Comparison of the Degree of Deconditioning in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients with and without Orthostatic Intolerance
Main Article Content
Abstract
Background: Orthostatic intolerance (OI) is a core finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Deconditioning is often proposed as an important determinant for OI. Deconditioning can be objectively classified using the predicted peak oxygen consumption (%VO2 peak) values as derived from cardiopulmonary exercise testing (CPET) and OI can be objectively quantified using cerebral blood flow (CBF) changes during tilt testing. Therefore, if deconditioning contributes to OI, a correlation between peak VO2 and the %CBF reduction is expected.
Methods and results: 18 healthy controls (HC) and 122 ME/CFS patients without hypotension or tachycardia on tilt testing were studied. Deconditioning was classified as follows: %VO2 peak ≥85%= no deconditioning, %VO2 peak 65-85%= mild deconditioning, %VO2 peak<65%= severe deconditioning. HC had higher %VO2 peak compared to ME/CFS patients (p<0.0001). ME/CFS patients had significantly larger CBF reduction than HC (p<0.0001). No relation between the degree of deconditioning by the %VO2 peak and the %CBF reduction in ME/CFS patients was found. Moreover, we separately analyzed ME/CFS patients without an abnormal CBF reduction. Despite equal CBF reductions compared to HC and large differences between these patients and the patients with an abnormal CBF reduction, cardiac index (CI) changes (measured by suprasternal Doppler) were significantly less compared to ME/CFS patients with an abnormal CBF reduction (p<0.0001) but larger than in HC (p=0.004). Despite these different hemodynamic findings, %VO2 values were not different between the two patient groups, argumenting again against the causative role of hemodynamic abnormalities in deconditioning.
Conclusion: In ME/CFS patients without hypotension or tachycardia there is no relation between the %VO2 peak during CPET and the %CBF and %CI reduction during tilt testing, whether or not patients have an abnormal CBF reduction during tilt testing. It suggests again that deconditioning does not play an important role in OI.
Keywords:
chronic fatigue syndrome, myalgic encephalomyelitis, peak oxygen consumption, cardiopulmonary exercise test, deconditioning, cerebral blood flow, orthostatic hypotension, orthostatic intolerance, head-up tilt testing
Article Details
How to Cite
VAN CAMPEN, C (Linda) M.C.; VISSER, Frans C..
Comparison of the Degree of Deconditioning in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients with and without Orthostatic Intolerance.
Medical Research Archives, [S.l.], v. 10, n. 6, june 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2858>. Date accessed: 14 nov. 2024.
doi: https://doi.org/10.18103/mra.v10i6.2858.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Institute Of Medicine (IOM), ed. Beyond mayalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. The National Academies Press; 2015.
2. van Campen CLMC, Verheugt FWA, Rowe PC, Visser FC. Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography. Clin Neurophysiol Pract. 2020;5:50-58. doi:10.1016/j.cnp.2020.01.003
3. Lee SM, Feiveson AH, Stein S, Stenger MB, Platts SH. Orthostatic Intolerance After ISS and Space Shuttle Missions. Aerosp Med Hum Perform. Dec 2015;86(12 Suppl):A54-67. doi:10.3357/AMHP.EC08.2015
4. Low PA, Sandroni P, Joyner M, Shen WK. Postural tachycardia syndrome (POTS). J Cardiovasc Electrophysiol. Mar 2009;20(3):352-358. doi:10.1111/j.1540-8167.2008.01407.x
