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Dynamics of noninvasively estimated microvascular O₂ extraction during ramp exercise

¹Departments of Anatomy and Physiology and Kinesiology, Kansas State University, Manhattan, Kansas; and ²Applied Physiology Laboratory, Kobe Design University, Kobe, Japan

Submitted 14 December 2006 ; accepted in final form 31 August 2007

	ABSTRACT

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Utilization of near-infrared spectroscopy (NIRS) in clinical exercise testing to detect microvascular abnormalities requires characterization of the responses in healthy individuals and theoretical foundation for data interpretation. We examined the profile of the deoxygenated hemoglobin signal from NIRS {deoxygenated hemoglobin + myoglobin [deoxy-(Hb+Mb)] O₂ extraction} during ramp exercise to test the hypothesis that the increase in estimated O₂ extraction would be close to hyperbolic, reflecting a linear relationship between muscle blood flow (_m) and muscle oxygen uptake (O_2m) with a positive _m intercept. Fifteen subjects (age 24 ± 5 yr) performed incremental ramp exercise to fatigue (15–35 W/min). The deoxy-(Hb+Mb) response, measured by NIRS, was fitted by a hyperbolic function [f(x) = ax/(b + x), where a is the asymptotic value and b is the x value that yields 50% of the total amplitude] and sigmoidal function {f(x) = f₀ + A/[1 + e^–(–c+dx)], where f₀ is baseline, A is total amplitude, and c is a constant dependent on d, the slope of the sigmoid}, and the goodness of fit was determined by F test. Only one subject demonstrated a hyperbolic increase in deoxy-(Hb+Mb) (a = 170%, b = 193 W), whereas 14 subjects displayed a sigmoidal increase in deoxy-(Hb+Mb) (f₀ = –7 ± 7%, A = 118 ± 16%, c = 3.25 ± 1.14, and d = 0.03 ± 0.01). Computer simulations revealed that sigmoidal increases in deoxy-(Hb+Mb) reflect a nonlinear relationship between microvascular _m and O_2m during incremental ramp exercise. The mechanistic implications of our findings are that, in most healthy subjects, _m increased at a faster rate than O_2m early in the exercise test and slowed progressively as maximal work rate was approached.

oxygen extraction; muscle; kinetics; oxygen delivery

Incremental ramp exercise has a dynamic nature and spans a wide range of exercise intensities that might elicit profiles of cardiovascular and metabolic responses to exercise different from steady-state responses. The kinetics of systemic cardiovascular and metabolic responses to changes in work rate lead to a nonlinear relationship between cardiac output and pulmonary O₂ uptake (O₂) during ramp exercise (3, 39). In contrast, during steady-state exercise, the relationship between muscle blood flow (_m) and O_2m is linear, with a positive intercept in the blood flow axis [systemic (15) and periphery (16, 34)]. Consequently, arteriovenous O₂ difference [(a-v)O₂] or fractional O₂ extraction displays a hyperbolic profile when plotted as a function of O₂ (or work rate) (15, 16, 28, 34). Accordingly, the profile of microvascular O₂ extraction during incremental ramp exercise will depend on the relative kinetics of _m and O_2m across exercise intensity domains (light, moderate, heavy, and maximal).

There is ongoing controversy as to whether the kinetics of _m are slower (22), similar to (2, 18, 21, 25), or faster (4, 19, 30) than O_2m kinetics during moderate or heavy constant work rate exercise. The characteristics of this relationship and implications for muscle O₂ exchange during ramp exercise are unknown. Moreover, there are no models for interpretation of these responses in healthy subjects and how they might be impacted by aging or chronic diseases that disrupt microvascular function. Elucidation of these responses, aided by interpretation provided by computer simulations, should help in the understanding of microvascular O₂ exchange during incremental exercise and facilitate implementation of NIRS to detect vascular dysfunction during routine clinical exercise testing of patient populations.

