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Original Research |
1 Department of Radiology, Universitaetsklinik Marienhospital, Hoelkeskampring
40, Herne, NRW 44625, Germany.
2 Institute of Neurology, University Hospital Bergmannsheil, Bochum,
Germany.
Received May 14, 2005;
accepted after revision September 27, 2005.
Address correspondence to C. A. Stueckle
(christoph.stueckle{at}rub.de).
Abstract
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SUBJECTS AND METHODS. Twenty-seven people were included in this study: 10 patients with PAOD and a pain-free walking distance of less than 200 m served as the patient group and 17 young healthy subjects served as a control group. Hydrogen-1 MR spectroscopy was performed on a 1.5-T scanner using an extremity coil and a point-resolved spectroscopy (PRESS) sequence (TR/TE, 1,500/30; 256 repetitions). For the patient group, a voxel was localized in the gastrocnemius muscle of the diseased leg. The data were processed using standard 1H MR spectroscopy tools. The identification of resonances detected on all MR spectra was made: intramyocellular lipids at 1.2 ppm, extramyocellular lipids at 1.6 ppm, lactate at 4.1 ppm, glucose with two main peaks at 3.4 and 3.8 ppm, choline at 3.2 ppm, and creatine at 3.0 and 3.9 ppm. To avoid operator bias, three spectral intensities were measured after correcting baseline and phase of MR spectra each time. The creatine signal was used as an internal reference; thus, all spectra were scaled relative to creatine. We compared the resultant intensity ratios between the two groups using the Mann-Whitney U test.
RESULTS. The lactate-creatine quotient was higher in the patient group, with a ratio of 1.6, than in the control group, with a ratio of 0.6. The glutamate-creatine ratio was higher in the patient group than in the control group (1.3 vs 0.8, respectively). All other ratios were higher in the control group. The best ratio for differentiating between healthy subjects and patients with PAOD was the glucose-lactate ratio. The patient group had a glucose-lactate quotient of 5.4, whereas the control group had a glucose-lactate quotient of 21.5 (p = 0.001).
CONCLUSION. Proton MR spectroscopy has the potential to allow identification of patients who have PAOD on the basis of altered muscle metabolism.
Keywords: H-1 MR spectroscopy • metabolism • MRI • MRS • MR spectroscopy • peripheral arterial occlusive disease • peripheral vascular disease
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The risk of limb amputation largely increases with the number and severity of cardiovascular risk factors (e.g., smoking, hypertension, diabetes). Continued smoking has been identified as the major risk factor in the progression of PAOD. Additional factors are the severity of disease at the time of the initial patient encounter and, according to several studies, the presence of diabetes mellitus [2].
The survival of patients with vascular disease is compromised compared with agematched control subjects. The outcome of vascular disease is significantly limited in cases of coronary manifestation because of the high risk of subsequent myocardial events. The predicted mortality rates for patients with claudication at 5, 10, and 15 years of follow-up are approximately 30%, 50%, and 70%, respectively [3].
The underlying mechanism of PAOD is reduced local blood flow causing compromised metabolism during exercise. Depletion of muscle glycogen content is considered a limiting factor of exercise performance [4, 5].
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The diagnosis of PAOD should be determined on the basis of skin temperature and color, pulse status, stenotic sounds, and Doppler occlusive pressures. If intermittent claudication is present, angiography of the pelvis and legs should be performed [8, 9].
In several studies, researchers have presented and validated the use of proton MR spectroscopy (hydrogen-1 [1H] MR spectroscopy) methods for the noninvasive quantification of different muscle metabolites [10-12]. We designed the present study to examine differences in muscle metabolites of patients with PAOD and healthy control subjects using 1H MR spectroscopy.
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The control group consisted of 10 healthy men and seven healthy women, with an average age of 29 years (range, 22-43 years), and included two smokers with histories of 3 and 5 pack-years, respectively, and one person with insulin-dependent diabetes mellitus. None of the control subjects was overweight, and six exercised or participated in a sport regularly. Subjects were told to not exercise or participate in a sport for 36 hours before each study.
Experimental procedures were performed in accordance with the guidelines of the human investigation committee of Ruhr-University Bochum School of Medicine. All patients and subjects gave informed consent after the purpose, nature, and potential risks of the study were explained to them.
All the patients in the patient group had an ankle-brachial index of less than 0.6, whereas the subjects in the control group had an ankle-brachial index of 1.6 or more. Four patients in the patient group had inflamed ulcers in the distal leg. In all of these patients, the diagnosis of PAOD was confirmed on angiography. Six patients showed a high-grade stenosis of the superficial femoral artery; two patients, an occlusion of the superficial femoral artery; and two patients, a high-grade stenosis of the external iliac artery.
