Applied Psychophysiology and Biofeedback

, Volume 35, Issue 4, pp 303–315 | Cite as

Voluntarily Produced Increases in Heart Rate Variability Modulate Autonomic Effects of Endotoxin Induced Systemic Inflammation: An Exploratory Study

  • Paul Lehrer
  • Maria Katsamanis Karavidas
  • Shou-En Lu
  • Susette M. Coyle
  • Leo O. Oikawa
  • Marie Macor
  • Steve E. Calvano
  • Stephen F. Lowry


Exposure of healthy people to lipopolysaccharide (LPS; endotoxin) produces a pro-inflammatory response, subjective symptoms, and decreased heart rate variability (HRV). Given the efficacy of HRV biofeedback (BF) for treating asthma, the large autonomic effects of HRV BF, and the link between vagus nerve activity and inflammation, we hypothesized that HRV BF would dampen the acute manifestations of systemic inflammation induced by LPS challenge. Healthy participants age 18-40 were randomly assigned to four-one-hour training sessions of either HRV BF (n = 6) or a control 15/min paced breathing condition (n = 5) prior to acute experimentally induced LPS exposure. Participants were coached to do the procedures for 10 min each at five hourly time points after LPS injection, and then 2 h later. Subjective symptoms, HRV parameters, and plasma cytokine levels were measured at each time point, 2 h afterward, and the following morning. Participants were able to perform the procedures both during four pre-exposure training sessions and while experiencing LPS-induced symptoms. The HRV BF group showed significant attenuation of the LPS-induced decline in HRV for the 6 h following LPS exposure, suggesting that HRV BF decreased autonomic dysfunction produced by LPS-induced inflammation. HRV BF also reduced symptoms of headache and eye sensitivity to light, but did not affect LPS-induced levels of pro-inflammatory cytokines or symptoms of nausea, muscle aches, or feverishness. Further evaluation of HRV BF appears to be warranted among patients with inflammatory conditions.


Biofeedback Vagus nerve Endotoxinemia Sepsis Endotoxin Dysregulation Adaptability 



This work was supported by the National Institutes of Health (NIGMS Grant R01 GM34695).


  1. Akaike, H. A. (1974). A new look at the statistical model identification. IEEE Transactions on Automatic Control, 19, 716–723.CrossRefGoogle Scholar
  2. Alvarez, S. M., Katsamanis Karavidas, M., Coyle, S. M., Lu, S.-E., Macor, M., Oikawa, L. O., et al. (2007). Low-dose steroid alters in vivo endotoxin-induced systemic inflammation but does not influence autonomic dysfunction. Journal of Endotoxin Research, 13, 358–368.CrossRefPubMedGoogle Scholar
  3. Appelhans, B. M., & Luecken, L. J. (2008). Heart rate variability and pain: Associations of two interrelated homeostatic processes. Biological Psychology, 77, 174–182.CrossRefPubMedGoogle Scholar
  4. Berntson, G. G., Bigger, J. T., Eckberg, D. L., Grossman, P., Kaufman, P. G., Malik, M., et al. (1997). Heart rate variability: Origins, methods, and interpretive caveats. Psychophysiology, 34, 623–648.CrossRefPubMedGoogle Scholar
  5. Bluzaite, I., Brazdzionyte, J., Zaliunas, R., Rickli, H., & Ammann, P. (2006). QT dispersion and heart rate variability in sudden death risk stratification in patients with ischemic heart disease. Medicina (Kaunas, Lithuania), 42, 450–454.Google Scholar
  6. Calvano, S. E., Xiao, W., Richards, D. R., Felciano, R. M., Baker, H. V., Cho, R. J., et al. (2005). A network-based analysis of systemic inflammation in humans. Nature, 437, 1032–1037.CrossRefPubMedGoogle Scholar
