Intravascular Radiation Detectors for the Detection of Vulnerable Atheroma
H. William Strauss, MD, FACC*,a,*,
Carina Mari, MD
,
Bradley E. Patt, PhD
,b and
Vartan Ghazarossian, PhD
,a
* Section of Nuclear Medicine, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
Nuclear Medicine Program and Center for Molecular and Functional Imaging, University of California-San Francisco, UCSF, San Francisco, California
Gamma Medica Inc., Northridge, California
Imetrx Inc., Mountain View, California
Manuscript received August 30, 2005;
revised manuscript received October 25, 2005,
accepted November 4, 2005.
* Reprint requests and correspondence: Dr. H. William Strauss, Memorial Sloan Kettering Cancer Center, Clinical Director, Nuclear Medicine, 1275 York Avenue, New York, New York 10021 (Email: straussh{at}mskcc.org).
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Abstract
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An intravascular catheter was developed to identify inflammation in coronary atheroma. Inflammation in atheroma is associated with large numbers of macrophages. These cells have increased metabolism, increased expression of chemotactic receptors, and a high frequency of apoptosis-associated phosphatidylserine expression. Each of these parameters can be identified in vivo using specific radiolabeled agents: metabolism can be identified with 18F fluorodeoxyglucose (FDG), receptor expression with 99mTc monocyte chemotactic peptide-1, and apoptosis with 99mTc annexin V. The locally increased concentration of these tracers is readily demonstrable in experimental lesions by ex vivo autoradiography; however, the small lesion size makes it difficult to identify atheroma in the coronaries with conventional imaging equipment. In contrast, with a radiation-sensitive catheter, optimized to sense charged particle rather than gamma or x-radiation, specific lesions could be identified and localized. Charged particle radiation is emitted as a byproduct of nearly all radioactive decay but is typically most abundant in radionuclides that decay by beta emission (either positrons or negatrons). Prototype catheters, using a plastic scintillator mated to an optical fiber, have been tested in the laboratory with the positron-emitting radiopharmaceutical 18FDG. The catheter had sufficient sensitivity to detect lesions concentrating nanocurie concentrations of 18FDG. Ex vivo experiments in apo-e–/– mice confirmed the ability of the catheter to detect 18FDG in aortic lesions. These feasibility studies demonstrate the sensitivity of a beta-sensitive catheter system. Additional mechanical refinements are needed to optimize the system in anticipation of in vivo animal studies.
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Abbreviations and Acronyms
| | FDG = fluorodeoxyglucose | | MACE = major acute coronary events |
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Patients with symptomatic major acute coronary events (MACE) or sudden cardiac death often have many lesions that meet the histologic criteria for vulnerable plaque (1). Although a single lesion might cause the acute event, angioscopic (2) studies demonstrate numerous "yellow" lipid-laden lesions that could also cause a similar event. Plaque rupture in non-culprit plaques occurs frequently, as demonstrated by thermograpy (3) and serial angioscopy. In one series (4) of 30 patients, ranges of 1 to 4 (average 1.67) plaque ruptures per patient were seen in non-culprit lesions. The specific stimulus leading to thrombus formation on the culprit lesion is not well defined; the same stimulus can also act on the remaining vulnerable lesions, potentially contributing to the 4.7% incidence of recurrent infarction (5) during the recovery period. The management of patients with MACE must address both the acute event (usually with a percutaneous intervention) and reduce the likelihood of another event during convalescence. To reduce the possibility of another event, aggressive pharmacologic therapies are advocated, including marked reductions of low-density lipoprotein cholesterol, to reduce inflammation and stabilize the remaining vulnerable lesions (6). This strategy is effective over several months, but the immediate risk of an event from one of the other vulnerable plaques is likely to persist in the short term. Specific identification of these lesions would offer the potential of investigating their natural history as well as exploring the role of local therapy for immediate stabilization of vulnerable non-culprit lesions with a percutaneous catheter-based intervention. A major challenge to this concept is the need to identify and localize these lesions with certainty. Because many of these lesions are not visible in coronary angiograms and are too small for external imaging, a catheter-based detection technique might be most useful. The catheter could detect: cap thickness (measurable with intravascular magnetic resonance imaging [7] or intravascular ultrasound); local increase in temperature (with a multiwire basket catheter carrying multiple thermistors to detect increased temperature [8] [Fig. 1]); protein/lipid ratio of lakes within the lesion (detectable with near infrared imaging [9]); local acidosis due to the combination of high metabolic activity within the lesions in the presence of limited oxygen delivery by the vasa vasorum (identified with optical imaging with dyes that change colors at various pH values); as well as the metabolic activity (10) and chemotactic receptor expression (11) of inflammatory cells (detectable with radionuclide techniques).
