Chronic Cardiopulmonary Disease and the Skeletal Muscles
Chronic Cardiopulmonary Disease and the Skeletal Muscles
US Respiratory Care 2006
Published: October 2008
Published: October 2008
Reference Section 1 a report by Peter D Wagner, MD Professor of Medicine and Bioengineering and Chief, Division of Physiology, University of California, San Diego Chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) are common diseases whose clinical manifestations have generally been regarded as being dominated by functional limitation of a single major organ—the lungs and the heart, respectively.
However, there has been a recent surge of interest in exploring the hypothesis that diseases such as COPD and CHF may have a systemic component that affects additional tissues, such as muscles, independently of the failed central organ.1–3 Such an effect on skeletal muscles would likely compound the diminished exercise capacity known to occur in these diseases on the basis of the failure of the heart or lungs. This concept has been raised not only in the obvious context of cachexia with muscle wasting, which occurs in some but not all patients with these diseases, but also when muscle mass is preserved. It is the latter situation—abnormalities in muscle structure and function in the absence of muscle wasting—that forms the focus of this review. There is no doubt that in COPD and CHF, even without muscle wasting, there is evident skeletal muscle dysfunction based on comparison with normal subjects.1–3 The question at hand is whether this reflects more than simple disuse from inactivity and, therefore, has additional pathological effect(s) of chronic disease. The idea that muscle dysfunction (even without wasting) may reflect a systemic effect of heart or lung disease has sprung from several independent observations, listed in Table 1. Exercise Capacity Correlates Poorly with Spirometry or Cardiac Function In COPD, it is generally agreed that exercise capacity is poorly explained by the degree of airway obstruction as reflected by forced expiratory volume in one second (FEV1).Thus, Jones et al.4 found that, although exercise capacity was related significantly to FEV1,r2 was just 0.39, leaving 60% of the variance in exercise capacity to be explained by other factors, perhaps muscle. However, due to the fact that exercise capacity depends on the integrated effects of many systems working together—heart, circulation, blood, muscles, lungs and, to some extent, the central nervous system (CNS))5—identifying a correlation between any one of these and exercise capacity will be difficult if the other factors are not controlled for. Lack of correlation with FEV1 might also indicate that FEV1 is the wrong parameter of lung involvement in COPD for the current purpose. Perhaps the degree of hyperinflation or the severity of hypoxemia are more relevant. Presence of Circulating Inflammatory Mediators or Impaired Antioxidant Capacity Patients with CHF or COPD have been found to have elevated circulating levels of inflammatory cytokines, such as tumor necrosis factor alpha (TNF- _) and certain interleukins, which could provide a basis for inflammatory changes in muscle affecting function.6–8 Moreover, Rabinovich et al.9 have recently suggested that muscle antioxidant capacity (in the form of glutathione) does not respond to exercise training in COPD, in contrast to normal subjects. This prompted an editorial suggesting COPD as a muscle disease.10 However, the amount of training was necessarily less in the COPD patients, and one cannot exclude the hypothesis that the lesser response in COPD reflected a lesser training stimulus ordained by severely limited lung function. The question is thus not yet answered. Decreased Anabolic Hormone Levels Reduced levels of anabolic hormones, such as testosterone and insulin-like growth factor (IGF), have been reported in COPD and CHF and are likely involved in loss of muscle mass when it occurs.11–13 Even in the absence of loss of mass,they have been implicated in abnormal muscle function. For example, Niebauer et al.12 found that patients with CHF and low levels of IGF had reduced muscle strength per unit of muscle mass. While these patients exhibited similar exercise capacity to CHF patients with normal IGF levels, this finding suggests that anabolic hormone alteration might be a factor in muscle dysfunction. Chronic Cardiopulmonary Disease and the Skeletal Muscles Peter D Wagner, MD, is Professor of Medicine and Bioengineering and Chief of the Division of Physiology at the University of California, San Diego in La Jolla. He is principal investigator of one National Institutes of Health (NIH) R01 and two Institutional Research Training Grants. Over the years, he has had many roles in the American Thoracic Society (ATS), culminating in serving as President for 2005/2006. Professor Wagner’s research addresses the theoretical and experimental basis of oxygen transport and its limitations in the lungs and skeletal muscles in health and disease. These questions are posed in experimental animals, normal subjects and patients with chronic obstructive pulmonary disease (COPD), chronic heart failure or chronic renal failure, and have resulted in over 400 publications. A particular focus is muscle capillary growth regulation using molecular biological approaches—the role of O2,physical factors, nitric oxide and inflammatory mediators in transcriptional regulation of vascular endothelial growth factor (VEGF). 2 Reference Section Decreased Oxygen Availability Leading to Tissue Hypoxia Arterial hypoxemia in COPD and low tissue perfusion in CHF both likely result in intracellular muscle hypoxia. It has been proposed that such alterations in intracellular oxygenation could generate reactive oxygen species (ROS), which could contribute to local tissue dysfunction as well,1,3,14 especially if patients have impaired antioxidant responses to exercise.9 That hypoxia might be important is suggested by the degree to which many genes important to muscle function in exercise (metabolic enzymes and angiogenic growth factors) are affected by hypoxia.15,16 As one example, Sauleda et al.17 found that muscle cytochrome oxidase activity was related to arterial partial pressure of oxygen (pO2) in patients with COPD. Interestingly, the relationship was an inverse one, such that more severe hypoxemia was associated with greater oxidase activity. Per se,this suggests positive adaptation to disease,but the illustration is made to point out the potential for the state of oxygenation to play a role in skeletal muscle function in chronic disease in ways that are not yet understood. Compatible with this notion, Sridhar18 suggested in 1995 that tissue hypoxia might lead to increased circulating TNF-_ levels and explain loss of muscle mass in COPD patients. However, these observations represent correlations and it cannot be claimed that such data prove the existence of intrinsic muscle disease. Mancini et al.19 suggested that intracellular hypoxia alone does not explain muscle dysfunction. They found similar intracellular O2 in CHF and control subjects during exercise. Metabolic Indicators of Reduced Muscle Function Several metabolic differences have been found between normal subjects and patients with COPD, leading some authors to suggest intrinsic muscle pathology.
References:
1. Casaburi R, Gosselink R, Decramer M et al.,“Skeletal muscle dysfunction in chronic obstructive pulmonary disease”, Am. J. Respir. Crit. Care Med. (1999);159: pp. S1–S40.
2. Palange P,Wagner P D,“The skeletal muscle in chronic respiratory diseases”, summary of the ERS Research Seminar in Rome, Italy, February 11–12 1999, Eur. Respir. J. (2000);15: p. 815.
3. Maltais F, LeBlanc P,“Peripheral muscle dysfunction in chronic obstructive pulmonary disease”, Clin. Chest Med. (2000);21: pp. 665–677.
4. Jones N L, Jones G, Edwards R H T,“Exercise tolerance in chronic airway obstruction”, Am. Rev. Respir. Dis. (1971);103: pp. 477–491.
5. Wagner P D,“Determinants of maximal oxygen transport and utilization”, Annu. Rev. Physiol. (1996);58: pp. 21–50.
6. Schols A M W J, Buurman W A, Staal-van den Brekel A J, Dentener M A,Wouters E F,“Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease”, Thorax (1996);51: pp. 819–824.
7. DiFrancia M, Barbier D, Mege J L, Orehek J,“Tumor necrosis factor-alpha levels and weight loss in chronic obstructive pulmonary disease”, Am. J. Respir. Crit. Care Med. (1994);150: pp. 1,453–1,455.
8. Levine B, Kalman J, Mayer L, Fillit H M, Packer M,“Elevated circulating levels of tumor necrosis factor in severe chronic heart failure”, N. Engl. J. Med. (1990);323: pp. 235–241.
9. Rabinovich R A,Ardite E,Troosters T et al.,“Reduced muscle redox capacity after endurance training in patients with chronic obstructive pulmonary disease”, Am. J. Respir. Crit. Care Med. (2001);164: pp. 1,114–1,118.
10. Reid M B,“COPD as a muscle disease”, Am. J. Respir. Crit. Care Med. (2001);164: pp. 1,101–1,102.
11. Kamischke A, Kemper D E, Castel M A et al.,“Testosterone levels in men with chronic obstructive pulmonary disease with or without glucocorticoid therapy”, Eur. Respir. J. (1998);11: pp. 41–45.
12. Niebauer J, Pflaum C-D, Clark A L et al.,“Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation”, J. Am. Coll. Cardiol. (1998);32: pp. 393–397.
