Unexplained exertional intolerance associated with impaired systemic oxygen extraction



The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).


We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6].


Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2 nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).


We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5



Brigham and Women’s Hospital

CaO2 :

Oxygen content in arterial blood

Ca-vO2 :

Difference between oxygen content in arterial and venous blood


Cardiac index

CvO2 :

Oxygen content in mixed venous blood


Diastolic blood pressure


Hemoglobin concentration

HCO3 :



Heart failure


Heart failure with preserved ejection fraction


Heart rate




Invasive cardiopulmonary exercise testing


Left ventricular ejection fraction


Mean arterial pressure


Mitochondrial myopathies


Mean pulmonary arterial pressure


Normal subjects

PaCO2 :

Partial pressure of carbon dioxide in arterial blood


Pulmonary arterial hypertension

PaO2 :

Partial pressure of oxygen in arterial blood


Pulmonary capillary wedge pressure


Pulmonary hypertension


Arterial pH


Venous pH


Pulmonary mechanical limit

PvCO2 :

Partial pressure of carbon dioxide in venous blood

PvO2 :

Partial pressure of oxygen in venous blood


Pulmonary vascular resistance

Q t :

Cardiac output

Q tmax :

Cardiac output at maximum exercise


Right atrial pressure


Respiratory exchange ratio


Respiratory rate

SaO2 :

Oxygen saturation in arterial blood


Systolic blood pressure


Systemic oxygen extraction


Poor SOE group with high PvO2


Poor SOE group with low PvO2


Systemic vascular resistance

SvO2 :

Oxygen saturation in mixed venous blood

VCO2 :

Carbon dioxide output

V E :

Minute ventilation

V Emax :

Minute ventilation at peak exercise

VO2 :

Oxygen uptake

VO2max :

Maximum oxygen uptake


  1. Aaker A, Laughlin MH (2002) Diaphragm arterioles are less responsive to alpha1-adrenergic constriction than gastrocnemius arterioles. J Appl Physiol 92(5):1808–1816

    CAS  PubMed  Article  Google Scholar 

  2. Aaron EA, Johnson BD, Seow CK, Dempsey JA (1992) Oxygen cost of exercise hyperpnea: measurement. J Appl Physiol 72(5):1810–1817

    CAS  PubMed  Article  Google Scholar 

  3. Abudiab MM, Redfield MM, Melenovsky V, Olson TP, Kass DA, Johnson BD, Borlaug BA (2013) Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction. Eur J Heart Fail 15(7):776–785

    PubMed  PubMed Central  Article  Google Scholar 

  4. Albert MS, Dell RB, Winters RW (1967) Quantitative displacement of acid–base equilibrium in metabolic acidosis. Ann Intern Med 66(2):312–322

    CAS  PubMed  Article  Google Scholar 

  5. Amann M, Blain GM, Proctor LT, Sebranek JJ, Pegelow DF, Dempsey JA (2010) Group III and IV muscle afferents contribute to ventilatory and cardiovascular response to rhythmic exercise in humans. J Appl Physiol 109(4):966–976

    PubMed  PubMed Central  Article  Google Scholar 

  6. Arena R, Meyers J, Aslam SS, Varughese EB, Peberdy MA (2003) Technical considerations related to the minute ventilation/carbon dioxide output slope in patients with heart failure. Chest 124(2):720–727

    PubMed  Article  Google Scholar 

  7. Argov Z, Bank WJ, Maris J, Peterson P, Chance B (1987) Bioenergetic heterogeneity of human mitochondrial myopathies: phosphorus magnetic resonance spectroscopy study. Neurology 37(2):257–262

    CAS  PubMed  Article  Google Scholar 

  8. Arnold DL, Taylor DJ, Radda GK (1985) Investigation of human mitochondrial myopathies by phosphorus magnetic resonance spectroscopy. Ann Neurol 18(2):189–196

    CAS  PubMed  Article  Google Scholar 

  9. Bested AC, Marshall LM (2015) Review of myalgic encephalomyelitis/chronic fatigue syndrome: an evidenced-based approach to diagnosis and management by clinicians. Rev Environ Health 30(4):223–249

    PubMed  Article  Google Scholar 

  10. Bhella PS, Prasad A, Heinicke K, Hastings JL, Arbab-Zadeh A, Adams-Huet B, Pacini EL, Shibata S, Palmer MD, Newcomer BR, Levine BD (2011) Abnormal haemodynamic response to exercise in heart failure with preserved ejection fraction. Eur J Heart Fail 13(12):1296–1304

    PubMed  PubMed Central  Article  Google Scholar 

  11. Boerrigter BG, Waxman AB, Westerhof N, Vonk-Noordegraaf A, Systrom DM (2014) Measuring central pulmonary pressures during exercise in COPD: how to cope with respiratory effects. Eur Respir J 43(5):1316–1325

