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Published online before print September 18, 2006, 10.1148/radiol.2412050701
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(Radiology 2006;241:477-484.)
© RSNA, 2006

Musculoskeletal Imaging

Calf Muscles Imaged at BOLD MR: Correlation with TcPO2 and Flowmetry Measurements during Ischemia and Reactive Hyperemia—Initial Experience1

Hans Peter Ledermann, MD, Hanns-Georg Heidecker, MD, Anja-Carina Schulte, PhD, Christoph Thalhammer, MD, Markus Aschwanden, MD, Kurt A. Jaeger, MD, Klaus Scheffler, PhD and Deniz Bilecen, MD, PhD

1 From the Departments of Radiology (H.P.L., H.G.H., K.S., D.B.) and Angiology (C.T., M.A., K.A.J.), University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; and MR- und Biocenter, University of Basel, Basel, Switzerland (A.C.S.). From the 2004 RSNA Annual Meeting. Received April 28, 2005; revision requested June 22; revision received September 13; accepted October 13; final version accepted March 1, 2006. Supported by the Swiss National Science Foundation Project-Nr: SNF: 3200B0-100359 and 3100A0-100633. Address correspondence to D.B. (e-mail: dbilecen{at}uhbs.ch).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Purpose: To prospectively compare the blood oxygen level–dependent (BOLD) magnetic resonance (MR) signal intensity of calf muscle during ischemia and reactive hyperemia with laser Doppler flowmetry (LDF) and transcutaneous oxygen pressure (TcPO2) measurements, two parameters routinely used to evaluate peripheral arterial occlusive disease.

Materials and Methods: The study was institutional review board approved; all volunteers gave informed consent. Fifteen healthy volunteers (eight male, seven female; mean age, 33.0 years ± 6.1 [standard deviation]) underwent LDF, TcPO2 measurement, and BOLD MR imaging of the calf during ischemia and reactive hyperemia. The BOLD signal intensity of the gastrocnemius muscle was measured at 1.5-T single-shot multiecho gradient-echo echo-planar imaging. Time to half ischemia minimum (THIM), time to half hyperemia peak (THHP), and time to peak (TTP) after cuff deflation were measured with each method. Correlation coefficients (CCs) for associations of BOLD response with LDF and TcPO2 time courses were calculated. Student t testing of key BOLD MR, LDF, and TcPO2 measurement parameters was performed.

Results: During ischemia, normalized LDF and TcPO2 measurements decreased similarly to BOLD MR signal intensity (CCs: 0.86 and 0.96 for associations with LDF and TcPO2 measurements, respectively). Mean THIM values were 136.0, 82.5, and 121.3 seconds for BOLD MR, LDF (P < .01), and TcPO2 (P > .05) measurements, respectively. During early reactive hyperemia, LDF and TcPO2 measurements increased rapidly to peak values, similarly to BOLD MR signal intensity (CCs: 0.81 and 0.78, respectively). Mean THHP values were 26.0, 12.5, and 44.0 seconds for BOLD MR, LDF (P < .01), and TcPO2 (P < .01) measurements, respectively. Mean TTP values were 48.7, 47.5, and 98.0 seconds for BOLD MR, LDF (P > .05), and TcPO2 (P < .01) measurements, respectively.

Conclusion: BOLD MR imaging of calf muscles—depending on underlying key parameters—has moderate to good correlation with LDF and TcPO2 measurements during ischemia and reactive hyperemia.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Blood oxygenation level–dependent (BOLD) magnetic resonance (MR) imaging is an established functional MR imaging technique that was primarily developed for and is widely used in neuroradiology. The examination is based on local changes in oxyhemoglobin and deoxyhemoglobin (1,2). A relative increase in the deoxyhemoglobin concentration results in a signal intensity decrease on T2*-weighted images that is due to an increase in intravoxel spin dephasing (1).

On the other hand, to our knowledge, muscle BOLD MR imaging has been investigated by only a few research groups. The exact origin of the BOLD signal in calf muscle is not yet completely understood (3–5). It is generally assumed, however, that the muscle BOLD signal intensity depends primarily on capillary and postcapillary blood oxygenation (4,6,7). Since muscle BOLD signal intensity has been shown to also correlate with muscle perfusion (8–11), several authors suggested that muscle BOLD MR imaging may be used in the future to determine muscle perfusion in peripheral arterial occlusive disease (PAOD) (5,11,12).