13. Anker S D, Chua T P, Ponikowski P et al.,“Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia”, Circulation (1997);96: pp. 526–534.
14. Repine J E, Bast A, Lankhorst I,“Oxidative stress in chronic obstructive pulmonary disease”, Am. J. Respir. Crit. Care Med. (1997);156: pp. 341–357.
15. Breen E C, Johnson E C,Wagner H et al.,“Angiogenic growth factor mRNA responses in muscle to a single bout of exercise”, J. Appl. Physiol. (1996);81: pp. 355–361.
16. Semenza G L,“HIF-1: mediator of physiological and pathophysiological responses to hypoxia”, J. Appl. Physiol. (2000);88: pp. 1,474–1,480.
17. Sauleda J, Garcia-Palmer F,Wiesner R J et al.,“Cytochrome oxidase activity and mitochondrial gene expression in skeletal muscle of patients with chronic obstructive pulmonary disease”, Am. J. Respir. Crit. Care Med. (1998);157: pp. 1,413–1,417.
18. Sridhar M K,“Why do patients with emphysema lose weight?”, Lancet (1995);345: pp. 1,190–1,191.
19. Mancini D M,Wilson J R, Bolinger L et al.,“In vivo magnetic resonance spectroscopy measurement of deoxymyoglobin during exercise in patients with heart failure: demonstration of abnormal muscle metabolism despite adequate oxygenation”, Circulation (1994);90: pp. 500–508.
20. Maltais F, LeBlanc P,Whittom F et al.,“Oxidative enzyme activities of the vastus lateralis muscle and the functional status in patients with COPD”, Thorax (2000);55: pp. 848–853.
21. Maltais F, Jobin J, Sullivan M J et al., “Metabolic and hemodynamic responses of lower limb during exercise in patients with COPD”, J. Appl. Physiol. (1998);84: pp. 1,573–1,580.
22. Maltais F, Simard A A, Simard C et al., “Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD”, Am. J. Respir. Crit. Care Med. (1996);153: pp. 288–293.
23. Sala E, Roca J, Marrades R M et al., “Effects of endurance training on skeletal muscle bioenergetics in chronic obstructive pulmonary disease”, Am. J. Respir. Crit. Care Med. (1999);159: pp. 1,726–1,734.
24. Maltais F, LeBlanc P, Simard C et al., “Skeletal muscle adaptation to endurance training in patients with chronic obstructive pulmonary disease”, Am. J. Respir. Crit. Care Med. (1996);154: pp. 442–447.
25. Gea J G, Pasto M, Carmona M A et al., “Metabolic characteristics of the deltoid muscle in patients with chronic obstructive pulmonary disease”, Eur. Respir. J. (2001);17: ppp. 939–945.
26. Maltais F, Sullivan M J, LeBlanc P et al.,“Altered expression of myosin heavy chain in the vastus lateralis muscle in patients with COPD”, Eur. Respir. J. (1999);13: pp. 850–854.
27. Sullivan M J, Green H J, Cobb F R,“Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure”, Circulation (1990);81: pp. 518–527.
28. Larsson L,Ansved T,“Effects of long-term physical training and detraining on enzyme histochemical and functional skeletal muscle characteristics in man”, Muscle & Nerve (1985);8: pp. 714–722.
29. Jobin J, Maltais F, Doyon J-F et al.,“Chronic obstructive pulmonary disease: capillarity and fiber-type characteristics of skeletal muscle”, J. Cardiopulm. Rehab. (1998);18: pp. 432–437.
30. Whittom F, Jobin J, Simard P M et al.,“Histochemical and morphological characteristics of the vastus lateralis muscle in patients with chronic obstructive pulmonary disease”, Med. Sci. Sports Exerc. (1998);30: pp. 1,467–1,474.
31. Williams T J, Grossman R F, Maurer J R,“Long-term functional follow-up of lung transplant recipients”, Clin. Chest Med. (1990);11: pp. 347–358.
32. Theodore J, Morris A T, Burke C M, Glanville A R,VanKessel A, Baldwin J C, “Cardiopulmonary function at maximum tolerable work rate following human heart-lung transplantation”, Chest (1987);92: pp. 433–439.
