Catherine Carrington

CT angiography is playing an increasingly important role in planning for cardiovascular interventions. Improvements in spatial and temporal resolution, scan times, and scan range-together with advanced image postprocessing-have made CTA a critical tool for identifying patients in need of invasive therapy and for mapping out the best percutaneous or surgical approach.

In some cases, CTA provides complementary information to that of conventional angiography. In others, it is sufficient on its own.

"Previously, with the four-slice scanner, we'd look at an image and say, 'That's an interesting finding, but I'd rather see the angiogram.' Now we often look at the CTA and make a decision," said Dr. Peter S. Fail, director of cardiac catheterization and interventional research at the Cardiovascular Institute of the South (CIS), in Lafayette, LA., between New Orleans and Texas.

CTA is particularly promising for carotid artery, aortoiliac, and coronary imaging, as well as for electrophysiologic procedures.

About a year ago, CIS took the leap and purchased a 16-slice CT scanner rather than continue to refer patients to a nearby hospital for imaging. Since then, CTA has proved to be a valuable tool in interventional planning.

In patients with suspected carotid stenosis, for example, CTA defines the anatomy of the aortic arch and common, external, and internal carotid arteries, all the way to the circle of Willis. CTA also accurately assesses the degree of stenosis, which gives it an edge over other commonly used technologies. Ultra sound, for example, may indicate that a carotid artery is 60% to 80% stenosed. That range is uncomfortably wide, Fail said.

"You might leave a 60% stenosis alone but treat an 80% stenosis," he said. "CTA can refine the assessment of stenosis and guide you in deciding whether to proceed to angiography and intervention."

CTA's ability to define lesion characteristics can also guide decision making. Plaque that appears to be fibrotic on CTA would be suitable for stenting, whereas one that appears to be filled with lipid and thrombus might be better treated surgically.

Sometimes CTA can reveal a lesion that is completely missed by conventional angiography, particularly at the takeoff of the left common carotid artery from the aortic arch. If the angiography catheter is advanced past the stenosis before the injection of contrast medium, a lesion that would be obvious on CTA may not show up on the invasive angiogram.

CTA is earning a place in neuroimaging of trauma patients as well, said Dr. W. Dennis Foley, a professor of radiology at the Medical College of Wisconsin.

"We're beginning to see that physicians are excluding injury to the vertebral and carotid arteries by doing multidetector CT angiography in patients who have suffered blunt trauma," he said.

CTA has staked out a leading role in evaluating patients with abdominal aortic aneurysm. Serial surveillance can indicate when intervention is indicated. CTA can then help determine whether a patient should undergo surgery or is a good candidate for stent-grafting, as well as the size and type of stent-graft to use.

In evaluating a patient for possible stent-grafting, the radiologist needs visual and quantitative information on such key anatomic features as vascular access, length and diameter of the stent-graft's proximal placement zone, dimensions and configuration of the aneurysm, length and diameter of the stent-graft's distal placement zone, and degree of atherothrombosis or calcification in the vessel walls.

Details are critical in planning for stent-grafting. For example, the endovascular approach may not be possible if atheroma has invaded more than 25% of the circumference of the proximal landing zone or if the angle between the superior neck and the long arm of the aneurysm is too great. A patient with a short proximal landing zone may need a stent-graft designed for transrenal fixation.

If the aneurysm involves the iliac bifurcation, extension into the external iliac artery will be necessary. Distal fixation in the external iliac artery occludes the hypogastric artery supplying the pelvis, however, so this approach can be done on only one side of the body. It is also important to determine whether any of the major aortic branches are occluded.

Earlier generation scanners have proved adept at providing this information and more, but 64-slice scanners represent a clear advance, Foley said.

"The 64 is an extremely rapid and versatile system. If you inject contrast appropriately and time the scan accurately, you'll get extremely good studies," he said. (See accompanying article.)

An aortoiliac study takes just 3.5 seconds with a 64-slice scanner, as opposed to 14 seconds with a 16-slice scanner. Foley selects a 0.625-mm slice width with both types of scanner. The resulting beam width, however, is 40 mm on the 64-slice scanner, as compared with 10 mm on the 16-slice scanner. Therefore, the scan is four times as fast for the same longitudinal resolution.

One advantage of such rapid scanning is increased safety when imaging patients who are extremely ill. Another is a reduction in pulsation artifact in certain vessels, such as the mesenteric arteries, which run along the plane of acquisition. With earlier generation scanners, pulsation would lend an irregular appearance to the walls of the mesenteric arteries. Because images are acquired so quickly with the 64-slice scanner, the arterial wall appears markedly smoother, Foley said. The faster scan speed also means that the scan range can be increased, perhaps to include the carotid arteries and the thoracoabdominal aorta in a single scan.

The 64-slice scanners permit new uses for gating as well. In a patient with chest pain of unknown etiology, a gated scan could acquire data from the coronary arteries, pulmonary arteries, and thoracic aorta, all in one rapid study.

"Even when we're fully gated at a pitch of 0.25, we can do the chest in 12 seconds," Foley said. "It still gives us a pretty rapid acquisition."

Such an approach would enable a high-quality coronary scan while improving image quality in the thoracic and pulmonary arteries pby eliminating the cardiac pulsation effect.

Whether 64-slice scanners will have the right combination of spatial and temporal resolution to finally conquer coronary artery imaging is unknown. The consensus is that although 16-slice scanners have made substantial strides in cardiac imaging, they have fallen short of that goal.

"Grading percent stenosis, which is a strength of coronary angiography, is not reliably possible with 16-slice scanners," said Dr. Paul Schoenhagen, a cardiovascular imaging specialist at the Cleveland Clinic. "Certainly, we're moving in that direction, but we're not at that point yet."

CT has so far been unable to pass another crucial test in interventional cardiology. Primarily because of the small size of coronary artery stents, CT is unable to reliably assess in-stent restenosis.

CTA is at an inherent disadvantage compared with invasive angiography on two fronts: Spatial resolution is lower, and calcification-common in high-grade coronary lesions-causes blooming artifacts that may result in overestimation of lesion size. Both of these problems are expected to recede in importance, though not disappear, with the 64-slice scanner.

But CTA does have an important potential role in preparing for coronary interventions, Schoenhagen said. It can be used to identify patients with significant coronary artery disease who would benefit from invasive coronary angiography and intervention. CTA can also reliably assess bypass graft patency, determining how diffusely diseased the graft is and identifying atherothrombotic material with the potential for distal embolization.

