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J Appl Physiol 104: 1341-1350, 2008. First published March 20, 2008; doi:10.1152/japplphysiol.01364.2007
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Kinetics of muscle deoxygenation are accelerated at the onset of heavy-intensity exercise in patients with COPD: relationship to central cardiovascular dynamics

Gaspar R. Chiappa,1 Audrey Borghi-Silva,1,2 Leonardo F. Ferreira,1,3 Claúdia Carrascosa,1 Cristino Carneiro Oliveira,1 Joyce Maia,1 Ana Cristina Gimenes,1 Fernando Queiroga, Jr,1 Danilo Berton,1 Eloara M. V. Ferreira,1 Luis Eduardo Nery,1 and J. Alberto Neder1

1Pulmonary Function and Clinical Exercise Physiology Unit, Division of Respiratory Diseases, Department of Medicine, Federal University of Sao Paulo, São Paulo; and 2Cardiopulmonary Laboratory, Nucleus of Research in Physical Exercise, Federal University of São Carlos, São Carlos, Brazil; and 3Department of Physiology, University of Kentucky, Lexington, Kentucky

Submitted 21 December 2007 ; accepted in final form 13 March 2008


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Patients with chronic obstructive pulmonary disease (COPD) have slowed pulmonary O2 uptake (VO2p) kinetics during exercise, which may stem from inadequate muscle O2 delivery. However, it is currently unknown how COPD impacts the dynamic relationship between systemic and microvascular O2 delivery to uptake during exercise. We tested the hypothesis that, along with slowed VO2p kinetics, COPD patients have faster dynamics of muscle deoxygenation, but slower kinetics of cardiac output (QT) following the onset of heavy-intensity exercise. We measured VO2p, QT (impedance cardiography), and muscle deoxygenation (near-infrared spectroscopy) during heavy-intensity exercise performed to the limit of tolerance by 10 patients with moderate-to-severe COPD and 11 age-matched sedentary controls. Variables were analyzed by standard nonlinear regression equations. Time to exercise intolerance was significantly (P < 0.05) lower in patients and related to the kinetics of VO2p (r = –0.70; P < 0.05). Compared with controls, COPD patients displayed slower kinetics of VO2p (42 ± 13 vs. 73 ± 24 s) and QT (67 ± 11 vs. 96 ± 32 s), and faster overall kinetics of muscle deoxy-Hb (19.9 ± 2.4 vs. 16.5 ± 3.4 s). Consequently, the time constant ratio of O2 uptake to mean response time of deoxy-Hb concentration was significantly greater in patients, suggesting a slower kinetics of microvascular O2 delivery. In conclusion, our data show that patients with moderate-to-severe COPD have impaired central and peripheral cardiovascular adjustments following the onset of heavy-intensity exercise. These cardiocirculatory disturbances negatively impact the dynamic matching of O2 delivery and utilization and may contribute to the slower VO2p kinetics compared with age-matched controls.

blood flow; chronic obstructive pulmonary disease; hemodynamics; near-infrared spectroscopy; oxygen consumption; kinetics

FOLLOWING THE ONSET OF EXERCISE, the dynamic increase in pulmonary oxygen uptake (VO2p) is slowed in patients with chronic obstructive pulmonary disease (COPD) compared with age-matched controls (12, 34, 36, 40, 41, 45). The slowed kinetics of VO2p leads to greater reliance on oxygen-independent metabolic pathways and accumulation of by-products that might be related to increased muscle fatigability (e.g., phosphate and H+) (38). Thus the slow increase in VO2p may be mechanistically associated with the marked decrement in exercise tolerance that characterizes this patient population (1, 3, 30, 33, 42, 44).

Derangements in the diffusive and convective transport of O2 to skeletal muscle mitochondria (44, 45) and intramyocyte metabolic machinery (3, 54) could explain the slowness of VO2 kinetics in COPD. During moderate-intensity (sub-"lactate threshold") exercise, the existing literature suggests that VO2 kinetics are limited by intramyocyte perturbations associated with COPD (34, 40, 45). However, a different scenario may emerge during heavy (supra-"lactate threshold") exercise. In this situation, higher ventilation and disturbances in mechanics of breathing (1, 2, 49, 50), hypoxemia (36, 45), pulmonary hemodynamics (14), autonomic balance (26), and peripheral vasodilation (see DISCUSSION for details) could slow the response of systemic (central) and peripheral (microvascular) O2 delivery to a point where the kinetics of VO2 might become limited by O2 availability (38).

In this context, it can be anticipated that, if COPD slows the dynamic increase in muscle microvascular O2 delivery (QFormula to a greater extent than the rate of O2 utilization, as indicated by the VO2 response following the onset of exercise, muscle microvascular O2 extraction would be accelerated (9, 16, 18). In this circumstance, the microvascular pressure of O2 might transiently reach levels sufficiently low to impair O2 transfer from capillary to mitochondria (38), predisposing the kinetics of VO2 to O2 delivery (convective and/or diffusive) limitation (39). In contrast, if the rate of increase in muscle microvascular O2 extraction is slowed in COPD patients at the onset of exercise, it would suggest that muscle O2 delivery is in excess of utilization throughout this transitional phase. These responses have been interpreted as VO2 kinetics being limited by activation of intracellular metabolic pathways (5, 10). This issue has been explored in healthy aging (9, 15, 16) and some chronic diseases [e.g., diabetes (6), peripheral arterial disease (5), and heart failure (10)]. However, the effects of COPD on the dynamics of (estimated) muscle microvascular O2 extraction and central cardiovascular responses following the onset of heavy exercise remain unclear.

The main hypothesis tested in the present study is that the sluggish kinetics of VO2p commonly found in COPD patients are accompanied by faster adjustment of skeletal muscle deoxygenation (or estimated O2 extraction) and slower "central" cardiovascular dynamics [cardiac output (QT)] following the onset of heavy-intensity exercise. Our secondary aims were to determine whether 1) an indicator of the dynamics of QFormula is associated with the kinetics of QT (approximately systemic O2 delivery); and 2) the ability of COPD patients to sustain exercise of heavy intensity is related to the kinetics of VO2p during the same exercise bout.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects

The study population comprised 10 men with clinical and functional diagnosis of COPD, according to the Global Initiative for Obstructive Lung Disease (GOLD) criteria (33), and 11 age- and sex-matched sedentary controls. The patients were a subgroup of individuals referred from the outpatient clinic of our institution to participate on a larger clinical trial. Subjects were considered for study inclusion if the gas exchange threshold (GET) had been previously identified in a progressive exercise test (see below). Inclusion criteria for COPD patients were as follows: forced expiratory volume in 1 s (FEV1)-to-forced vital capacity ratio <0.7 and postbronchodilator FEV1 < 60% predicted; resting arterial PO2 > 60 Torr at room air; no evidence of severe pulmonary hypertension (estimated systolic pulmonary arterial pressure <40 mmHg) and preserved left ventricular function (ejection fraction >60%) by echo-Doppler cardiography; and clinical stability for at least 3 mo before the study and no use of oral steroids in the preceding 6 mo. Subjects in the control group were free of chronic pulmonary, cardiovascular, immune, and metabolic disease. Before entering the study, all healthy controls were submitted to clinical evaluation, and they were screened by pulmonary function tests, analysis of blood biochemistry, electrocardiography, echocardiography, and a stress exercise testing. To minimize the confounding effects of regular physical activity on the pathophysiology of exercise intolerance in COPD, we studied only patients and healthy controls who were sedentary during the year preceding admission to the study.