33. Levy R D, Ernst P, Levine S M, Shennib H,Anzueto A, Bryan C L et al.,“Exercise performance after lung transplantation”, J. Heart Lung Transp. (1993);12: pp. 27–33.
34. Miyoshi S,Trulock E P, Schaefers H-J et al.,“Cardiopulmonary exercise testing after single and double lung transplantation”, Chest (1990);97: pp. 1,130–1,136.
35. Williams T J, Patterson G A, McClean P A, Zamel N, Maurer J R,“Maximal exercise testing in single and double lung transplant recipients”, Am. Rev. Respir. Dis. (1992);145: pp. 101–105.
36. Williams T J, Howard M, Roget J, Esmore D S,“Exercise capacity after combined heart-lung transplantation”, Transplant. Proc. (1992);24: p. 2,018.
37. Nixon P A, Fricker F J, Noyes B E et al.,“Exercise testing in pediatric heart, heart-lung and lung transplant recipients”, Chest (1995);107: pp. 1,328–1,335.
38. Kimoff R J, Cheong T H, Cosio M G, Guerraty A, Levy R D,“Pulmonary denervation in humans”, Am. Rev. Respir. Dis. (1990);142: pp. 1,034–1,040.
39. Sciurba F C, Owens G R, Sanders M H et al.,“Evidence of altered pattern of breathing during exercise in recipients of heart- lung transplants”, N. Engl. J. Med. (1988);319: pp. 1,186–1,192.
40. Gibbons W J, Levine S M, Bryan C L et al.,“Cardiopulmonary exercise responses after single lung transplantation for severe obstructive lung disease”, Chest (1991);100: pp. 106–111.
41. Orens J B, Becker F S, Lynch J P et al.,“Cardiopulmonary exercise testing following allogeneic lung transplantation for different underlying disease states”, Chest (1995);107: pp. 144–149.
42. Ross D J,Walters P F, Mohenifar Z et al.,“Hemodynamic responses to exercise after lung transplantation”, Chest (1993);103: pp. 46–53.
43. Decramer M, Lacquet L M, Fagard R, Rogiers P,“Corticosteroids contribute to muscle weakness in chronic airflow obstruction”, Am. Rev. Respir. Dis. (1994);150: pp. 11–16.
44. Breil M, Chariot P,“Muscle disorders associated with cyclosporine treatment”, Muscle & Nerve (1999);22: pp. 1,631–1,636.
45. Richardson R S, Leek B T, Haseler L J et al.,“Normal skeletal muscle function in patients with COPD when exercise is not centrally limited”, Med. Sci. Sports Exerc. (1999);31: p. S276 (abstract).
46. Esposito F, Entin P L, Gavin T P et al.,“Response to knee extensor (small muscle mass) endurance training in chronic heart failure”, The Physiologist (2000);43: p. 364 (abstract).
47. Tamm M, Higenbottam T W, Dennis C M, Sharples L D,Wallwork J,“Donor and recipient predicted lung volume and lung size after heart-lung transplantation”, Am. J. Respir. Crit. Care Med. (1994);150: pp. 403–407.
48. Casaburi R, Patessio A, Ioli F et al.,“Reductions in exercise lactic acidosis and ventilation as a result of exercise training in patients with obstructive lung disease”, Am. Rev. Respir. Dis. (1991);143: pp. 9–18.
49. Magnusson G, Gordon A, Kaijser L et al.,“High intensity knee extensor training, in patients with chronic heart failure”, Eur. Heart J. (1996);17: pp. 1,048–1,055.
50. Levine S M,Anzueto A, Peters J I et al.,“Medium term functional results of single-lung transplantation for endstage obstructive lung disease”, Am. J. Respir. Crit. Care Med. (1994);150: pp. 398–402.
51. Al-Kattan K,Tadjkarimi S, Cox A et al.,“Evaluation of the long-term results of single lung versus heart-lung transplantation for emphysema”, J. Heart Lung Transp. (1995);14: pp. 824–831.
52. Ambrosino N, Bruschi C, Callegari G et al.,“Time course of exercise capacity, skeletal and respiratory muscle performance after heart-lung transplantation”, Eur. Respir. J. (1996);9: pp. 1,508–1,514.