Because it is a tomographic imaging technique, CT can evaluate aspects of arterial disease that angiography cannot, much like intravascular ultrasound does. In the case of high-grade stenosis, for example, the adjacent reference vessel may look comparatively normal on angiography but in fact be significantly diseased. Such a condition would be apparent on CTA and might prompt the use of a longer stent or consideration of bypass surgery. Similarly, CTA evidence that a target lesion is highly calcified may lead the interventionalist to predilate the lesion before stenting or use an atherectomy catheter.

"These are situations where the CT scan may provide information that would help the interventionalist determine how to approach the lesion," Schoenhagen said. "If you compare four- to 16- to 64-detector scanners, the assessment of plaque in the vessel wall is certainly improved."

In fact, with the introduction of the 64-slice scanner, the time may have come to put CT plaque characterization to the test, validating it against IVUS, the gold standard.

"There have been multicenter trials evaluating the ability of CT to identify significant stenosis in comparison to conventional angiography, and this will be done again for the newer scanners. But the same is necessary for plaque assessment in comparison to IVUS. I think it's certainly the right time," he said.

If the 64-slice scanner proves able to meet the challenges of coronary imaging, its role in guiding interventions could become even broader, as the definition of intervention itself expands. A patient who undergoes stent placement almost certainly has atherosclerotic plaque elsewhere in the coronary vasculature, some of it vulnerable and inflamed. CT could help in making that assessment and in prompting the physician to initiate lipid-lowering therapy with statins and newer drugs, Schoenhagen said.

Fail foresees CTA being used to guide medical intervention even earlier in the disease process for evaluation of people who have a worrisome risk profile but are symptom-free.

"When CTA gets to the point where you can define a 30% or 40% lesion relatively comfortably, then we'll use it as part of the risk profile, and that is when we're going to see an impact on myocardial infarctions," he said. "The CT scanner could become the next stress test."

Fail feels confident that with the right cardiac imaging software, the 64-slice scanner will come very close to achieving comprehensive coronary angiography. Certainly, the next generation of scanners will.

"I've seen coronary images acquired on 64- and 128-slice scanners. On the 64-slice scanner, the coronary anatomy is absolutely phenomenal," he said. "With the 128, the images are unbelievable. They're as clear as an angiogram I would do in a lab."

At Long Beach Memorial Hospital in southern California, Dr. Serge Tobias uses CTA for a different type of cardiac application: to guide certain electrophysiologic procedures in which detailed depiction of the cardiac chambers is helpful.

One example is the placement of biventricular pacemakers. These devices synchronize contraction in the two sides of the heart in patients with electrical conduction delays. Unlike standard pacemakers, they require insertion of a lead in a branch of the coronary sinus to pace the left ventricle. Tobias, who directs electrophysiology at Long Beach Memorial, has performed hundreds of left-ventricular lead placements without the aid of CT. Still, he wants to know more about the anatomy in certain patients before considering the procedure.

"Just like CT can depict coronary artery anatomy of large proximal vessels, it can generate the coronary venous anatomy. It allows us to know ahead of time whether there are branches of the coronary sinus that we can readily access," Tobias said. "It's very impressive."

CTA is also being used as part of a new program at Long Beach Memorial: radio-frequency catheter ablation for atrial fibrillation. Research has shown that in many cases, the abnormal electrical impulses that cause atrial fibrillation arise in tissue adjacent to the pulmonary veins that drain into the left atrium. Before ablating that tissue, Tobias turns to CTA for 3D images of the left atrium and the pulmonary veins.

Advance knowledge about pulmonary venous anatomy is important because RF energy must be delivered in the left atrium near the ostia of the pulmonary veins but not in the veins themselves. Anatomy varies from one patient to another, however. Some patients have four separate orifices, as expected, and others do not. Pulmonary venous branches take various configurations as well.

"A CT image can give you a preoperative idea of what those veins look like, so you're not surprised by a very large orifice or a common orifice that immediately splits into two separate veins. You know what to expect," Tobias said.

It is also important to take baseline measurements of the diameter of the pulmonary vein. Mistakenly ablating inside the pulmonary vein can result in scarring and stenosis. Comparison of a baseline and follow-up CT can diagnose the problem if the patient develops symptoms such as shortness of breath or cough weeks or months after the procedure.

Electrophysiologists have traditionally used a cruder, more time-consuming method to map the left atrium and pulmonary veins, generating a 3D image point by point as an electrical mapping catheter makes contact with the cardiac vessels and chamber walls. Using this method, the boundary between the pulmonary vein and left atrium is defined by catheter drop-off and changes in the amplitude of the electrical signal.

"To have a very accurate representation, we'd have to collect hundreds of points from every possible recess in the atrial chamber," Tobias said.

One day, electrophysiologists may have the best of both worlds. Researchers are working to integrate the CTA image of the left atrium with data gathered by electrophysiological recording equipment. Ultimately, it may be possible to manipulate an electrophysiology catheter in the heart, using the CT image as the correct anatomic guide.

"Instead of traveling through a generated 3D image, which is not necessarily accurate, we'd be navigating through a true 3D CT image," Tobias said. "This work is in very, very early stages, but the time will come."

Speed means lower dose and quicker injections but longer waits

To get the most out of advanced CT scanners, modification of the contrast delivery protocol is a must. Consider aortoiliac CTA. At the Medical College of Wisconsin, Dr. W. Dennis Foley has found that faster scanners enable a reduction in the volume of contrast material. With a 16-slice scanner, Foley typically uses about 80 mL of 350 to 370 mgI/mL contrast material. With the 64-slice scanner, he has been able to reduce contrast volume to 50 mL.

Contrast administration has changed in other key ways as well. Regardless of the type of scanner, Foley injects a minibolus of contrast material to gauge contrast transit time in each patient. With the 16-slice scanner, he measures time to peak aortic enhancement. After injection of the contrast bolus, he initiates scan acquisition at the time to aortic peak as determined by the preliminary minibolus. With the 64-slice scanner, he adds an additional four seconds to the waiting time. In addition, Foley increases the contrast injection rate from 5 mL/sec with the 16-slice scanner to 6 mL/sec with the 64-slice scanner.

