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Skeletal Muscle Perfusion in Peripheral Arterial Disease

A Novel End Point for Cardiovascular Imaging^_*

Departments of Medicine and Radiology and the Cardiovascular Imaging Center, University of Virginia, Charlottesville, Virginia.

Effective medical therapy for PAD in 2008 is limited but includes cilostazol and statins, both of which increase walking time (5,6). A major problem for testing therapeutic approaches for PAD that might improve tissue perfusion, such as exercise (7) or angiogenic gene therapy (8), is the lack of adequate end points for clinical trials, especially for serial assessment. For example, a recent unblinded study of bone marrow mononuclear stem cell therapy showed symptomatic improvement in patients without a measurable change in the ABI (9). Hence there is a need for novel imaging approaches to measure end-organ effects of PAD such as skeletal muscle perfusion and metabolism. This sets the stage for studies, such as that by Lindner et al. (10) in this issue of JACC: Cardiovascular Imaging, that aim to measure end-organ physiology in PAD.

In their study, Lindner et al. (10) studied 26 controls and 39 patients with mild but symptomatic PAD (one-half with diabetes mellitus [DM], mean ABI 0.74 to 0.79). They measured tissue perfusion with contrast-enhanced ultrasound of the gastrocnemius and soleus at rest and after 2 min of plantar-flexion exercise. This approach was previously validated in a canine model of skeletal muscle contraction or adenosine-mediated vasodilation (11). Treadmill exercise testing with measurement of oxygen consumption was also performed. They found that exercise duration decreased stepwise from controls to patients with PAD without DM to those with PAD with DM. Diabetes mellitus and contrast-enhanced ultrasound measures of flow and flow reserve were all univariate predictors of disease severity based on time to claudication. In patients with DM, flow and flow reserve were the only predictors of PAD severity. On multivariate analysis, flow and flow reserve added incremental benefit to clinical and other variables for predicting PAD severity. The technique was even able to identify reduced flow in patients with ABI >0.90. Thus, a new quantitative method for measuring exercise-induced flow and flow reserve in the end organ appears promising for detecting even mild PAD and in patients with preserved ABI, especially diabetics. This is an exciting development in a field with an urgent need for quantitative measures of tissue perfusion.

Some additional questions are raised by the study of Lindner et al. (10). There appears to be some overlap in the perfusion values for exercise blood flow and flow reserve, especially between controls and PAD without DM. A receiver operator characteristic curve would be helpful to identify just how well this measure discriminates patients from controls. Test-retest reproducibility is not presented. The controls are somewhat younger than the patients with PAD and DM. Older age and female gender may contribute to reduced skeletal muscle perfusion with exercise (12). By design, the patients studied had only mild disease, so feasibility and applicability in patients with more severe disease should be investigated in the future. Angiography did not correlate with perfusion in patients with DM, but weighting the angiogram for inflow versus outflow disease may improve the correlation. It is unclear whether there were differences in flow between muscle groups (gastrocnemius vs. soleus). Magnetic resonance imaging (MRI) studies from our group demonstrate visual and quantitative differences in contrast-induced signal intensity at peak exercise between muscle groups that depend upon how the subject performs plantar-flexion exercise (13) (Fig. 1).

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Contrast-Enhanced Inversion Recovery MR Image of the Calf at Peak Exercise This is a cross-sectional inversion recovery magnetic resonance (MR) image of the right calf of a normal subject obtained immediately after cessation of plantar-flexion exercise to exhaustion while in a 1.5-T MR scanner and after infusion of 0.1 mM/kg of a gadolinium chelate contrast agent. Note that in this subject, work was performed by the anterior tibialis and soleus muscles (arrows), which appear bright due to the rapid arrival of contrast. There is much less signal and thus less perfusion noted in the gastrocnemius (in the posterior portion of the calf).

Other MRI techniques that do not require the use of exogenous contrast agents are coming to the fore. Arterial spin labeling is a technique that measures perfusion quantitatively in a spatially and temporally resolved fashion (17). It involves tagging inflowing blood and observing its affect on signal intensity after it enters the imaging plane and was first developed for quantification of cerebral blood flow. Arterial spin labeling measurements have been validated against venous occlusion plethysmography in normal subjects using both cuff occlusion hyperemia and exercise with excellent correlation (18). Another such technique is blood oxygen level-dependent imaging, which measures changes in deoxyhemoglobin concentration on the basis of local magnetic susceptibility changes and spin dephasing. This approach has been compared against laser Doppler flowmetry and transcutaneous oxygen pressure in healthy volunteers with cuff occlusion/hyperemia and shown to have a moderate to good correlation for time course of change (19). The PAD patients demonstrated a reduced T2_^* signal increase (blood oxygen level-dependent effect) and delayed time to peak values compared to age matched controls after cuff occlusion/hyperemia (20).

We are thus reaching a time when advanced imaging approaches will allow quantification of skeletal muscle perfusion in patients with PAD. Contrast-enhanced ultrasound is one such technique and MR perfusion measures are another. The ABI is an excellent screening test that is relatively easy to perform. It has a long track record and excellent prognostic ability and will be difficult to improve upon. Screening is not likely to be the role of these innovative imaging approaches. Instead, they will likely be used as end points for clinical trials and methodologies for serial tracking of response to therapy. It matters little what imaging technique is used as long as it is accurate, reproducible, relatively easy to perform, and applicable in multicenter trials for serial measurement of the effect of novel therapies on skeletal muscle perfusion. Imaging again leads the way.

	Acknowledgments

 
The author appreciates the thoughtful input of Frederick Epstein, PhD, and Justin Anderson, MD.

	Footnotes

 
Supported by grant no. R01 HL075792 from the National Institutes of Health. Dr. Kramer also receives research support from Siemens Medical Solutions and research grants from Reliant Pharmaceuticals and Merck Schering-Plough.

^_* Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.

^_* Reprint requests and correspondence: Dr. Christopher M. Kramer, University of Virginia Health System, Departments of Medicine and Radiology, 1215 Lee Street, Box 800170, Charlottesville, Virginia 22908. (Email: ckramer{at}virginia.edu).

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