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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 118-120, (2002)
© 2002 American Thoracic Society

Correspondence

Mitochondrial disorders and exertional intolerance

Controversy continues

To the Editor :

This letter is written out of concern that clinicians may be led to inappropriately overdiagnose primary myopathies and miss other important diagnoses on the basis of the report by Flaherty and coworkers (1). Their conclusion that mitochondrial myopathies are the primary cause of exercise limitation in 8.5% or more of patients referred to them for unexplained exercise dyspnea or limitation demands further assessment.

First, the nature of the mitochondrial myopathy in these patients is unclear. We are told that all had "abnormal mitochondrial staining" and "biochemical mitochondrial abnormalities" (not further described), but these findings are hardly specific enough to rule out muscle abnormalities secondary to other systemic diseases (2). Further, neither femoral vein nor mixed venous O2 content during exercise was presented to document that muscle extraction of O2 was reduced (3) and to demonstrate that myopathy impaired muscle function.

Second, although patients presented tend to have low peak oxygen consumption (V·O2) and increased ventilatory response to exercise, in other respects they are remarkably heterogeneous: e.g., the ratio of peak ventilation to resting maximal voluntary ventilation (MVV) ratio ranges from 0.35 to 1.44 (the highest ratios suggest poor performance of the MVV maneuver) and the duration of symptoms varies from 2 months to 60 years.

Third, the authors repeatedly assert that their 28 patients have "normal gas exchange." Yet the absence of exercise blood gas measures in half and the high mean and SD values presented contradict that assertion. The very high minute ventilation/carbon dioxide production (V·E/V·CO2) at 50% of peak V·O2 (57 ± 23), abnormal dead space/tidal volume (VD/VT) in over half at maximal exercise (0.32 ± 0.14) (Table 3 [1]) and frequently decreased SpO2 (95 ± 4%) (Table 4 [1]) are all evidence for frequent abnormal gas exchange (2). The mean V·E/V·CO2 values, if correct, could only have occurred with severe hyperventilation (very low PaCO2 values) or abnormally high VA/Q areas (high VD/VT). Unfortunately neither end-tidal CO2, pH, nor bicarbonate values are presented to support their hypotheses.

Fourth, the typical "illustrative case" presented in Figure 2 (1) demonstrates after 1 minute of incremental exercise a respiratory exchange ratio over 1.30 and a rapidly increasing V·E/V·O2 to over 80 (three times normal), followed by a decline. This pattern strongly suggests primary pulmonary hypertension with right-to-left shunting through a patent foramen ovale (4) and/or anxiety hyperventilation. Repeat exercise testing with measurements of partial pressure of end-tidal CO2 (PETCO2) and blood pH, PaCO2 and PaO2 as well as further workup would be valuable.

Respectfully, the reported data do not support the conclusion that their patients' exertional limitation is primarily due to mitochondrial myopathy rather than other disorders. Many of these patients may have primary pulmonary hypertension, interstitial lung disease, cardiomyopathy, heart failure, peripheral arterial disease, endocrinopathy, severe deconditioning, or anxiety hyperventilation that account for their exercise intolerance. We worry that if the authors' conclusions are accepted, large numbers of patients will undergo needless muscle biopsies without having their primary disorder diagnosed.

James E. Hansen and Richard Casaburi

Harbor-UCLA Medical Center Torrance, California

REFERENCES

  1. Flaherty KR, Wald J, Weisman IM, Zeballos RJ, Schork MA, Blaivas M, Rubenfire M, Martinez FJ. Unexplained exertional limitation. Characterization of patients with a mitochondrial myopathy. Am J Respir Crit Care Med 2001;164:425–432.[Abstract/Free Full Text]
  2. Bogaard JM, Scholte HR, Busch HFM, Stam H, Versprille A. Anaerobic threshold as detected from ventilatory and metabolic exercise responses in patients with mitochondrial respiratory chain defect. Adv Cardiol 1986;35:135–145.[Medline]
  3. Wasserman K, Hansen JE, Sue DY, Casaburi R, Whipp BP. Principles of exercise testing and interpretation, 3rd ed. Baltimore: Lippincott, Williams & Wilkins; 1999.
  4. Sun XG, Hansen JE, Oudiz R, Wasserman K. Gas exchange detection of exercise-induced right-to-left shunt in patients with primary pulmonary hypertension. Circulation 2002;105:54–60.[Abstract/Free Full Text]
 
To the Editor :

We are concerned about the characterization of the patients reported by Flaherty and colleagues (1) in their study on unexplained exercise intolerance. Inclusion criteria were the absence of cardiac, pulmonary or neuromuscular causes, and a muscle biopsy showing "abnormal mitochondrial staining" said to prove mitochondrial myopathy.