53. Oelberg D A, Systrom D M, Markowitz D H et al., “Exercise performance in cystic fibrosis before and after bilateral lung transplantation”, J. Heart Lung Transp. (1998);17: pp. 1,104–1,112.
54. Systrom D M, Pappagianopoulos P, Fishman R S,Wain J C, Ginns L C,“Determinants of abnormal maximum oxygen uptake after lung transplantation for chronic obstructive pulmonary disease”, J. Heart Lung Transp. (1998);17: pp. 1,220–1,230.
55. Tirdel G B, Girgis R, Fishman R S,Theodore J,“Metabolic myopathy as a cause of the exercise limitation in lung transplant recipients”, J. Heart Lung Transp. (1998);17: pp. 1,231–1,237.
56. Lands L C, Smountas A A, Mesiano G et al.,“Maximal exercise capacity and peripheral skeletal muscle function following lung transplantation”, J. Heart Lung Transp. (1999);18: pp. 113–120.
57. Wang X N, Williams T J, McKenna M J et al., “Skeletal muscle oxidative capacity, fiber type, and metabolites after lung transplantation”, Am. J. Respir. Crit. Care Med. (1999);160: pp. 57–63.
2. Palange P,Wagner P D,“The skeletal muscle in chronic respiratory diseases”, summary of the ERS Research Seminar in Rome, Italy, February 11–12 1999, Eur. Respir. J. (2000);15: p. 815.
3. Maltais F, LeBlanc P,“Peripheral muscle dysfunction in chronic obstructive pulmonary disease”, Clin. Chest Med. (2000);21: pp. 665–677.
4. Jones N L, Jones G, Edwards R H T,“Exercise tolerance in chronic airway obstruction”, Am. Rev. Respir. Dis. (1971);103: pp. 477–491.
5. Wagner P D,“Determinants of maximal oxygen transport and utilization”, Annu. Rev. Physiol. (1996);58: pp. 21–50.
6. Schols A M W J, Buurman W A, Staal-van den Brekel A J, Dentener M A,Wouters E F,“Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease”, Thorax (1996);51: pp. 819–824.
7. DiFrancia M, Barbier D, Mege J L, Orehek J,“Tumor necrosis factor-alpha levels and weight loss in chronic obstructive pulmonary disease”, Am. J. Respir. Crit. Care Med. (1994);150: pp. 1,453–1,455.
8. Levine B, Kalman J, Mayer L, Fillit H M, Packer M,“Elevated circulating levels of tumor necrosis factor in severe chronic heart failure”, N. Engl. J. Med. (1990);323: pp. 235–241.
9. Rabinovich R A,Ardite E,Troosters T et al.,“Reduced muscle redox capacity after endurance training in patients with chronic obstructive pulmonary disease”, Am. J. Respir. Crit. Care Med. (2001);164: pp. 1,114–1,118.
10. Reid M B,“COPD as a muscle disease”, Am. J. Respir. Crit. Care Med. (2001);164: pp. 1,101–1,102.
11. Kamischke A, Kemper D E, Castel M A et al.,“Testosterone levels in men with chronic obstructive pulmonary disease with or without glucocorticoid therapy”, Eur. Respir. J. (1998);11: pp. 41–45.
12. Niebauer J, Pflaum C-D, Clark A L et al.,“Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation”, J. Am. Coll. Cardiol. (1998);32: pp. 393–397.
13. Anker S D, Chua T P, Ponikowski P et al.,“Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia”, Circulation (1997);96: pp. 526–534.
14. Repine J E, Bast A, Lankhorst I,“Oxidative stress in chronic obstructive pulmonary disease”, Am. J. Respir. Crit. Care Med. (1997);156: pp. 341–357.
15. Breen E C, Johnson E C,Wagner H et al.,“Angiogenic growth factor mRNA responses in muscle to a single bout of exercise”, J. Appl. Physiol. (1996);81: pp. 355–361.
16. Semenza G L,“HIF-1: mediator of physiological and pathophysiological responses to hypoxia”, J. Appl. Physiol. (2000);88: pp. 1,474–1,480.
17. Sauleda J, Garcia-Palmer F,Wiesner R J et al.,“Cytochrome oxidase activity and mitochondrial gene expression in skeletal muscle of patients with chronic obstructive pulmonary disease”, Am. J. Respir. Crit. Care Med. (1998);157: pp. 1,413–1,417.