Laser Doppler flowmetry (LDF) is a technique used to assess lower leg microcirculation (13). With this technique, the Doppler effect of red blood cells as they traverse the surface of microvessels is used (14). In practice, a sensor affixed to the skin samples the circulating speeds of all red blood cells located within a measuring area in the arterial and venous vessels of the superficial and middle parts of the skin (15). Laser Doppler measurements are considered to represent semiquantitative indexes of tissue perfusion (16,17).

Tissue oxygenation in the lower extremity is, in clinical practice, most commonly assessed by measuring the transcutaneous oxygen pressure (TcPO2) with modified Clark electrodes (18). The transcutaneously diffused oxygen available at the electrode is proportional to the partial pressure of oxygen in the local tissue of the skin under the sensor (13). TcPO2 measurements are routinely used as indirect measures of the degree of ischemia in the lower extremities (19,20).

To our knowledge, muscle BOLD MR imaging had not been compared with the techniques commonly used to assess lower leg perfusion and oxygenation. The future application of muscle BOLD imaging in clinical practice requires calibration with the currently used methods. Thus, the purpose of this study was to prospectively compare calf muscle BOLD MR signal intensity during ischemia and reactive hyperemia with LDF and TcPO2 measurements, two parameters routinely used to evaluate PAOD.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Study Subjects
Fifteen healthy volunteers (eight male, seven female) with a mean age of 33.0 years ± 6.1 (standard deviation) (range, 28–37 years) participated in this study. The volunteers were normotensive: Their mean systolic and diastolic blood pressures were 122 mm Hg ± 13 and 81 mm Hg ± 8, respectively. Their mean body mass index was in the normal range: 22.3 kg/m2 ± 2.2. None of the volunteers had symptoms of PAOD, all had a normal peripheral pulse status (ankle-brachial indexes > 1), and all were nonsmokers. All of the volunteers, who were recruited from the radiology department of University Hospital Basel, gave written informed consent. The study protocol was approved by the hospital's institutional review board.

Study Protocol
BOLD MR, LDF, and TcPO2 measurements were performed on the same leg within a maximum time span of 7 days in each volunteer, with a resting period of at least 24 hours between each measurement. The measurements were performed in a fixed order: We performed BOLD MR imaging first, LDF next, and TcPO2 measurements last. An ischemia-hyperemia paradigm, as described in previous articles (6,13,21), was used for all measurements: 60 seconds of preocclusive baseline blood level and blood flow, then 360 seconds of ischemia, and then 360 seconds of reactive hyperemia. A conventional sphygmomanometer cuff was wrapped around the thigh of the investigated leg and fixed with a Velcro strap to prevent loosening. To achieve ischemia, the cuff was rapidly inflated to an occlusion pressure of 50 mm Hg above the individual systolic blood pressure. Cuff compression was performed by one author (H.G.H.). Air cuff inflation and deflation of the sphygmomanometer were manually performed within a 5-second period. The MR measurements were performed in the MR suite, and the TcPO2 and LDF measurements were performed in an examination room in the angiology department. The MR, TcPO2, and laser Doppler measurements were performed on different days and on the same leg of each volunteer.

MR Imaging
All muscle BOLD MR measurements were performed by using a 1.5-T MR unit (Sonata; Siemens Medical Solutions, Erlangen, Germany) equipped with a high-performance gradient system with an amplitude of 40 mT/m and a slew rate of 200 T/m/sec. All volunteers were placed feet first within the bore of the magnet. The examination was performed with the subject in the supine position.