The purpose of the present study was to examine the dynamic increase in estimated muscle microvascular O₂ extraction during ramp exercise test. Specifically, from findings from studies that used a baseline of unloaded exercise (2, 18, 21, 25), we hypothesized that the increase in estimated O₂ extraction would be close to hyperbolic, reflecting a (quasi) linear relationship between _m and O_2m during incremental ramp exercise, suggesting similar kinetics of _m and O_2m across a wide range of exercise intensities (see Fig. 1). In addition, we performed computer simulations to interpret our observations and gain mechanistic insight into _m-to-O_2m matching during exercise. It should be noted that NIRS is an indirect measurement, and the assumptions made to conduct this study were 1) the deoxy-(Hb+Mb) reflects the temporal profile of fractional O₂ extraction (the ratio of O₂ delivery and uptake) in the microvascular compartment investigated (predominantly capillaries), 2) the contribution of Mb to the NIRS signal does not affect the temporal relationship between deoxy-(Hb+Mb) and fractional O₂ extraction, 3) the microvascular compartment contributing to the NIRS signal does not change with exercise and exercise intensities, and 4) changes from baseline to exercise reflect the response of muscle fractional O₂ extraction. Such assumptions are inherent to noninvasive techniques and do not undermine the validity of our study. By using a noninvasive technique and mechanistic approach to data interpretation, our study should be useful to clinicians and applied physiologists.

View larger version (18K): [in this window] [in a new window]   Fig. 1. Illustration of hypothesis. The increase in blood flow and O2 uptake (O2) during a ramp test of 10-min duration (top) was simulated as proposed by Whipp et al. (44). O2 extraction (bottom) was calculated as the ratio of O2 to blood flow (Fick principle). Left: responses for kinetics of blood flow are 3-fold faster than the kinetics of O2 (top left); resulting profile of O2 extraction is presented at bottom left. Right: similar kinetics of blood flow and O2 (top right) and the consequent quasi-hyperbolic increase in O2 extraction (bottom right). Dotted line (bottom right) indicates the response of O2 extraction from bottom left to facilitate visualization of difference between responses. Note that, with similar kinetics for blood flow and O2, the response of O2 extraction is kinetic independent and closely reflects the steady-state relationship. If blood flow kinetics are faster than the O2 response, O2 extraction more closely resembles an S-shaped response (bottom left). From previous studies (2, 18, 21, 25), we anticipate that O2 extraction estimated from near-infrared spectroscopy will resemble the response shown in bottom right. All responses are presented as relative increase from rest to peak exercise.

	METHODS

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The protocol consisted of an incremental cycling exercise test. All tests were performed on an electronically braked cycle ergometer. The incremental exercise test was preceded by 4 min of baseline cycling at the desired cadence (60 rpm) followed by a progressive (ramp) increase in work rate (15–35 W/min, depending on the subject's fitness level) until volitional fatigue or until pedal cadence could not be maintained despite strong verbal encouragement. Pulmonary gas exchange and skeletal muscle deoxygenation were measured during exercise tests. Peak oxygen uptake (O_2peak) was defined as the highest O₂ achieved during the test averaged over a 15-s interval. The lactate threshold was estimated from gas-exchange measurements using the V-slope method, ventilatory equivalents, and end-tidal gas tensions.

Pulmonary gas exchange (O₂ and CO₂ production) and minute expired ventilation were measured breath by breath (CardiO₂, Medical Graphics). The flowmeter and O₂-CO₂ analyzers were calibrated before each test according to the manufacturer's instructions.

Skeletal muscle deoxygenation was evaluated by NIRS (OxiplexTS; ISS, Champaign, IL). The NIRS probe consisted of eight light-emitting diodes and two wavelengths (690 and 830 nm) and one detector fiber bundle. Source-detector separations were 2.0, 2.5, 3.0, and 3.5 cm. NIRS variable calculations incorporated continuous measurements of reduced scattering coefficients. The data were stored at an output frequency of 25 Hz and averaged into 1-s bins during offline analysis. The probe was positioned longitudinally on the belly of the muscle vastus lateralis (15 cm above the patella), bonded to the skin (Skin-Bond, Smith & Nephew, Largo, FL), and secured with Velcro straps around the thigh after the skin was carefully shaved. No movement of the probe was observed in any exercise test.