18. Sridhar M K,“Why do patients with emphysema lose weight?”, Lancet (1995);345: pp. 1,190–1,191.
19. Mancini D M,Wilson J R, Bolinger L et al.,“In vivo magnetic resonance spectroscopy measurement of deoxymyoglobin during exercise in patients with heart failure: demonstration of abnormal muscle metabolism despite adequate oxygenation”, Circulation (1994);90: pp. 500–508.
20. Maltais F, LeBlanc P,Whittom F et al.,“Oxidative enzyme activities of the vastus lateralis muscle and the functional status in patients with COPD”, Thorax (2000);55: pp. 848–853.
21. Maltais F, Jobin J, Sullivan M J et al., “Metabolic and hemodynamic responses of lower limb during exercise in patients with COPD”, J. Appl. Physiol. (1998);84: pp. 1,573–1,580.
22. Maltais F, Simard A A, Simard C et al., “Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD”, Am. J. Respir. Crit. Care Med. (1996);153: pp. 288–293.
23. Sala E, Roca J, Marrades R M et al., “Effects of endurance training on skeletal muscle bioenergetics in chronic obstructive pulmonary disease”, Am. J. Respir. Crit. Care Med. (1999);159: pp. 1,726–1,734.
24. Maltais F, LeBlanc P, Simard C et al., “Skeletal muscle adaptation to endurance training in patients with chronic obstructive pulmonary disease”, Am. J. Respir. Crit. Care Med. (1996);154: pp. 442–447.
25. Gea J G, Pasto M, Carmona M A et al., “Metabolic characteristics of the deltoid muscle in patients with chronic obstructive pulmonary disease”, Eur. Respir. J. (2001);17: ppp. 939–945.
26. Maltais F, Sullivan M J, LeBlanc P et al.,“Altered expression of myosin heavy chain in the vastus lateralis muscle in patients with COPD”, Eur. Respir. J. (1999);13: pp. 850–854.
27. Sullivan M J, Green H J, Cobb F R,“Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure”, Circulation (1990);81: pp. 518–527.
28. Larsson L,Ansved T,“Effects of long-term physical training and detraining on enzyme histochemical and functional skeletal muscle characteristics in man”, Muscle & Nerve (1985);8: pp. 714–722.
29. Jobin J, Maltais F, Doyon J-F et al.,“Chronic obstructive pulmonary disease: capillarity and fiber-type characteristics of skeletal muscle”, J. Cardiopulm. Rehab. (1998);18: pp. 432–437.
30. Whittom F, Jobin J, Simard P M et al.,“Histochemical and morphological characteristics of the vastus lateralis muscle in patients with chronic obstructive pulmonary disease”, Med. Sci. Sports Exerc. (1998);30: pp. 1,467–1,474.
31. Williams T J, Grossman R F, Maurer J R,“Long-term functional follow-up of lung transplant recipients”, Clin. Chest Med. (1990);11: pp. 347–358.
32. Theodore J, Morris A T, Burke C M, Glanville A R,VanKessel A, Baldwin J C, “Cardiopulmonary function at maximum tolerable work rate following human heart-lung transplantation”, Chest (1987);92: pp. 433–439.
33. Levy R D, Ernst P, Levine S M, Shennib H,Anzueto A, Bryan C L et al.,“Exercise performance after lung transplantation”, J. Heart Lung Transp. (1993);12: pp. 27–33.
34. Miyoshi S,Trulock E P, Schaefers H-J et al.,“Cardiopulmonary exercise testing after single and double lung transplantation”, Chest (1990);97: pp. 1,130–1,136.
35. Williams T J, Patterson G A, McClean P A, Zamel N, Maurer J R,“Maximal exercise testing in single and double lung transplant recipients”, Am. Rev. Respir. Dis. (1992);145: pp. 101–105.
36. Williams T J, Howard M, Roget J, Esmore D S,“Exercise capacity after combined heart-lung transplantation”, Transplant. Proc. (1992);24: p. 2,018.
37. Nixon P A, Fricker F J, Noyes B E et al.,“Exercise testing in pediatric heart, heart-lung and lung transplant recipients”, Chest (1995);107: pp. 1,328–1,335.
38. Kimoff R J, Cheong T H, Cosio M G, Guerraty A, Levy R D,“Pulmonary denervation in humans”, Am. Rev. Respir. Dis. (1990);142: pp. 1,034–1,040.