    PubMed  Article  Google Scholar 

  12. Borlaug BA, Nishimura RA, Sorajja P, Lam CSP, Redfield MM (2010) Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 3(5):588–595

    PubMed  PubMed Central  Article  Google Scholar 

  13. Bravo DM, Gimenes AC, Nascimento RB, Ferreira EV, Siqueira AC, Meda ED, Neder JA, Nery LE (2012) Skeletal muscle reoxygenation after high-intensity exercise in mitochondrial myopathy. Eur J Appl Physiol 112(5):1763–1771

    CAS  PubMed  Article  Google Scholar 

  14. Brudin T (1975) Temperature of mixed venous blood during exercise. Scand J Clin Lab Invest 35(6):539–543

    Article  Google Scholar 

  15. Calbet JA, Boushel R (2015) Assessment of cardiac output with transpulmonary thermodilution during exercise in humans. J Appl Physiol 118(1):1–10

    PubMed  Article  CAS  Google Scholar 

  16. Carrick-Ranson G, Hastings JL, Bhella PS, Fujimoto N, Shibata S, Palmer MD, Boyd K, Livingston S, Dijk E, Levine BD (2014) The effect of lifelong exercise dose on cardiovascular function during exercise. J Appl Physiol 116(7):736–745

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Chin LM, Heigenhauser GJ, Paterson DH, Kowalchuk JM (2010) Pulmonary O2 uptake and leg blood flow kinetics during moderate exercise are slowed by hyperventilation-induced hypocapnic alkalosis. J Appl Physiol 108(6):1641–1650

    PubMed  PubMed Central  Article  Google Scholar 

  18. Chin LM, Heigenhauser GJ, Paterson DH, Kowalchuk JM (2013) Effect of voluntary hyperventilation with supplemental CO2 on pulmonary O2 uptake and leg blood flow kinetics during moderate-intensity exercise. Exp Physiol 98(12):1668–1682

    CAS  PubMed  Article  Google Scholar 

  19. Chinnery PF, Johnson MA, Wardell TM, Singh-Kler R, Hayes C, Brown DT, Taylor RW, Bindoff LA, Turnbull DM (2000) The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol 48(2):188–193

    CAS  PubMed  Article  Google Scholar 

  20. Dhakal BP, Malhotra R, Murphy RM, Pappagianopoulos PP, Baggish AL, Weiner RB, Houstis NE, Eisman AS, Hough SS, Lewis GD (2015) Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction. Circ Heart Fail 8(2):286–294

    PubMed  Article  Google Scholar 

  21. Eldridge FL (1994) Central integration of mechanisms in exercise hyperpnea. Med Sci Sports Exerc 26(3):319–327

    CAS  PubMed  Article  Google Scholar 

  22. Elliot DL, Buist NR, Goldberg L, Kennaway NG, Powell BR, Kuehl KS (1989) Metabolic myopathies: evaluation by graded exercise testing. Medicine (Baltimore) 68(3):163–172

    CAS  Article  Google Scholar 

  23. Evans AB, Tsai LW, Oelberg DA, Kazemi H, Systrom DM (1998) Skeletal muscle ECF pH error signal for exercise ventilatory control. J Appl Physiol 84(1):90–96

    CAS  PubMed  Article  Google Scholar 

  24. Flaherty KR, Wald J, Weisman IM, Zeballos RJ, Schork MA, Blaivas M, Rubenfire M, Martinez FJ (2001) Unexplained exertional limitation: characterization of patients with a mitochondrial myopathy. Am J Respir Crit Care Med 164(3):425–432

    CAS  PubMed  Article  Google Scholar 

  25. Gimenes AC, Neder JA, Dal Corso S, Nogueira CR, Nápolis L, Mello MT, Bulle AS, Nery LE (2011) Relationship between work rate and oxygen uptake in mitochondrial myopathy during ramp-incremental exercise. Braz J Med Biol Res 44(4):354–360

    CAS  PubMed  Article  Google Scholar 

  26. Greaney JL, Schwartz CE, Edwards DG, Fadel PJ, Farquhar WB (2013) The neural interaction between the arterial baroreflex and muscle metaboreflex is preserved in older men. Exp Physiol 98(10):1422–1431

    PubMed  Article  Google Scholar 

  27. Groves BM, Reeves JT, Sutton JR, Wagner PD, Cymerman A, Malconian MK, Rock PB, Young PM, Houston CS (1987) Operation everest II: elevated high-altitude pulmonary resistance unresponsive to oxygen. J Appl Physiol 63(2):521–530