A single-shot multiecho gradient-echo echo-planar imaging sequence with fat suppression was used to obtain a consecutive series of 780 BOLD MR measurements (one measurement per second). Four 5-mm-thick axial sections (intersection gap, 2.5 mm) were positioned on a T1-weighted coronal scout image. BOLD MR imaging parameters were a 380 mm x 238 mm field of view; a 128 x 40 matrix interpolated to 128 x 80, which resulted in an in-plane pixel size of (2.97 x 2.97)mm2; a repetition time of 1000 msec; and a flip angle of 90° in the upper calf at maximal calf diameter. For each excitation, four images with increasing echo times of 16, 38, 61, and 83 msec were acquired. The echo-planar images were supplemented with anatomic reference images of the four corresponding sections (0.7 mm x 0.7 mm x 2.5 mm voxel size, 450/10 [repetition time msec/echo time msec]) obtained by using a T1-weighted spin-echo sequence.

LDF Measurements
LDF measurements were acquired by using a PeriScan PIM II Imager (Perimed AB, Stockholm, Sweden). On the basis of the laser Doppler principle (14), the device collects backscattered light and generates color-coded images of the spatial distribution of tissue perfusion. The laser beam is collimated with a spot size of approximately 1 mm. We used an image format with 10 horizontal and 10 vertical measurement sites, which resulted in a 10 x 10-mm sample area with 100 sampling points. To have a short sampling time, we chose medium temporal resolution. The laser beam was placed on the medial upper third of the calf at the level of maximal calf diameter corresponding to the level of MR measurements and avoiding venous structures. In repeat mode and with an imaging time of 9 seconds, which was interrupted by a 1-second pause, a complete examination was performed during the 13-minute examination time and resulted in the acquisition of 780 images. One author (C.T., 8 years of experience in LDF) performed both data acquisition and postprocessing by using PeriScan LDPIwin software (Perimed AB). The laser Doppler data were then exported to Excel software (Microsoft, Redmond, Wash) for further analysis.

TcPO2 Measurements
The TcPO2 measurements were performed by using a TcPO2-monitoring system (TCM400; Radiometer, Copenhagen, Denmark). This device includes an automatic calibration system and operates at electrode temperatures of 37°–45°C. The same author (C.T., 10 years of experience in TcPO2 measurement) placed the electrode on the medial upper third of the calf at the maximal calf diameter corresponding to the site of the BOLD MR and LDF measurements. The skin beneath the electrodes was shaved, if necessary, and cleansed with alcohol before the electrode rings were attached. All measurements were performed with electrode temperatures of 37°C. Before each measurement, the electrode was calibrated to the required temperature. TcPO2 values were constantly recorded, with a time resolution of one measurement per 10 seconds.

Data Analysis
We generated BOLD MR imaging T2* maps from the multiecho echo-planar data sets by using a parameter fit implemented on the image reconstruction system of the MR unit. The inflow (ie, perfusion) and T2* (ie, oxygenation) effects were separated by a pixel-by-pixel least-square fit of a monoexponential decay to the signal intensities of the four images at different echo times: S(I0,TE1-4), where I0 is the initial signal intensity, which is modulated by the proton density, T1, and inflow (22), and TE1-4 represents the increasing echo time of the four acquired images. T2* parameter maps were obtained according to the following equation:

Formula
where TEeff is the effective echo time.

Region-of-interest analysis of the T2* maps was performed by using Brain Voyager (Brain Innovation, Maastricht, the Netherlands) statistical parametric mapping software. After motion correction of the T2* maps, T2* time courses were extracted from regions of interest in the gastrocnemius muscle. All regions of interest were placed by the same author (D.B., 8 years of experience in musculoskeletal MR imaging). To minimize the contributions of static extravascular susceptibility gradients that occur around large draining vessels, regions of interest that excluded pixels of large arteries and veins were chosen. Large vessels were identified on the corresponding T1-weighted anatomic images. The mean size of the regions of interest was 91 pixels ± 19 (standard deviation), which corresponded to a mean size of 8.0 cm2 ± 1.7 for the regions of interest in muscle tissue. The regions of interest were placed medially in the gastrocnemius muscle at the maximal calf diameter comparable to the LDF and TcPO2 measurements.

One author (A.C.S.) performed further data analysis by using self-developed Matlab (Mathworks, Natick, Mass) routines. The mean T2* time course of the gastrocnemius BOLD signal was averaged over the four image sections acquired in each volunteer and normalized, with the mean T2* during the preocclusive baseline set to 100% (so that all T2* values were expressed as a percentage relative to the baseline value).

