Olinical Investigator
Clin Investig (1993) 71:S 162 S 166
Conferenceon OoenzymeQ
© Springer-Verlag 1993
Effects of coenzymeQ1 o administration on pulmonary function and exercise performance in patients with chronic lung diseases* S. Fujimoto, N. Kurihara, K. Hirata, T. Takeda First Department of Internal Medicine, Osaka City University Medical School
Summary. Serum coenzyme Qlo (CoQto) levels
Key words: CoenzymeQ~o - Chronic obstructive
were measured at rest and during incremental exercise in 21 patients with chronic obstructive pulmonary disease (COPD) and 9 patients with idiopathic pulmonary fibrosis (IPF). The mean serum CoQ~ o levels at rest in patients with COPD and IPF were 0.56_+0.20 and 0.45_+0.16 gg/ml, respectively. In both groups these levels were decreased compared with those of healthy subjects. In the patients with COPD, CoQ~ 0 levels were significantly correlated with body weight, however, there was no correlation between CoQw levels and ventilatory function, PaO a, £O2/kg at rest, or maximal £ 0 2. In eight of nine patients whose PaO z at rest was lower than 75 torr, serum CoQ~ 0 levels were lower than 0.5 pg/ml. We studied the effects of the oral administration of CoQ10 at 90 mg/day for 8 weeks on pulmonary function and exercise performance in eight patients with COPD. Serum CoQ1 o levels were significantly elevated in association with an improvement in hypoxemia at rest, whereas pulmonary function was unaltered. Oxygen consumption during exercise was not changed, whereas P a Q was significantly improved, and heart rate was significantly decreased compared with the results obtained at an identical workload at baseline. Furthermore, lactate production was suppressed during the anaerobic exercise stage after CoQlo administration, and exercise performance tended to increase. These data suggested that CoQt 0 has favorable effects on musclar energy metabolism in patients with chronic lung diseases who have hypoxemia at rest and/or during exercise.
pulmonary disease - Hypoxemia - Exercise performance - Blood lactate
Abbreviations: COPD = chronic obstructive pulmonary disease; IPF = idiopathic pulmonary fibrosis
* Paper presented at the 7th International Symposium on The Biomedical and Clinical Aspects of Coenzyme Q (September 18-19, 1992, Copenhagen, Denmark)
Most patients with chronic obstructive pulmonary disease(COPD) or idiopathic pulmonary fibrosis (IPF) discontinue exercise due to dyspnea and leg fatigue [10, 14]. An important factor in these exercise limitations is ventilatory disturbance [14,20] because of air flow limitation and increased work of breathing in the diaphragm and other respiratory muscles [3, 9]. Furthermore, arterial oxygen tension (PaO2) in patients with COPD or IPF is often low at rest and gradually decreases during exercise [13]. Under this hypoxic condition, oxygen transport to the leg muscles as well as the heart and respiratory muscles is disturbed. Hypoxia in the leg muscles enhances lactate production and leads to early leg fatigue. Hypoxemia increases heart rate and impairs cardiac function [6]. In addition, it has recently been reported that hypoxia in the respiratory muscles, including the intercostal muscles and diaphragm results in muscle fatigue [5]. Therefore exercise induced hypoxemia may result in the cessation of exercise with ventilatory limitations accompanied by an increased feeling of dyspnea [14, 19]. Coenzyme Qlo (CoQlo) is contained in mitochondria and has an important role in aerobic energy production and metabolism [8]. It has been reported that serum CoQ10 levels are lower in patients with certain cardiovascular diseases [7] and hyperthyroidism [17] than in normal subjects. However, there is no report concerning with its level in patients with pulmonary diseases. The purpose of this study was to investigate the significance of serum CoQI 0 levels in patients with chronic lung diseases in relation to ventilatory capacity, PaO2 and exercise performance. Furthermore, we investigated the effects of CoQ1 o administration on exercise performance in these patients.