5. Parsaik A, Allison TG, Singer W, et al. Deconditioning in patients with orthostatic intolerance. Neurology. Oct 2 2012;79(14):1435-1439. doi:10.1212/WNL.0b013e31826d5f95
6. Garland EM, Celedonio JE, Raj SR. Postural Tachycardia Syndrome: Beyond Orthostatic Intolerance. Curr Neurol Neurosci Rep. Sep 2015;15(9):60. doi:10.1007/s11910-015-0583-8
7. Joyner MJ, Masuki S. POTS versus deconditioning: the same or different? Clin Auton Res. 12/2008 2008;18(6):300-307. Not in File. doi:10.1007/s10286-008-0487-7
8. Benarroch EE. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc. Dec 2012;87(12):1214-1225. doi:10.1016/j.mayocp.2012.08.013
9. Shibata S, Fu Q, Bivens TB, Hastings JL, Wang W, Levine BD. Short-term exercise training improves the cardiovascular response to exercise in the postural orthostatic tachycardia syndrome. J Physiol. 8/1/2012 2012;590(Pt 15):3495-3505. Not in File. doi:10.1113/jphysiol.2012.233858
10. Rozenbaum Z, Khoury S, Aviram G, et al. Discriminating Circulatory Problems From Deconditioning: Echocardiographic and Cardiopulmonary Exercise Test Analysis. Chest. Feb 2017;151(2):431-440. doi:10.1016/j.chest.2016.09.027
11. van Campen CLMC, Visser FC. The abnormal Cardiac Index and Stroke Volume Index changes during a normal Tilt Table Test in ME/CFS patients compared to healthy volunteers, are not related to deconditioning. Research article. Journal Of Thrombosis and Circulation. 2018;(2):1-8. doi:10.29011/ JTC -107. 000007
12. van Campen CLMC, Rowe PC, Visser FC. Deconditioning does not explain orthostatic intolerance in ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med. 2021;19:193-203.
13. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 12/15/1994 1994;121(12):953-959. Not in File. doi:10.7326/0003-4819-121-12-199412150-00009
14. Carruthers BM, van de Sande MI, DE Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 10/2011 2011;270(4):327-338. Not in File. doi:10.1111/j.1365-2796.2011.02428.x
15. van Campen CLMC, Rowe PC, Visser FC. Heart Rate Thresholds to Limit Activity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients (Pacing): Comparison of Heart Rate Formulae and Measurements of the Heart Rate at the Lactic Acidosis Threshold during Cardiopulmonary Exercise Testing. Advances in Physical Education. 2020;10:138-154. doi:10.4236/ape.2020.102013
16. Davenport TE, Stevens SR, VanNess MJ, Snell CR, Little T. Conceptual model for physical therapist management of chronic fatigue syndrome/myalgic encephalomyelitis. Phys Ther. 4/2010 2010;90(4):602-614. Not in File. doi:10.2522/ptj.20090047
17. Vanness JM, Snell CR, stevens SR. Diminished cardiopulmonary capacity during post-exertional malaise. Journal of chronic fatigue syndrome. 2007;14:77-85. doi:10.1300/J092v14n02_07
18. van Campen CLMC, Rowe PC, Visser FC. Two-day cardiopulmonary exercise testing in females with a severe grade of myalgic encephalomylitis /chornic fatigue syndrome: comparison with patients with a mild and moderate disease. Healthcare. 2020;8(3):192. doi:10.3390/healthcare8030192
19. van Campen CLMC, Rowe PC, Visser FC. Validity of 2-day cardiopulmonary exercise testing in male patients with myalgic encephalomyelities/chronic fatigue syndrome. Advances in Physical Education. 2020;10:68-80. doi:10.4236/ape.2020.101007
20. van Campen CLMC, Verheugt FWA, Visser FC. Cerebral blood flow changes during tilt table testing in healthy volunteers, as assessed by Doppler imaging of the carotid and vertebral arteries. Clin Neurophysiol Pract. 2018;3:91-95. doi:10.1016/j.cnp.2018.02.004
