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Unexplained exertional intolerance associated with impaired systemic oxygen extraction

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Abstract

Purpose

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).

Methods

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].

Results

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).

Conclusions

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.

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Abbreviations

BWH:

Brigham and Women’s Hospital

CaO2 :

Oxygen content in arterial blood

Ca-vO2 :

Difference between oxygen content in arterial and venous blood

CI:

Cardiac index

CvO2 :

Oxygen content in mixed venous blood

DBP:

Diastolic blood pressure

[Hb]:

Hemoglobin concentration

HCO3 :

Bicarbonate

HF:

Heart failure

HFpEF:

Heart failure with preserved ejection fraction

HR:

Heart rate

HV:

Hyperventilators

iCPET:

Invasive cardiopulmonary exercise testing

LVEF:

Left ventricular ejection fraction

MAP:

Mean arterial pressure

MM:

Mitochondrial myopathies

mPAP:

Mean pulmonary arterial pressure

NL:

Normal subjects

PaCO2 :

Partial pressure of carbon dioxide in arterial blood

PAH:

Pulmonary arterial hypertension

PaO2 :

Partial pressure of oxygen in arterial blood

PCWP:

Pulmonary capillary wedge pressure

PH:

Pulmonary hypertension

pHa:

Arterial pH

pHv:

Venous pH

PML:

Pulmonary mechanical limit

PvCO2 :

Partial pressure of carbon dioxide in venous blood

PvO2 :

Partial pressure of oxygen in venous blood

PVR:

Pulmonary vascular resistance

Q t :

Cardiac output

Q tmax :

Cardiac output at maximum exercise

RAP:

Right atrial pressure

RER:

Respiratory exchange ratio

RR:

Respiratory rate

SaO2 :

Oxygen saturation in arterial blood

SBP:

Systolic blood pressure

SOE:

Systemic oxygen extraction

SOEH :

Poor SOE group with high PvO2

SOEL:

Poor SOE group with low PvO2

SVR:

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

References

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

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

    CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

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

    Article  PubMed  Google Scholar 

  • 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 

  • 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Julie Tracy, MS.

Funding

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

Author information

Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, University of California at Los Angeles, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA, 90095, USA

    Kathryn H. Melamed

  2. Division of Pulmonary and Critical Care Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA

    Mário Santos, Mariana Faria Urbina, Aaron B. Waxman & David M. Systrom

  3. Division of Respiratory Diseases, Dept of Medicine, Federal University of São Paulo (Unifesp), São Paulo, Brazil

    Rudolf K. F. Oliveira

  4. Infectious Disease Unit, Medical Services, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA

    Donna Felsenstein

  5. Boston Adult Congenital Heart Service, Harvard Medical School, Boston Children’s Hospital, Boston, MA, USA

    Alexander R. Opotowsky

  6. Heart and Vascular Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Mário Santos, Mariana Faria Urbina, Alexander R. Opotowsky & David M. Systrom

Authors
  1. Kathryn H. Melamed
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  2. Mário Santos
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  3. Rudolf K. F. Oliveira
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  4. Mariana Faria Urbina
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  7. Aaron B. Waxman
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  8. David M. Systrom
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Contributions

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.

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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.

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

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Communicated by I. Mark Olfert.

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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

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  • DOI: https://doi.org/10.1007/s00421-019-04222-6

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