S 163 Materials and methods Twenty-one patients with COPD and nine with IPF were studied. Patient characteristics and pulmonary function test results are shown in Table 1. All of the patients were clinicaly stable and did not have heart failure or other diseases. The patients with COPD had moderate to severe obstructive ventilatory changes with hyperinflation and decreased diffusion capacity. The patients with IPF displayed moderate restrictive changes and moderate decrease in diffusion capacity. Treadmill exercise testing was performed in progressive multistage methods with each stage lasting 3 min. The initial workload involved a speed of 0.75 miles per hour and a zero grade incline. Speed was subsequently increased in increments of 0.25 miles per hour and the incline by a 4% grade at each stage [14]. Exercise was continued until the patients displayed symptoms and/or reached the predicted maximal heart rate [15]. Minute ventilation, oxygen consumption, carbon dioxide production, tidal volumes, and respiratory frequency were measured by the respiromonitor RM-200. ECG was continuously monitored by telemetry. Arterial blood gases, blood lactate, and CoQlo were measured at each exercise stage. The serum CoQ10 concentration was measured by highspeed liquid chromatography [1]. Next, CoQm was administered to 8 of the 21 patients with COPD. (Table 3) Treatment consisted of oral CoQm 90 rag/day for 8 weeks. Pulmonary function tests were performed after the 4th and 8th weeks of CoQa o administration, and exercise testing was performed after the 8th week following the above exercise protocol. Standard statistical methods were employed for data analysis, and the paired t test was used when applicable. Data in the text, tables, and figures are presented as the mean values _+ 1 SD. Results The mean serum CoQI o level at rest was 0.56_+ 0.20 gg/ml in patients with COPD and 0.45 _+0.16 gg/ml in those with IPF (Table 1). These levels were lower than those of healthy subjects [11]. In patients with COPD, CoQ10 levels were significantly correlated with body weight and obesity index; however, there was no correlation between CoQ1 o levels and ventilatory functon, PaO2, 9"O2/kg at rest, or 9 0 2 maximum (Table 2). Although serum CoQl o levels did not correlate with PaO 2 in either group, they were lower than 0.5 gg/ml in 8 of 9 patients whose PaO 2 was lower than 75 torr (Fig. 1).
Table 1. Patient characteristics and pulmonary functiondata
Age (years) Body weight (kg) Obesity index (%) VC (1) %VC(%) FEVI.o(I
)
FEVI.o% (%) RV/TLC (%) %FRC (%) %DLco (%) PaO2 (torr) COQlo(pg/ml)
CODP (n= 21)
Pulmonary fibrosis (n=9)
59.5 _+ 9.0 50.2 _+ 9.3 90.8 _+12.0 2.53_+ 0.64 79.8 _+13.8 0.98_+ 0.39 39.1 _+ 9.0 53.9 _+ 6.3 108.6 -+24.9 57.6 -+25.8 80.5 4- 7.7 0.56_+ 0.20
56.3 _+15.3 54.7 _+12.4 105.8 _+13.1 2.254- 0.92 73.0 _+21.6 1.80_+ 0.84 80.1 _+12.0 29.5 _+10.0 62.0 _+17.8 63.5 _+35.7 74.3 _+ 8.7 0.45_+ 0.16
Table 2. The relationshipbetween CoQ10and body weight,pulmonary function parameters and maximal 02 consumption in COPD patients (n= 21) COPD
Body weight Obesity index VC %VC FEVI.o FEVI.o% RV/TLC %FRC Vo2 at rest
0.44* 0.43* 0.03 -0.13 - 0.17 - 0.13 -0.17 -0.30 0.24 -0.19 0.25 0.11
VE/9o2 at rest P a O 2 at rest 902 at maximal stage * P<0.05
O : COPD(N=21) Co. Q (/,g/m.~)
• : Pul. Fib. (N= 9 ) NS
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Fig. 1. The relationship between C o Q 1 o levels and arterial 02 tension at rest
S 164 b) H.R.