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Figure 1 Photograph of the wire basket thermal catheter (as depicted in U.S. patent 6,763,261 by Casscells et al. [8]). Multiple thermistors are placed on the surface of the wire. The thermistors are brought in contact with the endothelium of the vessel to take the temperature of the vessel.
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Inflammatory cells (macrophages, granulocytes, and lymphocytes) in the lesions have markedly elevated metabolic activity, causing the lesion to have an elevated temperature. The acidotic pH is likely caused by the limited oxygen supply in the lesion, causing the macrophages to function in a relatively anerobic environment. Energy for the metabolic activity of these cells is provided by exogenous glucose. In large vessels, such as the aorta and carotid arteries, areas of vascular inflammation appear as regions of increased tracer localization on positron emission tomograms in patients imaged with the 18fluorodeoxyglucose (FDG) (12–14), although the small size of atheroma in the coronary vessels combined with residual blood pool and myocardial activity reduces the image contrast recorded with positron emission tomography images. This target/background problem can be addressed with an intravascular beta radiation-sensitive catheter.
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Considerations in radiation catheter design
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The utility of a radiation-sensitive catheter to detect and localize the lesions will depend on both the physical properties of the radionuclide and the biologic behavior of the selected tracer. Although external imaging uses gamma and x-radiation, this is not desirable for intravascular detection (15). Because gamma and x-radiation is very penetrating, activity outside the vessel (e.g., in the myocardium, kidneys) could create a potentially overwhelming background, making it difficult, if not impossible, to see the relatively weak signal from the vulnerable plaque. Beta radiation (either positron or negatron), in contrast, has a path length of a few millimeters. As a result, in using a detector with a high sensitivity for charged particle radiation and negligible sensitivity for gamma and X-ray radiation, the detected beta radiation must be emitted from sites in close proximity to the detector. An additional advantage of detecting charged particle radiation is elimination of the requirement for conventional collimation. To use these physical properties, the detector has to be within millimeters of the lesion. The energy of the particle must be sufficient to have a high probability of traversing the lesion, endothelium, adjacent blood, and catheter sheath to deposit its energy in the radiation detector. Radionuclides that preferentially decay with emission of a charged particle, such as fluorine-18 (beta+ max = 633.5 keV; beta+ average = 242.8 keV; average path length is approximately 1.5 mm), are particularly well-suited for this task.
The very low density of a plastic scintillator makes the device much more sensitive for charged particle than photon radiation, but some gamma radiation will cause scintillation in the detector, although as the detector is made thinner, the ratio of charged particle to photon sensitivity increases. In experiments with a prototype device, Janecek et al. (15) measured a ratio of 1100:1 (with a 0.3-mm scintillator). An additional factor is the amount of energy deposited by beta and gamma radiation. A 300-keV charged particle is likely to deposit all of its energy in a 1-mm-thick detector, resulting in the generation of light that can be conducted through an optical fiber to an external phototube. A gamma photon, in contrast, is much more likely to have a Compton interaction, depositing only a small fraction of its energy in the detector. A second factor is the geometric sensitivity of the device. Atheroma typically surrounds the vessel. Particles, which are discharged into the vessel, are likely to be detected, whereas those emitted toward the basement membrane of the vessel (traveling away from the detector) will not be detected. This gives an overall geometric sensitivity of approximately 50%. Because decay of a radionuclide is a random event, it is necessary to collect a sufficient number of counts (1,000 counts yields approximately 3% uncertainty) to reliably distinguish a lesion from the background. To detect this number of events in 2 s, assuming a detector efficiency of 100% and a geometric efficiency of 50%, the lesion must contain about 0.00003 mCi to be certain that the measurement is accurate (in the absence of background).
