. In: Cardiac autonomic control in obstructive sleep apnea: effects of long-term CPAP therapy. Am. J. Respir. Crit. Care Med.,Frontiers in Modeling and Control of Breathing: Integration at Molecular, Cellular, and Systems Levels, eds. C.-S. Poon and H. Kazemi, p. 465-470, Kluwer Academic: NY, 2001.

Khoo, M.C.K., V. Belozeroff, R.B. Berry & C.S.H. Sassoon. Cardiac autonomic control in obstructive sleep apnea: effects of long-term CPAP therapy. American Journal of Respiratory and Critical Care Medicine 164:807-812, 2001. [PDF]

Regalado, M., V. Schechtman and M.C.K. Khoo. Spectral analysis of heart rate variability and respiration during sleep in cocaine-exposed neonates. Clinical Physiology 21:428-436, 2001.

Khoo, M.C.K., T.S. Kim & R.B. Berry. Spectral indices of cardiac autonomic function in obstructive sleep apnea. Sleep 22:443-451, 1999. [PDF]