39. Sciurba F C, Owens G R, Sanders M H et al.,“Evidence of altered pattern of breathing during exercise in recipients of heart- lung transplants”, N. Engl. J. Med. (1988);319: pp. 1,186–1,192.
40. Gibbons W J, Levine S M, Bryan C L et al.,“Cardiopulmonary exercise responses after single lung transplantation for severe obstructive lung disease”, Chest (1991);100: pp. 106–111.
41. Orens J B, Becker F S, Lynch J P et al.,“Cardiopulmonary exercise testing following allogeneic lung transplantation for different underlying disease states”, Chest (1995);107: pp. 144–149.
42. Ross D J,Walters P F, Mohenifar Z et al.,“Hemodynamic responses to exercise after lung transplantation”, Chest (1993);103: pp. 46–53.
43. Decramer M, Lacquet L M, Fagard R, Rogiers P,“Corticosteroids contribute to muscle weakness in chronic airflow obstruction”, Am. Rev. Respir. Dis. (1994);150: pp. 11–16.
44. Breil M, Chariot P,“Muscle disorders associated with cyclosporine treatment”, Muscle & Nerve (1999);22: pp. 1,631–1,636.
45. Richardson R S, Leek B T, Haseler L J et al.,“Normal skeletal muscle function in patients with COPD when exercise is not centrally limited”, Med. Sci. Sports Exerc. (1999);31: p. S276 (abstract).
46. Esposito F, Entin P L, Gavin T P et al.,“Response to knee extensor (small muscle mass) endurance training in chronic heart failure”, The Physiologist (2000);43: p. 364 (abstract).
47. Tamm M, Higenbottam T W, Dennis C M, Sharples L D,Wallwork J,“Donor and recipient predicted lung volume and lung size after heart-lung transplantation”, Am. J. Respir. Crit. Care Med. (1994);150: pp. 403–407.
48. Casaburi R, Patessio A, Ioli F et al.,“Reductions in exercise lactic acidosis and ventilation as a result of exercise training in patients with obstructive lung disease”, Am. Rev. Respir. Dis. (1991);143: pp. 9–18.
49. Magnusson G, Gordon A, Kaijser L et al.,“High intensity knee extensor training, in patients with chronic heart failure”, Eur. Heart J. (1996);17: pp. 1,048–1,055.
50. Levine S M,Anzueto A, Peters J I et al.,“Medium term functional results of single-lung transplantation for endstage obstructive lung disease”, Am. J. Respir. Crit. Care Med. (1994);150: pp. 398–402.
51. Al-Kattan K,Tadjkarimi S, Cox A et al.,“Evaluation of the long-term results of single lung versus heart-lung transplantation for emphysema”, J. Heart Lung Transp. (1995);14: pp. 824–831.
52. Ambrosino N, Bruschi C, Callegari G et al.,“Time course of exercise capacity, skeletal and respiratory muscle performance after heart-lung transplantation”, Eur. Respir. J. (1996);9: pp. 1,508–1,514.
53. Oelberg D A, Systrom D M, Markowitz D H et al., “Exercise performance in cystic fibrosis before and after bilateral lung transplantation”, J. Heart Lung Transp. (1998);17: pp. 1,104–1,112.
54. Systrom D M, Pappagianopoulos P, Fishman R S,Wain J C, Ginns L C,“Determinants of abnormal maximum oxygen uptake after lung transplantation for chronic obstructive pulmonary disease”, J. Heart Lung Transp. (1998);17: pp. 1,220–1,230.
55. Tirdel G B, Girgis R, Fishman R S,Theodore J,“Metabolic myopathy as a cause of the exercise limitation in lung transplant recipients”, J. Heart Lung Transp. (1998);17: pp. 1,231–1,237.
56. Lands L C, Smountas A A, Mesiano G et al.,“Maximal exercise capacity and peripheral skeletal muscle function following lung transplantation”, J. Heart Lung Transp. (1999);18: pp. 113–120.
57. Wang X N, Williams T J, McKenna M J et al., “Skeletal muscle oxidative capacity, fiber type, and metabolites after lung transplantation”, Am. J. Respir. Crit. Care Med. (1999);160: pp. 57–63.
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