Imbalance in Cardiac Autonomic Nervous System Mediates Fatigue

Main Article Content

Aaron I. Vinik, M.D., Ph.D. Etta J. Vinik, MEd. Ying-Chuen Lai, M.D. Steven Morrison, Ph.D. Sheri R. Colberg, Ph.D. Serina Neumann, Ph.D. Joshua Edwards, MS. Scott Gerwe, M.D Carolina Casellini, M.D. Henri Parson, Ph.D.


Aims To explore the impact of the autonomic nervous system function in “disease-free” people for testing and appropriate therapies in different age-groups.

Methods Seventy-five disease-free volunteers who participated in a previous study were randomly selected from five age-groups (30-79 years) for a cross/sectional study to assess the impact of fatigue on cardiac/autonomic function by analysis of heart rate variability (HRV) and measures of cognitive and physical fatigue on quality-of-life-fatigue (QOLF) scores. Written informed consent was obtained and protocol approved. To induce fatigue, three 5-minute walking trials were performed on an instrumental treadmill, increasing the incline in increments of 2°/min to measure perceived exertion (RPE) at the beginning and end of each trial. Polar monitors measured heart rate (HR); a modified Borg 10-point scale measured RPE. Cardiac autonomic reflex tests (CART) with time/frequency domains analyzed HRV. QOLF scores were measured and analyzed for correlation with sympathetic/parasympathetic function on the Norfolk QOL-F fatigue scale.

Results QOL-F scores were not significantly different among 5 age groups, likely due to wide standard deviations and small subject numbers. Significant correlations between overall fatigue severity and several indices of HRV were found, independent of age, gender, and body mass index (p<0.05). Self-rated physical fatigue and compromised activities of daily living (ADLs) were related to sympathetic hyperactivity and autonomic imbalance (p=0.04). Participants in the (70–79-year-olds) category had impaired scores.

Conclusions The study identifies a relationship between autonomic nervous system function and cognitive and physical fatigue even in “disease-free” people in different age- groups and suggests that fatigue is impacted by somatic and autonomic nerve function. Higher self-ratings of perceived fatigue were associated with sympathovagal hyperactivity. Impaired HR response to exercise in older people corresponding with vagal over-activity, and paradoxically, best self-rated QOL-F, mandates clinical autonomic dysfunction testing and lifestyle therapies to prevent catastrophic events.

Keywords: Autonomic imbalance, Cognitive, Physical Fatigue, Quality of Life

Article Details

How to Cite
VINIK, Aaron I. et al. Imbalance in Cardiac Autonomic Nervous System Mediates Fatigue. Medical Research Archives, [S.l.], v. 10, n. 2, feb. 2022. ISSN 2375-1924. Available at: <>. Date accessed: 27 may 2024. doi:
Research Articles