"We're injecting faster and waiting longer after the contrast has arrived to begin scanning," Foley said. -CC

Articles

CT angiography steps up role in interventional planning

 In acute myocardial infarction (AMI), the culprit thrombus sometimes dissolves before the patient arrives in the emergency room, leaving the cardiologist with few clues as to the source of the chest pain. A new iron oxide-labeled "ischemic memory agent" may make it possible to use cardiac MR to identify myocardium that has been temporarily deprived of blood and oxygen. These findings were reported at the 2006 Society for Cardiovascular Magnetic Resonance meeting by Brent A. French, Ph.D., an associate professor of biomedical engineering at the University of Virginia, Charlottesville.

 French used a rat monoclonal antibody targeted against mouse platelet-endothelial cell adhesion molecule-1. PE-CAM-1 is located in the endothelial junction between cells. After a heart attack, damaged endothelial cells are believed to retract, exposing the junctional molecule and making it an ideal marker for ischemia and infarction.

Investigators surgically induced AMI in six mice. After myocardial reperfusion, three mice were injected intravenously with the PE-CAM-1-targeted monoclonal antibody, which had been conjugated to Feridex. Three mice were injected with a Feridex-labeled immunoglobulin molecule. An hour later, all mice underwent cardiac MR imaging with an electrocardiographically gated, 2D cine FLASH sequence on a 4.7T scanner.

The UVA researchers found that the PE-CAM-1-targeted contrast agent homed to areas of myocardial ischemia, an observation that was confirmed by histopathology.

 There is no evidence of the contrast agent in the mice injected with immunoglobulin (A). In the mice injected with the PE-CAM-1-targeted contrast agent (B), MRI demonstrates hypointense speckles in the anterolateral wall of the left ventricle that correspond to the white infarct zone on histologic staining (C).

 Using a PE-CAM-1-targeted contrast agent, cardiac MR could guide interventional treatment of patients with a stuttering type of acute MI. French expects to begin studying the use of the contrast agent in identifying jeopardized myocardium in a mouse model of unstable angina.

CONTEXT: In acute myocardial infarction (AMI), the culprit thrombus sometimes dissolves before the patient arrives in the emergency room, leaving the cardiologist with few clues as to the source of the chest pain.

MR agent targets PE-CAM-1 molecule to see transitory myocardial infarction

Molecular imaging is playing a central role in shaping the future of cell-based therapies. Even as human studies near approval by the FDA, critical questions remain to be answered in preclinical work. Researchers rely on MI to produce those answers.

"One of the big things we want to know and the FDA wants to know about stem cell therapy is, Did the cells get there?" said Dr. Joseph Frank, chief of the Experimental Neuroimaging Section of the Laboratory of Diagnostic Radiology Research at the National Institutes of Health Clinical Center.

Ensuring accurate cell delivery is fundamental to determining whether cell therapy lives up to its early promise.

"If we don't find an effect, we have two questions: Did the cells not work, or did the cells not get there? Imaging can play an important role in assessing that," said Jeff W.M. Bulte, Ph.D, an associate professor of radiology at Johns Hopkins University School of Medicine.

Although MRI, PET, and optical imaging are all used to track stem cells, the underlying imaging strategy, regardless of modality, is based on the nuclear medicine tracer principle discovered by George de Hevesy. He was awarded the 1943 Nobel Prize in chemistry for discovering that molecules labeled with a radioisotope can be followed as they pass through an organism or as they contribute to complex biochemical processes, such as photosynthesis.

Indium-111 oxine SPECT is a logical choice for tracking stem cells for a limited time, said Dr. Sanjiv "Sam" Gambhir, chair of nuclear medicine at Stanford University Medical Center. But, like all radioistopes safe enough use in humans, I-111 has a short half-life that limits its value to measurements taken within a few days after its administration.

Cell therapists need to follow stem cells for weeks, months, and even years after they are introduced as therapy, according to Gambhir. This requirement has led molecular imaging researchers to experiment with contrast-enhanced MR and radically different reporter gene nuclear imaging techniques as potential alternatives.

"This is an area where molecular imaging can play a significant role," Gambhir said at the 2005 Society of Nuclear Medicine meeting.

Reporter gene imaging involves genetically tagging precursor cells to permanently alter their genetic composition (see Molecular Imaging Outlook 2005;2:1-3). The altered gene imprints the cell with a specific protein that distinguishes it and its cellular progeny from other cells after they divide and redivide. Complementary reporter probes, based on either nuclear medicine or optical imaging technologies, can identify reporter gene-labeled cells as long as the original stem cells or their offspring are present in the body.

Dr. Joseph C. Wu, a cardiologist in Stanford's molecular imaging program, is genetically tagging paired myocardial myoblasts transduced with a lentivirus to express a green fluorescent protein and firefly luciferase. The myoblasts are infused in myocardial muscles of rats where they have been successfully tracked with optical imaging for up to two weeks.

Newer reporter gene imaging strategies promise to lengthen the time in which stem cells can be tracked. One MRI approach taken by researchers at Carnegie Mellon University in Pittsburgh uses a metalloprotein from the ferritin family as a reporter gene. Gene expression causes the cell to sequester endogenous iron, which changes MR relaxivity. No external contrast agent is needed.

Another MRI approach, spearheaded by researchers at Johns Hopkins, relies on an artificial lysine-rich protein, which expresses amide protons that can be detected by chemical exchange saturation transfer imaging. Small differences in signal intensity against a background are plotted on statistical maps and highlighted in red. The technique has been successful in vitro, and studies in rodents are under way.

"If this reporter gene approach works, it could revolutionize how we label and track cells with MR," Bulte said. "We're adventurers on a new frontier."

A key technique in optimizing cell therapy is MRI of cells labeled with superparamagnetic iron oxides (SPIOs). With its ability to precisely target cell delivery, track cell migration, and noninvasively evaluate living subjects over time, this technique is helping to bridge the gap between bench and bedside.

Researchers at the University of Nijmegen in the Netherlands, led by Carl Figdor, Ph.D., director of the Nijmegen Centre for Molecular Life Sciences, are conducting one of the first studies of magnetically labeled therapeutic cells in humans. Using dextran-coated SPIO nanoparticles (Endorem in Europe, Feridex in the U.S.) and indium-111 oxine, they are colabeling dendritic cells taken from the blood of melanoma patients. These immune system cells present antigens on their surface, migrate to the lymph nodes, and stimulate T cells to mount an assault against a foreign invader. Phagocytic by nature, they spontaneously take up the iron oxide and indium oxine labels without need for a transfection agent.