21. Eeftinck Schattenkerk DW, van Lieshout JJ, van den Meiracker AH, et al. Nexfin noninvasive continuous blood pressure validated against Riva-Rocci/Korotkoff. Am J Hypertens. Apr 2009;22(4):378-83. doi:10.1038/ajh.2008.368
22. Martina JR, Westerhof BE, van Goudoever J, et al. Noninvasive continuous arterial blood pressure monitoring with Nexfin(R). Anesthesiology. May 2012;116(5):1092-103. doi:10.1097/ALN.0b013e31824f94ed
23. Kusumoto F, Venet T, Schiller NB, Sebastian A, Foster E. Measurement of aortic blood flow by Doppler echocardiography: temporal, technician, and reader variability in normal subjects and the application of generalizability theory in clinical research. J Am Soc Echocardiogr. Sep-Oct 1995;8(5 Pt 1):647-53. doi:10.1016/s0894-7317(05)80378-5
24. van Campen CLMC, Visser FC, de Cock CC, Vos HS, Kamp O, Visser CA. Comparison of the haemodynamics of different pacing sites in patients undergoing resynchronisation treatment: need for individualisation of lead localisation. Heart. Dec 2006;92(12):1795-1800. doi:10.1136/hrt.2004.050435
25. van Campen C, Verheugt FWA, Rowe PC, Visser FC. Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography. Clin Neurophysiol Pract. 2020;5:50-58. doi:10.1016/j.cnp.2020.01.003
26. van Campen CLMC, Visser FC. Validity of 2-day cardiopulmonary exercise testing in female patients with myalgic encephalomyelitis/chronic fatigue syndrome. International Journal of Current Research. 2020;12(3):10436-10442. doi:10.24941/ijcr.38263.03.2020
27. Beaver WL, Wasserman K, Whipp BJ. A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol (1985). Jun 1986;60(6):2020-2027. doi:10.1152/jappl.1986.60.6.2020
28. Glaser S, Koch B, Ittermann T, et al. Influence of age, sex, body size, smoking, and beta blockade on key gas exchange exercise parameters in an adult population. Eur J Cardiovasc Prev Rehabil. Aug 2010;17(4):469-476. doi:10.1097/HJR.0b013e328336a124
29. Wasserman K, Hansen JE, Sue DY, Stringer W, Whipp BJ. Normal values. In: Weinberg R, ed. Principles of Exercise Testing and Interpretation. 4th ed. Lippincott Williams and Wilkins; 2005:160-182.
30. Cureton K, Bishop P, Hutchinson P, Newland H, Vickery S, Zwiren L. Sex difference in maximal oxygen uptake. Effect of equating haemoglobin concentration. Eur J Appl Physiol Occup Physiol. 1986;54(6):656-660. doi:10.1007/bf00943356
31. Fletcher GF, Balady GJ, Amsterdam EA, et al. Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association. Circulation. Oct 2 2001;104(14):1694-1740. doi:10.1161/hc3901.095960
32. Fomin A, Ahlstrand M, Schill HG, et al. Sex differences in response to maximal exercise stress test in trained adolescents. BMC Pediatr. Aug 20 2012;12:127. doi:10.1186/1471-2431-12-127
33. Higginbotham MB, Morris KG, Coleman RE, Cobb FR. Sex-related differences in the normal cardiac response to upright exercise. Circulation. Sep 1984;70(3):357-366. doi:10.1161/01.cir.70.3.357
34. Sharma HB, Kailashiya J. Gender Difference in Aerobic Capacity and the Contribution by Body Composition and Haemoglobin Concentration: A Study in Young Indian National Hockey Players. J Clin Diagn Res. Nov 2016;10(11):CC09-CC13. doi:10.7860/JCDR/2016/20873.8831
35. Wheatley CM, Snyder EM, Johnson BD, Olson TP. Sex differences in cardiovascular function during submaximal exercise in humans. Springerplus. 2014;3:445. doi:10.1186/2193-1801-3-445
36. Vercoulen JH, Bazelmans E, Swanink CM, et al. Physical activity in chronic fatigue syndrome: assessment and its role in fatigue. JPsychiatrRes. 11/1997 1997;31(6):661-673. Not in File.
37. De Lorenzo F, Xiao H, Mukherjee M, et al. Chronic fatigue syndrome: physical and cardiovascular deconditioning. QJM. 7/1998 1998;91(7):475-481. Not in File.