1. Lewis G, Wessely S. The epidemiology of fatigue: more questions than answers. J Epidemiol Community Health 1992;46:92-7.
2. Ranjith G. Epidemiology of chronic fatigue syndrome. Occup Med (Lond) 2005;55:13-9.
3. Wessely S, Chalder T, Hirsch S, Wallace P, Wright D. The prevalence and morbidity of chronic fatigue and chronic fatigue syndrome: a prospective primary care study. Am J Public Health 1997;87:1449-55.
4. van't Leven M, Zielhuis GA, van der Meer JW, Verbeek AL, Bleijenberg G. Fatigue and chronic fatigue syndrome-like complaints in the general population. Eur J Public Health 2010;20:251-7.
5. Kim CH, Shin HC, Won CW. Prevalence of chronic fatigue and chronic fatigue syndrome in Korea: community-based primary care study. J Korean Med Sci 2005;20:529-34.
6. Ricci JA, Chee E, Lorandeau AL, Berger J. Fatigue in the U.S. workforce: prevalence and implications for lost productive work time. J Occup Environ Med 2007;49:1-10.
7. Gibbons CH, Bonyhay I, Benson A, Wang N, Freeman R. Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome. PLoS One 2013;8:e84716.
8. Smets EM, Garssen B, Bonke B, De Haes JC. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995;39:315-25.
9. Morrison S, Colberg SR, Parson HK, et al. Walking-Induced Fatigue Leads to Increased Falls Risk in Older Adults. J Am Med Dir Assoc 2016;17:402-9.
10. Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation 2007;115:387-97.
11. Casellini CM, Parson HK, Richardson MS, Nevoret ML, Vinik AI. Sudoscan, a Noninvasive Tool for Detecting Diabetic Small Fiber Neuropathy and Autonomic Dysfunction. Diabetes Technol Ther 2013;15:948-53.
12. Sheldon RS, Grubb BP, Olshansky B, et al. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm 2015;12:e41-e63.
13. Bagai K, Song Y, Ling JF, et al. Sleep disturbances and diminished quality of life in postural tachycardia syndrome. J Clin Sleep Med 2011;7:204-10.
14. Tanaka M, Mizuno K, Yamaguti K, et al. Autonomic nervous alterations associated with daily level of fatigue. Behav Brain Funct 2011;7:46.
15. Mizuno K, Tanaka M, Yamaguti K, Kajimoto O, Kuratsune H, Watanabe Y. Mental fatigue caused by prolonged cognitive load associated with sympathetic hyperactivity. Behav Brain Funct 2011;7:17.
16. Togo F, Natelson BH. Heart rate variability during sleep and subsequent sleepiness in patients with chronic fatigue syndrome. Auton Neurosci 2013;176:85-90.
17. Crosswell AD, Lockwood KG, Ganz PA, Bower JE. Low heart rate variability and cancer-related fatigue in breast cancer survivors. Psychoneuroendocrinology 2014;45:58-66.
18. Newton JL, Okonkwo O, Sutcliffe K, Seth A, Shin J, Jones DE. Symptoms of autonomic dysfunction in chronic fatigue syndrome. QJM 2007;100:519-26.
19. Vinik EJ, Vinik AI, Neumann SA, et al. Development and Validation of the Norfolk Quality of Life Fatigue Tool (QOL-F): A New Measure of Perception of Fatigue. J Am Med Dir Assoc 2020; 21(9):1267-1272.e2.
20. Spallone V, Bellavere F, Scionti L, et al. Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy. Nutr Metab Cardiovasc Dis 2011;21:69-78.
21. Cardiology TFotESo. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 1996;93:1043-65.
22. Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods 2009;41:1149-60.
23. Christou DD, Jones PP, Jordan J, Diedrich A, Robertson D, Seals DR. Women have lower tonic autonomic support of arterial blood pressure and less effective baroreflex buffering than men. Circulation 2005;111:494-8.
24. Ge X, Pan SM, Zeng F, Tang ZH, Wang YW. A simple Chinese risk score model for screening cardiovascular autonomic neuropathy. PLoS One 2014;9:e89623.
25. Porges SW. The polyvagal theory: new insights into adaptive reactions of the autonomic nervous system. Cleve Clin J Med 2009;76 Suppl 2:S86-S90.
26. Porges SW. Social engagement and attachment: a phylogenetic perspective. Ann N Y Acad Sci 2003;1008:31-47.
27. Butler EA, Wilhelm FH, Gross JJ. Respiratory sinus arrhythmia, emotion, and emotion regulation during social interaction. Psychophysiology 2006;43:612-22.
28. Convertino VA. Neurohumoral mechanisms associated with orthostasis: reaffirmation of the significant contribution of the heart rate response. Front Physiol 2014;5:236.
29. Moak JP, Goldstein DS, Eldadah BA, et al. Supine low-frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation. Heart Rhythm 2007;4:1523-9.
30. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000;101:1899-906.
31. Freeman R, Komaroff AL. Does the chronic fatigue syndrome involve the autonomic nervous system? Am J Med 1997;102:357-64.
32. Mallien J, Isenmann S, Mrazek A, Haensch CA. Sleep disturbances and autonomic dysfunction in patients with postural orthostatic tachycardia syndrome. Front Neurol 2014;5:118.
33. Gradisar M, Lack L, Richards H, et al. The Flinders Fatigue Scale: preliminary psychometric properties and clinical sensitivity of a new scale for measuring daytime fatigue associated with insomnia. J Clin Sleep Med 2007;3:722-8.
34. Li M, Xu C, Yao W, et al. Self-reported post-exertional fatigue in Gulf War veterans: roles of autonomic testing. Front Neurosci 2014;7:269.
35. Vinik AI. The conductor of the autonomic orchestra. Front Endocrinol 2012;71:1-13.