    CAS  PubMed  Article  Google Scholar 

  28. Guazzi M, Reina G, Tumminello G, Guazzi MD (2005) Exercise ventilation inefficiency and the cardiovascular mortality in heart failure: the critical independent prognostic value of the arterial CO2 partial pressure. Eur Heart J 26(5):472–480

    PubMed  Article  Google Scholar 

  29. Hansen JE (1989) Arterial bood gas. Clin in Chest Med 10(2):227–237

    CAS  Google Scholar 

  30. Hansen JE, Sue DY, Wasserman K (1984) Predicted values for clinical exercise testing. Am Rev Respir Dis 129(2):S49–S55

    CAS  PubMed  Article  Google Scholar 

  31. Hayashi N, Ishihara M, Tanaka A, Yoshida T (1999) Impeding O(2) unloading in muscle delays oxygen uptake repsonse to exercise onset in humans. Am J Physiol 277(5):R1274–1281

    CAS  PubMed  Google Scholar 

  32. Haykowsky MJ, Brubaker PH, John JM, Stewart KP, Morgan TM, Kitzman DW (2011) Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction. J Am Coll Cardiol 58(3):265–274

    PubMed  PubMed Central  Article  Google Scholar 

  33. Heinicke K, Taivassalo T, Wyrick P, Wood H, Babb TG, Haller RG (2011) Exertional dyspnea in mitochondrial myopathy: clinical features and physiological mechanisms. Am J Physiol Regul Integr Comp Physiol 301(4):R873–R884

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Jensen TD, Kazemi-Esfarjani P, Skomorowska E, Vissing J (2002) A forearm exercise screening test for mitochondrial myopathy. Neurology 58(10):1533–1538

    PubMed  Article  Google Scholar 

  35. Kaufman MP (2010) Control of breathing during dynamic exercise by thin fiber muscle afferents. J Appl Physiol 109(4):947–948

    PubMed  Article  Google Scholar 

  36. Kaufman MP, Hayes SG (2002) The exercise pressor reflex. Clin Auton Res 12(6):429–439

    PubMed  Article  Google Scholar 

  37. Kowalchuk JM, Heigenhauser GJ, Lindinger MI, Sutton JR, Jones NL (1988) Factors influences hydrogen ion concentration in muscle after intense exercise. J Appl Physiol 65(5):2080–2089

    CAS  PubMed  Article  Google Scholar 

  38. Lindholm H, Löfberg M, Somer H, Näveri H, Sovijärvi A (2004) Abnormal blood lactate accumulation after exercise in patients with multiple mitochondrial DNA deletions and minor muscular symptoms. Clin Physiol Funct Imaging 24(2):109–115

    CAS  PubMed  Article  Google Scholar 

  39. Mar PL, Raj SR (2014) Neuronal and hormonal perturbations in postural tachycardia syndrome. Front Physiol 5(220):1–8

    Google Scholar 

  40. Maron BA, Cockrill BA, Waxman AB, Systrom DM (2013) Invasive cardiopulmonary exercise test. Circulation 127(10):1157–1164

    PubMed  Article  Google Scholar 

  41. Meulemans A, Gerlo E, Seneca S, Lissens W, Smet J, Van Coster R, De Meirleir L (2007) The aerobic forearm exercise test, a non-invasive tool to screen for mitochondrial disorders. Acta Neurol Belg 107(3):78–83

    PubMed  Google Scholar 

  42. Oelberg DA, Evans AB, Hrovat MI, Pappagianopoulos PP, Patz S, Systrom DM (1998) Skeletal muscle chemoreflex and pHi in exercise ventilatory control. J Appl Physiol 84(2):676–682

    CAS  PubMed  Article  Google Scholar 

  43. Piepoli MF, Crisafulli A (2014) Pathophysiology of human heart failure: importance of skeletal muscle myopathy and reflexes. Exp Physiol 99(4):609–615

    CAS  PubMed  Article  Google Scholar 

  44. Pinkstaff S, Peberdy MA, Kontos MC, Finucane S, Arena R (2010) Quantifying exertion level during exercise stress testing using percentage of age-predicted maximal heart rate, rate pressure product, and perceived exertion. Mayo Clin Proc 85(12):1095–1100

    PubMed  PubMed Central  Article  Google Scholar 

  45. Reeves JT, Moon RE, Grover RF, Groves BM (1988) Increased wedge pressure facilitates decreased lung vascular resistance during upright exercise. Chest 93(3):97S–99S

    CAS  PubMed  Article  Google Scholar 

  46. Santos M, Opotowsky AR, Shah AM, Tracy J, Waxman AB, Systrom DM (2015) Central cardiac limit to aerobic capacity in patients with exertional pulmonary venous hypertension: implications for heart failure with preserved ejection fraction. Circ Heart Fail 8(2):278–285