38. Riley MS, O'Brien CJ, McCluskey DR, Bell NP, Nicholls DP. Aerobic work capacity in patients with chronic fatigue syndrome. BMJ. 10/27/1990 1990;301(6758):953-956. Not in File.
39. Fulcher KY, White PD. Strength and physiological response to exercise in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 9/2000 2000;69(3):302-307. Not in File. doi:10.1136/jnnp.69.3.302
40. De Becker P, Roeykens J, Reynders M, McGregor N, De Meirleir K. Exercise capacity in chronic fatigue syndrome. Arch Intern Med. 11/27/2000 2000;160(21):3270-3277. In File. doi:10.1001/archinte.160.21.3270
41. Bazelmans E, Bleijenberg G, van der Meer JW, Folgering H. Is physical deconditioning a perpetuating factor in chronic fatigue syndrome? A controlled study on maximal exercise performance and relations with fatigue, impairment and physical activity. Psychol Med. 1/2001 2001;31(1):107-114. Not in File. doi:10.1017/s0033291799003189
42. Inbar O, Dlin R, Rotstein A, Whipp BJ. Physiological responses to incremental exercise in patients with chronic fatigue syndrome. Med Sci Sports Exerc. 9/2001 2001;33(9):1463-1470. Not in File. doi:10.1097/00005768-200109000-00007
43. Wallman KE, Morton AR, Goodman C, Grove R. Physiological responses during a submaximal cycle test in chronic fatigue syndrome. Med Sci Sports Exerc. 10/2004 2004;36(10):1682-1688. Not in File. doi:10.1249/01.mss.0000142406.79093.90
44. Sargent C, Scroop GC, Nemeth PM, Burnet RB, Buckley JD. Maximal oxygen uptake and lactate metabolism are normal in chronic fatigue syndrome. Med Sci Sports Exerc. 1/2002 2002;34(1):51-56. Not in File. doi:10.1097/00005768-200201000-00009
45. Franklin JD, Atkinson G, Atkinson JM, Batterham AM. Peak Oxygen Uptake in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Meta-Analysis. Int J Sports Med. Feb 2019;40(2):77-87. doi:10.1055/a-0802-9175
46. van Campen CLMC, Rowe PC, Verheugt FWA, Visser FC. Physical activity measures in patients with myalgic encephalomyalitis/chronic fatigue syndrome: correlations between peak oxygen consumption, the physical functioning scale of the SF-36 scale, and the number of steps from an activity meter. J Transl Med. 2020;18:228-238. doi:10.1186/s12967-020-02397-7
47. Jammes Y, Retornaz F. Skeletal muscle weakness often occurs in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Journal of Experimental Neurology. 2020;1(2):35-39.
48. Davenport TE, Lehnen M, Stevens SR, VanNess JM, Stevens J, Snell CR. Chronotropic Intolerance: An Overlooked Determinant of Symptoms and Activity Limitation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Front Pediatr. 2019;7:82. doi:10.3389/fped.2019.00082
49. Castle-Kirszbaum M, Parkin WG, Goldschlager T, Lewis PM. Cardiac Output and Cerebral Blood Flow: A Systematic Review of Cardio-Cerebral Coupling. J Neurosurg Anesthesiol. Mar 29 2021;doi:10.1097/ANA.0000000000000768
2. van Campen CLMC, Verheugt FWA, Rowe PC, Visser FC. Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography. Clin Neurophysiol Pract. 2020;5:50-58. doi:10.1016/j.cnp.2020.01.003
3. Lee SM, Feiveson AH, Stein S, Stenger MB, Platts SH. Orthostatic Intolerance After ISS and Space Shuttle Missions. Aerosp Med Hum Perform. Dec 2015;86(12 Suppl):A54-67. doi:10.3357/AMHP.EC08.2015
4. Low PA, Sandroni P, Joyner M, Shen WK. Postural tachycardia syndrome (POTS). J Cardiovasc Electrophysiol. Mar 2009;20(3):352-358. doi:10.1111/j.1540-8167.2008.01407.x
5. Parsaik A, Allison TG, Singer W, et al. Deconditioning in patients with orthostatic intolerance. Neurology. Oct 2 2012;79(14):1435-1439. doi:10.1212/WNL.0b013e31826d5f95