After culturing, the researchers inject 15 million labeled dendritic cells under ultrasound guidance into a lymph node at the site of the tumor. To monitor the migration of the dendritic cells, patients undergo both SPECT and 3T MRI before and 48 hours after injection of the dendritic cells. The lymph nodes are then resected and examined histologically and with a 7T MR spectrometer. The researchers have found that MR can easily track dendritic cell migration and assess accurate cell delivery.

At Johns Hopkins, cardiologists are beginning to do bone marrow stem cell therapy in patients with acute myocardial infarction, also using unlabeled cells. Dara Kraitchman, Ph.D., an associate professor of radiology at Hopkins, acknowledges that performing these procedures without cell tracking is a pragmatic decision, but she is concerned that it leaves too many questions unanswered.

"The problem with the clinical trials is that people don't know if the cells got to the target. Where else did they end up? Were they still there at some later time?" she said.

Moreover, an assessment of changes in ventricular function offers only a rough gauge of the effectiveness of stem cell therapy. If cardiac function does not improve, no one knows if it is because too few cells arrived at the site of infarct or because the cells simply did not persist long enough. If cardiac function does improve, the question remains whether improvement would have been greater if more cells had been delivered.

Meanwhile, research spadework continues in animals. Early studies of cell tracking with MR showed that a wide range of labeled cells-from organ-specific stem cells to mesenchymal stromal cells and endothelial progenitor cells-could be tracked in the liver, kidney, heart, brain, spinal cord, and other organs.

A team led by Michael Chopp, Ph.D., director of the Neuroscience Institute at Henry Ford Health Sciences Center in Detroit, took neural stem cells from the subventricular zone of the brain, labeled them with ferromagnetic particles, and implanted them in the cisterna magna of rats with ischemic stroke (Figure 2). The cells selectively migrated toward the ischemic zone.

Frank's team at the NIH has shown that MRI can track endothelial precursor cells as they home into sites of tumor vasculogenesis. In a study published in the January 2005 issue of Blood, they labeled endothelial progenitor cells with Feridex, intravenously injecting them in immunocompromised mice implanted with glioma tumor cells. Over time, a continuous dark hypointense ring developed around the outside of the tumor, which was shown on histology to coincide with areas of angiogenesis.

"This shows incorporation of stem cells into the ongoing vasculogenesis that occurs in a growing tumor. We're actually visualizing with MRI the neovasculature of this tumor," Frank said.

Frank is in discussions with the FDA, seeking approval for a follow-up safety study in humans. Feridex-labeled hematopoietic cells-transfected using clinically approved protamine sulfate-would be injected intravenously in human patients with glioblastoma multiforme. Patient enrollment may begin in early 2006.

The clinical implications of such a study are intriguing, said Dr. Neil D. Theise, a professor of pathology at Albert Einstein School of Medicine, who has conducted stem cell research in the liver and other organs. It raises the possibility of using tagged endothelial progenitors to identify early de novo tumors, either as a screening device for high-risk patients or for finding micrometastases in patients with more advanced tumors.

Iron oxides are being used to label more than stem cells. In work that could shed light on the treatment of diabetes in humans, Paula Foster, Ph.D., a scientist with the Imaging Research Laboratories at Robarts Research Institute in London, ON, Canada, is using MR to image SPIO-labeled pancreatic islet cells (Figure 3).

The islets of Langerhans, small clusters of endocrine cells scattered throughout the pancreas, house the beta cells that produce insulin. Islet transplantation is emerging as a possible cure for diabetes, but it is unclear how long islets survive or how well they function after transplantation. Observations made possible because of iron oxide labeling of implanted islets may produce answers.

"We're able to resolve individual islets," Foster said. "The ability to create 3D high-resolution images is another advantage of MR."

Next, Foster plans to monitor islet viability and investigate how the characteristics of the FIESTA signal change if the islet dies and loses its iron.

For all of the advances in MR, experts agree that cell imaging will draw on a range of complementary imaging modalities. MR is ideal for imaging cellular therapy of the heart when the cells are delivered directly by intramyocardial or intracoronary injection, Bulte said. A recent study in dogs, however, showed that intravenous delivery calls for use of nuclear imaging techniques.

In this study, the Johns Hopkins team labeled MSCs with both Feridex and indium oxine, injecting about 100 million cells into dogs in which acute myocardial infarction had been induced (Figure 4). On day one, fused SPECT/CT images showed cells accumulating in the lungs. On day two, researchers observed cells in the liver and spleen, as well as a hot spot in the heart, which persisted for at least five days.

Quantitative analysis showed that only 50,000 to 100,000 cells actually reached the heart, no more than 0.1% of the injected cells. MR was unable to detect any Feridex-labeled cells.

"We could not detect very small quantities of cells with MR, whereas SPECT/CT could," Bulte said.

Researchers continue to explore new MR techniques. Several groups are working on turning darkness into light when imaging SPIO-labeled cells. Iron oxide causes significant signal dephasing due to the magnetic field inhomogeneity induced in the water near the cell. The resulting signal void causes iron-labeled cells to appear black on MR images.

A new technique suppresses the on-resonance signal to which MR is ordinarily tuned and, instead, images the off-resonance water surrounding the labeled cells. A team at Stanford described this technique in the May issue of Magnetic Resonance in Medicine.

At the International Society for Magnetic Resonance in Medicine meeting in May, Matthias Stuber, Ph.D., from Johns Hopkins reported on a similar technique, dubbed inversion recovery with ON-resonant water suppression, or IRON.

"We're taking that typical dark artifact and making it bright to better identify exactly where the stem cells are and also perhaps to have a higher sensitivity to a smaller number of cells," said Kraitchman, who participated in the study.

A potential benefit of IRON and similar techniques is the ability to distinguish iron-labeled cells from other causes of magnetic field inhomogeneity, such as hemorrhage. Frank, whose team is also working on positive contrast techniques, said distinguishing labeled cells from hemorrhage remains an ongoing research challenge.

By creating a virtual window to observe cellular behavior, stem cell tracking promises to become MI's gateway into clinical practice. MI's importance extends far beyond just stem tracking, according to Frank. It may ultimately play a role in patient selection, the characterization of pathology, and determination of whether direct implantation or vascular routing of stem cells will be more effective.

As stem cell implantation techniques grow in sophistication, Frank envisions MI aiding in the optimization of implant surgery.