  7. Carney, R. M., & Freedland, K. E. (2009). Depression and heart rate variability in patients with coronary heart disease. Cleveland Clinic Journal of Medicine, 76(Suppl 2), S13–S17.Google Scholar
  8. Chan, C. T. (2008). Heart rate variability in patients with end-stage renal disease: An emerging predictive tool for sudden cardiac death? Nephrology, Dialysis, Transplantation, 23, 3061–3062.CrossRefPubMedGoogle Scholar
  9. Chen, J.-L., Chiu, H.-W., Tseng, Y.-J., & Chu, W.-C. (2006). Hyperthyroidism is characterized by both increased sympathetic and decreased vagal modulation of heart rate: Evidence from spectral analysis of heart rate variability. Clinical Endocrinology, 64, 611–616.CrossRefPubMedGoogle Scholar
  10. Christensen, J. H. (2003). n-3 fatty acids and the risk of sudden cardiac death. Emphasis on heart rate variability. Danish Medical Bulletin, 50, 347–367.PubMedGoogle Scholar
  11. Christou, D. D., & Seals, D. R. (2008). Decreased maximal heart rate with aging is related to reduced {beta}-adrenergic responsiveness but is largely explained by a reduction in intrinsic heart rate. Journal of Applied Physiology, 105, 24–29.CrossRefPubMedGoogle Scholar
  12. Cooley, J. W., & Tukey J. W. (1965). An algorithm for machine calculation of complex Fourier series. Mathematics of Computation, 19, 297–301.Google Scholar
  13. Czura, C. J., & Tracey, K. J. (2005). Autonomic neural regulation of immunity. Journal of Internal Medicine, 257, 156–166.CrossRefPubMedGoogle Scholar
  14. Drummond, P. D. (2006). Mechanisms of autonomic disturbance in the face during and between attacks of cluster headache. Cephalalgia, 26, 633–641.CrossRefPubMedGoogle Scholar
  15. Eckberg, D. L. (2003). The human respiratory gate. Journal of Physiology, 548, 339–352.PubMedGoogle Scholar
  16. Fazan, R., Jr., de Oliveira, M., da Silva, V. J. D., Joaquim, L. F., Montano, N., Porta, A., et al. (2005). Frequency-dependent baroreflex modulation of blood pressure and heart rate variability in conscious mice. American Journal of Physiology Heart & Circulatory Physiology, 289, H1968–H1975.CrossRefGoogle Scholar
  17. Giakoumaki, S. G., Hourdaki, E., Grinakis, V., Theou, K., & Bitsios, P. (2005). Effects of peripheral sympathetic blockade with dapiprazole on the fear-inhibited light reflex. Journal of Psychopharmacology, 19, 139–148.CrossRefPubMedGoogle Scholar
  18. Godin, P. J., Fleisher, L. A., Eidsath, A., Vandivier, R. W., Preas, H. L., Banks, S. M., et al. (1996). Experimental human endotoxemia increases cardiac regularity: Results from a prospective, randomized, crossover trial. Critical Care Medicine, 24, 1117–1124.CrossRefPubMedGoogle Scholar
  19. Grippo, A. J., & Johnson, A. K. (2002). Biological mechanisms in the relationship between depression and heart disease. Neuroscience and Biobehavioral Reviews, 26, 941–962.CrossRefPubMedGoogle Scholar
  20. Grossman, P., Karemaker, J., & Wieling, W. (1991). Prediction of tonic parasympathetic cardiac control using respiratory sinus arrhythmia: The need for respiratory control. Psychophysiology, 28, 201–216.CrossRefPubMedGoogle Scholar
  21. Guzzetti, S., Borroni, E., Garbelli, P. E., Ceriani, E., Della Bella, P., Montano, N., et al. (2005). Symbolic dynamics of heart rate variability: A probe to investigate cardiac autonomic modulation. Circulation, 112, 465–470.CrossRefPubMedGoogle Scholar
  22. Halamek, J., Kara, T., Jurak, P., Soucek, M., Francis, D. P., Davies, L. C., et al. (2003). Variability of phase shift between blood pressure and heart rate fluctuations: A marker of short-term circulation control. Circulation, 108, 292–297.CrossRefPubMedGoogle Scholar