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Testing prototype radiation-sensitive catheters
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Experimental studies in apo-e–/– hyperlipidemic mice and New Zealand white rabbits fed a hyperlipidemic diet with catheter-induced lesions in the aorta suggest that the arterial lesions concentrate 1/10,000 of the administered dose. Using 18FDG as an example, a typical clinical 18FDG imaging study is performed with an injected dose of 15 mCi. One–ten-thousandth of the dose is 0.0015 mCi. After one half-life of radioactive decay, 0.00075 mCi would be resident in the lesion. Measurements made with a single plastic scintillator mated to an optical fiber (Fig. 2) (15,16) demonstrated that this was 25-fold greater than the detection limit of the catheter. These calculations suggest that measurements could be recorded during a catheter pullback with a velocity of approximately 1 to 2 mm/s.
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Figure 2 (A) Diagram of radiation-sensitive intravascular catheter (as depicted in U.S. patent 6,782,289 by Strauss [16]). The lesion in the vessel is labeled "Lesion." (B) A photograph of the prototype catheter, undergoing testing with a small beta radiation source. The catheter connects to a phototube in a lightproof housing, which changes the individual light pulses to an electrical signal for display on the readout. The catheter position is determined by localizing the radio-opaque tip, which is superimposed on the coronary arteriogram. The radiation intensity is displayed as a false color signal on the arteriogram. I = catheter sheath; II = vessel wall; III = vessel lumen; IV = optical fiber (to conduct light from the scintillator); V = connection between scintillator and optical fiber; VI = plastic scintillator.
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In addition to 18FDG, other radiolabeled tracers (17–19) that could be used for the detection of vulnerable plaque are summarized in Table 1.
The catheter must also have sufficient flexibility and be of small enough diameter to navigate tight lesions. In an effort to increase sensitivity and determine the radial location of the plaque, we constructed several multifiber catheters (Fig. 3). Multifiber catheters have marked limitations of flexibility, however, especially at the tip, because of the stiffness of the coupling point of the scintillator and the optical fiber. Another design requirement is to make the final device <4-F (1.3 mm external diameter) or, if possible, about the diameter of a guidewire.
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Figure 3 Diagram of a multiple scintillating fiber catheter, capable of providing radial information about plaque location. The data from multiple fibers are detected simultaneously with a position sensitive photomultiplier tube (15).
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Other investigators, such as Wahl et al. (20), Zhu et al. (21), and Mukai et al. (22) have also suggested designs for radiation-sensitive catheters. Most of these prototype devices were 2 to 3 mm diameter (6 to 9-F), suggesting that additional engineering is required to make the devices practical.
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Potential future approaches
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To enhance both the sensitivity and specificity for detection of vulnerable lesions, it would be helpful to measure multiple parameters that are altered by inflammation simultaneously. This can be accomplished by adding a small thermistor to the tip of a radiation-sensitive catheter to take the temperature of the lesion during the pullback. In addition, an optical sensor could be used to detect the extent of apoptosis (following intravenous administration of fluorescein-labeled annexin).
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Conclusions
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Radiation-sensitive catheters have been tested in animal models of atheroma. These devices can provide information about the location and metabolic status of the plaque. With further technical refinement, these catheters might be useful to interrogate vessels of patients with MACE for the presence of other highly vulnerable lesions that might benefit from a local intervention.
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Footnotes
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Development of the plastic scintillator intravascular catheter was supported by Imetrx Inc. and NIH SBIR R43 HL065837.
Dr. William A. Zoghbi acted as guest editor.
a Drs. Strauss and Ghazarossian hold equity interests in Imetrx. 
b Dr. Patt is a subcontractor for construction of the catheter.
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Abstract
Considerations in radiation...
