Associations of Exercise Tolerance and Clinical Parameters in Japanese Patients With Chronic Obstructive Pulmonary Disease: Impact of Skeletal Muscle

Decreasing exercise tolerance is one of the key features related to a poor prognosis in patients 25 with chronic obstructive pulmonary disease (COPD). Cardiopulmonary exercise testing (CPET) 26 is useful for evaluating exercise tolerance. The present study was performed to clarify the 27 correlation between exercise tolerance and clinical parameters, focusing especially on the cross- 28 sectional area (CSA) of skeletal muscle. The present study retrospectively investigated 69 patients with COPD who underwent CPET. The correlations between oxygen uptake ( V̇ O 2 ) at peak exercise and clinical parameters of 32 COPD, including skeletal muscle area measured using single-section axial computed 33 tomography (CT), were evaluated.


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The present study retrospectively investigated 69 patients with COPD who underwent CPET.

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The correlations between oxygen uptake (V O 2 ) at peak exercise and clinical parameters of 32 COPD, including skeletal muscle area measured using single-section axial computed 33 tomography (CT), were evaluated.

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Decreasing exercise tolerance, normally measured by the 6-minute walk test or 62 cardiopulmonary exercise testing (CPET), is one of the important clinical features related to a 63 poor prognosis in COPD patients 3, 9, 10 , and with CPET one can evaluate exercise tolerance with 64 exertional ventilatory parameters precisely and safely 11, 12 . For example, oxygen uptake (V O2 ) at 65 peak exercise, which represents exercise tolerance, is significantly correlated with FEV 1 66 and %FEV 1 reflecting the severity of COPD 13, 14 . Notably, with CPET, one can detect physical 67 problems including cardiac dysfunction and functional skeletal muscle disorders during the test, 68 which contributes to rapid initiation of treatment 15 .

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Weight loss is a common systemic characteristic of patients with COPD 16 , and skeletal muscle 70 loss has greater impact on the severity of COPD than decreased BMI 17 . Radiological analysis of 71 skeletal muscles on computed tomography (CT) is a useful procedure for quantitation without 72 onerous physical intervention 18, 19 , and the cross-sectional area (CSA) of skeletal muscle on 5 addition, the CSA of the erector spinae muscles (ECMs), which are anti-gravity muscles, but not 75 of the pectoralis muscles (PMs), is significantly associated with mortality in Japanese patients 76 with COPD 21 . Obviously, skeletal muscles are important for exercise tolerance, but the impact 77 of exertional ventilatory parameters on CPET compared to clinical parameters in patients with 78 COPD is not fully understood.

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In the present real-world study, correlations between exercise tolerance indicated by V O 2 at 80 peak exercise and clinical parameters including skeletal muscle area were examined in Japanese 81 patients with COPD. Decreases of FEV 1 and FEV 1 /FVC are significantly correlated with a low 82 level of exercise tolerance, and, importantly, skeletal muscle area, especially of the ECMs as 83 anti-gravity muscles, is more correlated with V O2 at peak exercise than PM area on CT imaging.

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These data suggest that decreased FEV 1 and FEV 1 /FVC are correlated with decreased exercise 85 tolerance and loss of skeletal muscles, especially the anti-gravity muscles, that contribute to a 86 low level of exercise tolerance.   (Table 1).

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Parameters of cardiopulmonary exercise testing 107 V O2 , which is a marker that reflects exercise tolerance 22 , was 295.6 ml/min at rest and 926.0 108 ml/min at peak exercise. Body weight-adjusted V O2 was 5.3 ml/min/kg at rest and 16.2 109 ml/min/kg at peak exercise. V T and V E were 773.2 ml and 12.9 L/min at rest and 1245.7 ml and 110 36.6 L/min at peak exercise, respectively. V E / V CO2 , which reflects pulmonary clearance of CO 2 111 22 , was 49.3 at rest and 41.1 at peak exercise. V D /V T , which reflects the efficacy of pulmonary 112 gas exchange, was 0.28 at rest and 0.26 at peak exercise. The respiratory rate was 17.7 113 breaths/min at rest and 30.5 breaths/min at peak exercise (Table 2).