It is unfortunate that very few details of the muscle biopsy findings were given, making it impossible to judge the claim that they prove mitochondrial myopathy. The authors claimed that there was biochemical evidence for mitochondrial abnormalities in 26 of the 28 patients. However, it was not stated which, if any, specific enzyme defects were identified. Secondary abnormalities of mitochondrial function and density have previously been described in subjects with heart failure (2), zidovudine treatment (3), and chronic fatigue syndrome (4), and mitochondrial function varies with training status (5). The authors did not describe how other diseases, especially cardiac disease, were excluded. The patient group was 79% female against only 45% in the control group, making the comparison of exercise variables of doubtful validity. It was claimed that the cardiopulmonary exercise results were characteristic of mitochondrial myopathy. However, the impairment in maximum oxygen consumption reported by Flaherty and colleagues (1) (69% predicted) is considerably less than that found by Bogaard and colleagues (6) (43% predicted) in six patients with mitochondrial myopathy due to a specific defect in NADH-CoQ reductase. The cardiovascular (excessive heart rate response, reduced anaerobic threshold) and the excessive ventilatory responses described by Flaherty and colleagues (1) are by no means specific for mitochondrial myopathy and may occur in other diseases, for example in patients with heart failure.

The authors claimed that a significant proportion of unexplained exercise intolerance could be attributed to mitochondrial myopathy. It is possible that some of the patients did suffer from a primary mitochondrial myopathy due to a specific mitochondrial enzyme defect. However, without more detailed description of the studies carried out on the biopsy material and/or genetic studies and the rigorous exclusion of potential confounding diseases, the report is unconvincing.

Marshall S. Rileya and D. Paul Nichollsb

a Belfast City Hospital Belfast, Northern Ireland
b Royal Victoria Hospital Belfast, Northern Ireland

REFERENCES

  1. Flaherty KR, Wald J, Weisman IM, Zeballos RJ, Schork MA, Blaivas M, Rubenfire M, Martinez FJ. Unexplained exertional limitation. Characterization of patients with a mitochondrial myopathy. Am J Respir Crit Care Med 2001;164:425–432.[Abstract/Free Full Text]
  2. Drexler H, Riede U, Münzel T, König H, Funk E, Just H. Alterations of skeletal muscle in chronic heart failure. Circulation 1992;85:1751–1759.[Abstract/Free Full Text]
  3. Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL. Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 1990;322:1098–1105.[Abstract]
  4. Byrne E, Trounce I. Chronic fatigue and myalgia syndrome: mitochondrial and glycolytic studies in skeletal muscle. J Neurol Neurosurg Psych 1987;50:743–746.[Abstract]
  5. Tonkonogi M, Sahlin K. Rate of oxidative phosphorylation in isolated mitochondria from human skeletal muscle: effect of training status. Acta Physiol Scand 1997;161:345–353.[CrossRef][Medline]
  6. Bogaard JM, Busch HFM, Scholte HR, Stam H, Versprille A. Exercise responses in patients with an enzyme deficiency in the mitochondrial respiratory chain. Eur Resp J 1988;1:445–452.[Abstract]
 
To the Editor:

In the article by Flaherty and colleagues (1) the authors conclude, "The characteristic physiological profile may be useful in the diagnostic evaluation of mitochondrial myopathy." The physiological profile that they describe is "hypercirculatory and hyperventilatory responses with normal gas exchange."

Patients with primary mitochondrial myopathies must be hypercirculatory; because of the very nature of the disease, they cannot extract O2 from the blood normally. Therefore, they have a narrow arteriovenous O2 difference (2–4) and a high {Delta}cardiac output/{Delta}V·O2 ratio in response to exercise. But Flaherty and colleagues did not measure cardiac output, and therefore could not document a hypercirculatory response in their patients. They report only a high heart rate (HR)/V·O2 ratio. A high HR/V·O2 ratio occurs in a great many diseases, particularly in patients with cardiovascular diseases when stroke volume is reduced. Thus, the authors give no proof that their patients were hypercirculatory.

Patients with mitochondrial myopathies have a high ventilatory response to exercise because they develop a lactic acidosis at low work rates (5), and in this respect have a lactate–V·O2 relationship similar to that found in patients with heart failure (6). The hyperventilatory response is characterized by a pronounced low work rate acidemia due to decreasing HCO3- secondary to lactate accumulation. Can the authors provide the pH changes with exercise in their so-called mitochondrial myopathies?

Neither change in pH, PETCO2, nor PaCO2 is shown in their typical case (Figure 2 [1]). The V·E/V·O2 increased from 50 to 80 after 1 minute of exercise (Figure 2D [1]). This is an inordinately high value for someone with normal gas exchange. In normal subjects and in most disease states, this ratio decreases or remains the same, but does not increase unless a right-to-left shunt developed or the patient had psychogenic hyperventilation.