The deoxy-(Hb+Mb) signal from NIRS is less sensitive than oxygenated Hb+Mb [oxy-(Hb+Mb)] to changes in blood volume under the probe and has been considered an estimate of fractional O₂ extraction (O_2m/_m) in the microcirculation (18, 20). Therefore, the deoxy-(Hb+Mb) data were used to investigate the dynamic increase in microvascular O₂ extraction during ramp exercise.

Data analyses and statistics.   The deoxy-(Hb+Mb) data were averaged by applying a 10-point moving average and sampling every 10th data point, yielding a mean of 10 s. Thereafter, the data were normalized to the total amplitude of response from baseline (average of 60 s) to peak exercise (average of 30 s before cessation of exercise) and fitted with two models based on previous studies (16, 39) and inspection of the deoxy-(Hb+Mb) profiles. Specifically, the deoxy-(Hb+Mb) response as a function of work rate (Watts) was fitted by 1) a hyperbolic relation

(1)

where a is the asymptotic value and b is the x value that yields 50% of the total amplitude, and 2) a sigmoidal relation

(2)

where f₀ is baseline, A is total amplitude, c is a constant dependent on d, the slope of the sigmoid, where c/d gives the x value corresponding to (f₀ + A)/2. The parameters for each equation were not constrained to the normalized data range of deoxy-(Hb+Mb) studied here (i.e., 0–100%). The best fitting procedure was determined based on a visual inspection and an F test.

	RESULTS

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The mean peak work rate achieved was 270 ± 80 W (O_2peak = 3.4 ± 0.95 l/min), and the gas-exchange threshold occurred at a O_2peak of 1.9 ± 0.57 l/min. The results of residual sum of squares for sigmoidal and hyperbolic model fitting and P values for F test for each subject are shown in Table 1. In only one subject (ramp = 20 W/min, peak work rate = 320 W), the increase in deoxy-(Hb+Mb) was close to hyperbolic (a = 170%, b = 193 W). In 14 subjects (ramp = 24 ± 6 W/min, peak work rate = 288 ± 76 W), the increase in deoxy-(Hb+Mb) was best described by a sigmoidal relation to work rate, where the mean values for parameters estimates were f₀ = –7 ± 7%, A = 118 ± 16%, c = 3.25 ± 1.14, and d = 0.03 ± 0.01 (e.g., Fig. 2). Two of these 14 subjects (peak work rate = 225 ± 106 W) did not show a plateau region of deoxy-(Hb+Mb).

View larger version (10K): [in this window] [in a new window]   Fig. 2. Increase in deoxygenated hemoglobin + myoglobin (HHb) during incremental ramp exercise. , Deoxygenated hemoglobin and myoglobin [deoxy-(Hb+Mb)] data averaged every 10 s. Solid line, best regression fit from sigmoidal function (see METHODS). The deoxy-(Hb+Mb) data are normalized to the amplitude of response from baseline to peak exercise.

	DISCUSSION

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Physiological interpretation of estimated O₂ extraction during ramp exercise.   Using data from a representative subject to estimate the _m-O_2m relationship, we observed an initial nonlinear association between _m and O_2m that became approximately linear as O_2peak was approached (Fig. 3). The linear portion of the _m-O_2m relationship corresponded to the plateauing region of estimated O₂ extraction. For subjects who did not display a plateau in estimated O₂ extraction, the analysis should be constrained to the quasi-linear portion of estimated O₂ extraction shown in Fig. 3, which suggests a nonlinear _M-O_2m relationship in the microcirculation. This finding agrees with previous studies that examined the relationship between cardiac output and pulmonary O₂ (39). Thus the mechanistic implications of our findings are that _m increased at a faster rate than O_2m early in the exercise test but slowed progressively as maximal work rate was approached such that, for most subjects, at heavy work rates the kinetics of O_2m and _m were similar, yielding a linear _m-O_2m relationship and plateau in estimated microvascular O₂ extraction [i.e., deoxy-(Hb+Mb)].