  23. Jamner, L. D., & Tursky, B. (1987a). Discrimination between intensity and affective pain descriptors: A psychophysiological evaluation. Pain, 30, 271–283.CrossRefPubMedGoogle Scholar
  24. Jamner, L. D., & Tursky, B. (1987b). Syndrome-specific descriptor profiling: A psychophysiological and psychophysical approach. Health Psychology, 6, 417–430.CrossRefPubMedGoogle Scholar
  25. Jan, B. U., Coyle, S. M., Oikawa, L. O., Lu, S.-E., Calvano, S. E., Lehrer, P. M., et al. (2009). Influence of acute epinephrine infusion on endotoxin-induced parameters of heart rate variability: A randomized controlled trial. Annals of Surgery, 249, 750–756.CrossRefPubMedGoogle Scholar
  26. Jankowska, E. A., Ponikowski, P., Piepoli, M. F., Banasiak, W., Anker, S. D., & Poole-Wilson, P. A. (2006). Autonomic imbalance and immune activation in chronic heart failure—Pathophysiological links. Cardiovascular Research, 70, 434–445.CrossRefPubMedGoogle Scholar
  27. Karrow, N. A. (2006). Activation of the hypothalamic-pituitary-adrenal axis and autonomic nervous system during inflammation and altered programming of the neuroendocrine-immune axis during fetal and neonatal development: Lessons learned from the model inflammagen, lipopolysaccharide. Brain, Behavior, & Immunity, 20, 144–158.CrossRefGoogle Scholar
  28. Kiba, T. (2006). Relationships between the autonomic nervous system, humoral factors and immune functions in the intestine. Digestion, 74, 215–227.PubMedGoogle Scholar
  29. Lehrer, P. M. (2007). Biofeedback training to increase heart rate variability. In S. W. Lehrer, & R. L. Woolfolk (Eds.), Principles and practice of stress management, 3rd edn (pp. 227–248). New York: Guilford Press.Google Scholar
  30. Lehrer, P., Carr, R. E., Smetankine, A., Vaschillo, E., Peper, E., Porges, S., et al. (1997). Respiratory sinus arrhythmia versus neck/trapezius EMG and incentive inspirometry biofeedback for asthma: A pilot study. Applied Psychophysiology & Biofeedback, 22, 95–109.CrossRefGoogle Scholar
  31. Lehrer, P., Smetankin, A., & Potapova, T. (2000a). Respiratory sinus arrhythmia biofeedback therapy for asthma: A report of 20 unmedicated pediatric cases using the Smetankin method. Applied Psychophysiology & Biofeedback, 25, 193–200.CrossRefGoogle Scholar
  32. Lehrer, P., Vaschillo, E., Lu, S.-E., Eckberg, D., Vaschillo, B., Scardella, A., et al. (2006). Heart rate variability biofeedback: Effects of age on heart rate variability, baroreflex gain, and asthma. Chest, 129, 278–284.CrossRefPubMedGoogle Scholar
  33. Lehrer, P. M., Vaschillo, E., & Vaschillo, B. (2000b). Resonant frequency biofeedback training to increase cardiac variability: Rationale and manual for training. Applied Psychophysiology & Biofeedback, 25, 177–191.CrossRefGoogle Scholar
  34. Lehrer, P. M., Vaschillo, E., Vaschillo, B., Lu, S.-E., Eckberg, D. L., Edelberg, R., et al. (2003). Heart rate variability biofeedback increases baroreflex gain and peak expiratory flow. Psychosomatic Medicine, 65, 796–805.CrossRefPubMedGoogle Scholar
  35. Lehrer, P. M., Vaschillo, E., Vaschillo, B., Lu, S.-E., Scardella, A., Siddique, M., et al. (2004). Biofeedback treatment for asthma. Chest, 126, 352–361.CrossRefPubMedGoogle Scholar
  36. Lowry, S. F. (2005). Human endotoxemia: A model for mechanistic insight and therapeutic targeting. Shock, 24(Suppl 1), 94–100.Google Scholar
  37. Lowry, S. F. (2009). The stressed host response to infection: The disruptive signals and rhythms of systemic inflammation. Surgical Clinics of North America, 89, 311–326.CrossRefPubMedGoogle Scholar
  38. Lowry, S. F., & Calvano, S. E. (2008). Challenges for modeling and interpreting the complex biology of severe injury and inflammation. Journal of Leukocyte Biology, 83, 553–557.CrossRefPubMedGoogle Scholar