We extrapolated the normalized T2* time courses to the acquisition intervals of LDF and TcPO2 measurements by averaging every 10 T2* time points, which corresponded to an interval of 10 seconds. This process enabled a numerical comparison of BOLD MR imaging signal intensity with LDF and TcPO2 measurements where data acquisition was 10-fold slower. The LDF and TcPO2 time courses in the medial calf of each volunteer were normalized with respect to the corresponding mean LDF and TcPO2 values at preocclusive baseline.

The BOLD MR imaging, LDF, and TcPO2 measurement time courses for each volunteer were characterized by three parameters: During ischemia, the time to reach half the ischemia minimum was determined. During reactive hyperemia, the time to peak—that is, the time that elapsed between cuff deflation and maximum T2*—and the time to half hyperemia peak (THHP) were calculated. For each measurement method, the values of these key parameters were averaged across all volunteers. Furthermore, the mean time course of BOLD MR imaging was compared with the mean time courses of LDF and TcPO2.

Statistical Analyses
Statistical analysis was performed to compare the key parameters of BOLD MR imaging with those of LDF and TcPO2 measurements. We calculated the 95% confidence intervals for each key parameter value to estimate the magnitude of the differences in parameter values measured with the three modalities. A paired two-sided Student t test was used to assess significant differences in time to reach half ischemia minimum, THHP, and time to peak between BOLD MR imaging, LDF, and TcPO2, respectively. Statistical significance was established at P < .05. BOLD MR signal was compared with LDF and TcPO2.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Muscle BOLD MR Signal Intensity
No significant muscle contraction was observed during MR data acquisition in any volunteer. Figure 1 shows a representative echo-planar image (obtained at first echo time), the corresponding T2* map, and the anatomic T1-weighted image.


Figure 1
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  		Figure 1a: Representative (a) echo-planar image (EPI, obtained at first echo time; 1000/16), (b) corresponding T2* map (repetition time, 1000 msec; echo times, 16, 38, 61, and 83 msec), and (c) T1-weighted anatomic reference image of calf muscle (450/10). Findings on the reference image enable precise localization of the different muscle groups in the calf.

 

Figure 1
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  		Figure 1b: Representative (a) echo-planar image (EPI, obtained at first echo time; 1000/16), (b) corresponding T2* map (repetition time, 1000 msec; echo times, 16, 38, 61, and 83 msec), and (c) T1-weighted anatomic reference image of calf muscle (450/10). Findings on the reference image enable precise localization of the different muscle groups in the calf.

 

Figure 1
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  		Figure 1c: Representative (a) echo-planar image (EPI, obtained at first echo time; 1000/16), (b) corresponding T2* map (repetition time, 1000 msec; echo times, 16, 38, 61, and 83 msec), and (c) T1-weighted anatomic reference image of calf muscle (450/10). Findings on the reference image enable precise localization of the different muscle groups in the calf.

 
During ischemia, all volunteers had a BOLD signal intensity decrease in the gastrocnemius muscle, with a steep initial decrease and then subsequent steady but less pronounced decrease that persisted until the end of the ischemic phase (Fig 2). After deflation of the compression cuff, the mean gastrocnemius muscle BOLD signal intensity increased rapidly to hyperemic peak values, with a mean THHP of 26.0 seconds ± 6.3 (standard deviation) and a mean time to peak of 48.7 seconds ± 9.9 (Fig 3). The reactive signal intensity peak was followed by an initially steep decrease and a subsequent slower decrease toward a steady-state mean signal intensity of 93.9% ± 1.8 of the baseline value.


Figure 2
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  		Figure 2a: Graphs illustrate comparison of mean values (expressed as percentages of baseline values [set at 100%]) of normalized gastrocnemius BOLD signal intensity, LDF, and TcPO2 time courses during 6 minutes of progressive ischemia. (a) Correlation of BOLD signal intensity with LDF measurement. Note accelerated laser Doppler signal loss at onset of ischemia and steady-state value after approximately 90 seconds of ischemia. The correlation coefficient (cc) for the association between BOLD signal intensity and microcirculation at LDF was 0.86. (b) Correlation of BOLD signal intensity decrease with TcPO2 decrease. Note the steady state of TcPO2 values after 2 minutes of ischemia. The correlation coefficient for the association between BOLD signal intensity response and TcPO2 was 0.96. SL = signal of laser Doppler/TcPO2 during ischemia–reactive hyperemia, SL BASELINE = signal of laser Doppler/TcPO2 during baseline condition. {Delta}S = BOLD signal intensity change during ischemia–reactive hyperemia, {Delta}SBASELINE = BOLD signal intensity change during baseline condition.