All participants signed a written, informed consent form. The study protocol was approved by the Medical Ethics Committee of the Federal University of São Paulo/São Paulo Hospital, Brazil.

Study Protocol

Subjects performed a ramp-incremental exercise test (5–10 W/min in patients and 15–20 W/min in controls) to determine parameters of aerobic function during exercise (52). The tests were performed on an electronically braked cycle ergometer (Corival 400, Lode) at 60 rpm, and they were preceded by an unloaded baseline pedaling at 0 W for 2 min.

The difference between VO2p at the GET (VO2p GET) and VO2p at peak exercise (VO2p peak) ({Delta}VO2p peak-GET) was determined from the ramp test. On a separate day, subjects performed a constant work rate exercise test at the same pedaling rate to the Tlim (min) at an intensity chosen to elicit a VO2p that exceeded the VO2p GET by a value of ~40–50% of the {Delta}VO2p peak-GET (~75% peak work rate). Tlim was defined as the time point in which the patients signaled to stop exercising or could not maintain the required pedaling rate for 10 s, despite being encouraged by the investigators.

Measurements

Pulmonary function tests.   Spirometric tests were performed by using the CPF System (Medical Graphics-MGC, St. Paul, MN), with airflow being measured by a calibrated Pitot tube (PreVent Pneumotach). The subjects completed at least three acceptable maximal forced and slow expiratory maneuvers after the inhalation of 400 µg of salbutamol via metered-dose inhaler. Forced vital capacity (liters), FEV1 (liters), and inspiratory capacity (liters) were recorded. Carbon monoxide diffusing capacity was measured by the single-breath technique, and "static" lung volumes were obtained by body plethysmography. Arterial partial pressure for O2 and CO2 were determined in standard anaerobic conditions (Torr).

Exercise tests.   VO2p (ml/min), pulmonary carbon dioxide output (VCO2p; ml/min), minute ventilation (VE; l/min), and end-tidal partial pressures for O2 and CO2 (Torr) were measured breath by breath using a computer-based system (CardiO2 System, Medical Graphics). Gas exchange variables measured during the incremental test were averaged every 15 s, and VO2p peak was defined as the highest value achieved during the test. Heart rate (HR; beats/min) was determined using the R-R interval from a 12-lead electrocardiogram. Arterial oxyhemoglobin saturation was determined by pulse oximetry Formula %; POX 010-340, Mediaid, Torrance, CA] with its analog signal being directed to the system. Subjects were also asked to rate their "shortness of breath" at exercise cessation using the 0–10 Borg's category ratio scale. The VO2p GET was estimated by the gas-exchange method, inspecting visually the inflection point of VCO2p with regard to VO2p (modified V-slope) (8) and by the ventilatory method when VE-to-VO2p ratio and end-tidal partial pressure of O2 increased, while VE-to-VCO2p ratio and end-tidal partial pressure of CO2 remained stable. The reading was performed independently by two experienced observers without knowledge of other results or subject identities.

Skeletal muscle oxygenation.   Skeletal muscle oxygenation profiles of the left vastus lateralis were evaluated with a commercially available near-infrared spectroscopy (NIRS) system (Hamamatsu NIRO 200, Hamamatsu Photonics KK). The theory of NIRS has been described in detail elsewhere (17). Briefly, one fiber-optic bundle carried the near-infrared light produced by the laser diodes to the tissue of interest, while a second fiber-optic bundle returned the transmitted light from the tissue to a photon detector in the spectrometer. The intensity of incident and transmitted light were recorded continuously and, along with the relevant specific extinction coefficients, used to measure changes in the oxygenation status of hemoglobin + myoglobin (Hb + Mb). A set of optodes was placed on the belly of the vastus lateralis muscle midway between the lateral epicondyle and greater trochanter of the femur. The optodes were housed in an optically dense plastic holder, thus ensuring that the position of the optodes, relative to each other, was fixed and invariant. The optode assembly was secured on the skin surface with tape and then covered with an optically dense, black vinyl sheet, thus minimizing the intrusion of extraneous light and loss of near-infrared light.

The variables assessed by NIRS are the concentration of oxygenated, deoxygenated, and total Hb. Among the NIRS variables, several laboratories have adopted the deoxy-Hb/Mb signal (deoxy-Hb concentration [HHb]) as the preferred indicator of changes in muscle microvascular oxygenation during exercise (15, 16, 19, 24, 28). The [HHb] response to exercise is then considered a proxy of O2 extraction in the microcirculation, reflecting the balance between O2 delivery and utilization. The device used herein did not measure the reduced scattering of the tissue, preventing determination of absolute values of [HHb] (in µM). Therefore, the [HHb] values were recorded as a change ({Delta}) from baseline in units of micromoles per centimeter. The NIRS system was "zeroed" during the unloaded cycling portion of the tests.

Central hemodynamics.   QT (l/min) and stroke volume (SV; liters) were measured noninvasively throughout the constant work rate test using impedance cardiography (PhysioFlow PF-05, Manatec Biomedical). The PhysioFlow device and its methodology have been thoroughly described elsewhere (13). Before each exercise test, the system was autocalibrated, taking into consideration age, stature, body mass, and blood pressure values. Signal quality was verified by visualizing the ECG tracing and its first derivative and the impedance waveform with its first derivative. In preliminary experiments, the coefficient of variation for changes in QT and SV during exercise were 3.3 and 4.1%, respectively. In these preliminary trials, the changes in QT measured by impedance cardiography were consistent with those predicted from VO2p values using the submaximal QT-VO2p relationship described in COPD patients (data not shown) (29, 35).

