Progress in PAD: Where MR Steps In

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Source: occluded-SFA-cropped.jpg - occluded-SFA-cropped
Contrast-enhanced magnetic resonance angiogram (MRA) shows a segment of irregular severe narrowing in the distal right superficial femoral artery (green arrow) and complete occlusion of the left superficial femoral artery (green arrow). Multiple large and small collateral vessels (blue arrow) reconstitute the left superficial femoral artery at the level of the adductor canal.

In the assessment of peripheral artery disease (PAD), the initial test requires only a blood pressure cuff and CT angiography (CTA) to noninvasively image small vessels. This would seem to leave MRI to play a bit part, but as techniques improve, MR’s role in both clinical use and research grows more important.

PAD is characterized by blockages in blood vessels in the lower extremities caused by atherosclerosis. More than 200 million people worldwide suffered from the condition in 2010, a number that rose by 23.5 percent in the previous decade (The Lancet online Aug. 1, 2013). Low- and middle-income countries demonstrate the greatest PAD burden, but the condition still affects approximately 8 million patients in the U.S. While interventions can reintroduce blood flow to the legs, tens of thousands of people still must undergo amputations.

For most patients, pain in the lower extremities that could be symptomatic of PAD is first evaluated by ankle-brachial index testing. This simple test compares blood pressure in the feet to blood pressure in the arm, and in cases of PAD, ankle pressure.

Imaging becomes more important when patients are candidates for revascularization through stent or surgery, and digital subtraction angiography (DSA) and CTA lead as the imaging modalities for evaluating PAD. Cassidy Duran, MD, of Methodist DeBakey Heart & Vascular Center in the Methodist Hospital in Houston, says a prejudice developed against MR angiography (MRA) because of the limitation of the traditional 2D time-of-flight technique. Since it is dependent on flow to capture the image, time-of-flight MRA tends to overestimate stenosis in patients with reduced flow.

“When you’re imaging a patient who may have very poor velocities down in the runoff vessels to the feet, it all breaks down and you don’t know what to make of it,” says Duran.

Enter contrast-enhancement with gadolinium, which cardiologists at Duran’s institution use to perform 3D MRA in PAD patients. “Initially there was a lot of excitement about MR and gadolinium because it allowed you to get a contrast enhanced image in a patient whose kidneys made them not a good candidate for receiving iodinated contrast,” she says.

But gadolinium cannot circumvent all the roadblocks related to kidney function. While it does not cause contrast-induced nephropathy like iodinated contrast, exposure to gadolinium can result in a separate, but still painful and debilitating syndrome, nephrogenic systemic fibrosis (NSF). This prompted Duran and colleagues to look for another alternative for patients at-risk for NSF. What they found was Feraheme, an FDA-approved drug for the intravenous treatment of iron deficiency anemia in chronic kidney disease patients. Feraheme’s molecular structure also makes it useful as an imaging agent, though this is currently an off-label use. Duran and colleagues found Feraheme works as well as gadolinium for imaging peripheral vasculature, and she expects the FDA to approve it as an agent soon, speeding its further adoption.

Contrasting techniques

Aside from Feraheme, another contrast agent making waves is gadofosveset, a blood pool agent. Whereas standard contrast agents are extracellular and are removed by the kidneys, gadofosveset binds to the protein albumin and remains in the intravascular space, explains James Carr, MD, of the Department of Radiology at Northwestern University-Feinberg School of Medicine in Chicago.“Because it’s bound to albumin, the contrast agent circulates for a prolonged period of time, therefore you get the effect of the contrast agent for much longer than you would get with a standard agent,” says Carr.

The intravascular half-life of gadofosveset is up to 60 minutes and this extended period of time allows for images with increased spatial resolution. Limited spatial resolution was one of the drawbacks of MRA compared with CTA, notes Carr.

In an article reviewing the use of gadofosveset, Carr and colleagues wrote that MRA performed using gadofosveset with both a first-pass (which includes the abdomen, pelvis and thighs) and equilibrium phase five to 10 minutes after contrast injection yielded a sensitivity and specificity of 97 percent for detection of significant disease in the lower extremities (J Vasc Surg 2013;57:837-841).