The authors failed to describe the characteristics of the biopsy that proved a mitochondrial myopathy, and they also did not describe the biopsies of a control population. Secondary changes in mitochondria occur in patients with lung and heart diseases. These changes are likely due to inactivity. But in contrast to patients with primary mitochondrial disorders, the arteriovenous O2 difference is normal to high. The authors show no data on arteriovenous O2 difference during exercise, despite it being the essential measurement needed to differentiate between failure of the mitochondria to utilize O2 for ATP regeneration from failure to transport O2 to the muscles.

Karlman Wasserman

Harbor-UCLA Medical Center Torrance, California

REFERENCES

  1. Flaherty KR, Wald J, Weisman IM, Zeballos RJ, Schork MA, Blaivas M, Rubenfire M, Martinez FJ. Unexplained exertional limitation. Characterization of patients with a mitochondrial myopathy. Am J Respir Crit Care Med 2001;164:425–432.[Abstract/Free Full Text]
  2. Haller RG, Henriksson KG, Jorfeldt L, Hultman E, Wibom R, Sahlin K, Areskog NH, Gunder M, Ayyad K, Blomqvist CG. Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect. J Clin Invest 1991; 88:1197–1206.[Medline]
  3. Haller RG, Lewis SF, Estabrook RW, DiMauro S, Servidei S, Foster DW. Exercise intolerance, lactic acidosis, and abnormal cardiopulmonary regulation in exercise associated with adult skeletal muscle cytochrome c oxidase deficiency. J Clin Invest 1989;84:155–161.[Medline]
  4. Taivassalo T, Shoubridge EA, Chen J, Kennaway NG, DiMauro S, Arnold DL, Haller RG. Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects. Ann Neurol 2001;50:133–141.[CrossRef][Medline]
  5. Vissing J, Galbo H, Haller RG. Exercise fuel mobilization in mitochondrial myopathy: a metabolic dilemma. Ann Neurol 1996;40:655–662.[CrossRef][Medline]
  6. Bogaard JM, Busch HFM, Scholte HR, Stam H, Versprille A. Exercise responses in patients with an enzyme deficiency in the mitochondrial respiratory chain. Eur Respir J 1988;1:445–452.[Abstract]
 
From the Authors

Drs. Hansen and Casaburi, Riley and Nicholls, and Wasserman express concerns about our description of patients with mitochondrial disorders (1) and highlight important concepts regarding the evaluation of exertional intolerance. Specific responses include:

  1. Diagnosis. They highlight the difficulties in interpreting muscle biopsies in this setting (2, 3). Inclusion in our study required abnormal mitochondrial appearance as confirmed by the independent review of a histopathologist (M. A. B.) with expertise in muscle histology. The nonspecific nature of the findings is acknowledged and requires close evaluation for alternative disorders; we excluded these within the limitations of clinical diagnostic modalities. Measurement of mixed venous oxygen content during exercise, although ideal, is not currently considered a diagnostic criterion for metabolic disorders (2, 4). Importantly, no alternative clinical diagnoses were noted in our patients during an average of 4.2 ± 2.1 years follow-up. Confounding by deconditioning is a valid concern identified in similar patient populations by other investigators (5–7) and cannot be excluded in our cohort. Additional data will better define mitochondrial abnormalities in patients suffering solely from deconditioning.
  2. Heterogeneity of exercise response. Drs. Hansen and Casaburi correctly identify the presence of heterogeneity in exercise response. Hypercirculatory and hyperventilatory abnormalities similar to those in our report have been consistent findings in other publications using similar diagnostic criteria (5, 8, 9). Dr. Wasserman is correct that measurement of cardiac output would be ideal, although cardiovascular disease was excluded in our patients. Our use of heart rate response is consistent with the cardiology (10) and mitochondrial literature (9). Drs. Hansen and Casaburi suggest the high V·E/MVV as indicative of poor performance of the MVV maneuver. Our patients used standard measurement techniques and were required to reproduce efforts during testing. Patients with a documented decrement in respiratory muscle function demonstrated a lower MVV, a plausible explanation for variability in the V·E/MVV ratios. Drs. Riley and Nicholls suggest that the maximal achieved V·O2 in our study is lower than that in Bogaard and colleagues (11). The % predicted value used for analysis used appropriate published reference standards accounting for age, sex, weight, and if overweight, height, thereby making the difference in gender distribution irrelevant. The mean value for V·O2 peak in our study is remarkably similar to those reported by others (5, 9); the heterogeneity of responses is also similar to those previously reported (22–84% predicted) (9).
  3. Gas exchange/ventilatory response. As noted, the lack of arterial blood gases in 14 of 28 patients made it difficult to comment fully on mechanisms for hyperventilation. It would have been more appropriate to state that our patients had normal PaO2 and P(A-a)O2 responses, when available. The mean change in saturation was -0.2 ± 1.7%, suggesting that significant desaturation was not present. The high standard deviation of the peak SpO2 (95 ± 4%) reflected the impact of two patients with peak saturation less than 90% (both exhibited normal PaO2 at peak exercise). Drs. Hansen and Casaburi are correct that V·E/V·CO2 was abnormal and VD/VT was slightly elevated at peak exercise. We agree that the high V·E/V·CO2 could be due to hyperventilation and/or high VD/VT. The decreased PaCO2 at peak exercise is consistent with hyperventilation. However, the mildly elevated VD/VT is likely multifactorial, reflecting the impact of breathing pattern, lower exercise level achieved compared with controls, and/or methodological issues (impact of 2 mm changes in PaCO2 on VD/VT). Dr. Wasserman raises an interesting question regarding the nature of hyperventilation; the underlying mechanisms remain largely speculative as discussed in our paper. Additional work is required.
  4. Typical illustrative response described by Figure 2 (1). This patient, a former triathlete, had undergone extensive, unrevealing cardiopulmonary testing (including stress echocardiography). We noted no arterial desaturation, but confirmed a significant decrement in respiratory muscle function. Muscle biopsy with typical mitochondrial abnormalities provided an alternative explanation for the exercise pattern and her symptoms. During 3 years of follow-up, no additional cardiopulmonary disease developed.