Kinetics Analysis

The breath-by-breath VO2p, Formula NIRS oxygenation, and hemodynamic (QT, SV, and HR) data were interpolated second by second before kinetics analysis (SigmaPlot 10.0, Systat Software, San Jose, CA). The VO2p responses to exercise in the intensity domain used in our investigation are characterized by the presence of a slow component, which may also be observed in QT measurements. Based on our experience with pulmonary gas exchange responses to exercise in COPD patients, we anticipated that determination of the onset or emergence of the slow component in this population would require ensemble averaging of several transitions. Since we used data from a single transition (see Methodological Considerations), we opted to fit VO2p, QT, SV, and HR data from 30 s of baseline pedaling to 180 s after the onset of exercise. Using this approach and Eq. 2 (see below), we ensured that the same amount of data was included in the kinetic analysis of VO2p and hemodynamics for each subject (controls and patients), minimizing model-dependent effects on our results. For [HHb] kinetics, the analyses were conducted on data from 30-s baseline cycling to the first 60 s following the increase in work rate to minimize distortion of the curve-fitting seen when longer periods are analyzed (15, 16, 18, 19). Theoretical (18) and empirical studies (15, 16, 24) suggest the primary phase of the HHb response is complete within this time window. To reduce the potential influence of low Formula values on [HHb] in the patient group, the following correction ([HHb]corr) was applied:

Formula 1(1)
The model used for fitting the kinetic response of Formula 1O2p, Formula 1T, SV, HR, and [HHb] was

Formula 2(2)
where [Y] is the variable under analysis the subscripts b and p are baseline unloaded cycling and primary component, respectively; and A is amplitude, TD is time delay, and {tau} is time constant of the exponential response of interest. In the analysis of Formula 2T, HR, and SV, the TDp was dropped from the equation. For Formula 2O2p analysis, we deleted the data relative to the first 20 s after exercise onset, i.e., the cardio-dynamic phase (34). Therefore, {tau}pFormula 2O2p represents the time course of the primary component of the response, an estimate of the muscle Formula 2O2 kinetics (23, 53). The overall kinetics of [HHb] (approximate time to reach 63% of the response following the onset of exercise) were determined by the mean response time (MRT = {tau} + TD). In addition, the amplitude of the "slow component" of Formula 2O2p, Formula 2T, and [HHb] was estimated as the change from 3 min to the end of exercise (end-3') (39).

Statistical Analysis

The SPSS version 13.0 statistical software was used for data analysis (SPSS, Chicago, IL). Results were summarized as means ± SD, or median and ranges for symptom scores. To contrast between-subject resting and exercise responses, nonpaired t or Mann-Whitney tests were used, as appropriate. One-way ANOVA was used to contrast MRT values: a post hoc analysis was performed with Scheffé's test when appropriate. Pearson's product-moment correlation was used to assess the level of association between continuous variables. A z-test was used to determine if the amplitude of the slow component of Formula 2O2p, Formula 2T, and [HHb] was significantly different from zero. The level of statistical significance was set at P < 0.05 for all tests.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subject Characteristics and Exercise Tolerance

Subjects' resting characteristics are presented in Table 1. There were no between-group differences in age and body mass index. As expected from the inclusion criteria, patients had moderate-to-severe airflow obstruction with increased "static" lung volumes and moderate reductions in carbon monoxide diffusing capacity. Seven patients were classified as GOLD stage II, with the remaining patients being considered as GOLD stages III-IV (33).


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  		Table 1. Resting characteristics of normal controls and patients with COPD

 
Formula 2O2p peak, peak work rate, and Formula 2O2p GET were significantly reduced in patients compared with controls; in contrast, Formula 2E-to-maximal voluntary ventilation ratio and dyspnea scores were higher in patients (Table 2). Six patients had exercise-related oxyhemoglobin desaturation, i.e., Formula 2 decrease ≥4% (lowest values at peak exercise ranging from 86 to 89%). The tolerance to high-intensity, constant work rate exercise (Tlim) was significantly reduced in patients compared with controls (640 ± 95 s vs. 371 ± 100 s; P < 0.001). In similarity with the maximal exercise test, Formula 2E-to-maximal voluntary ventilation ratio and dyspnea were higher in patients, with six patients showing a significant decrease in SpFormula 2 (lowest values at exercise cessation ranging from 86 to 88%).


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  		Table 2. Physiological and perceptual responses at peak incremental and constant work rate exercise cessation in controls and patients with COPD

 
Pulmonary Gas Exchange and Cardiovascular Adjustments

Representative responses of Formula 2O2p and Formula 2T are shown in Figs. 1 and 2, respectively. The dynamics of Formula 2O2p were slower in patients than controls (Table 3, Fig. 3). In asubgroup of subjects in whom the tests were repeated (4 patients and 5 controls), the coefficient of variation for {tau}Formula 2O2p averaged 6.8 and 8.4%, respectively. There was a significant inverse relationship between {tau}Formula 2O2p and Tlim in COPD patients (r = –0.70, P < 0.01; Fig. 4) and when data from all subjects were pooled together (r = –0.56, P < 0.05). As expected, a Formula 2O2p "slow" component was found in all subjects (P < 0.05). There were no between-group differences in the magnitude of the Formula 2O2 slow component [{Delta}Formula 2O2p (end-3') = 202 ± 99 vs. 185 ± 89 ml/min for patients and controls, respectively], and the relationship between {Delta}Formula 2O2p (end-3') and Tlim was not significant in either group (P > 0.05).


Figure 1
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  		Fig. 1. Pulmonary O2 uptake (Formula 2O2p) kinetics (phases II and III) at the onset of heavy-intensity exercise in a representative age-matched control (A) and a patient with chronic obstructive pulmonary disease (COPD; B). Note the slower kinetics [higher time constant ({tau}) of the "primary" component] in the COPD patient compared with the control subject.

 

Figure 2
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  		Fig. 2. Cardiac output (Formula 2T) adjustment at the onset of heavy-intensity exercise in a representative age-matched control (A) and a patient with COPD (B). Note the slower "central" cardiovascular adaptation to exercise [higher mean response time (MRT) = {tau} + time delay (TD)] in the COPD patient compared with the control subject.

 

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  		Table 3. Kinetic parameters of Formula 2O2p, Formula 2T, and [HHb] for controls and patients with COPD

 

Figure 3
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  		Fig. 3. MRT (in s) (MRT = {tau} + TD) of Formula 2O2p, Formula 2T, and deoxy-hemoglobin concentration ([HHb]) measured by near-infrared spectroscopy at the onset of heavy-intensity exercise in age-matched controls (open bars) and patients with COPD (solid bars). Note that the dynamics of Formula 2O2p and Formula 2T were slower in patients with COPD; in contrast, they presented with faster [HHb] kinetics than the healthy controls. Values are means (SD). *P < 0.05 for between-group comparisons; {dagger}P < 0.05 for within-group comparisons of Formula 2O2p vs. Formula 2T and [HHb]; {ddagger}P < 0.05 for within-group comparisons of Formula 2T vs. [HHb].

 

Figure 4
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  		Fig. 4. Significant inverse relationship between time to intolerance in response to heavy-intensity exercise and the {tau} of the "primary" component of the on-transient Formula 2O2p kinetics in patients with COPD (bullet) but not in healthy controls ({circ}).