"This is a big one," he said at the ISMRM meeting. "We won't just be tracking migration, survival, and differentiation in the target anatomy. Through our work, questions of how many, how often, and when to give cells will be answered."

MI techniques will help the therapist to determine whether gene therapy alone will be sufficient or whether it should be combined with other techniques, such as adaptive immunotherapy. Future research will determine which imaging modality or combination of modalities is best suited for specific therapeutic applications.

Labeling studies follow human stem cell therapies

Advances in CT technology have generally met with unrestrained enthusiasm. In peripheral vascular imaging, however, some experts are beginning to question whether more really is better.

Four-slice scanners made peripheral CT angiography possible, and they have played a role in nearly all published research validating the technique. Experts readily point to the advantages of eight- and 16-slice CT scanners as well.

"An eight- or 16-detector scanner allows you to scan faster and with thinner slices than a four-detector scanner," said Dr. Michael Martin, an assistant professor of radiology at the University of British Columbia. "You have better spatial resolution and far less helical reconstruction, motion, and breathing artifact."

Martin uses four-, eight-, and 16-slice CT scanners in his busy Vancouver practice. Improved spatial resolution is the payoff everyone using such scanners talks about first.

"When we scanned the peripheral vasculature with the four-row scanner, we used a 2.5-mm thickness. Ever since we went to the eight-row scanner, we have used a 1.25-mm thickness," said Dr. Geoffrey Rubin, a professor of medicine and chief of cardiovascular imaging at Stanford University School of Medicine. "There is no question that, from a visual standpoint, image quality is substantially improved."

With the introduction of 32-, 40-, and 64-slice scanners, however, the response is more restrained. Potential improvements in spatial and temporal resolution must be balanced against increased image noise, concerns about radiation dose, and more complex contrast administration protocols. The trade-off leaves some radiologists skeptical about the role of the most advanced multislice CT scanners for imaging the lower extremities.

"If there are advantages with the 64-slice scanner for peripheral vascular imaging, they're incremental and relatively fine increments at that, compared with the advances we saw with the four-row scanner, and then the eight and 16," Rubin said.

Higher spatial resolution has the potential to improve not only the visual quality of images, but also diagnosis. With eight- and 16-slice scanners, it is possible to image lower in the legs with greater confidence, according to Martin.

"It's easier to interpret those images than with a four-slice scanner, unquestionably," he said.

Dr. Tobias Jakobs, a radiologist at the University of Munich, Grosshadern campus, has been working with a 64-slice scanner for several months. He notes that this latest advance in scanner technology adds further value to peripheral vascular imaging, but only in certain clinical situations. A patient with an acute onset of symptoms suggestive of embolic disease might not need imaging with an advanced scanner.

"If the patient has an acute onset, there might be occlusion of a major vessel, and you can easily detect this with even a four-detector-row CT, with a high confidence," Jakobs said.

Improved spatial resolution may pay off more in other cases. The 16-slice scanner enables detection of stenoses down to the popliteal arteries, but the 64-slice scanner makes it possible to more accurately grade stenoses and determine their hemodynamic significance, particularly in the case of a patient with multiple lesions, he said.

A 64-slice scanner might offer an advantage in a patient with chronic peripheral vascular disease (PVD). On follow-up examination, the scanner must be able to detect subtle changes in disease burden.

"It is really helpful to have the higher spatial resolution for the chronic disease patient," Jakobs said. "It can change management."

Although submillimeter slice widths are possible on all the latest scanners, many radiologists select a detector collimation of 1 to 1.5 mm when imaging a patient with PVD.

"Although our 16-slice scanner is capable of 0.625-mm slice thickness, we choose not to use the narrowest possible thickness," Martin said. "We found that it did not add to diagnostic accuracy. The images were noisier and grainier and much more difficult to interpret."

The potential drawbacks of submillimeter slice widths in peripheral vascular imaging are more obvious in some portions of the exam than others.

"Many regions of the body don't tolerate that much noise, particularly the aorta and its branches. When you're talking about peripheral arterial disease, you cannot consider the legs without considering the aorta and iliac arteries, because inflow is critical," Rubin said.

Although very thin slice widths are likely to improve image quality from the knees to the toes, the impact even in the thighs may vary, depending on the size of the thighs. And imaging with very thin sections in the abdomen could take careful planning.

"For many of our patients, the noise levels that result from using that very thin detector width outweigh the benefits of the added spatial resolution," Rubin said.

The interplay of speed, slice thickness, and radiation dose isn't the only complication in decisions dictating which scanner to choose. Other factors come into play.

-Blooming artifact. This inherent shortcoming of CTA can result in overestimation of the size of calcified lesions and underestimation of luminal diameter. With the 64-slice scanner, problems with blooming artifact are less common, Jakobs said.

"We do not have much blooming artifact anymore," he said. "I think with the 64-slice scanner, you can be sure what you see really is the lumen. You can be more confident in making the correct diagnosis."

-Scan range. A clear benefit of advanced scanner technology has been an improvement in scan range. Today, all relevant anatomy can be included in a distal runoff study.

"With the four-detector scanner, we're limited to imaging roughly from the level of the celiac artery to the ankles. When you go to an eight- or 16-detector scanner, there is essentially no limitation. You can go from the top of the chest to the tips of the toes without any problem," Martin said.

The 64-slice scanner would make it easy to go even further and scan from the neck to the toes. Such an approach would give a nod to the concept of atherosclerosis as a systemic disease and enable detection of plaque in the carotid and coronary arteries, thoracic and abdominal aorta, and lower extremities. This prospect appeals not just to radiologists but to other cardiovascular physicians as well.

"When I was in training, we were interested only in the heart, and all these other vessels were just a way to get to the heart. Over the years, we've come to the understanding that it is all part of the same disease process," said Dr. Peter S. Fail, director of cardiac catheterization and interventional research at the Cardiovascular Institute of the South in Lafayette, LA.

It may be a while before that vision is realized. In the absence of validation and outcomes studies, total-body CTA is not yet considered justified in everyday practice, although it is a focus of research at Stanford and other institutions.

"Scanning people from neck to toes to see where they have atherosclerosis and using that information to make treatment decisions could come in the future, but I think it's pretty far off," Rubin said.

-Temporal resolution. Gantry rotation times have become even faster on some of the most advanced CT scanners, ranging from 0.33 to 0.4 second. Although a reduction in temporal resolution is helpful in imaging the coronary arteries and other vessels prone to pulsation artifact, it has less impact when imaging the peripheral vasculature.