 

Figure 2
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  		Figure 2b: Graphs illustrate comparison of mean values (expressed as percentages of baseline values [set at 100%]) of normalized gastrocnemius BOLD signal intensity, LDF, and TcPO2 time courses during 6 minutes of progressive ischemia. (a) Correlation of BOLD signal intensity with LDF measurement. Note accelerated laser Doppler signal loss at onset of ischemia and steady-state value after approximately 90 seconds of ischemia. The correlation coefficient (cc) for the association between BOLD signal intensity and microcirculation at LDF was 0.86. (b) Correlation of BOLD signal intensity decrease with TcPO2 decrease. Note the steady state of TcPO2 values after 2 minutes of ischemia. The correlation coefficient for the association between BOLD signal intensity response and TcPO2 was 0.96. SL = signal of laser Doppler/TcPO2 during ischemia–reactive hyperemia, SL BASELINE = signal of laser Doppler/TcPO2 during baseline condition. {Delta}S = BOLD signal intensity change during ischemia–reactive hyperemia, {Delta}SBASELINE = BOLD signal intensity change during baseline condition.

 

Figure 3
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  		Figure 3a: Graphs illustrate comparison of mean values (expressed as percentages of baseline values [set at 100%]) of normalized gastrocnemius BOLD signal intensity, LDF, and TcPO2 values during 6 minutes of reactive hyperemia. (a) Correlation of gastrocnemius BOLD signal intensity with LDF measurement reveals a steeper initial laser Doppler value increase and a simultaneous peak approximately 50 seconds after cuff deflation (correlation coefficient, 0.81). (b) Correlation of gastrocnemius BOLD signal intensity with TcPO2 measurement reveals a faster BOLD signal intensity increase and a delayed TcPO2 peak after approximately 90 seconds (correlation coefficient, 0.78). SL = signal of laser Doppler/TcPO2 during ischemia–reactive hyperemia, SL BASELINE = signal of laser Doppler/TcPO2 during baseline condition. {Delta}S = BOLD signal intensity change during ischemia–reactive hyperemia, {Delta}SBASELINE = BOLD signal intensity change during baseline condition.

 

Figure 3
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  		Figure 3b: Graphs illustrate comparison of mean values (expressed as percentages of baseline values [set at 100%]) of normalized gastrocnemius BOLD signal intensity, LDF, and TcPO2 values during 6 minutes of reactive hyperemia. (a) Correlation of gastrocnemius BOLD signal intensity with LDF measurement reveals a steeper initial laser Doppler value increase and a simultaneous peak approximately 50 seconds after cuff deflation (correlation coefficient, 0.81). (b) Correlation of gastrocnemius BOLD signal intensity with TcPO2 measurement reveals a faster BOLD signal intensity increase and a delayed TcPO2 peak after approximately 90 seconds (correlation coefficient, 0.78). SL = signal of laser Doppler/TcPO2 during ischemia–reactive hyperemia, SL BASELINE = signal of laser Doppler/TcPO2 during baseline condition. {Delta}S = BOLD signal intensity change during ischemia–reactive hyperemia, {Delta}SBASELINE = BOLD signal intensity change during baseline condition.

 
Correlation of Muscle BOLD MR Signal Intensity with LDF and TcPO2 Measurements
Ischemia.—Compared with the decrease in mean normalized BOLD signal intensity, the initial decrease in mean normalized LDF values during ischemia was significantly greater, with a shorter mean time to half ischemia minimum (82.5 seconds ± 24.9 versus 136.0 seconds ± 40.0, P < .01) (Table, Fig 2). In contrast to progressively decreasing BOLD signal intensity, LDF measurements reached a steady state after approximately 90 seconds of ischemia (Fig 2a). The correlation coefficient for the association between mean LDF and mean gastrocnemius BOLD signal intensity was 0.86 during ischemia.