6. Garland EM, Celedonio JE, Raj SR. Postural Tachycardia Syndrome: Beyond Orthostatic Intolerance. Curr Neurol Neurosci Rep. Sep 2015;15(9):60. doi:10.1007/s11910-015-0583-8
7. Joyner MJ, Masuki S. POTS versus deconditioning: the same or different? Clin Auton Res. 12/2008 2008;18(6):300-307. Not in File. doi:10.1007/s10286-008-0487-7
8. Benarroch EE. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc. Dec 2012;87(12):1214-1225. doi:10.1016/j.mayocp.2012.08.013
9. Shibata S, Fu Q, Bivens TB, Hastings JL, Wang W, Levine BD. Short-term exercise training improves the cardiovascular response to exercise in the postural orthostatic tachycardia syndrome. J Physiol. 8/1/2012 2012;590(Pt 15):3495-3505. Not in File. doi:10.1113/jphysiol.2012.233858
10. Rozenbaum Z, Khoury S, Aviram G, et al. Discriminating Circulatory Problems From Deconditioning: Echocardiographic and Cardiopulmonary Exercise Test Analysis. Chest. Feb 2017;151(2):431-440. doi:10.1016/j.chest.2016.09.027
11. van Campen CLMC, Visser FC. The abnormal Cardiac Index and Stroke Volume Index changes during a normal Tilt Table Test in ME/CFS patients compared to healthy volunteers, are not related to deconditioning. Research article. Journal Of Thrombosis and Circulation. 2018;(2):1-8. doi:10.29011/ JTC -107. 000007
12. van Campen CLMC, Rowe PC, Visser FC. Deconditioning does not explain orthostatic intolerance in ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med. 2021;19:193-203.
13. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 12/15/1994 1994;121(12):953-959. Not in File. doi:10.7326/0003-4819-121-12-199412150-00009
14. Carruthers BM, van de Sande MI, DE Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 10/2011 2011;270(4):327-338. Not in File. doi:10.1111/j.1365-2796.2011.02428.x
15. van Campen CLMC, Rowe PC, Visser FC. Heart Rate Thresholds to Limit Activity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients (Pacing): Comparison of Heart Rate Formulae and Measurements of the Heart Rate at the Lactic Acidosis Threshold during Cardiopulmonary Exercise Testing. Advances in Physical Education. 2020;10:138-154. doi:10.4236/ape.2020.102013
16. Davenport TE, Stevens SR, VanNess MJ, Snell CR, Little T. Conceptual model for physical therapist management of chronic fatigue syndrome/myalgic encephalomyelitis. Phys Ther. 4/2010 2010;90(4):602-614. Not in File. doi:10.2522/ptj.20090047
17. Vanness JM, Snell CR, stevens SR. Diminished cardiopulmonary capacity during post-exertional malaise. Journal of chronic fatigue syndrome. 2007;14:77-85. doi:10.1300/J092v14n02_07
18. van Campen CLMC, Rowe PC, Visser FC. Two-day cardiopulmonary exercise testing in females with a severe grade of myalgic encephalomylitis /chornic fatigue syndrome: comparison with patients with a mild and moderate disease. Healthcare. 2020;8(3):192. doi:10.3390/healthcare8030192
19. van Campen CLMC, Rowe PC, Visser FC. Validity of 2-day cardiopulmonary exercise testing in male patients with myalgic encephalomyelities/chronic fatigue syndrome. Advances in Physical Education. 2020;10:68-80. doi:10.4236/ape.2020.101007
20. van Campen CLMC, Verheugt FWA, Visser FC. Cerebral blood flow changes during tilt table testing in healthy volunteers, as assessed by Doppler imaging of the carotid and vertebral arteries. Clin Neurophysiol Pract. 2018;3:91-95. doi:10.1016/j.cnp.2018.02.004