 
The increase in Formula 2T was slower in patients compared with controls and longer than those of Formula 2O2p in both groups (Table 3, Fig. 3). To gain further insights into the slowing of Formula 2T of COPD patients, we evaluated the kinetics of HR and SV (Fig. 5). The dynamics of both variables were significantly slower in patients compared with controls (HR: 61.4 ± 14.2 vs. 86.7 ± 13.9 s; SV: 42.3 ± 10.1 vs. 64.3 ± 11.0 s, P < 0.01). In similarity with Formula 2O2p, a slow component of Formula 2T was found in all subjects (P < 0.05). There were no significant differences in the magnitude of the Formula 2T slow component in patients and controls [{Delta}Formula 2T(end-3') = 1.74 ± 0.51 vs. 1.61 ± 0.70 l/min, respectively]. Moreover, {Delta}Formula 2T(end-3') and Tlim were not significantly related in either group (P > 0.05).


Figure 5
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  		Fig. 5. Heart rate (top) and stroke volume (bottom) dynamics at the onset of heavy-intensity exercise in a representative age-matched control (left) and a patient with COPD (right). Note that both responses were slower (higher MRT = {tau} + TD) in the COPD patient compared with the control subject. bpm, Beats/min.

 
Muscle Oxygenation Responses

The dynamics of Formula 2-corrected [HHb] values for a representative patient and a normal control are shown in Fig. 6. As previously described, the [HHb] response displayed a region in which the signal remained stable or decreased transiently (determined here by the time delay) (e.g., Fig. 6). All subjects showed a transient decrease in [HHb] early into the exercise, with similar duration in both groups (Table 3). After this phase, the [HHb] increased rapidly with response kinetics that were faster than the Formula 2O2p and Formula 2T responses in both groups (Table 3, Fig. 3). {tau}[HHb] (Table 3) and MRT-[HHb] (Fig. 3) were significantly faster in patients compared with normal controls.


Figure 6
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  		Fig. 6. Changes in [HHb] measured by near-infrared spectroscopy at the onset of heavy-intensity exercise in a representative age-matched control and a patient with COPD. Values are expressed relative to the change of variation found in each test. Note the faster kinetics (lower MRT = {tau} + TD) in the COPD patient, i.e., O2 extraction rate was faster in patients than controls.

 
A slow-component of [HHb] was observed in all subjects of the control group {Delta}[HHb](end-3') (P < 0.05). In contrast, only four patients displayed a slow component of the [HHb] response. The {Delta}[HHb](end-3') was significantly related to {Delta}Formula 2O2p (end-3') in the control group (r = 0.72, P < 0.01), but not in patients (P = 0.38).

Dynamics of Estimated Formula 2O2 mv

We also calculated an indirect index of the dynamics of Formula 2Formula 2Formula 2 ~ {tau}Formula 2O2p/MRT[HHb]) (see DISCUSSION for further elaboration). This ratio was significantly higher in patients compared with controls (4.9 ± 1.2 vs. 2.5 ± 0.6, respectively; P < 0.01), suggesting that Formula 2Formula 2 adapted at a slower rate in patients. Interestingly, Formula 2Formula 2 was closely related to MRT-Formula 2T (Fig. 7), suggesting that the dynamics of Formula 2Formula 2 followed the response characteristics of systemic ("central") O2 delivery.


Figure 7
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  		Fig. 7. Significant positive relationship between an index of the kinetics of microvascular O2 delivery ({tau} of the "primary" component of the on-transient Formula 2O2p/MRT of the changes in [HHb]) and the kinetics of systemic O2 delivery, as estimated by the dynamics of Formula 2T (MRT-Formula 2T), at the onset of heavy-intensity exercise in healthy controls and patients with COPD.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Several aspects make this study a novel investigation. Specifically, this is the first study to measure Formula 2O2p, Formula 2T, and tissue oxygenation kinetics simultaneously following the onset of heavy-intensity leg cycling exercise in patients with moderate-to-severe COPD. This is the initial step to establish if key determinants of the dynamic matching of central and peripheral (microvascular) O2 delivery-to-Formula 2O2 are impaired by COPD and set the stage for future interventional studies. We found that Formula 2O2p kinetics were slower in COPD patients than in controls and correlated with the tolerance to sustain heavy-intensity exercise. In addition, compared with the age-matched controls, COPD patients displayed slower kinetics of Formula 2T and faster dynamics of [HHb]. Interpretation of the latter as an estimate of muscle microvascular O2 extraction suggests that the dynamics of muscle Formula 2Formula 2 were slower in COPD patients. Accordingly, a qualitative index of Formula 2Formula 2 kinetics (ratio of {tau}Formula 2O2p to MRT[HHb]) was greater in COPD patients and was closely related to the overall kinetics of Formula 2T. These data, therefore, indicate that impaired central and peripheral cardiocirculatory adjustments following the onset of heavy-intensity exercise negatively impact the dynamic matching of O2 delivery and utilization in patients with COPD.

Formula 2O2p Kinetics and Tolerance to Heavy-intensity Exercise

Several groups have reported that Formula 2O2p kinetics are slowed by healthy aging (9, 11, 15, 16), and this could be due to impairments in the dynamics of O2 delivery (15, 16). In general, data from our control group describing the kinetics of Formula 2O2p and central cardiovascular responses to heavy exercise are in close agreement with previous studies (9, 11, 15, 16). In COPD patients, the kinetics of Formula 2O2p during moderate-intensity (sublactate threshold) exercise are ~45–65% slower than in healthy aged controls (34, 36, 40). We extended these findings to show that Formula 2O2p kinetics during heavy-intensity exercise were, on average, ~74% slower in COPD patients (Table 3). Moreover, phase II Formula 2O2p kinetics displayed an inverse relationship with tolerance to sustain heavy-intensity exercise (Fig. 4). These data are consistent with those from the study of Puente-Maestu and coworkers (40), who found a significant inverse correlation between increase in Tlim during moderate exercise and the decrease in {tau}Formula 2O2p induced by exercise training in patients with advanced COPD. Our data and those of Puente-Maestu et al. (40) collectively suggest that abnormalities on muscle energetics following the onset of exercise may contribute to the patient's ability to sustain dynamic exercise for prolonged periods of time. Thus resolution of factors that promote the slowing of Formula 2O2p response in COPD might prove to be useful in guiding therapeutic efforts to increase the tolerance to heavy-intensity exercise in this population.

