© 1997 American Heart Association, Inc.
Articles |
In Vitro and In Situ Magnetic Resonance Imaging Signal Features of Atherosclerotic Plaque-Associated Lipids
From the Diagnostic Imaging Sciences Center, Department of Radiology (C.Y., C.P., J.F.E.), the Division of Cardiology, Department of Medicine (K.D.O., B.G.B.), and the Department of Surgery (T.S.H.), University of Washington, Seattle.
Correspondence to Chun Yuan, PhD, Diagnostic Imaging Sciences Center, Department of Radiology, Box 357115, University of Washington, 1959 Pacific St, Seattle, WA 98195-7115. E-mail cyuan{at}u.washington.edu
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Abstract |
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Abstract The goal of this study was to evaluate magnetic resonance imaging (MRI) signal features of the different types of lipids found in human atherosclerotic plaques. A 1.5-T SIGNA scanner was used to acquire T1-, T2-, and proton density– weighted data at four different temperatures for individual lipids and lipid mixtures designed to replicate the proportions of lipids found in plaques. Individual lipids and lipid mixtures were scanned both in a test tube and after implantation in the media of normal porcine aortas. Each of the three broad classes of lipids (triglycerides, unesterified and esterified cholesterol, and phospholipids) had different and distinct MR signal patterns, which allowed discrimination of these classes of lipids in vitro. Further, lipid implantation studies demonstrated that these distinct MR signal patterns could be used to readily distinguish each lipid type from surrounding porcine aortic media. MR signals from lipid mixtures demonstrated marked regional heterogeneity, similar to the heterogeneous lipid distribution characteristic of human atherosclerotic plaques. In summary, MR signals from lipid mixtures that mimic plaque lipid proportions can be detected at body temperature, especially in those mixtures with an increased percentage of cholesteryl esters. These studies raise the possibility that with further advances in technology, MRI may become a useful tool for determining the lipid content and composition of human atherosclerotic plaques in vivo.
Key Words: magnetic resonance imaging • lipids • atherosclerosis
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Introduction |
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Atherosclerotic cardiovascular disease is one of the leading causes of morbidity and mortality in Western societies. Recent studies have demonstrated that most clinical cardiovascular events result from plaque ulceration, intraplaque hemorrhage, and/or plaque rupture, all of which can result in acute narrowing or occlusion of the arterial lumen. A number of recent studies have also linked the presence of a lipid-rich atherosclerotic plaque core to plaque instability and rupture.1 2 3 4 5 6 Davies et al3 suggested that in aorta, ulceration and thrombosis were characteristic of plaques with a high proportion of their volume occupied by extracellular lipid. Falk4 and Leen et al5 theorized that the formation of a lipid core and the weakening of the overlying fibrous cap may predispose the plaque to disruption. Stary7 and Guyton et al8 found that the growth of the lipid core may be associated with progressive tissue destruction and necrosis within the plaque. Davies et al,3 Richardson et al,6 and Leen et al5 have suggested that the presence of a lipid core increases the mechanical stress on the fibrous cap, thereby increasing its likelihood to rupture. At least two lines of evidence suggest that the plaque lipid core also may increase the likelihood of plaque rupture by serving as a nidus for the recruitment of protease-producing macrophages. Lendon et al9 found that, compared with the fibrous caps of intact plaques, the fibrous caps of ruptured plaques had higher macrophage densities. In addition, Nikkari et al10 have demonstrated recently that macrophages expressing interstitial collagenase, an enzyme that degrades the major structural collagen types found in plaques, are particularly prominent at the border of the plaque lipid core and correlate with the amount of intraplaque hemorrhage. Recent studies in patients with hyperlipidemia and coronary disease have suggested that reduction in plasma LDL cholesterol, known experimentally to deplete lipid from plaque core and macrophage pools, effectively stabilizes these high-risk plaques.11