View larger version (8K): [in this window] [in a new window]   Fig. 3. Schematic representation of the relationship between arteriovenous O2 difference [a-vO2diff or (a-v)O2] and muscle O2 (top) and blood flow and muscle O2 (bottom). (a-v)O2 was estimated from the profile of deoxy-(Hb+Mb) response (data from subject shown in Fig. 2) using published values for (a-v)O2 (24, 25, 35). We assumed a baseline and peak exercise (a-v)O2 equal to 10 and 18 ml/dl, respectively. To convert the change in deoxy-(Hb+Mb) (in %) to (a-v)O2 (in ml/dl), we used the following formula: (a-v)O2 = 10 + [deoxy-(Hb+Mb)/100] x 8, where 10 corresponds to assumed (a-v)O2 during baseline cycling and 8 is the assumed change in (a-v)O2 from baseline to peak exercise. The increase in O2 was calculated from the ramp protocol (20 W/min) with the equation described by Whipp et al. (44) assuming O2/work rate ( = change) = 10 ml·min–1·W–1 and time constant for O2 = 30 s. Blood flow was calculated as O2/(a-v)O2 (Fick equation). The relationship was nonlinear up to a O2 of 1.5 l/min (in this example) and became close to linear thereafter.

View larger version (9K): [in this window] [in a new window]   Fig. 4. Computer simulations of sigmoidal (a-v)O2 during incremental ramp exercise. These responses are qualitatively similar to the profile shown in Fig. 2. Simulations of (a-v)O2 were performed with a sigmoidal function (see METHODS), whereas the increase in O2 as a function of work rate (ramp 20 W/min) was simulated assuming a time constant of 30 s for the increase in O2 (44). The physiological interpretation, where (a-v)O2 is the dependent variable, is that accentuated curvatures of the nonlinear portion of the relationship between blood flow and O2 (bottom), reflecting greater differences between blood flow and O2 dynamics, yield shallow slopes for the change in (a-v)O2 (from left to right) as a function of O2 (top). The plateau region of (a-v)O2 reflects a linear blood flow-O2 relationship.

Putative mechanisms for nonlinear _m-O_2m relationship.   The muscle pump (29, 37) and rapid vasodilation (9, 41) that arise from the mechanical effects of muscle contraction (42) appear to contribute to a rapid kinetics of _m during light exercise, which progressively becomes less important during heavy exercise (29). Consistent with this notion, _m kinetics were faster during the transition from rest to light exercise than during light to moderate exercise (31, 36).

A progressive slowing of central hemodynamics by changing the sympathetic-parasympathetic balance likely affects the blood flow in the periphery. The systemic cardiovascular responses to sympathetic stimulation, occurring primarily at work rates greater than 50% O_2peak (34), are substantially slower than those to parasympathetic withdrawal, which predominate early in exercise and at lower work rates (43). Moreover, -adrenergic vasoconstriction due to the elevated sympathetic activation will prevent rapid increases in arteriolar diameter (40), further contributing to the slowing of _m kinetics going from light to heavy exercise.

Alterations in fiber-type recruitment with increased work rates (e.g., Ref. 26) during incremental ramp exercise might also explain the relationship between _m and O_2m (6, 16, 32). Rat muscles of different fiber-type composition and oxidative capacity have demonstrated profiles of muscle deoxygenation dynamics that are consistent with faster _m than O_2m kinetics in slow-twitch highly oxidative muscles but an opposite effect (i.e., dynamics of _m slower than O_2m kinetics) evident in fast-twitch low oxidative muscles (6, 32). Therefore, the slowing of _m kinetics relative to the dynamics of O_2m response might be a consequence of recruitment of fast-twitch low oxidative muscle fibers at high work rates.