Potential Mechanisms for a Slower Formula 2O2p Kinetics at Heavy-intensity Exercise in COPD

The factors generally considered as limiting the kinetics of Formula 2O2 are the adequacy of O2 delivery during the transient phase following the onset of exercise (27) and/or the activity of intracellular biochemical reactions that stimulate mitochondrial Formula 2O2, also called "metabolic inertia" (23). Several groups emphasize the role of O2 delivery limitation to Formula 2O2 kinetics in the elderly (9, 15, 16) and in chronic diseases (5, 6, 10). The argument for O2 delivery limitation of Formula 2O2 kinetics in old subjects is based on slower adaptation of HR (16) and age-related changes in arteriolar vasodilation (7). More recently, these arguments have been strengthened by faster kinetics of muscle deoxygenation at the onset of heavy-intensity exercise in old compared with young individuals (9, 15, 16), suggesting that, in the former group, the dynamics of muscle perfusion were slower in relation to the kinetics of muscle Formula 2O2 (18). Moreover, interventions that appear to increase muscle oxygenation promoted a speeding of Formula 2O2p kinetics in the elderly (15). If derangements in O2 delivery explain, at least partially, the slowing of Formula 2O2 kinetics with healthy aging, it is conceivable that any pathological condition that could further slow the dynamics of convective O2 delivery in old individuals (e.g., COPD) would have a negative impact on the kinetics of Formula 2O2p during heavy-intensity exercise. However, to elucidate the main determinant of slower Formula 2O2p kinetics, one must consider which of the potential limiting factors (intramyocyte metabolic machinery or O2 delivery) is affected to a greater extent, if any, by the disease.

Patients with COPD have decreased oxidative enzyme activity and mitochondrial volume density and an increase in the percentage of type II fibers (as reviewed in Ref. 3). This intrinsic skeletal muscle dysfunction could, at least partially, explain the slowing of Formula 2O2p kinetics in COPD patients. Consistent with this notion, Formula 2O2p kinetics of COPD patients performing moderate exercise were not affected by hyperoxic gas breathing (45), which was assumed to increase muscle O2 delivery. Moreover, exercise training speeded the kinetics of Formula 2O2p with no effect on HR dynamics, which is usually considered an indicator of Formula 2T (and O2 delivery) kinetics (12). Thus, in lieu of similar O2 delivery following the onset of heavy-intensity exercise, intrinsic skeletal muscle dysfunction would solely explain the slower Formula 2O2p kinetics observed in the present study (Figs. 1 and 3). Several variables measured and estimated in our study suggest this may not be the case during heavy-intensity exercise in patients with moderate-to-severe COPD.

Dynamics of Formula 2T During Dynamic Exercise in COPD

A slower adjustment of HR to moderate exercise in patients with COPD than in age-matched controls has been previously described (34, 40). Numerous factors (see below) can also impair the adjustment of SV following the onset of exercise in COPD, such that HR dynamics may underestimate the impact of the disease on the kinetics of Formula 2T. Our study is the first to show that Formula 2T (approximately O2 delivery) kinetics were ~44% slower in COPD patients compared with healthy peers. This was a consequence of slower SV and HR kinetics, where, on average, the SV response appeared to be affected to a greater extent than HR (~52 vs. ~40% higher time constant). This demonstrates that central cardiovascular responses that help maintain the adequacy of O2 delivery to contracting muscles are impaired in COPD. In the present study, these derangements are unlikely to be related to intrinsic cardiovascular disease, as the patients were clinically and functionally screened for significant inotropic dysfunction and severe pulmonary hypertension.

Potential explanations for slower on-transient Formula 2T (i.e., HR and SV) kinetics in COPD are as follows: 1) autonomic imbalance (26), 2) pulmonary vascular alterations (including pulmonary hypertension) (14), and/or 3) effects of mechanics of breathing on SV (1, 2, 49, 50). The increase in HR through sympathetic activation is slower than that accomplished by parasympathetic withdrawal (51). The shift toward greater sympathetic activity with COPD (26) would promote slowing of HR and thereby Formula 2T dynamics. Regarding the SV response, the deleterious cardio-circulatory consequences of increasing lung volumes in patients with COPD, especially during exercise, have been emphasized (1). More specifically, the development of high mean intrathoracic pressures as Formula 2E increases in the transitional phase could dynamically impair the rate of right ventricle filling and left ventricle emptying in these patients. Recently, Vogiatzis et al. (49) showed that normal subjects breathing with simulated expiratory flow limitation, similar to that found in advanced COPD, had significantly slower off-transient Formula 2O2p kinetics compared with control values, suggesting that alterations in the mechanics of breathing can reduce muscle O2 delivery enough to affect the kinetics of Formula 2O2p.

Another relevant mechanism for a reduced O2 delivery to the working muscles could be related to the pattern of respiratory muscle recruitment in patients with advanced COPD. Aliverti and Macklem (1) postulated that slowing the velocity of shortening of the abdominal expiratory muscles, by increasing expiratory pressures, had major adverse effects on the circulation impeding venous return and decreasing Formula 2T. Considering that some patients seem to recruit massively the abdominal muscles (2), it is conceivable that these adjustments could impair peripheral O2 delivery. Moreover, respiratory muscle work during heavy exercise can divert a fraction of the Formula 2T from leg muscles, contributing to exercise intolerance (25). Since the work of breathing is particularly increased in COPD patients (1), following the onset of exercise, a larger portion of Formula 2T may be directed to the diaphragm, predisposing to slower kinetics of peripheral muscle blood flow in COPD compared with controls. These findings support the notion that central cardiovascular responses to exercise and peripheral O2 delivery can be significantly impaired by abnormal pulmonary-mechanical responses in patients with moderate-to-severe COPD.

Kinetics of Muscle Oxygenation

Tissue oxygenation kinetics during exercise are probably the most relevant assessment to determine the effects of COPD on the dynamic supply of O2 in relation to Formula 2O2 of the muscle. The finding that [HHb] kinetics were faster than the phase II Formula 2O2p and Formula 2T dynamics in both COPD patients and controls is in close agreement with data from previous investigations in young (15, 19, 24) and old adults (15, 16). This appears to stem from differences in the profile of muscle Formula 2O2 (monoexponential) and muscle O2 delivery (a biphasic response) (18, 38, 39). The faster increase in [HHb] in patients than controls, an estimate of muscle microvascular O2 extraction kinetics (16, 18, 24), suggests that any cardiovascular dysfunction related to COPD was sufficient to impair the dynamic matching of muscle Formula 2Formula 2 and Formula 2O2 during the on-transient phase of heavy exercise (Figs. 3 and 6).

The slowing of Formula 2T reported here is a feasible explanation for the sluggish increase in Formula 2Formula 2 and speeding of [HHb] response. This theory is supported by the close association between the kinetics of Formula 2T and our qualitative index of Formula 2Formula 2 dynamics ({tau}Formula 2O2p/MRT[HHb]) (Fig. 7). However, a temporally reduced O2 availability could also be related to impaired muscle microvascular function in response to exercise in patients with COPD, independent of the central cardiovascular dysfunction (see above). Heightened sympathetic vasoconstriction at rest will slow the increase in muscle blood flow (48). Among the known muscle vasodilatory mediators, much emphasis has been given to nitric oxide (NO), especially in disease states. Blockade of NO synthase hastens the increase in O2 extraction in healthy rat muscles (20). Furthermore, it has been demonstrated that conditions associated with vascular endothelial dysfunction and reduced vascular NO availability, such as diabetes (6), aging (9, 46), and heart failure (10), are characterized by slowing of muscle O2 delivery and speeding of the increase in microvascular O2 extraction during contractions. Surprisingly, there is a lack of data on peripheral endothelial function in COPD patients. However, COPD patients are usually former smokers, have increased plasma levels of tumor necrosis factor-{alpha}, and reactive oxygen species (as reviewed in Ref. 21). All of these factors will contribute to lower NO availability, predisposing the patients to microvascular dysfunction (55). Therefore, although the sluggish increase in muscle Formula 2Formula 2 may be determined mainly by the central cardiovascular effects of COPD that slows the kinetics of Formula 2T, as suggested by Fig. 7, microvascular dysfunction should not be neglected in these patients.