The combination of thinner slices and faster gantry rotation may necessitate scanning patients at a higher mA. This places greater demands on the x-ray tube and also increases the radiation dose. Several vendors have responded by redesigning or enhancing the x-ray tube in the latest generation of scanners. Dose-management software can modulate tube output according to the type of scan and region of the body. In this way, tube output is at its maximum only when necessary to obtain diagnostic-quality images, minimizing both radiation exposure and the risk that the x-ray tube will overheat.

The experts agree on the bottom line: CTA of the peripheral vasculature can be accomplished on a wide range of scanners, but some are better than others for particular uses.

"If you work in an institution with only a four-detector scanner, you should still be offering this as a modality for investigation of lower limb ischemia," Martin said. "But if you have a choice between a four and an eight, go for the eight."

Martin considers a four-slice scanner sufficient for imaging most patients with claudication. Better spatial resolution is necessary, however, when imaging patients with critical ischemia of the legs, rest pain, tissue loss, or ulceration. These conditions suggest a more significant degree of arterial insufficiency, often involving smaller vessels.

"When the contrast bolus is properly handled, we see vessels as small as any surgeon would ever target, using an eight- or 16-row scanner and a 1.25-mm thickness," he said. "We've scanned two-year-olds with crush injuries and have visualized 1-mm vessels in their feet. I don't think that we need to see vessels smaller than that."

Properly handling the contrast bolus becomes increasingly tricky as scan speeds rise. With the introduction of the 16-slice scanner, radiologists found it necessary to adjust contrast and image acquisition protocols or risk having the scanner outrun the contrast bolus.

"To some degree, you have to scan slower than the scanner is capable of," Martin said. "If you don't, your table will move faster than the blood flow, and by the time you get to the calves, there will be no more arterial enhancement."

Making this adjustment requires counterintuitive thinking. When scan times fall to 20 seconds or less, the natural inclination is to reduce the duration of contrast injection accordingly and increase the injection rate.

But research at Stanford suggests that injecting faster and for a shorter time is not the best approach to use when imaging patients with PVD. There can be a sixfold difference from one patient to another in the time it takes for contrast material to flow from the aorta to the popliteal arteries. And a patient's flow rate cannot be predicted by the severity of disease.

Therefore, both Martin and Rubin inject contrast material over about 35 seconds, regardless of the type of scanner they are using. Rubin uses automated bolus triggering and adds a 20-second delay in addition to the time to contrast arrival in the aorta.

"We start out behind, but not too far behind," Rubin said. "If the patient's flow rate is very slow, we catch up to the head of the bolus by the time we get to the feet. But if the flow rate is very fast, we still have enough bolus behind us that we don't lose out."

The rate of contrast injection is also determined by patient size. In a large patient, Rubin injects 350 to 370 mgI/mL contrast material at 5 mL/sec, whereas in a small patient, he injects contrast at 4 mL/sec (in both cases, over 35 seconds). Ultimately, a good contrast injection protocol can be as critical as scanner technology, he said.

"Anyone who isn't seeing distal vessels very well would be better served by reviewing their contrast delivery protocol than by getting the latest scanner," Rubin said. "The key to visualization of those small vessels is the concentration of iodine in that artery when the scanner arrives there."

Advances prompt rethinking of imaging priorities

In the world of preclinical research, bioluminescence imaging is creating a stir. Like fluorescence imaging, it enables the visualization of genetic expression and physiological processes at the molecular level in living tissues. But because there is no competing background signal, it can be used to detect much lower levels of light.

Another key difference between the two optical imaging methods is that bioluminescence does not rely on an external light source. Instead, borrowing from nature (usually a firefly), bioluminescence imaging detects light that is emitted from within experimental animals through the action of luciferase on its substrate, luciferin. Finally, because luciferase imaging requires genetic transfection, it is unlikely to ever find a place in human studies, although it can be useful for predicting human response to therapy in the early stages of drug development.

During imaging, an anesthetized mouse is placed in a dark chamber, and a photographic image is taken. Sensitive CCD cameras are used to capture the bioluminescent data, which are superimposed on the photographic image for easier interpretation.

Luciferase can be incorporated into a wide array of cells, organisms, and genes. Bioluminescence imaging has been used primarily to track tumor and immune system cells, bacterial and fungal infections, and gene expression.

Prostate tumor cells, for example, can be transfected with the luciferase gene. Once they are injected into mice, bioluminescence imaging can be used to monitor tumor growth and metastasis and to gauge the response to chemotherapy.

Xenogen in Alameda, CA, has even incorporated luciferase into a line of light-producing transgenic animals, including one that can detect tumor-associated angiogenesis. In this case, the gene for a vascular endothelial growth factor (VEGF) surface receptor promoter is incorporated into a mouse chromosome along with a gene for luciferase. When VEGF is secreted during angiogenesis, induction of the VEGF promoter prompts production of luciferase as well.

Bioluminescence creates a stir

Optical imaging may address one of the great paradoxes in radiology. X-ray mammography can depict breast microcalcifications, the smallest object relevant to a radiological diagnosis that can be seen with the human eye. Yet two of every 10 breast cancers still escape detection.

Although beset with technical challenges, near-infrared (NIR) optical imaging can potentially detect and monitor the treatment of breast cancers before the first suggestion of a problem appears with mammography, PET, or MR imaging. On a broader front, optical imaging techniques have already been embraced as an essential instrument for molecular-based drug research and development. Optical imaging has for years fueled discoveries in molecular biology laboratories. Today, researchers are applying its strengths-and wrestling with its challenges-in an effort to shed light on molecular secrets deep within living tissues.

Driving progress in optical molecular imaging are the development of biocompatible fluorescent markers, advances in imaging technology, and refinements in the mathematical models that make sense of the chaotic paths photons travel as they careen through the body. These advances are helping researchers accomplish important goals in securing the future of optical molecular imaging: improvement of light penetration, image resolution, and the quantification and localization of disease.

Several research teams are using diffuse optical tomography to detect breast tumors by searching out two intrinsic cancer signatures: increased blood flow, as shown by the total hemoglobin concentration, and hypermetabolism, as shown by a drop in oxygen concentration (Figure 1). Britton Chance, Ph.D, emeritus professor of biophysics, biochemistry, and radiology at the University of Pennsylvania, and colleagues have studied more than 100 women, including 30 with breast cancer, using diffuse optical tomography. They are finding the sensitivity and specificity for breast cancer detection to be more than 90% with this approach.