  39. Lupien, S. J., Ouellet-Morin, I., Hupbach, A., Tu, M. T., Buss, C., Walker, D., et al. (2006). Beyond the stress concept: Allostatic load—A developmental biological and cognitive perspective. Hoboken, NJ: Wiley.Google Scholar
  40. Mallen, E. A. H., Gilmartin, B., & Wolffsohn, J. S. (2005). Sympathetic innervation of ciliary muscle and oculomotor function in emmetropic and myopic young adults. Vision Research, 45, 1641–1651.CrossRefPubMedGoogle Scholar
  41. McEwen, B., & Lasley, E. N. (2007). Allostatic load: When protection gives way to damage. Westport, CT: Praeger Publishers/Greenwood Publishing Group.Google Scholar
  42. McEwen, B. S., & Wingfield, J. C. (2003). The concept of allostasis in biology and biomedicine. Hormones and Behavior, 43, 2–15.CrossRefPubMedGoogle Scholar
  43. Pinerua-Shuhaibar, L., Prieto-Rincon, D., Ferrer, A., Bonilla, E., Maixner, W., & Suarez-Roca, H. (1999). Reduced tolerance and cardiovascular response to ischemic pain in minor depression. Journal of Affective Disorders, 56, 119–126.CrossRefPubMedGoogle Scholar
  44. Politano, L., Palladino, A., Nigro, G., Scutifero, M., & Cozza, V. (2008). Usefulness of heart rate variability as a predictor of sudden cardiac death in muscular dystrophies. Acta Myologica, 27, 114–122.PubMedGoogle Scholar
  45. Porges, S. W. (1995). Orienting in a defensive world: Mammalian modifications of our evolutionary heritage. A polyvagal theory. Psychophysiology, 32, 301–318.CrossRefPubMedGoogle Scholar
  46. Porges, S. W. (2001). The polyvagal theory: Phylogenetic substrates of a social nervous system. International Journal of Psychophysiology, 42, 123–146.CrossRefPubMedGoogle Scholar
  47. Porges, S. W. (2007). The polyvagal perspective. Biological Psychology, 74, 116–143.CrossRefPubMedGoogle Scholar
  48. Porges, S. W., Doussard-Roosevelt, J. A., Portales, A. L., & Greenspan, S. I. (1996). Infant regulation of the vagal “brake” predicts child behavior problems: A psychobiological model of social behavior. Developmental Psychobiology, 29, 697–712.CrossRefPubMedGoogle Scholar
  49. Rainville, P., Bao, Q. V. H., & Chretien, P. (2005). Pain-related emotions modulate experimental pain perception and autonomic responses. Pain, 118, 306–318.CrossRefPubMedGoogle Scholar
  50. Ritz, T., & Dahme, B. (2006). Implementation and interpretation of respiratory sinus arrhythmia measures in psychosomatic medicine: Practice against better evidence? Psychosomatic Medicine, 68, 617–627.CrossRefPubMedGoogle Scholar
  51. Rosas-Ballina, M., Ochani, M., Parrish, W. R., Ochani, K., Harris, Y. T., Huston, J. M., et al. (2008). Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proceedings of the National Academy of Sciences of the United States of America, 105, 11008–11013.CrossRefPubMedGoogle Scholar
  52. Rubin, P. A., Chen, V. N., & Acquadro, M. A. (1996). Cluster headache presenting with orbital inflammation. Ophthalmic Surgery and Lasers, 27, 143–146.PubMedGoogle Scholar
  53. Saeed, R. W., Varma, S., Giebelen, I. A., Florquin, S., Dallhuisen, J., Bruno, M. J., et al. (2005). Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation. Journal of Experimental Medicine, 201, 1113–1123.CrossRefPubMedGoogle Scholar
  54. Schuh-Hofer, S., Richter, M., Israel, H., Geworski, L., Villringer, A., Munz, D. L., et al. (2006). The use of radiolabelled human serum albumin and SPECT/MRI co-registration to study inflammation in the cavernous sinus of cluster headache patients. Cephalalgia, 26, 1115–1122.CrossRefPubMedGoogle Scholar