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Correlations between V O2 (ml/min/kg) at peak exercise and other parameters on CPET 116 and the 6-minute walk distance 117 Because V O2 (ml/min) is affected by body weight differences, V O2 adjusted by body weight 118 (ml/min/kg) at peak exercise is considered a precise marker for exercise tolerance 22 . Therefore, 119 the evaluation focused on that and its correlations with other CPET parameters and the 6-minute 120 walk distance. V O2 at peak exercise was significantly correlated with V E / V CO2 at rest (ρ = -0.46, 121 p < 0.0001) and at peak exercise (ρ = -0.45, p < 0.0001), V D /V T at rest (ρ = -0.36, p = 0.002) and  (Table 4). Examining the difference in V O2 at peak exercise 137 by COPD stage, COPD stage III and IV patients had significantly lower levels of V O2 at peak 138 exercise than stage II patients (Fig. 2a). Additionally, examining the difference in V O2 at peak

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In the present real-world study, the exercise tolerance of COPD patients was evaluated by 152 CPET, and it was confirmed that V O2 at peak exercise was significantly correlated with 6-153 minute walk distance and other CPET parameters, such as V E / V CO2, V D /V T, and respiratory rate, 154 which suggested that V O2 at peak exercise is a useful marker of exercise tolerance for COPD 155 patients. The analysis of correlation coefficients showed that the COPD assessment test, FEV 1 , 156 FEV 1 /FVC, PM CSA , and ECM CSA were correlated with V O2 at peak exercise. Additionally, 157 ECM CSA , reflecting anti-gravity muscles, was more correlated with V O2 at peak exercise than 158 PM CSA , showing that the loss of skeletal muscles, especially anti-gravity muscles, contributed to 159 a low level of exercise tolerance.   (Table 4, Fig. 1a, Fig. 1b). The severity of COPD 173 predicted by %FEV 1 is also related to the decrease of exercise tolerance, and Yamamoto et al 174 reported that V O2 at peak exercise was significantly higher in COPD patients in GOLD stages I of V O2 at peak exercise tended to be decreased depending on the GOLD stage, except for stage I 177 (Fig. 2a), although the correlation between V O2 at peak exercise and %FEV 1 was weak (Table   178 4).

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Loss of skeletal muscles with bodyweight reduction, called sarcopenia, is also an important 180 characteristic of COPD patients 20, 23, 24 . Reduction of fat-free mass containing skeletal muscle is 181 associated with mortality in patients with COPD 25 . In addition, a previous report showed that 182 COPD patients with decreased skeletal muscles, calculated by bioelectrical impedance analysis, 183 walked a significantly shorter distance on the incremental shuttle walk test, which is another 184 index of exercise tolerance, than those with preserved skeletal muscles 26 . With respect to the 185 mechanisms, loss of skeletal muscles causes increased O 2 demand as exercise intensity increases 186 and earlier reaching of the anaerobic threshold with metabolic acidosis and increased lactate, 187 which limits exercise tolerance in patients with COPD 27, 28 . The present study showed that 188 skeletal muscle area including PM CSA and ECM CSA was significantly correlated with V O2 at peak 189 exercise, which is consistent with these data (Table 4, Fig. 1c, Fig. 1d).

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Importantly, the present results showed that ECM CSA , representing anti-gravity muscles, was 191 more correlated with V O2 at peak exercise than PM CSA (Table 4)

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The present study showed that decreases in FEV 1 and FEV 1 /FVC are significantly correlated 225 with a low level of exercise tolerance and skeletal muscle area, and the area of the ECMs, as 226 anti-gravity muscles, is more correlated with V O2 at peak exercise than the area of the PMs.

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These data suggest that decreased pulmonary function and loss of skeletal muscles, especially 228 anti-gravity muscles, contribute to the low level of exercise tolerance in patients with COPD.

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and breathing frequency at rest and at peak exercise were evaluated. Oxygen saturation, blood exercise resting measurements were obtained within the steady state period for more than 3 257 minutes. Incremental testing was then started by increasing the load by 10 W per minute. The 258 examination was continued until exhaustion or above the predicted maximum heart rate or