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The homogeneity of the magnetic field over the volume of interest was optimized with the spatial-selective PRESS sequence by observing the proton MR signals of tissue water. Water suppression was performed using the presaturation method. A TR of 1,500 milliseconds and a TE of 30 milliseconds were used, which resulted in a total acquisition time of 9 minutes 7 seconds for 300 signals averaged. We used 512 sampled points per acquisition. After zero filling of 1,024 points in all the free-induction decay data, exponential line broadening (center, 0 milliseconds; half-time, 200 milliseconds) was applied before Fourier transformation. Phase correction was applied to all spectra. An interactive baseline correction was performed by calculating the eighth order polynomial of the manually defined baseline. Data processing was performed with the help of standard 1H MR spectroscopy tools (MR Spectroscopy Evaluation Tool, Siemens Medical Solutions).
Identification of resonances detected on all MR spectra was made: intramyocellular lipids at 1.2 ppm, extramyocellular lipids at 1.6 ppm, lactate at 4.1 ppm, glucose with two main peaks at 3.4 and 3.8 ppm, choline at 3.2 ppm, and creatine at 3.0 and 3.9 ppm [11]. To avoid operator bias, three spectral intensities were measured after correcting the baseline and phase of MR spectra each time. The resulting mean values were used for the analysis performed in this study (Figs. 1 and 2).
For the statistical analysis, we calculated total glucose as the sum of the
two glucose peaks. The total creatine signal (creatine at 3.0 ppm + creatine
at 3.9 ppm) was used as an internal reference because creatine is a stable
metabolite that does not correlate with physical activity, obesity, or illness
[13,
14]. Thus, all of the spectra
were scaled to creatine equivalently:
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The lactate-creatine quotient was higher in the patient group, with a ratio of 1.6, than in the control group, with a ratio of 0.6 (p = 0.2). The glucose-creatine ratio was higher in the control group at 2.6 than in the patient group at 2.3 (p = 0.2). The intramyocellular lipids-creatine quotient was higher in the control group, with a ratio of 246.2, compared with 167.8 in the patient group (p = 0.9). The extramyocellular lipids-creatine quotient showed lower values in the patient group, with a ratio of 96.4, compared with 150.2 in the control group (p = 0.6) (Fig. 3). The patient group showed a glucose-lactate quotient of 5.4, whereas the control group showed a glucose-lactate quotient of 21.5 (p = 0.001) (Figs. 4 and 5).
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Rexroth and Hild [20] reported a decrease in the concentration of intracellular phosphocreatine in patients with PAOD and an increase in the femoral arteriovenous differences in lactate, ammonia, and alanine. Similar results were presented in a different study in which blood samples were taken from the femoral artery and femoral vein in study subjects while resting and while exercising [21]. The patients with PAOD showed significant increases in lactate and ammonia compared with the healthy subjects. The PAOD group showed elevated lactate levels in blood analyses and anaerobic muscle metabolism on phosphorus MR spectroscopy [22]. These findings are consistent with our results: The lactate-creatine ratio was increased in the patient group compared with the control group (1.6 vs 0.6, respectively), whereas the glucose-creatine ratio was decreased (2.3 vs 2.6, respectively). The patient group presented significantly lower glucose-lactate ratios than the control group (5.4 vs 21.5, respectively).
Taking our results into account, the differences between both groups involve more than one metabolite, but because of the limited number of patients in our study, we could trace a decrease of only the glucose-lactate ratio in the patient group, which proved to be significant. An elevated lactate level is not specific for PAOD; it can also be found associated with other conditions such as shock, dermatomyositis, and coenzyme and enzyme deficiencies [23-25].
Previous studies have shown that most resonances in the spectra from human muscle are orientation-dependent, which means that they change when the angle between the muscle and the magnetic field in the magnet is varied. These effects are a consequence of the microscopically well-defined structures in skeletal muscle. These ordering effects separate the signals from intramyocellular lipids and extramyocellular lipids [10, 26]. Boesch et al. [10] and Schick et al. [27] suggested that these signals originate from two distinct compartments: an adipocyte pool and intramyocellular lipid pool. Magnetic susceptibility differences between compartments and the geometric arrangement of the tissue in the musculature might cause the observed frequency shift.
The two pool types are kinetically distinct in that extramyocellular lipid is thought to turn over slowly and serve as a long-term storage depot, whereas intramyocellular lipid is thought to be in dynamic and rapid equilibrium with substrate utilization and supply [28-30]. Extramyocellular lipid is defined as compact portions of adipose tissue in subcutaneous layers or along fasciae, whereas intramyocellular lipid is stored in droplets in the cytoplasm of muscle cells. The geometric arrangement of these lipid pools leads to different MR characteristics, which are used to differentiate them.