In summary, the key message of our manuscript is that some patients with exertional limitation may have mitochondrial disorders. It is important to emphasize that at our respective institutions we now consider a muscle biopsy in the evaluation of unexplained dyspnea only after completion of an extensive clinical evaluation and pulmonary rehabilitation. We agree that a careful evaluation to exclude other cardiopulmonary disorders is mandatory before considering a muscle biopsy when evaluating patients with exertional limitation.

Kevin R. Flahertya, M. Mila Blaivasa, John Walda, Melvyn Rubenfirea, Fernando J. Martineza, Idelle M. Weismanb and R. Jorge Zeballosb

a University of Michigan Health System Ann Arbor, Michigan
b Texas Tech University Health Sciences Center El Paso, Texas

REFERENCES

  1. Flaherty KR, Wald J, Weisman IM, Zeballos RJ, Schork MA, Blaivas M, Rubenfire M, Martinez FJ. Unexplained exertional limitation. Characterization of patients with a mitochondrial myopathy. Am J Respir Crit Care Med 2001;164:425–432.[Abstract/Free Full Text]
  2. Clay AS, Behnia M, Brown KK. Mitochondrial disease: a pulmonary and critical-care medicine perspective. Chest 2001;120:634–648.[Abstract/Free Full Text]
  3. Zeviani M, Tiranti V, Piantadosi C. Mitochondrial disorders. Medicine (Baltimore) 1998;77:59–72.[CrossRef][Medline]
  4. Shoffner JM. Metabolic myopathies: mitochondrial myopathy diagnosis. Neurol Clin 2000;18:105–124.[CrossRef][Medline]
  5. Dandurand RJ, Matthews PM, Arnold DL, Eidelman DH. Mitochondrial disease: pulmonary function, exercise performance, and blood lactate levels. Chest 1995;108:182–189.[Abstract/Free Full Text]
  6. Taivassalo T, DeStefano N, Argov Z, Matthews PM, Chen J, Genge A, Karpati G, Arnold DL. Effects of aerobic training in patients with mitochondrial myopathies. Neurology 1998;50:1055–1060.[Abstract/Free Full Text]
  7. Taivassalo T, DeStefano N, Chen J, Karpati G, Arnold DL, Argov Z. Short-term aerobic training response in chronic myopathies. Muscle Nerve 1999;22:1239–1243.[CrossRef][Medline]
  8. Haller RG, Lewis SF, Estabrook RW, DiMauro S, Servidei S, Foster DW. Exercise intolerance, lactic acidosis, and abnormal cardiopulmonary regulation in exercise associated with adult skeletal muslce cytochrome c oxidase deficiency. J Clin Invest 1989;84:155–161.[Medline]
  9. Hooper RG, Thomas AR, Kearl RA. Mitochondrial enzyme deficiency causing exercise limitation in normal-appearing adults. Chest 1995;107:317–322.[Abstract/Free Full Text]
  10. Eschenbacher WL, Mannina A. An algorithm for the interpretation of cardiopulmonary exercise tests. Chest 1990;97:263–267.[Abstract/Free Full Text]
  11. Bogaard JM, Busch HF, Scholte HR, Stam H, Versprille A. Exercise responses in patients with an enzyme deficiency in the mitochondrial respiratory chain. Eur Respir J 1988;1:445–452.[Abstract]




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Copyright © 2002 American Thoracic Society