The lipid core of atherosclerotic plaques consists of cholesteryl esters, cholesterol monohydrate, phospholipid, and a small amount of triglyceride and has been found to undergo both chemical and physical changes in composition as atherosclerotic lesions progress.12 13 14 15 Small and Shipley14 found that the percent dry weight of lipids increases as lesions progress from normal intima (1.2%) to fatty streaks (25%) and then to atheromatous (gruel) plaques (60%). Concurrently, the cholesterol monohydrate component of the plaque increases and precipitates as crystals, while the cholesteryl ester component, found as droplets, decreases.13 15 If the presence and distribution of these lipids could be monitored with a noninvasive imaging modality such as MRI, then it might be possible to identify patients with plaques at high risk for various manifestations of plaque instability (ulceration, intraplaque hemorrhage, and fibrous cap rupture) that result in clinical cardiovascular events. Compared with the conventional imaging modalities used to study atherosclerotic plaques (including contrast angiography and ultrasound), MRI provides better soft-tissue contrast. Its potential to determine both the lumen size and the constituents of atherosclerotic plaques has been demonstrated previously.16 17 18 19 20 21
However, several studies have reached contradictory conclusions about the utility of MRI in identifying plaque lipid components. Shahrokh et al22 found that the plaque lipid components contribute to the T2 signals of plaques when they are in their liquid phase. These investigators also suggested that since lipids are a small fraction of the total plaque compared with water and that the majority of the lipids present in plaques are not liquid, the ability to monitor the lipid component of plaques by MRI may be limited. Martin et al16 used T2W imaging to study plaques and concluded that plaque lipids are invisible to imaging. However, other studies have indicated that in contrast to solid-phase lipids, atheromatous lipids in a liquid crystalline phase have longer T2 values and are visible on MR images.19 23 Thus, the inability of earlier investigators to image plaque lipids may be due not to a lack of utility of MRI but rather to an incomplete appreciation of the marked heterogeneity in the types and phases of lipids present in human atherosclerotic plaques.
Because of the clinical potential for lipid imaging, it is important to develop our understanding of the similarities and differences in MR signal patterns for specific plaque-associated lipids and of how these plaque lipid MR signal patterns may differ from those of arterial regions without lipid accumulation as well as those of perivascular fat. The purpose of this study was to evaluate the MRI signal patterns of individual lipids implanted in the media of normal porcine aorta in volumes approximating the core lipid region of human atherosclerotic plaques. The most prominent lipids found in human plaques were studied at four temperatures. MRI signal differences between the anhydrous and hydrated lipids also were studied. In addition, the signal patterns of mixtures of lipids that mimic the known concentrations of lipids found in plaques were studied at the same four temperatures.15 Another purpose of this study was to determine whether individual types of lipids could be distinguished by determining the contrast patterns for each in T1W, T2W, and PDW MR images.
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Methods |
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Artery Samples
Fresh 15- to 20-cm segments of porcine abdominal aortas without macroscopic evidence of plaque were obtained from healthy 2-year-old pigs (Kapowsin Meats, Graham, Wash) and stored at -10°C until used for study. For each experiment, the aorta was allowed to thaw, then cut axially into 5- to 7-cm sections, dissected sagittally, and trimmed of most perivascular fat. A custom-built plastic platform was made to support the sections for imaging (Fig 1
).24 The plastic used
throughout the 5x10-cm platform had minimal MR signal. Clamps, made of
two long plastic strips bound on either end by plastic screws, were
used to bind the axially spread aorta on the left and right side,
displaying the endothelial surface in the ventral
direction (Fig 1). Lipid injections then were performed.
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Preparation and Injection of Individual Lipids
A series of representative lipids of
atherosclerotic plaques were injected into the abdominal aortas. These
lipids and their melting points and grade are listed in Table 1. The lipids, with the exception of
triolein, were obtained commercially in purified form as a crystalline
powder (Sigma Chemical Company). Triolein was obtained in liquid phase
from the same company. The lipids were injected into the aortas in
three ways: (1) as lipid rods through a needle, using a technique
described by Brown and Fry,25 (2) as solid crystals
through slits in the aortas, and (3) as liquid through a needle.