In our older controls, muscle deoxygenation displayed a slow-component response similar, and directly related, to that observed in Formula 2O2p. This is in close agreement with studies in younger subjects (15, 16) and consistent with the notion that most of the slow-component observed in the Formula 2O2p response comes from the exercising legs (37). Another interesting finding in the present study was the dissociation between the presence and magnitude of the slow component of Formula 2O2p and [HHb] in patients with COPD. While the slow component of Formula 2O2p was found in all patients, only four of them showed a similar profile in the [HHb] response. These data might indicate that the determinants of the "extra" Formula 2O2p can vary in individual COPD patients. Future studies, for instance, should investigate whether the extra Formula 2O2p could be explained, at least partially, by increased ventilatory cost of exercise and/or higher work of breathing at a given ventilation.

Methodological Considerations

Due to the noninvasive nature of our study, several methodological aspects need further clarification. First and foremost, we assumed that the kinetics of deoxy-Hb/Mb measured at a single site reflects the time course of muscle microvascular O2 extraction following the onset of exercise. Although there is ongoing controversy regarding the primary determinant of the NIRS signal (31, 47), several studies have used [HHb] from a single site in the quadriceps muscle as a proxy of tissue "fractional" O2 extraction (6, 15, 16, 18, 19, 24) and provided extensive discussion on this topic. A key argument supporting the use of [HHb] as an approximation of O2 extraction dynamics is the generally similar characteristics of [HHb] response in humans (15, 16, 18, 19, 24) compared with O2 extraction dynamics measured in skeletal muscles (9, 10, 23) and calculated in computer simulations (18). In addition, the NIRS technology employed in our study does not allow measurement of tissue-scattering properties. This prevented calculation of absolute values of [HHb], but it is unlikely that it would have affected the kinetics profile of HHb compared with results yielded by measuring scattering and incorporating it in our calculations (31).

Other important issues are the use of data from a single transition to determine differences in Formula 2O2p, Formula 2T, and [HHb] kinetics, and assumption that the primary component of Formula 2O2p kinetics represents the dynamics of muscle Formula 2O2 in COPD patients. Although the use of one transition may limit resolution of small differences in kinetic responses, especially for Formula 2O2p and Formula 2T, the differences between COPD and controls were large enough to be detected statistically, as suggested by the study of Puente-Maestu et al. (41). The kinetics of the primary component of Formula 2O2p response is widely used as an indicator of the muscle Formula 2O2 response, as the time course of the primary component has been shown (24) or predicted (4) to closely reflect (within 10%) the muscle Formula 2O2 response. Grassi et al. (24), for instance, found a close similarity between the kinetics of leg Formula 2O2 and Formula 2O2p during cycling exercise, and Rossiter et al. (43) demonstrated that phosphocreatine breakdown (from 31P-NMR), which is considered to be closely linked to mitochondrial O2 consumption (32), followed a similar dynamic profile to that of the primary component of Formula 2O2p during moderate-intensity exercise. However, slowing of muscle blood flow may create a discrepancy between muscle and pulmonary Formula 2O2 kinetics, where the Formula 2O2p response will become faster than the muscle Formula 2O2 dynamics due to changes in the leg-to-lung transit delay (39). Therefore, based on the Formula 2T and [HHb] kinetics determined in our study, we may have underestimated the slowness of muscle Formula 2O2 kinetics in patients with COPD performing heavy-intensity exercise.