  55. Sevoz-Couche, C., Comet, M. A., Bernard, J. F., Hamon, M., & Laguzzi, R. (2006). Cardiac baroreflex facilitation evoked by hypothalamus and prefrontal cortex stimulation: Role of the nucleus tractus solitarius 5-HT2A receptors. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 291, R1007–R1015.PubMedGoogle Scholar
  56. Song, H.-S., & Lehrer, P. M. (2003). The effects of specific respiratory rates on heart rate and heart rate variability. Applied Psychophysiology & Biofeedback, 28, 13–23.CrossRefGoogle Scholar
  57. Tabata, M., Takeshima, T., Burioka, N., Nomura, T., Ishizaki, K., Mori, N., et al. (2000). Cosinor analysis of heart rate variability in ambulatory migraineurs. Headache, 40, 457–463.CrossRefPubMedGoogle Scholar
  58. 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, clinical use. Circulation, 93, 1043–1065.Google Scholar
  59. Taylor, J. A., Carr, D. L., Myers, C. W., & Eckberg, D. L. (1998). Mechanisms underlying very-low-frequency RR-interval oscillations in humans. Circulation, 98, 547–555.PubMedGoogle Scholar
  60. Tracey, K. J. (2007). Physiology and immunology of the cholinergic antiinflammatory pathway. Journal of Clinical Investigation, 117, 289–296.CrossRefPubMedGoogle Scholar
  61. Tursky, B. (1974). Presidential address, 1973. Physical, physiological, and psychological factors that affect pain reaction to electric shock. Psychophysiology, 11, 95–112.CrossRefPubMedGoogle Scholar
  62. van Westerloo, D. J., Giebelen, I. A. J., Florquin, S., Daalhuisen, J., Bruno, M. J., de Vos, A. F., et al. (2005). The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis. Journal of Infectious Diseases, 191, 2138–2148.CrossRefPubMedGoogle Scholar
  63. Van Zee, K. J., Coyle, S. M., Calvano, S. E., Oldenburg, H. S., Stiles, D. M., Pribble, J., et al. (1995). Influence of IL-1 receptor blockade on the human response to endotoxemia. Journal of Immunology, 154, 1499–1507.Google Scholar
  64. Van Zee, K. J., Moldawer, L. L., Oldenburg, H. S., Thompson, W. A., Stackpole, S. A., Montegut, W. J., et al. (1996). Protection against lethal Escherichia coli bacteremia in baboons (Papio anubis) by pretreatment with a 55-kDa TNF receptor (CD120a)-Ig fusion protein, Ro 45–2081. Journal of Immunology, 156, 2221–2230.Google Scholar
  65. Vaschillo, E., Lehrer, P., Rishe, N., & Konstantinov, M. (2002). Heart rate variability biofeedback as a method for assessing baroreflex function: A preliminary study of resonance in the cardiovascular system. Applied Psychophysiology & Biofeedback, 27, 1–27.CrossRefGoogle Scholar
  66. Vaschillo, E. G., Vaschillo, B., & Lehrer, P. M. (2006). Characteristics of resonance in heart rate variability stimulated by biofeedback. Applied Psychophysiology & Biofeedback, 31, 129–142.CrossRefGoogle Scholar
  67. Yende, S., Tuomanen, E. I., Wunderink, R., Kanaya, A., Newman, A. B., Harris, T., de Rekeneire, N., & Kritchevsky, S. B. (2005). Pre-infection systemic inflammatory markers and risk of hospitalization due to pneumonia. American Journal of Respiratory & Critical Care Medicine, 172, 1440–1446.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Paul Lehrer
    • 1
  • Maria Katsamanis Karavidas
    • 1
  • Shou-En Lu
    • 1
    • 2
  • Susette M. Coyle
    • 3
  • Leo O. Oikawa
    • 1
  • Marie Macor
    • 3
  • Steve E. Calvano
    • 3
  • Stephen F. Lowry
    • 3
  1. 1.Department of PsychiatryUMDNJ-Robert Wood Johnson Medical SchoolPiscatawayUSA
  2. 2.Department of BiostatisticsUMDNJ-School of Public HealthNew BrunswickUSA
  3. 3.Division of Surgical SciencesUMDNJ-Robert Wood Johnson Medical SchoolPiscatawayUSA

Personalised recommendations