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T y p e ]1 I Fig. 2. The changes in PaO 2 in type 1 and type 2 patients. Type 1 patients showed an increase or lack of change in CoQ,o levels during exercise in comparison with resting levels. Type 2 patients showed a decrease in CoQm during exercise Type
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Fig. 3. The effects of CoQlo administration on oxygen consumption (a), heart rate (b), arterial oxygen tension (c), and blood lactate (d) during exercise at the same workload in 8 patients with COPD. Abscissa, baseline; ordinate, after the 8th week of CoQm administration; oblique line, the line of identity
Table 3. Serum CoQ1 o level, pulmonary function test results, and exercise tolerance at baseline and after 4 and 8 weeks of CoQao
administration in COPD patients (n = 8)
Coenzyme Q10 VC FEVI.o FEVI.o% MVV RV/TLC %DLc o PaO 2 PaCO2 Vo2 max Treadmill Time
(~g/ml) (1) (1) (%) (l/rain) (%) (%) (torr) (torr) (l/m) (min)
Baseline
After 4th week
After 8th week
0.33 ± 0.06 2.54± 0.77 0.92± 0.47 41.8 ±10.2 32.1 ± 19.5 55.7 ± 5.2 56.3 ±15.9 74.5 _ 9.1 40.1 +_ 3.1 0.85± 0.16 12.0 ± 2.1
not tested 2.77± 0.77 1.00± 0.45 41.3 _+11.5 35.9 ± 17.0 52.7 ± 6.2 55.3 _+16.9 not tested not tested not tested not tested
0.90 ± 0.18"** 2.71± 0.79 0.94__ 0.39 38.1 ± 8.0 37.5 ± 18.9" 53.8 ± 3.2 60.1 ±21.8 81.5 ±11.2" 37.3 ± 3.3 0.91± 0.17 14.0 ± 1.3"*
Significance of differences from corresponding values recorded at baseline: * P < 0.05; ** P < 0.02; *** P < 0.01
The changes in serum CoQm level during graded exercise were variable. In 13 of 20 evaluated patients with COPD, it increased or did not change. However, it decreased during exercise in the remaining 7 patients. We designated the former patients as type 1 and the latter as type 2. In the type 1 patients, the mean change in PaO 2 was 10.2 4- 11.3 torr, whereas in type 2 patients it was - 2 5 . 4 + 11.7 torr (Fig. 2). There was a significant difference between the two types. The influence of CoQm administration on pulmonary function test -
results, PaO 2 and exercise performance are shown in Table 3. The mean serum CoQ1 o level was significantly elevated. The various pulmonary function test parameters were not significantly changed except for maximal voluntary ventilation after 4 and 8 weeks of CoQt0 administraton. PaO2 at rest was significantly increased, but there was no change in PaCO 2. Maximal oxygen consumption tended to increase, and treadmill time increased significantly. However, other parameters did not show signifi-
S 165
cant changes after 8 weeks of CoQ10 administration. The effects of CoQ10 on physiological parameters during exercise were examined, and the results were compared with baseline values. There was no significant difference in oxygen consumption after CoQm administration (Fig. 3a). Heart rate during exercise was significantly decreased (Fig. 3b), and PaO 2 was significantly improved after CoQt o administration (Fig. 3c). Blood lactate concentration during exercise tended to decrease, but the change was not of statistical significance. All plots above 20 mg/dl at baseline study located below an identity line after CoQ10 (Fig. 3d). Discussion
In this study we found that serum COQl 0 levels were decreased in patients with chronic lung diseases. During exercise the level decreased further in patients with COPD who showed exercise induced hypoxemia. Serum CoQ1 o levels are reportedly decreased in patients with certain cardiovascular diseases [7], hyperthyroidism [17], and liver diseases [16]. Probable mechanisms in these diseases are thought to be a decreased source of CoQ1 o enzyme in the cardiac muscles, overuse of CoQ1 o in the hypermetabolic state, or decreased synthesis of CoQ1 o in the liver [7, 16, 171. The patients with chronic lung diseases in this study did not have