21. Eeftinck Schattenkerk DW, van Lieshout JJ, van den Meiracker AH, et al. Nexfin noninvasive continuous blood pressure validated against Riva-Rocci/Korotkoff. Am J Hypertens. Apr 2009;22(4):378-83. doi:10.1038/ajh.2008.368
22. Martina JR, Westerhof BE, van Goudoever J, et al. Noninvasive continuous arterial blood pressure monitoring with Nexfin(R). Anesthesiology. May 2012;116(5):1092-103. doi:10.1097/ALN.0b013e31824f94ed
23. Kusumoto F, Venet T, Schiller NB, Sebastian A, Foster E. Measurement of aortic blood flow by Doppler echocardiography: temporal, technician, and reader variability in normal subjects and the application of generalizability theory in clinical research. J Am Soc Echocardiogr. Sep-Oct 1995;8(5 Pt 1):647-53. doi:10.1016/s0894-7317(05)80378-5
24. van Campen CLMC, Visser FC, de Cock CC, Vos HS, Kamp O, Visser CA. Comparison of the haemodynamics of different pacing sites in patients undergoing resynchronisation treatment: need for individualisation of lead localisation. Heart. Dec 2006;92(12):1795-1800. doi:10.1136/hrt.2004.050435
25. van Campen C, Verheugt FWA, Rowe PC, Visser FC. Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography. Clin Neurophysiol Pract. 2020;5:50-58. doi:10.1016/j.cnp.2020.01.003
26. van Campen CLMC, Visser FC. Validity of 2-day cardiopulmonary exercise testing in female patients with myalgic encephalomyelitis/chronic fatigue syndrome. International Journal of Current Research. 2020;12(3):10436-10442. doi:10.24941/ijcr.38263.03.2020
27. Beaver WL, Wasserman K, Whipp BJ. A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol (1985). Jun 1986;60(6):2020-2027. doi:10.1152/jappl.1986.60.6.2020
28. Glaser S, Koch B, Ittermann T, et al. Influence of age, sex, body size, smoking, and beta blockade on key gas exchange exercise parameters in an adult population. Eur J Cardiovasc Prev Rehabil. Aug 2010;17(4):469-476. doi:10.1097/HJR.0b013e328336a124
29. Wasserman K, Hansen JE, Sue DY, Stringer W, Whipp BJ. Normal values. In: Weinberg R, ed. Principles of Exercise Testing and Interpretation. 4th ed. Lippincott Williams and Wilkins; 2005:160-182.
30. Cureton K, Bishop P, Hutchinson P, Newland H, Vickery S, Zwiren L. Sex difference in maximal oxygen uptake. Effect of equating haemoglobin concentration. Eur J Appl Physiol Occup Physiol. 1986;54(6):656-660. doi:10.1007/bf00943356
31. Fletcher GF, Balady GJ, Amsterdam EA, et al. Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association. Circulation. Oct 2 2001;104(14):1694-1740. doi:10.1161/hc3901.095960
32. Fomin A, Ahlstrand M, Schill HG, et al. Sex differences in response to maximal exercise stress test in trained adolescents. BMC Pediatr. Aug 20 2012;12:127. doi:10.1186/1471-2431-12-127
33. Higginbotham MB, Morris KG, Coleman RE, Cobb FR. Sex-related differences in the normal cardiac response to upright exercise. Circulation. Sep 1984;70(3):357-366. doi:10.1161/01.cir.70.3.357
34. Sharma HB, Kailashiya J. Gender Difference in Aerobic Capacity and the Contribution by Body Composition and Haemoglobin Concentration: A Study in Young Indian National Hockey Players. J Clin Diagn Res. Nov 2016;10(11):CC09-CC13. doi:10.7860/JCDR/2016/20873.8831
35. Wheatley CM, Snyder EM, Johnson BD, Olson TP. Sex differences in cardiovascular function during submaximal exercise in humans. Springerplus. 2014;3:445. doi:10.1186/2193-1801-3-445
36. Vercoulen JH, Bazelmans E, Swanink CM, et al. Physical activity in chronic fatigue syndrome: assessment and its role in fatigue. JPsychiatrRes. 11/1997 1997;31(6):661-673. Not in File.