Chance, Brian W. Pogue, Ph.D., an associate professor of engineering at Dartmouth, and others are part of a network funded by the National Institutes of Health that is working toward a multicenter trial of NIR optical tomography of the breast. The imaging industry has taken notice as well: Montreal-based Advanced Research Technologies has developed a time-domain optical tomographic breast imaging device known as SoftScan and is testing it clinically in collaboration with McGill University, the Ottawa Regional Women's Breast Health Centre, and others (Figure 2).

Researchers are also investigating whether changes in blood flow and oxygenation can effectively evaluate the response to chemotherapy, detect and quantify fetal hypoxia, and diagnose ischemic stroke. Chance has used NIR spectroscopy to open a window into the brain, charting the effects of cognitive activity on blood flow in the prefrontal cortex (Figure 3).

Optical imaging offers several advantages over other technologies for molecular investigations in small animals and, to a lesser extent, in humans. It's easy to use, a number of highly sensitive benchtop fluorescent probes have the potential for biocompatibility, there is no need for ionizing radiation, and the equipment is relatively inexpensive and rapidly advancing on the coattails of optoelectronic technology in general.

"This is why I have espoused optical imaging. It is an eminently practical field," Chance said.

Although optical imaging encompasses diverse techniques (see accompanying story) and makes use of various wavelengths of light, a great deal of excitement in molecular research lies in the use of tomographic and fluorescence techniques to image living tissues with near-infrared light.

NIR light is essential for examining molecular activity at a depth of more than a few millimeters. That's because in biologic tissues, hemoglobin, water, and fat are least absorbent in the near-infrared spectrum-roughly 650 to 900 nanometers-so photons can penetrate tissue most deeply.

"The name of the game is penetration through the skin and skull into the brain cortex, or through the layers of adipose tissue that may overlie a breast cancer," Chance said. "It is a question of using a color of light that will penetrate the tissue, and that is near-infrared."

Tissue autofluorescence is also at a minimum at NIR wavelengths. Eliminating background signal improves detection.

At its simplest, NIR optical imaging involves the illumination of tissue with a broad beam of light and detection of the resulting spectral or fluorescence data. In addition to surface examinations, planar techniques are useful for simple applications such as detecting the mere presence of fluorescence. Determining on-off genetic expression through use of an activatable probe, such as green fluorescent protein, is one example.

Work at Dartmouth College led by Pogue offers another intriguing example. Pogue is using planar imaging to detect the production of protoporphyrin IX, an endogenous fluorophore that accumulates in metabolically active tissues, particularly mitochondria-rich tumor cells.

Planar imaging yields limited information, however. Penetration depth is only a few millimeters. Equally important, it is impossible with planar techniques to accurately localize or quantify contrast materials because photons do not travel in ordered, linear paths through the body. Instead, they scatter wildly, skewing interpretation of the actual location or distribution of their source.

"To exploit the true potential of optical imaging you need to get below the surface," Pogue said. "Research is focused on how to get light signals out of thick tissues. It's a very difficult problem."

In Pogue's lab and in a handful of others across the country, researchers are using a combination of advanced-photon and tomographic techniques to overcome the limitations of conventional optical imaging. Light is delivered not as a continuous wave but, instead, either in short pulses (time-resolved imaging) or with rapidly oscillating intensity (frequency-domain imaging) at multiple points around the target tissue. It is then collected by detectors that also surround the tissue.

The process is repeated at various wavelengths that correspond to the absorption peak of intrinsic chromophores, such as oxy- and deoxyhemoglobin. In the case of extrinsic fluorophores, absorbed light is almost immediately re-emitted at a longer wavelength; therefore, both excitation and emission light are collected. Data are then reconstructed according to complex mathematical models that account for the diffuse propagation of photons in living tissue.

Together these advances enable better penetration of light (to as deep as 15 cm in breast tissue) and independent characterization of the absorption and scatter of photons. The result is improved resolution (typically a few millimeters, but less than 1 mm in one recent study) and better discrimination of normal and abnormal tissue. Perhaps most important, advanced imaging techniques produce an accurate, quantitative, 3D assessment of the target tissue.

To improve reconstruction quality, Vasilis Ntziachristos, Ph.D., and his colleagues at Massachusetts General Hospital have taken a further step. They have developed a system that replaces the standard fiber-optic array that delivers and detects light through direct contact with the skin, substituting a noncontact charge-coupled device. A similar system is being used at the University of Pennsylvania.

"With fiber-based systems, it is difficult to get the number of measurements you need to do high-quality reconstructions," said Ntziachristos, who directs the hospital's bio-optics and molecular imaging laboratory. "How many fibers can you bring in contact with tissue?"

Promising as optical tomography is when used with intrinsic contrast, cancer researchers are looking toward a brighter future as targeted fluorescent probes become available for human use, Ntziachristos said.

Of the many commercially available fluorescent agents, only indocyanine green (ICG) is approved for use in humans. A nontargeted blood pool agent, it is useful for tracking blood flow and gauging both the extent of angiogenesis in tumors and the characteristic "leakiness" of their chaotic blood vessels. In small animals, however, many more fluorescent options are available.

Chance's team, for example, is testing the utility of the fluorescent glucose compound pyropheophorbide 2-dexoyglucosamide (Pyro-2DG) to detect hypermetabolism in rat glioma tumors. There are targeted fluorescent reporter probes that home in to the genetic signatures of tumor cells, such as the somatostatin or folate receptor. Ntziachristos and his fellow researchers are studying fluorescent probes that not only are highly specific for certain proteins or proteases, but are activated by interaction with their targets. One example is a probe targeted to cathepsin B, an enzyme that is commonly upregulated in cancer cells. The probe is dark until a portion of its carrier molecule is cleaved by a cathepsin, an action that sends out a bright fluorescent signal. Using another probe targeted to phosphatidylserine, cyanine-labeled annexin V, the Boston researchers are testing whether the effectiveness of chemotherapy can be gauged by imaging apoptosis.

Although light penetration and spatial resolution are improving, they remain challenges for NIR optical imaging. Experts doubt that the technology will top the 15-cm penetration achieved in breast tissue, and they believe it will not even come close to that in blood-rich organ and muscular tissue, where light absorption by hemoglobin is a more critical factor. This means that NIR optical imaging is expected to have tailored, selected uses in humans. In small-animal research, however, the future is wide open.