Noncontrast MRA is currently flexing its muscle in trials and ECG-gated quiescent-interval single-shot (QISS) MRA is a promising new technique that has nearly equal efficacy to contrast enhanced MRA, says Carr. Current noncontrast sequences like QISS MRA are based on the steady state free procession pulse sequence, which was more widely used in the early 2000s as more powerful MR scanners became available. This new generation of noncontrast techniques is replacing noncontrast time-of-flight imaging, which Carr says is still being used in intracranial circulation, but progressively less so outside of that arena.

The cutting edge

In the research setting, MR is making its mark by helping researchers to better understand the extent of PAD in patients, whether treatments are effective and the mechanisms behind successful treatment.
For instance, an MRA-based study revealed that superficial femoral artery occlusions are associated with poorer functional performance, while a large number of collateral vessels was associated with improved functional performance (J Am Coll Cardiol Img 2013;6:687-694). It was the first study to use MRA to connect collateral data and walking performance, according to lead author Mary M. McDermott, MD, of Northwestern University’s Feinberg School of Medicine.

Worldwide Number of People with Peripheral Artery Disease

20002010Rate of Change
163,600202,06223 - 51%

Source: The Lancet online Aug. 1, 2013

“MRI is expected to be a good venue for measuring changes in perfusion and changes in blood vessel formation in response to the newer interventions that are under development,” says McDermott.
David Lopez, MD, of the Cardiovascular Division at the University of Virginia Health System in Charlottesville, echoes the optimism for MR in research, and says the focus of many trials is moving MR past assessing lumen patency in PAD patients. Spectroscopy, muscle perfusion and blood-oxygen dependent (BOLD) MR are among the leaders in this regard:

  • MR spectroscopy: This technique allows in vivo measurement of the concentration of phosphocreatine, which is the energy transport molecule for skeletal muscle, explains Lopez. By looking at the slope of recovery in the levels of phosphocreatine after exercise, healthy controls can be differentiated from those with PAD. This is important, says Lopez, because while an arterial brachial index also can differentiate patients from healthy participants, it may not always be concordant with the level of vessel obstruction. “You may have normal looking [arterial brachial index] but abnormal large vessels and vice versa,” says Lopez.
  • Muscle perfusion: MR methods for assessing muscle perfusion come in two flavors: contrast enhanced and noncontrast enhanced. The former is accomplished using first-pass MR with gadolinium and the latter is performed using arterial spin labeling MRI. Because arterial spin labeling does not require contrast, it allows for testing in patients with advanced renal disease.
    Stress is administered through exercise or a blood pressure cuff, and a perfusion index is computed that is basically a ratio of the slope of the signal intensity as it increases in the muscle over the signal intensity in the artery feeding those muscle groups, says Lopez. It’s a semi-quantitative method that provides a surrogate marker for blood flow. The next step, according to Lopez, is researching a reliable fully quantitative method to measure blood flow.
  • BOLD MRI: This method leverages the BOLD MRI technique that was developed for functional brain imaging, says Lopez. BOLD MRI is sensitive to deoxyhemoglobin, and using either exercise or cuff-occlusion, researchers can look at signal gain during the hyperemic effect that occurs post-stress. The curve of this signal gain offers another semi-quantitative measure of perfusion.

“These are all very exciting and would open up another dimension as far as assessing peripheral arterial disease beyond the large vessel lumen,” says Lopez. “Our ultimate goal, for the moment, is to try to learn how to use these techniques appropriately so we can then test different therapies for PAD where other methods may not be able to recognize the impact.”

Stem cells combat PAD progression in clinical trial

Researchers at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., are investigating a treatment that uses a peripheral artery disease (PAD) patient's stem cells to restore blood flow in the affected areas of the leg.

Led by Richard J. Powell, MD, chief of vascular surgery, the researchers separate stem cells from bone marrow in the patient's hip. After incubating for two weeks to allow for stem cell growth, the cells are re-injected intramuscularly in about 20 different spots on the patient's leg.

Second-stage trial results revealed that in the 550 patients included in the study—all of whom had PAD that was so advanced that amputation seemed to be the only treatment—those who received the stem cell therapy fared much better. While half of the patients who received a placebo saw their conditions worsen, required amputation or died, only one quarter of the stem cell therapy patients experienced such disease progression (Molecular Therapy 2012;20:1280–1286).

A Phase III trial has begun to measure outcomes one year following stem cell treatment.