37. De Lorenzo F, Xiao H, Mukherjee M, et al. Chronic fatigue syndrome: physical and cardiovascular deconditioning. QJM. 7/1998 1998;91(7):475-481. Not in File.
38. Riley MS, O'Brien CJ, McCluskey DR, Bell NP, Nicholls DP. Aerobic work capacity in patients with chronic fatigue syndrome. BMJ. 10/27/1990 1990;301(6758):953-956. Not in File.
39. Fulcher KY, White PD. Strength and physiological response to exercise in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 9/2000 2000;69(3):302-307. Not in File. doi:10.1136/jnnp.69.3.302
40. De Becker P, Roeykens J, Reynders M, McGregor N, De Meirleir K. Exercise capacity in chronic fatigue syndrome. Arch Intern Med. 11/27/2000 2000;160(21):3270-3277. In File. doi:10.1001/archinte.160.21.3270
41. Bazelmans E, Bleijenberg G, van der Meer JW, Folgering H. Is physical deconditioning a perpetuating factor in chronic fatigue syndrome? A controlled study on maximal exercise performance and relations with fatigue, impairment and physical activity. Psychol Med. 1/2001 2001;31(1):107-114. Not in File. doi:10.1017/s0033291799003189
42. Inbar O, Dlin R, Rotstein A, Whipp BJ. Physiological responses to incremental exercise in patients with chronic fatigue syndrome. Med Sci Sports Exerc. 9/2001 2001;33(9):1463-1470. Not in File. doi:10.1097/00005768-200109000-00007
43. Wallman KE, Morton AR, Goodman C, Grove R. Physiological responses during a submaximal cycle test in chronic fatigue syndrome. Med Sci Sports Exerc. 10/2004 2004;36(10):1682-1688. Not in File. doi:10.1249/01.mss.0000142406.79093.90
44. Sargent C, Scroop GC, Nemeth PM, Burnet RB, Buckley JD. Maximal oxygen uptake and lactate metabolism are normal in chronic fatigue syndrome. Med Sci Sports Exerc. 1/2002 2002;34(1):51-56. Not in File. doi:10.1097/00005768-200201000-00009
45. Franklin JD, Atkinson G, Atkinson JM, Batterham AM. Peak Oxygen Uptake in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Meta-Analysis. Int J Sports Med. Feb 2019;40(2):77-87. doi:10.1055/a-0802-9175
46. van Campen CLMC, Rowe PC, Verheugt FWA, Visser FC. Physical activity measures in patients with myalgic encephalomyalitis/chronic fatigue syndrome: correlations between peak oxygen consumption, the physical functioning scale of the SF-36 scale, and the number of steps from an activity meter. J Transl Med. 2020;18:228-238. doi:10.1186/s12967-020-02397-7
47. Jammes Y, Retornaz F. Skeletal muscle weakness often occurs in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Journal of Experimental Neurology. 2020;1(2):35-39.
48. Davenport TE, Lehnen M, Stevens SR, VanNess JM, Stevens J, Snell CR. Chronotropic Intolerance: An Overlooked Determinant of Symptoms and Activity Limitation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Front Pediatr. 2019;7:82. doi:10.3389/fped.2019.00082
49. Castle-Kirszbaum M, Parkin WG, Goldschlager T, Lewis PM. Cardiac Output and Cerebral Blood Flow: A Systematic Review of Cardio-Cerebral Coupling. J Neurosurg Anesthesiol. Mar 29 2021;doi:10.1097/ANA.0000000000000768