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The lipid rods of individual lipid types were fabricated by using blunt-ended inserters of 22-gauge spinal needles to pack the powdered lipids into normal 18-gauge needles. The lipid rods varied from 3 to 5 mm in length and from 1 to 2 mm in diameter. Under light microscopy, the crystals within lipid rods were observed to be randomly oriented.
The lipid rods were injected into the luminal side of the platform-bound aortas in the following manner: The lipid-containing 18-gauge needle was inserted in a cephalad direction as superficially as possible in a plane of dissection parallel to the endothelium. Once the needle tip was adequately advanced under the intima (5 to 12 mm), a 22-gauge spinal needle was used to push the lipid rod to the needle tip. While the 22-gauge spinal needle was held stationary, the 18-gauge needle was withdrawn. The 22-gauge spinal needle was then removed, leaving the lipid rod in place. There was a 1- to 4-mm space of tissue between the lipid rods and the needle injection site. The lipid rods were placed in rows inside the aorta.
In the case of liquid lipids, the lipids were drawn into 1.0-mL insulin syringes. The needles were inserted in the same manner as the lipid rods, advanced 4 to 5 mm, and the lipid was injected. While the needle was held in place, a suture was sewn around the needle and drawn tight. As the needle was retracted, the suture continued to be drawn tight, to close the needle hole and minimize leakage.
Solid crystals were inserted by making slits with a scalpel as superficially as possible in a plane of dissection just underneath and parallel to the aortic luminal endothelium. The slit was opened using clamps, and the mixtures of stimulated plaque lipids were placed as far down into the slits as possible. The slits then were closed using 6-0 monofilament sutures.
Preparation of Lipids for the Comparison Between Hydrated and
Anhydrous States
Lipids in atherosclerotic tissue are in contact with an aqueous
milieu, ie, are hydrated, while crystalline lipids obtained
commercially are anhydrous. To obtain lipids exposed to water and
therefore more likely to reflect the status of lipids in the aqueous
environment of plaques, anhydrous lipids were combined, in microfuge
tubes, with equal amounts of distilled H2O (50%:50%
wt/vol). Each lipid/H2O combination then was heated with a
heating block until the lipid was observed to melt or to a temperature
of 110°C, whichever came first. At that point, the
lipid/H2O combination was mixed by vigorous vortexing.
Preparation of Lipids Mixture
Samples (50 mg) of lipid mixtures that simulated the proportions
of lipids found in plaques (atheroma) with high, low, and
normal cholesteryl ester content were prepared using compositions
determined for these different plaque types by Small.15
Increases in the proportion of total cholesteryl esters were coupled
with corresponding decreases in the total proportion of unesterified
cholesterol, while the relative proportions of
sphingomyelin, triolein, and L-
-lecithin were kept
constant (Table 2). Due to the concerns
of accuracy of weighing small amounts of compounds, the number of
cholesteryl ester types was limited to three (cholesteryl oleate,
linoleate, and stearate). These compounds represent the most
abundant cholesteryl esters in plaques and have a range of melting
points representative of the other, less prevalent,
types. To determine how much of each of the three major cholesteryl
ester types to add, the melting points of all cholesteryl esters listed
by Small were determined and the amounts of these minor cholesteryl
esters were substituted for whichever of the three major cholesteryl
esters had the closest melting point.15
Lysolecithin was represented by
L--lecithin, and triglycerides were
represented by triolein, which is liquid at room
temperature. The same hydration and heating process used for individual
lipids was used for the lipid mixtures, which were placed in microfuge
tubes.
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MRI
The lipid-injected aorta or lipid-filled tubes were placed into
a polyethylene specimen container for MRI. This container was built to
accommodate the platform, a water solution for temperature control, and
a custom-built integrated RF surface coil (Fig 1
).24 A
tube passing through the container was used to control the sample
temperature by connecting to a heat bath. The experimental temperatures
of the container were calibrated individually.