Voxel placement is of special importance because extramyocellular lipid increases drastically when the voxel touches adipose tissue [31]. Imaging-guided MR spectroscopy therefore considerably improves anatomic localization of the spectra. This improvement is important for measuring muscle metabolites because contamination by adipose tissue, bone, or vessels can hide small signals or amplify outer volume signals [11, 32]. To avoid these effects, we select our voxel setting using T2-weighted images in the transverse, coronal, and sagittal orientations with a slice thickness of 3 mm. Creatine is accepted as a stable metabolite in muscle metabolism and was therefore used as our internal reference standard [33, 34].
The low signal-to-noise ratio (SNR) and, to some degree, the low contrast-to-noise ratio are always a critical point in MR spectroscopy. Theoretic improvements yielded by use of higher field strengths did not fulfill expectations. Barker et al. [35] compared 1H spectroscopy SNR at 1.5 and 3 T and noted an improvement in SNR of only 28%—not the expected 100%. Herminghaus et al. [36] reported similar experiences when comparing 1.5 and 3 T for brain spectroscopy. Prolonged longitudinal relaxation at higher field strengths causes some signal intensity losses at 3 T in comparison with 1.5 T [35, 36]. Improving field homogeneity in the voxel may help achieve optimum diagnostic performance of MR spectroscopy at 1.5 T in patients with PAOD.
Krssak et al. [37] showed a decrease in intramyocellular lipid content after 2-3 hours of exercise in healthy subjects. Consistent with their findings, our results showed a significant decrease of intramyocellular lipids in the patient group. The intramyocellular lipids-creatine quotient was lower in the patient group, with a ratio of 167.8, than in the control group, with a ratio of 246.2. We believe that the decrease may be triggered by decreased blood flow. Reduced blood flow means a lack of energy supply even under resting conditions. This lack of energy supply may lead to increased fat oxidation and reduced intramyocellular lipid content [37].
The interindividual variation in peak formation may have many explanations, including measurement inaccuracies and differences in diet, physical fitness, muscle fiber type, and therapies [10, 32, 38, 39]. In the small group we examined, we did not find significant metabolite changes between persons who exercised or participated in a sport regularly and those who did not. To ensure that the control group consisted of healthy subjects not suffering from PAOD, we chose young people (22-43 years) because PAOD is not likely to occur in the young population [1, 2]. Because all members of the control group were in good physical condition with no clinical signs of PAOD, they could be included in the control group without undergoing any invasive diagnostic evaluation.
Until now, there have been no reports in the literature indicating significant age-dependent differences in 1H MR spectroscopy of muscle metabolism. Some reports show the short-term effects of exercise on muscle metabolism. We are convinced that a sport- and exercise-free interval of 36 hours is sufficient to exclude significant exercise-induced alterations in muscle metabolism. Further studies must examine whether there are significant age-induced changes in muscle metabolism in healthy subjects and whether physical exercise can induce long-term effects on muscle metabolism.
With respect to our control group, there was no evidence of significant differences when subjects who exercised or participated in a sport regularly were compared with those who did not.
Until now, 31P MR spectroscopy has been shown to be useful in screening patients for metabolic myopathies. Some authors argue that 31P MR spectroscopy should be proposed as the first and pivotal investigation for young patients suspected of having muscle disease. If abnormalities are not detected on MR spectroscopy, generally no further investigation is necessary.
If abnormal metabolic changes are observed, a defined catalog of tests including muscle biopsy must be performed to make the diagnosis as accurate as possible because, to date, MR spectroscopy is not specific enough to yield differential diagnoses of myopathies [40, 41].
To the best of our knowledge, this study is the first that investigates energy metabolism in the gastrocnemius muscle using 1H MR spectroscopy in patients with PAOD compared with healthy volunteers. Although the statistical power of the present study is too weak to determine the significance of the results, we could show that 1H MR spectroscopy can be used to make a diagnosis of PAOD based on changes in muscle metabolism. The quantitative correlation between muscle metabolism measured on 1H MR spectroscopy and the degree of PAOD should be evaluated in further studies.
In conclusion, 1H MR spectroscopy is a diagnostic technique that sensitively reflects alterations in muscle metabolism with the potential to confirm a diagnosis of PAOD. As the most powerful marker of PAOD, the glucose-lactate ratio is markedly reduced in patients with PAOD compared with healthy volunteers.
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