Transit delay and flow quantification in muscle with continuous arterial spin labeling perfusion-MRI.

Flow within the microvasculature of muscle is altered in many disease states such as the vasculopathies of diabetes mellitus and peripheral vascular disease (1), the muscular dystrophies (2), myositis (3), and neoplasms (4). Microvascular flow (or perfusion) is hence believed to be a measure more tightly coupled with physiology and pathophysiology as compared with blood oxygenation dependent (BOLD) contrast, a composite output of blood flow, blood volume, and oxygen consumption rate. Several techniques such as venous occlusion plethysmography (5), radionuclide plethysmography (6), thallium scintigraphy (7), positron emission tomography (PET) (8), and magnetic resonance imaging (MRI) (9–13) have been applied to measure skeletal muscle perfusion, yet there remains no gold standard. While plethysmography is probably the most widely used method, it only provides a global measurement and the technique may underestimate the true flow (14,15). Development of a reliable technique for perfusion measurement may assist in clinical decisions in dealing with critical limb ischemia (e.g., revascularization vs. amputation) and in assessing overall vascular health. With MRI, muscle perfusion imaging can be achieved by first-pass contrast-enhanced (CE) imaging (9–11). The intravenous bolus injection of gadolinium chelates gives high signal-to-noise ratio (SNR) in CE-MRI but absolute flow quantification may be hindered by the uncertainty of the arterial input function. Alternatively, arterial spin labeling (ASL), originally developed for brain imaging (16), has been applied to measure skeletal muscle perfusion (12,13). Utilizing magnetically-labeled water as a tracer, this noninvasive method may benefit physiologic and pathophysiologic studies by virtue of the ability to repeat the study over tight time frames without tracer contamination. Somewhat unique to muscle is the low baseline flow (<10 mL/100 g/minute) (17), and rarely is this baseline flow particularly disturbed even in disease states. In light of this, and analogous to cardiac muscle, disease or functional capacity of this organ may be best tested under stress, which necessitates the use of paradigms such as exercise or temporary ischemia to allow measurement of flow or flow reserve in hyperdynamic or hyperemic states. While exercise presents unique MRI specific challenges, to include the need for gating of image acquisition, exercise may preferentially stimulate certain muscle groups more than others. This nonuniform stimulation across muscle groups and between subjects may not be optimal for pathophysiologic studies. An ischemic paradigm, created through the application of a brief tourniquet, may therefore be a better alternative for studies of the flow variability in diseased muscle. Quantification of hyperemic flow following a short period of ischemia has been found to be a valuable indicator of local (18,19) and systemic (20) vascular disease. Frank et al (12) offered a detailed discussion of several potential difficulties in the application of ASL to the measurement of muscle flow, such as accurately accounting for the dynamic changes in relaxation times and water uptake during stress paradigms. They also acknowledged that studies have not rigorously examined the importance of the postlabeling delay (PLD) in the application of ASL to the muscle. In exercise and from ischemic paradigms, blood flow velocity may range form very low to very high levels, potentially resulting in a wide range of transit time as well as a dynamic range in labeling efficiency. These issues could be even more complicated in patients with peripheral vascular disease. In addition, the use of exercise paradigms (12,13) has made the investigation of ASL repeatability in skeletal muscle less straightforward. In view of this, an ischemic paradigm is adopted in the present study. We first test the hypothesis that continuous ASL (CASL) measurements in muscle depend upon transit delay. Secondly, we examine the repeatability of CASL measurements in muscle. Last, numerical simulations are conducted to estimate the impact of altered water uptake by muscle tissue upon flow quantification.