The MR images were taken from a 1.5-T whole-body SIGNA imager, version
5.4 (GE Medical Systems). A two-dimensional spin echo sequence was used
to acquire T1W, T2W, and PDW images across regions with lipid
injections. The imaging parameters (TR [ms]/TE
[ms]/field-of-view [cm]/matrix size/slice thickness
[mm]/excitation) for T1W were 600/20/8/512x256/1.5/2; for T2W,
2500/80/8/512x256/1.5/2; and for PDW, 2500/20/8/512x256/1.5/2. For
each lipid-injected aorta, T1W, T2W, and PDW images were acquired at
four different temperatures (37°C, 40°C, 45°C, and 50°C).
Sample images are presented in Fig 2.
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CNR Analysis
For injected lipids, signal intensities were measured on the MR
images from sites of injection, from uninjected aorta, and from the
platform using the Independent Console (GE Medical Systems). Each image
was magnified by a factor of two and the signal intensities were
measured from all lipid areas by using an ROI of 0.122
mm2. For each lipid site, multiple intensity readings were
taken, with the lowest reading being chosen to minimize the partial
volume effects of the surrounding tissue. To determine the background,
signal intensities of a 10- to 12-mm2 area were taken from
the platform.
The CNR ratio was determined by the formula CNRi=(Si-So)/SD, where Si is the signal intensity of lipid/simulated plaque site i, So is the signal intensity of the platform, and SD is the noise equal to the SD of the background air. For each single lipid or simulated plaque, a mean CNR and SD were calculated on the basis of measurements from a minimum of five sites.
For lipids contained in the microfuge tubes, the measurements conducted were the same as for the injected lipid model, with the exception that the size of ROIs varied according to the amount of lipid presented. Due to the positioning of different vials, a surface coil correction program was used to remove signal variations due to coil sensitivity before measurements.26 A mean CNR and SD were calculated on the basis of measurements from a minimum of five sites.
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Results |
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Individual Lipids
Fig 3
shows the CNR changes over
different temperatures for single lipids in T1W, T2W, and PDW images.
Triolein, which is in liquid phase at body temperature, showed the
highest signal intensity and changed little with increasing
temperature. The artery wall, into which the lipids were injected, had
CNR values that were slightly less than triolein in PDW and T2W images
and half those of triolein in T1W images. Signal intensities for
cholesteryl stearate, cholesterol, and
L--lecithin varied little over the temperature range
studied. Cholesteryl linoleate, with a melting point of 42°C, showed
a dramatic increase in signal intensity in all three contrast
weightings after the experimental temperature passed its melting point.
Similarly, cholesteryl oleate (melting point of 46°C) showed a
similar increase in signal strength after it passed its melting point.
Sphingomyelin had relatively large T1W and PDW signal strengths but a
weak T2W signal strength. The CNR of the artery wall changed little in
T1W and PDW images and decreased in T2W images with increasing
temperature.
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Signal Differences Between Lipids in Anhydrous and Hydrated
State
Compared with their anhydrous counterparts, significant signal
increase was observed with hydration for sphingomyelin and
L--lecithin in T1W, T2W, and PDW images (Fig 4). In addition, the CNR features of
anhydrous sphingomyelin were different from those shown in Fig 3, likely indicating that the sphingomyelin injected into aorta in the
anhydrous state had become partially hydrated by the time of imaging.
Once hydrated, the CNR values of sphingomyelin were strong in all three
contrast weightings, especially in T2W imaging. The CNR values of
hydrated L--lecithin were significantly larger than
those of anhydrous state but less than the CNRs of sphingomyelin. No
significant signal changes were observed with hydration for
unesterified cholesterol and/or any of the three
cholesteryl esters tested (data not shown). Triolein was not tested,
since it already was in liquid phase at the temperatures studied.