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  		BOLD MR, LDF, and TcPO2 Measurements of Ischemia and Hyperemia Parameters

 
The initial TcPO2 decrease was associated with a mean time to half ischemia minimum of 121.3 seconds ± 29.2, which is similar to the value measured at BOLD MR imaging (P > .05). TcPO2 values, similar to LDF measurements, reached a steady state after approximately 140 seconds (Fig 2b). The correlation between mean TcPO2 and BOLD response was excellent (correlation coefficient, 0.96).

Reactive hyperemia.—After cuff deflation, the mean THHP was only 12.5 seconds ± 6.2 at LDF (Fig 3a), indicating a significantly faster signal response of the capillary skin circulation compared with the reactive BOLD signal intensity increase, which had a mean THHP of 26.0 seconds ± 6.3 (P < .01) (Table, Fig 3). The curve correlation coefficient for the association between muscle BOLD signal intensity and LDF measurement was 0.81. The mean THHP of TcPO2 (Fig 3b) was 44.0 seconds ± 20.6 and was clearly delayed compared with the mean THHP of the muscle BOLD signal intensity (P < .01). The peak BOLD signal intensity and LDF values occurred nearly simultaneously (P = .88): after mean times of 48.7 seconds ± 9.9 and 47.5 seconds ± 37.7, respectively. The mean time to TcPO2 peak, on the other hand, was significantly delayed (P < .01): 98.0 seconds ± 28.1. The correlation coefficient for the association between mean gastrocnemius muscle BOLD signal intensity and LDF measurements was 0.81. The correlation coefficient for the association between gastrocnemius muscle BOLD signal intensity and TcPO2 measurements was 0.78.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCE IN KNOWLEDGE
 References
 
The origin of the BOLD signal in muscle tissue is not definitely understood (5,23), but evidence from MR spectroscopy experiments (10), in vitro and animal experiments (23), and MR relaxivity experiments with hyperoxia (7) has shown that BOLD signal intensity measurements reflect primarily the oxygenation status of muscle tissue (5,7,9,10). Subsequently, BOLD signal intensity changes have also been shown to correlate with muscle perfusion at MR plethysmography and MR spectroscopy (8,24).

During ischemia, we observed a good correlation between dynamic muscle BOLD signal intensity alterations and both LDF and TcPO2 measurements: The steep initial decrease in BOLD signal intensity at the onset of ischemia was nearly identical to the TcPO2 decrease, with a high correlation. LDF values, on the other hand, decreased significantly faster and in a steeper slope during early ischemia than did muscle BOLD signal intensity. Therefore, the initial BOLD signal intensity decrease during ischemia does not seem to correlate primarily with the decrease in microcirculation, but it may primarily reflect progressive tissue deoxygenation due to decreasing capillary oxyhemoglobin (10).

By measuring the MR spectra of deoxymyoglobin and deoxyhemoglobin during postocclusive ischemia, Tran et al (25) found that the oxyhemoglobin signal intensity decreased rapidly within 1 minute after the onset of ischemia; this may explain the rapid initial decrease in muscle BOLD signal intensity seen in our study. This rapid and quickly completed desaturation of hemoglobin is explained by the high dissociation constant of this substance, which is more than 10 times higher than the dissociation constant of myoglobin. The slower steady decrease in BOLD signal intensity during the later part of the ischemic phase paralleled neither the LDF nor the TcPO2 measurements in our study. The LDF flow curve reached a steady state after approximately 90 seconds of ischemia (capillary flow arrest), whereas the TcPO2 measurements reached a plateau after approximately 140 seconds (26). The continuous BOLD signal intensity decrease during the latter part of ischemia could be attributable primarily to an increasing accumulation of paramagnetic deoxymyoglobin with a persistent decrease in T2* (6,27). A constant linear increase in deoxymyoglobin during the entire duration of ischemia has been observed at MR spectroscopy in a comparable experimental setup (6,25).