    PubMed  Article  Google Scholar 

  47. Stewart JM (2002) Pooling in chronic orthostatic intolerance: arterial vasoconstrictive but not venous compliance defects. Circulation 105(19):2274–2281

    PubMed  Article  Google Scholar 

  48. Stringer W, Wasserman K, Casaburi R, Pórszász J, Maehara K, French W (1994) Lactic acidosis as a facilitator of oxyhemoglobin dissociation during exercise. J Appl Physiol 76(4):1462–1467

    CAS  PubMed  Article  Google Scholar 

  49. Taivassalo T, Abbott A, Wyrick P, Haller RG (2002) Venous oxygen levels during aerobic forearm exercise: an index of impaired oxidative metabolism in mitochondrial myopathy. Ann Neurol 51(1):38–44

    PubMed  Article  Google Scholar 

  50. Taivassalo T, Jensen TD, Kennaway N, DiMauro S, Vissing J, Haller RG (2003) The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients. Brain 126(2):413–423

    PubMed  Article  Google Scholar 

  51. Tarnopolsky M (2004) Exercise testing as a diagnostic entity in mitochondrial myopathies. Mitochondrion 4(5–6):529–542

    CAS  PubMed  Article  Google Scholar 

  52. Tarnopolsky MA, Raha S (2005) Mitochondrial myopathies: diagnosis, exercise intolerance, and treatment options. Med Sci Sports Exerc 37(12):2086–2093

    CAS  PubMed  Article  Google Scholar 

  53. Taylor DJ, Kemp GJ, Radda GK (1994) Bioenergetics of skeletal muscle in mitochondrial myopathy. J Neurol Sci 127(2):198–206

    CAS  PubMed  Article  Google Scholar 

  54. Tolle J, Waxman A, Systrom D (2008a) Impaired systemic oxygen extraction at maximum exercise in pulmonary hypertension. Med Sci Sports Exerc 40(1):3–8

    CAS  PubMed  Article  Google Scholar 

  55. Tolle JJ, Waxman AB, Van Horn TL, Pappagianopoulos PP, Systrom DM (2008b) Exercise-induced pulmonary arterial hypertension. Circulation 118(21):2183–2189

    PubMed  PubMed Central  Article  Google Scholar 

  56. Trenell MI, Sue CM, Kemp GJ, Sachinwalla T, Thompson CH (2006) Aerobic exercise and muscle metabolism in patients with mitochondrial myopathy. Muscle Nerve 33(4):524–531

    CAS  PubMed  Article  Google Scholar 

  57. Vissing J, MacLean DA, Vissing SF, Sander M, Saltin B, Haller RG (2001) The exercise metaboreflex is maintained in the absence of muscle acidosis: insights from muscle microdialysis in humans with McArdle’s disease. J Physiol 537(2):641–649

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Wasserman K, Hansen JE, Sue DY, Stringer WW, Sietsma KE, Sun XG, Whipp BJ (2012) Principles of exercise testing and interpretation, 5th edn. Lipincott Williams & Wilkins, Philadelphia

    Google Scholar 

  59. Wasserman K, Cox T, Sietsema KE (2014) Ventilatory regulation of arterial H(+) (pH) during exercise. Respir Physiol Neurobiol 190:142–148

    CAS  PubMed  Article  Google Scholar 

  60. Williamson JW (2010) The relevance of central command for the neural cardiovascular control of exercise. Exp Physiol 95(11):1043–1048

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references


Julie Tracy, MS.


Funding was received from Solve ME/CFS Foundation (DS).

Author information




KM, MS, RO, MU, AO, AW, and DS performed data collection and analysis. DF and DM performed study design. KM and DS wrote the manuscript. All the authors reviewed, edited, and approved the manuscript.

Corresponding author

Correspondence to Kathryn H. Melamed.

Ethics declarations

Conflict of interest

ABW and DMS funded by NIH 2R01HL060234-12A1 and U01HL125215-01. ARO supported by the Dunlevie Family Fund. The remaining authors have no conflicts of interest.

Ethical approval

All the procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Communicated by I. Mark Olfert.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 94 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Melamed, K.H., Santos, M., Oliveira, R.K.F. et al. Unexplained exertional intolerance associated with impaired systemic oxygen extraction. Eur J Appl Physiol 119, 2375–2389 (2019). https://doi.org/10.1007/s00421-019-04222-6

Download citation


  • Cardiopulmonary exercise testing
  • Exertional intolerance
  • Poor systemic oxygen extraction
  • Hyperventilation
  • Chronic fatigue syndrome