Fluorescence molecular imaging is a boon to drug research and development, for example. When used with small animals, it enables visualization of the molecular distribution and action of drugs long before anatomic or functional effects can be observed. Multispectral techniques make it possible to examine more than one molecular process at a time. Equally important, fluorescence imaging will make animal research more efficient and cost-effective because it will reduce the need to sacrifice animals in order to assess drug efficacy.

As for limitations in spatial resolution, physiological information-not anatomic detail-is optical imaging's strength, according to Chance. With this is mind, the Penn group pioneered the coregistration of MR and optical images, combining the spatial resolution of MR and the spectroscopic information of optical imaging.

The approach has widespread appeal. Ntziachristos, for instance, has combined MR with planar and fluorescence-mediated optical tomography to improve visualization of tumors in mice (Figure 4). Pogue and his colleagues have integrated an NIR optical breast imaging system into a clinical MR scanner. Data are acquired by both systems during a single scan, and spectroscopic data on hemoglobin concentration are then superimposed on the MR T1-weighted images. This approach not only compensates for shortcomings in the spatial resolution of optical tomography, it improves MR breast imaging as well.

"The hemoglobin signature in the tumors could add a level of specificity that would improve the ability of MR to characterize tumors," Pogue said.

Optical imaging sheds light on cancer's signature

CONTEXT: The rupture of atherosclerotic plaque, followed by the formation of an occlusive thrombus, causes nearly all heart attacks and many strokes. Multidetector CT has shown increasing success in the detection of arterial stenoses and differentiation of calcified and soft plaque. It has not, however, been able to detect an important early warning sign of plaque rupture: fibrin-rich microthrombi that develop within microfissures of vulnerable lesions. New research reported at the 2003 annual meeting of the Society for Molecular Imaging suggests that could change.

RESULTS: Patrick M. Winter, Ph.D., Dr. Samuel Wickline, and Dr. Gregory Lanza, of the cardiovascular division at Washington University in St. Louis, worked with researchers from the U.K. and the Netherlands to develop a radio-opaque nanoparticle contrast agent through use of a special iodinated oil. After demonstrating the inherent radio-opacity of the contrast material with CT imaging, they linked antifibrin monoclonal antibodies to the surface of the nanoparticles and added the preparation to plasma clots suspended in saline on a suture line. For comparison, nanoparticulate contrast material without antifibrin antibodies was added to identical plasma clot suspensions.

CT was far better at imaging thrombus when the contrast material consisted of fibrin-targeted nanoparticles: Gray-scale contrast enhancement was significantly greater with fibrin-targeted nanoparticles when compared to unaltered nanoparticles (210 vs. 160; p < 0.05). Contrast-to-noise ratios were markedly greater as well (22 vs. 5; p < 0.05).

IMPLICATIONS: This study shows for the first time that a fibrin-specific molecular imaging agent can increase the sensitivity of CT for the detection of thrombus. This technique may spur early detection and localization of vulnerable plaques, perhaps enabling their treatment during routine cardiac catheterization or intervention.

Fibrin-targeted agent enhances detection of microthrombi of vulnerable plaque

CONTEXT: As atherosclerotic plaque invades the arterial wall, it develops a network of tiny new blood vessels. The integrin avBeta3 is a marker for angiogenesis and therefore represents an attractive target for molecular imaging aimed at the early identification of vulnerable and inflamed plaque.

RESULTS: Investigators at Washington University School of Medicine in St. Louis developed a nanoparticle targeted against avBeta3-integrin by incorporating hundreds of tailor-made peptide-like particles into its lipid outer layer. Also linked to each nanoparticle were some 90,000 molecules of gadolinium DTPA to enable detection by MR.

Patrick M. Winter, Ph.D., and colleagues injected the nanoparticles intravenously into atherosclerotic, cholesterol-fed rabbits. Using a 1.5T clinical MR scanner and T1-weighted imaging, they detected increased angiogenesis throughout the wall of the abdominal aorta in rabbits injected with integrin-targeted paramagnetic nanoparticles. On average, signal intensity increased by 47% at two hours. For comparison, rabbits were also injected with nontargeted paramagnetic particles; signal enhancement averaged just 26%. Equally important, pretreatment of the rabbits with integrin-targeted nonparamagnetic nanoparticles reduced contrast enhancement by at least 50% through competitive blocking, thus demonstrating the specificity of the nanoparticle's integrin targeting.

IMAGE: MR contrast enhancement appears in the cholesterol-fed rabbits two hours after injection with avBeta3-integrin in renal artery (A), mid-aorta (B), and diaphragm (C). (Provided by P. Winter; reprinted with permission from Circulation 2003;108:227-2274.)

IMPLICATIONS: The use of this novel paramagnetic nanoparticle may enable physicians not only to identify arterial plaque through its angiogenic blood supply, but also to track the effectiveness of anti-atherosclerosis therapies. 

MR nanoparticle contrast targets angiogenic markers of atherosclerosis

Perhaps even more than death itself, many cancer patients fear spending their final months in excruciating pain. New research points to radio-frequency ablation as a source of fast and lasting relief that works when other methods of pain control fail.

A multicenter study from nine medical centers in the U.S. and Europe focusing on patients with metastases to the bone found that RF ablation successfully reduced pain in 95%. More than half reported relief within one week.

"All these patients had failed other modalities, including chemotherapy, radiation therapy, and even implantation of analgesic pumps in the intrathecal or epidural space, and they were having terrible pain," said Dr. Matthew Callstrom, an assistant professor of radiology at Mayo Medical School in Rochester, Minnesota. "We talked about where their most intense pain was and made sure we focused on treating that particular area."

The study garnered a Merit Award at the annual meeting of the American Society of Clinical Oncology, where the findings were reported in May.

Catherine Carrington

Articles

CT angiography steps up role in interventional planning

MR agent targets PE-CAM-1 molecule to see transitory myocardial infarction

Labeling studies follow human stem cell therapies

Labeling studies follow human stem cell therapies

Advances prompt rethinking of imaging priorities

Bioluminescence creates a stir

Optical imaging sheds light on cancer's signature

Fibrin-targeted agent enhances detection of microthrombi of vulnerable plaque

MR nanoparticle contrast targets angiogenic markers of atherosclerosis

Comfort lasts months, with option for further treatments as needed