cardiac, muscular, hormonal, or hepatic complications. Their COQlo levels were not correlated with severity of ventilatory dysfunction. We have shown that patients with hypoxemia at rest tend to have a decreased serum CoQm levels, and that those with exercise-induced hypoxemia display significant reductions in serum CoQ10 during exercise. Therefore low serum CoQ~o levels seem to be closely related to hypoxemia. Under the presence of hypoxemia at rest and during exercise, some organs including the heart and liver as well as skeletal muscles may become hypoxic. We speculate that decreased CoQ10 levels may result from impaired synthesis due to hypoxia in the heart and liver. Costa et al. [4] has reported that ubiquinone levels in the heart muscle of animals is decreased during hypoxia, probably due to impaired synthesis rather than a reduction in mitochondorial oxidative capacity secondary to decreased tissue P Q . The nutritional state may also have an influence on CoQ1 o levels. It has been reported that the nutritional state of patients with COPD is poorer than that of normal subjects [2], and that this affects their prognosis [21]. In this study, body weight
and obesity index were positively correlated with CoQlo levels at rest. A suboptimal nutritional state may enhance the impaired synthesis of CoQ10 in the liver in addition to the effects of hypoxia. Another factor that may have affected CoQa o levels was the rapid movement of CoQ~o during exercise. In other words, serum CoQ~o may be transfered from serum to exercising muscles, where hypoxic conditions likely occurred in our patients. The effects of CoQ10 administraton in our patients were as followed. Since CoQ~ 0 plays a key role in aerobic energy production, elevated serum CoQlo levels may have a favorable effect on exercising muscles. It has been reported that CoQ~ o increases 2-3diphosphoglycerate levels in erythrocytes [18]. Because 2-3-diphosphoglycerate shifts the Hb-O 2 saturation curve to the right, O 2 delivery to the muscles increases at a given PaO 2 [11]. Therefore, ATP synthesis and lactate production may improve as a result of these increased muscular oxygenation. This could occur not only in skeletal muscle but also in cardiac and respiratory muscles. We speculate that this is the most important mechanism of action of CoQ10. The other effect of CoQ10 was improved O z transport to muscles during exercise. The reason for this was both improved PaO 2 and increased cardiac output during exercise after CoQ1 o administration. PaO 2 increased after CoQ10 despite a lack of change in ventilatory function and diffusion capacity. These changes may have been due to improved mixed venous 0 2 saturation secondary to improved O 2 utilizaton in peripheral tissue and increased cardiac output as central effect [22]. Our results suggest that CoQl o administration has a favorable effect on the energy production of exercising muscles in patients with chronic lung diseases who have hypoxemia at rest and/or during exercise. References 1. Abe K, Ishibashi K, Ohmae M, Kawabe K, Katui G (1978) Determination of ubiquinone in serum and liver by highspeed liquid chromatography. J Nutr Sci Vitaminol 24:555567 2. Baum SR, Keim NL, Dixon RM, Clagnas P, Andereg A, Shrago ES (1986) The prevalence and determinants of nutritional changes in chronic obstructive pulmonary disease. Chest 86:558-563 3. Cohen CA, Zagelbaum CMG, Gross D, Macklem PT (1982) Clinical manifestation of inspiratory muscle fatigue. Am J Med 73:308-316 4. Costa LE, Mirande IM, Taquini AC(1974) Effect of chronic hypobaric hypoxia on ubiquinone levels in heart muscle. Acta Physiol Latino americana 24:631-637
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S. Fujimoto, M.D. 1st Department of Internal Medicine Osaka City University Medical School 1-5-7 Asahi-machi, Abenoku Osaka 545, Japan