Conclusions

In general, our data show that patients with moderate-to-severe COPD have impaired central and peripheral cardiovascular responses to exercise that lead to slower kinetics of Formula 2T and faster muscle deoxygenation profile following the onset of heavy-intensity exercise. The latter effects are in opposite direction to that expected to be seen when the slowing of Formula 2O2p kinetics occur due only to intrinsic muscle metabolic disturbances, and there is a surplus of O2 delivery to contracting muscles. Our interpretation of the data, therefore, is that derangements in convective O2 delivery to skeletal muscles might contribute substantially to limit the kinetics of Formula 2O2p and exercise tolerance during heavy-intensity exercise in patients with moderate-to-severe COPD. However, without knowing the absolute values of microvascular PO2 following the onset of contractions, and if those were low enough to impair O2 transfer from blood to muscle, we cannot establish with certainty that the slothful kinetics of Formula 2O2p in COPD were a consequence of reduced O2 availability. This can be resolved by studies examining the effects of interventions that increase muscle O2 delivery, or speed its dynamics, on the kinetics of Formula 2O2 at high-intensity exercise in patients with COPD.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This study was supported by a Research Grant from Fundação de Amparo à Pesquisa do Estado de São Paulo, São Paulo, Brazil (no. 05/00722-0). G. R. Chiappa is a Postdoctoral Researcher at the Federal University of São Paulo, and J. A. Neder is an Established Investigator (level II) of the Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors thank all colleagues from the Pulmonary Function and Clinical Exercise Physiology Unit (Division of Respiratory Diseases, Department of Medicine, Federal University of Sao Paulo, Brazil) for friendly collaboration. We are also grateful to Laura D. Batista for technical support and Dircilene P. Moreira for competent secretarial assistance. More importantly, however, we are indebted to the patients for their effort and enthusiastic cooperation throughout the study.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. A. Neder, Pulmonary Function and Clinical Exercise Physiology Unit (SEFICE), Respiratory Division, Dept. of Medicine, Federal Univ. of São Paulo - Paulista School of Medicine (UNIFESP-EPM), Rua Professor Francisco de Castro 54, Vila Clementino, CEP: 04020-050, São Paulo, Brazil (e-mail: albneder{at}pneumo.epm.br)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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  1. Aliverti A, Macklem P. How and why exercise is impaired in COPD. Respiration 68: 229–239, 2001.[CrossRef][Web of Science][Medline]
  2. Aliverti A, Stevenson N, Dellaca RN, Lo Mauro A, Pedotti A, Calverley PM. Regional chest wall volumes during exercise in chronic obstructive pulmonary disease. Thorax 59: 210–216, 2004.[Abstract/Free Full Text]
  3. American Thoracic Society and European Respiratory Society. Skeletal muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 159: S1–S40, 1999.[Free Full Text]
  4. Barstow TJ, Mole PA. Simulation of pulmonary O2 uptake during exercise transients in humans. J Appl Physiol 63: 2253–2261, 1987.[Abstract/Free Full Text]
  5. Bauer TA, Brass EP, Barstow TJ, Hiatt WR. Skeletal muscle StO2 kinetics are slowed during low work rate calf exercise in peripheral arterial disease. Eur J Appl Physiol 100: 143–151, 2007.[CrossRef][Web of Science][Medline]
  6. Bauer TA, Reusch JE, Levi M, Regensteiner JG. Skeletal muscle deoxygenation after the onset of moderate exercise suggests slowed microvascular blood flow kinetics in type 2 diabetes. Diabetes Care 30: 2880–2885, 2007.[Abstract/Free Full Text]
  7. Bearden SE. Advancing age produces sex differences in vasomotor kinetics during and after skeletal muscle contraction. Am J Physiol Regul Integr Comp Physiol 293: R1274–R1279, 2007.[Abstract/Free Full Text]
  8. Beaver WL, Wasserman K, Whipp BJA. New method for detecting the anaerobic threshold by gas exchange. J Appl Physiol 60: 2020–2027, 1986.[Abstract/Free Full Text]
  9. Behnke BJ, Delp MD, Dougherty PJ, Musch TI, Poole DC. Effects of aging on microvascular oxygen pressures in rat skeletal muscle. Respir Physiol Neurobiol 146: 259–268, 2005.[CrossRef][Web of Science][Medline]
  10. Behnke BJ, Delp MD, Poole DC, Musch TI. Aging potentiates the effect of congestive heart failure on muscle microvascular oxygenation. J Appl Physiol 103: 1757–1763, 2007.[Abstract/Free Full Text]
  11. Bell C, Paterson DH, Kowalchuk JM, Cunningham DA. Oxygen uptake kinetics of older humans are slowed with age but are unaffected by hyperoxia. Exp Physiol 84: 747–759, 1999.[Abstract]
  12. Casaburi R, Porszasz J, Burns MR, Carithers ER, Chang RS, Cooper CB. Physiologic benefits of exercise training in rehabilitation of patients with severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 155: 1541–1551, 1997.[Abstract]
  13. Charloux A, Lonsdorfer-Wolf E, Richard R, Lampert E, Oswald- Mammosser M, Mettauer B, Geny B, Lonsdorfer J. A new impedance cardiograph device for the noninvasive evaluation of cardiac output at rest and during exercise: comparison with the "direct" Fick method. Eur J Appl Physiol 82: 313–320, 2000.[CrossRef][Web of Science][Medline]
  14. Christensen CC, Ryg MS, Edvardsen A, Skjønsberg OH. Relationship between exercise desaturation and pulmonary haemodynamics in COPD patients. Eur Respir J 24: 580–586, 2004.[Abstract/Free Full Text]
  15. DeLorey DS, Kowalchuk JM, Paterson DH. Effects of prior heavy-intensity exercise on pulmonary O2 uptake and muscle deoxygenation kinetics in young and older adult humans. J Appl Physiol 97: 998–1005, 2004.[Abstract/Free Full Text]
  16. DeLorey DS, Kowalchuk JM, Paterson DH. Adaptation of pulmonary O2 uptake kinetics and muscle deoxygenation at the onset of heavy-intensity exercise in young and older adults. J Appl Physiol 98: 1697–1704, 2005.[Abstract/Free Full Text]
  17. Ferrari M, Mottola L, Quaresima V. Principles, techniques, and limitations of near infrared spectroscopy. Can J Appl Physiol 29: 463–487, 2004.[Web of Science][Medline]
  18. Ferreira LF, Poole DC, Barstow TJ. Muscle blood flow-O2 uptake interaction and their relation to on-exercise dynamic of O2 exchange. Respir Physiol Neurobiol 147: 91–103, 2005.[CrossRef][Web of Science][Medline]
  19. Ferreira LF, Townsend DK, Lutjemeier BJ, Barstow TJ. Muscle capillary blood flow kinetics estimated from pulmonary O2 uptake and near-infrared spectroscopy. J Appl Physiol 98: 1820–1828, 2005.[Abstract/Free Full Text]
  20. Ferreira LF, Padilla DJ, Williams JB, Hageman KS, Musch TI, Poole DC. Effects of altered nitric oxide availability on rat muscle microvascular oxygenation during contractions. Acta Physiol (Oxf) 186: 223–232, 2006.[CrossRef][Medline]
  21. Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 59: 574–580, 2004.[Abstract/Free Full Text]
  22. Grassi B, Poole DC, Richardson RS, Knight DR, Erickson BK, Wagner PD. Muscle O2 uptake kinetics in humans: implications for metabolic control. J Appl Physiol 80: 988–998, 1996.[Abstract/Free Full Text]
  23. Grassi B, Gladden LB, Samaja M, Stary CM, Hogan MC. Faster adjustment of O2 delivery does not affect Formula 2O2 on-kinetics in isolated in situ canine muscle. J Appl Physiol 85: 1394–1403, 1998.[Abstract/Free Full Text]