Implications for clinical exercise testing.   Chronic diseases (e.g., heart failure) and aging cause cardiovascular alterations that disrupts the dynamic balance between _m and O_2m. For chronic heart failure (7, 13), diabetes (33), and aging (5, 11), the time course of muscle microvascular deoxygenation during constant-load exercise indicates that the kinetics of _m are consistently slower than the increase in O_2m. If the responses described in Fig. 4, top, are considered characteristic of healthy young subjects, we anticipate that perturbations of microvascular function in the initial stages of vascular disease will cause a leftward shift in (a-v)O₂ to O_2m, whereas exercise training (27, 38) and pharmacological treatment to improve vascular function [e.g., inhibitors of angiotensin-converting enzyme (14)] will shift the relationship to the right. Therefore, our computer simulations (present study and Ref. 17) suggest that NIRS is a suitable tool to assess microvascular function and to detect early stages of dysfunction during routine clinical exercise testing.

Methodological considerations.   The advantages and limitations of NIRS in humans have been discussed in detail by several investigators (12, 18, 20). Briefly, Hb and Mb have similar absorption spectra within the range of wavelengths used for NIRS measurements. However, deoxy-(Hb+Mb) has been used as a proxy for microvascular O₂ extraction (12, 20) because it is little influenced by changes in blood volume (20). Moreover, the temporal profile of deoxy-(Hb+Mb) resembles the time course for limb (21) and isolated muscle (19) (a-v)O₂ after the onset of contractions. The influence of skin blood flow in NIRS measurements cannot be neglected (10). However, Davis et al. (10) did not report the effects of local heating and increases in skin blood flow on deoxy-(Hb+Mb). It appears that local heating and presumably changes in skin blood flow affect total blood volume and oxyhemoglobin and tissue O₂ saturation with minor effects on deoxy-(Hb+Mb) in resting individuals (Dr. Darren S. DeLorey, personal communication).

We used a one-channel NIRS system to estimate O₂ extraction and assumed that this single-site measurement provided a good representation of the exercising muscle. Preliminary studies with multiple NIRS channels assessing proximal and distal portions of the rectus femoris and vastus lateralis muscles revealed that the pattern of deoxy-(Hb+Mb) response was qualitatively similar across muscles and muscle regions (Ferreira and Koga, unpublished observations).

For the computer simulations (Fig. 4), we assumed constant kinetics of O_2m and functional gain (O₂/work rate) from rest to peak exercise. Some studies (e.g., Refs. 8, 31) have suggested that the kinetics of O_2m are slower and the functional gain (O₂/work rate) is greater for light-to-moderate than for rest-to-light exercise transitions. Thus our assumptions are oversimplifications of the underlying physiology; however, they were designed to facilitate qualitative assessment of the _m-O_2m relationship.

Conclusions.   The present study demonstrated that, in healthy, physically active subjects, the increase in deoxy-(Hb+Mb) measured by NIRS during incremental ramp exercise followed a sigmoidal profile that is consistent with a nonlinear dynamic relationship between microvascular O₂ delivery and uptake. The implication is that, for light exercise, the kinetics of _m are faster than O_2m kinetics, slowing progressively as peak work rate is approached.

	GRANTS

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L. F. Ferreira was supported by a fellowship of the Ministry of Education (Capes, Brazil) and a short-term Postdoctoral Fellowship from the Japan Society for the Promotion of Science. The authors' laboratories were supported by grants from the American Heart Association to T. J. Barstow (0151183Z) and the Ministry of Education of Japan to S. Koga.

	ACKNOWLEDGMENTS

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The authors thank Drs. David C. Poole and Tadashi Saitoh for insightful discussions and suggestions.

Present address of L. F. Ferreira: Department of Physiology, University of Kentucky, Chandler Medical Center. Lexington, KY 40536-0298.

	FOOTNOTES

 

Address for reprint requests and other correspondence: T. J. Barstow, Dept. of Kinesiology, 1A Natatorium, Kansas State Univ., Manhattan, KS 66506-0302 (e-mail: tbarsto{at}ksu.edu)

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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