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Overall, at body temperature, among the individual lipids, the highest
MR signal intensities were obtained from the triglyceride
(triolein) and from the phospholipids (sphingomyelin and
L--lecithin). The signal intensities of
cholesterol and cholesteryl esters were quite low. Because
the signal intensities of normal aorta were intermediate between the
high triglyceride and phospholipid signals and the low
signal intensity of cholesterol and cholesteryl esters, all
four of these groups could be distinguished from normal aortic tissue
(P<.02). T1W imaging will be the choice to differentiate
aortas and single lipids, as evidenced by the contrast differences
between aortas, phospholipid, triglyceride, and cholesteryl
esters.
Lipid Mixtures
Signal intensities of lipid mixtures that simulate the proportions
of different lipids found in plaques showed marked regional
heterogeneity (Fig 5).
This heterogeneity was more prominent in the two lipid
mixtures with the lower cholesteryl ester (and therefore the higher
unesterified cholesterol) contents. Fig 5 shows a group of
images of the three contrast weightings taken from three sequential
(equal distanced) locations of microfuge tubes containing the three
lipid mixtures. A microfuge tube filled with H2O was also
included as reference. In these images, high signal intensity regions
were seen in all three types of mixtures interleaved with regions of
low signal intensity. These results indicate that the different lipid
types were not homogeneously mixed in these lipid mixtures
designed to simulate plaque lipid proportions. Despite these signal
variations, the overall signal intensities were higher in both T1W and
PDW images for lipid mixtures with high cholesteryl ester content and
lower for lipid mixtures with lower cholesteryl ester content.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study used lipid CNR values to express the MR signal patterns of cholesterol, cholesteryl esters (cholesteryl linoleate, stearate, and oleate), triglyceride (triolein), and phospholipid (L-
-lecithin and sphingomyelin) at
different temperatures to establish a realistic model for preclinical
testing. The contrast comparison was relative to the plastic platform,
which had a signal intensity similar to air. Thus, a CNR value of zero
corresponds to very low signal intensity.
Individual Lipid
The images taken from normal porcine aortas with implants of
individual lipids demonstrated that each of the lipid implants could be
distinguished from normal aortic media in each of the three contrast
weightings tested at the spatial resolution used. This spatial
resolution (0.16 mmx0.31 mm) is currently used in in vivo
human carotid artery imaging.17 Thus, our findings may
eventually have direct clinical applications. For example, an important
next step will be to assess the signal feature differences between
lipid cores of atherosclerotic plaques and the fibrous caps that
separate the core from flowing blood. In addition, other practical
issues of in vivo imaging will need to be considered, including the
effects of vessel motion due to pulsatile blood flow, the structural
complexity of normal and atherosclerotic human artery walls, and
improving spatial resolution. These problems have been addressed to
some extent for carotid arteries,17 but attempts to extend
these techniques to coronary arteries will provide additional
challenges, such as increased vessel motion due to cardiac contraction
and a need for higher spatial resolution due to smaller vessel
size.
The CNR values for individual lipids shown in Fig 3 indicated that,
with the exception of sphingomyelin, the individual lipids did not
contribute to MR signals until the imaging temperature reached or
exceeded their melting point. This is evidenced in CNR changes of
cholesteryl linoleate and oleate, both of which have melting points
between 40°C and 50°C. This result is expected, because once in the
liquid phase, lipid molecule motion increases to a rate near the MR
Larmor frequency. This results in faster energy exchange among
molecules, which translates into a shorter T1 relaxation time and
higher MR signals.27 The signal contribution of liquefied
cholesteryl linoleate and oleate may be higher than the results shown
in Fig 3. The slightly lower signal could be partially due to the fact
that only the lowest reading from the lipid site was used for
contrast-to-noise calculation.
Triolein, a triglyceride in liquid phase at body temperature, had strong signals compared with both porcine aortas and other type of lipids in all three contrast weightings. Further, there was little change in signal intensity over different temperatures. These signal features are similar to the adipose tissue signal observed in MR images. Aortas, with media as the main constituent, contain smooth muscle cells, elastin, and collagen. Their MR signals tend to be similar to those of muscular tissues.16 Thus, in T1W images, triolein had stronger (and hyperintensive) signals than aortas, and in T2W and PDW images, the signals of triolein and aortas are comparable.