During reactive hyperemia, a steep surge in muscle BOLD signal intensity was observed in the gastrocnemius muscle, with peak values after approximately 50 seconds and a consecutive decrease in signal intensity to a steady state around baseline values. At the onset of reactive hyperemia, LDF skin flow measurements increased significantly faster than BOLD signal intensity, but hyperemia peak values were reached at nearly the same time with both methods. The initial BOLD signal intensity delay, compared with the LDF increase, may have been caused by counteracting oxygen consumption by ischemic muscle tissue. The TcPO2 increase, on the other hand, was significantly delayed compared with the BOLD signal intensity increase. Instantaneous increases in skin microcirculation and delays in TcPO2 responses identical to those seen in our healthy volunteers have been previously reported (13,28). The significantly delayed TcPO2 peak may be primarily attributable to the fact that oxygen has to freely diffuse to the skin surface to be measured by the Clark probe.

Investigators in previous studies of calf muscle BOLD MR imaging have used either isometric exercise (29) or an ischemia-hyperemia paradigm (6,9,10) to induce measurable alterations in BOLD signal intensity in calf muscle tissue. Hyperoxia also has been successfully used to measure muscle BOLD signal intensity alterations in healthy volunteers (7). We chose a postocclusive hyperemia paradigm instead of an isometric exercise paradigm to avoid motion artifacts and facilitate the experimental setup in the MR suite.

Investigators in several studies have reported limited use of LDF (17,26) and TcPO2 measurements (30) to gain information about lower limb perfusion and diagnose PAOD. The limited use of these parameters may be attributable in part to the fact that LDF and TcPO2 measurements are confined to the skin microvasculature and thus do not enable direct analysis of muscle tissue, which represents the end point organ of symptomatic PAOD. BOLD MR imaging, on the other hand, enables direct measurements in muscle tissue and therefore might be used in the future to gain information about muscle oxygenation and perfusion with PAOD (5,31). At present, the diagnostic value of muscle BOLD MR imaging cannot be extrapolated to patients with PAOD. Because of the good correlation of muscle BOLD MR signal intensity with LDF and TcPO2 measurements in healthy volunteers, it can be hypothesized that the abnormal muscle perfusion in PAOD might alter the muscle BOLD signal response as it does LDF and TcPO2 measurements. Other potentially interesting applications for muscle BOLD MR imaging may include monitoring the effect of therapeutic interventions (especially medical therapies) in patients with PAOD and analysis of microangiopathy in patients with diabetes (5).

A major limitation of our study was the concern regarding its potential clinical value. We measured the muscle BOLD signal intensity in healthy subjects whose mean age was markedly lower than that of patients with PAOD. The influence of aging on BOLD MR signal intensity in the human brain has been described as mild (32). However, the BOLD MR contrast of muscle is detected after a prolonged deprivation of blood supply, whereas the contrast of the brain is detected after physiologic cortical activation. As a consequence, BOLD signal intensity changes in muscle tissue are substantially greater than those in the brain, which hardly exceed 3%–4% at 1.5-T MR imaging. In this context, it seems difficult to estimate the effect of aging on the BOLD signal intensity observed in skeletal muscle during reactive hyperemia.

We conclude that muscle BOLD MR signal intensity during ischemia and reactive hyperemia correlates well with LDF (ie, perfusion) and TcPO2 (ie, oxygenation) measurements in healthy volunteers. Further research to test muscle BOLD MR imaging as a diagnostic functional tool for patients with PAOD seems to be warranted.


   ADVANCE IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
References
 


   FOOTNOTES
 

Abbreviations: BOLD = blood oxygen level dependent • LDF = laser Doppler flowmetry • PAOD = peripheral arterial occlusive disease • TcPO2 = transcutaneous oxygen pressure • THHP = time to half hyperemia peak

Authors stated no financial relationship to disclose.

See also Science to Practice in this issue.

Author contributions: Guarantors of integrity of entire study, H.P.L., H.G.H., D.B.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, H.P.L., H.G.H., K.A.J., D.B.; clinical studies, H.P.L., H.G.H., A.C.S., C.T., M.A., K.A.J., D.B.; statistical analysis, H.G.H., A.C.S., D.B.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 

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