  24. Grassi B, Pogliaghi S, Rampichini S, Quaresima V, Ferrari M, Marconi C, Cerretelli P. Muscle oxygenation and pulmonary gas exchange kinetics during cycling exercise on-transitions in humans. J Appl Physiol 95: 149–158, 2003.[Abstract/Free Full Text]
  25. Harms CA, Wetter TJ, McClaran SR, Pegelow DF, Nickele GA, Nelson WB, Hanson P, Dempsey JA. Effects of respiratory muscle work on cardiac output and its distribution during maximal exercise. J Appl Physiol 85: 609–618, 1998.[Abstract/Free Full Text]
  26. Heindl S, Lehnert M, Criee CP, Hasenfuss G, Andreas S. Marked sympathetic activation in patients with chronic respiratory failure. Am J Respir Crit Care Med 164: 597–601, 2001.[Abstract/Free Full Text]
  27. Hughson RL, Tschakovsky ME, Houston ME. Regulation of oxygen consumption at the onset of exercise. Exerc Sport Sci Rev 29: 129–133, 2001.[CrossRef][Medline]
  28. Koga S, Poole DC, Ferreira LF, Whipp BJ, Kondo N, Saitoh T, Ohmae E, Barstow TJ. Spatial heterogeneity of quadriceps muscle deoxygenation kinetics during cycle exercise. J Appl Physiol 103: 2049–2056, 2007.[Abstract/Free Full Text]
  29. Light RW, Mintz HM, Linden GS, Brown SE. Hemodynamics of patients with severe chronic obstructive pulmonary disease during progressive upright exercise. Am Rev Respir Dis 130: 391–395, 1984.[Web of Science][Medline]
  30. Maltais F, Jobin J, Sullivan MJ, Bernard S, Whittom F, Killian KJ, Desmeules M, Belanger M, Leblanc P. Metabolic and hemodynamic responses of lower limb during exercise in patients with COPD. J Appl Physiol 84: 1573–1580, 1998.[Abstract/Free Full Text]
  31. Mancini DM, Bolinger L, Li H, Kendrick K, Chance B, Wilson JR. Validation of near-infrared spectroscopy in humans. J Appl Physiol 77: 2740–2747, 1994.[Abstract/Free Full Text]
  32. Meyer RA. A linear model of muscle respiration explains monoexponential phosphocreatine changes. Am J Physiol Cell Physiol 254: C548–C553, 1988.[Abstract/Free Full Text]
  33. National Heart, Lung, and Blood Institute and World Health Organization. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (Online). http://www.goldcopd.com [2006].
  34. Nery LE, Wasserman K, Andrews JD, Huntsman DJ, Hansen JE, Whipp BJ. Ventilatory and gas exchange kinetics during exercise in chronic airways obstruction. J Appl Physiol 53: 1594–1602, 1982.[Abstract/Free Full Text]
  35. Oelberg DA, Kacmarek RM, Pappagianopoulos PP, Ginns LC, Systrom DM. Ventilatory and cardiovascular responses to inspired He-O2 during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 158: 1876–1882, 1998.[Abstract/Free Full Text]
  36. Palange P, Galassetti P, Mannix ET, Farber MO, Manfredi F, Serra P, Carlone S. Oxygen effect on O2 deficit and Formula 2O2 kinetics during exercise in obstructive pulmonary disease. J Appl Physiol 78: 2228–2234, 1995.[Abstract/Free Full Text]
  37. Poole DC, Schaffartzik W, Knight DR, Derion T, Kennedy B, Guy HJ, Prediletto R, Wagner PD. Contribution of exercising legs to the slow component of oxygen uptake kinetics in humans. J Appl Physiol 71: 1245–1260, 1991.[Abstract/Free Full Text]
  38. Poole DC, Ferreira LF, Behnke BJ, Barstow TJ, Jones AM. The final frontier: oxygen flux into muscle at exercise onset. Exerc Sport Sci Rev 35: 166–173, 2007.[CrossRef][Web of Science][Medline]
  39. Poole DC, Jones AM. Towards an understanding of the mechanistic bases of Formula 2O2 kinetics. In: Oxygen Uptake Kinetics in Sport, Exercise and Medicine (1st Ed.), edited by Jones AM and Poole DC. New York: Routledge, 2005, p. 294–328.
  40. Puente-Maestu L, Sánz ML, Sánz P, Ruíz de Oña JM, Rodríguez-Hermosa JL, Whipp BJ. Effects of two types of training on pulmonary and cardiac responses to moderate exercise in patients with COPD. Eur Respir J 15: 1026–1032, 2000.[Abstract]
  41. Puente-Maestu L, Sánz ML, Sánz P, Nuñez A, González F, Whipp BJ. Reproducibility of the parameters of the on-transient cardiopulmonary responses during moderate exercise in patients with chronic obstructive pulmonary disease. Eur J Appl Physiol 85: 434–441, 2001.[CrossRef][Web of Science][Medline]
  42. Richardson RS, Leek BT, Gavin TP, Haseler LJ, Mudaliar SR, Henry R, Mathieu-Costello O, Wagner PD. Reduced mechanical efficiency in chronic obstructive pulmonary disease but normal peak Formula 2O2 with small muscle mass exercise. Am J Respir Crit Care Med 169: 89–96, 2004.[Abstract/Free Full Text]
  43. Rossiter HB, Ward SA, Doyle VL, Howe FA, Griffiths JR, Whipp BJ. Inferences from pulmonary O2 uptake with respect to intramuscular [phosphocreatine] kinetics during moderate exercise in humans. J Physiol 518: 921–932, 1999.[Abstract/Free Full Text]
  44. Sala E, Roca J, Marrades RM, Alonso J, Gonzalez De Suso JM, Moreno A, Barbera JA, Nadal J, Rodriguez-Roisin R, Wagner PD. Effects of endurance training on skeletal muscle bioenergetics in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 159: 1726–1734, 1999.[Abstract/Free Full Text]
  45. Somfay A, Pórszász Lee SM, Casaburi R. Effect of hyperoxia on gas exchange and lactate kinetics following exercise onset in nonhypoxemic COPD patients. Chest 121: 393–400, 2002.[CrossRef][Web of Science][Medline]
  46. Taddei S, Virdis A, Ghiadoni L, Salvetti G, Bernini G, Magagna A, Salvetti A. Age-related reduction of NO availability and oxidative stress in humans. Hypertension 38: 274–279, 2001.[Abstract/Free Full Text]
  47. Tran TK, Sailasuta N, Kreutzer U, Hurd R, Chung Y, Mole P, Kuno S, Jue T. Comparative analysis of NMR and NIRS measurements of intracellular PO2 in human skeletal muscle. Am J Physiol Regul Integr Comp Physiol 276: R1682–R1690, 1999.[Abstract/Free Full Text]
  48. Tschakovsky ME, Hughson RL. Rapid blunting of sympathetic vasoconstriction in the human forearm at the onset of exercise. J Appl Physiol 94: 1785–1792, 2003.[Abstract/Free Full Text]
  49. Vogiatzis I, Zakynthinos S, Georgiadou O, Golemati S, Pedotti A, Macklem PT, Roussos C, Aliverti A. Oxygen kinetics and debt during recovery from expiratory flow-limited exercise in healthy humans. Eur J Appl Physiol 99: 265–274, 2007.[CrossRef][Web of Science][Medline]
  50. Vogiatzis I, Georgiadou O, Golemati S, Aliverti A, Kosmas E, Kastanakis E, Geladas N, Koutsoukou A, Nanas S, Zakynthinos S, Roussos C. Patterns of dynamic hyperinflation during exercise and recovery in patients with severe chronic obstructive pulmonary disease. Thorax 60: 723–729, 2005.[Abstract/Free Full Text]
  51. Warner HR, Cox A. A mathematical model of heart rate control by sympathetic and vagus efferent information. J Appl Physiol 17: 349–355, 1962.[Free Full Text]
  52. Whipp BJ, Davis JA, Torres F, Wasserman K. A test to determine parameters of aerobic function during exercise. J Appl Physiol 50: 217–221, 1981.[Abstract/Free Full Text]
  53. Whipp BJ, Rossiter HB, Ward SA, Avery D, Doyle VL, Howe FA, Griffiths JR. Simultaneous determination of muscle 31P and O2 uptake kinetics during whole body NMR spectroscopy. J Appl Physiol 86: 742–747, 1999.[Abstract/Free Full Text]
  54. Wuyam B, Payen JF, Levy P, Bensaidane H, Reutenauer H, Le Bas JF, Benabid AL. Metabolism and aerobic capacity of skeletal muscle in chronic respiratory failure related to chronic obstructive pulmonary disease. Eur Respir J 5: 157–162, 1992.[Abstract]
  55. Yoshizumi M, Perrella MA, Burnett JC, Lee ME. Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life. Circ Res 73: 205–209, 1993.[Abstract]



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