Signal Differences Between Lipids of Anhydrous and Hydrated
State
The physical state of lipid can have significant impact on MR
signal intensities, as demonstrated in this study. Since the hydrated
state is the normal state of lipids in human atherosclerotic plaques,
the signal features obtained from hydrated lipids are more relevant to
gauging the results that might be expected from in vivo imaging. Among
all the lipids tested, including cholesterol,
cholesteryl esters, and phospholipids, significant increases
of signal intensities attributed to hydration were observed in the two
phospholipids (sphingomyelin and L--lecithin).
In contrast to other lipids, which are almost entirely hydrophobic,
both sphingomyelin and L--lecithin are amphiphilic,
possessing both hydrophilic polar head groups and hydrophobic
hydrocarbon tails. The polar head groups of these phospholipids allow
them to combine with water, causing them to swell into liquid
crystalline or "gel" structures when mixed with
water.28 It is likely that this mixture between water and
phospholipid molecules produces a proton-interactive environment that
generates MR signal features which differ from those of either pure
water or lipids, such as triglycerides, which are in the
liquid phase at body temperature. The observation that there were no
significant changes in the signal intensities of these hydrated
phospholipids over the range of temperatures tested suggests that the
structure of these gels did not change substantially under the
conditions of this experiment.
The stronger signal of sphingomyelin compared with
L--lecithin may be due to either or a combination of two
factors. First, sphingomyelin has greater relative polarity than
L--lecithin. This property should allow a higher
proportion of water molecules to be incorporated into the sphingomyelin
compared with the L--lecithin gel. Second, because
sphingomyelin has two nitrogens per molecule, while
L--lecithin has only one, sphingomyelin would be
expected to have higher nitrogen-related paramagnetic resonance than
L--lecithin.
Lipid Mixtures
Because atherosclerotic plaques contain a mixture of lipids, the
MRI contrast features of lipid mixtures simulating plaque lipid
proportions have more relevance to potential clinical application of
this technology.15 There were three major differences in
the MR signals between lipid mixtures and individual lipids: (1) at
body temperature, all three lipid mixtures contributed to MR signals,
which were more pronounced in T1W and PDW images; (2) signals from the
three different lipid mixtures were heterogeneous, more
pronounced in mixtures with intermediate and low cholesteryl ester
contents; and (3) at body temperature, lipid signals in lipid mixtures
with higher cholesteryl ester contents were stronger than those of the
other two lipid mixtures in T1W and PDW images and lower in T2W
images.
As expected from individual lipid studies, lipid mixtures simulating plaque lipid proportions can generate strong overall MR signals. However, a more important finding is that the signal can be heterogeneous, which strongly suggests that the different types of lipids are not in a uniformly mixed state, even though vigorous vortexing was applied in all cases after samples were heated to 110°C. The regional heterogeneity of the vortexed hydrated lipid mixture could be from differential regional concentrations of the lipid crystals. Thus, a subregion with high signal intensities in T1W images may locally contain more phospholipid, and a subregion with low signal may contain more free cholesterol.
The overall signal intensity of the three simulated plaques measured from a large ROI demonstrated that plaques with higher cholesteryl ester content had stronger signal and that the intensity increased with increasing temperature (data not shown), a strong indication that an increasing amount of cholesteryl esters was changing to liquid phase and thus contributed to the MR signal. This phenomenon of increasing signal intensity with temperature was not apparent in lipid mixtures with intermediate and low cholesteryl ester contents. The most likely explanation for the higher signal intensities of the lipid mixtures with high cholesteryl ester content is that the combination of these constituents lowered the overall melting point. Small28 showed that when cholesteryl linoleate, oleate, and palmitate are mixed at certain combinations, the overall melting point decreases. The same could be true of combinations of cholesteryl linoleate, oleate, and stearate. If a combination of these three cholesteryl esters lowered all of their melting points, then the MR signal intensity would increase even at body temperature.
The signal heterogeneity of mixed lipids raised two
important points: (1) It may be possible to further differentiate
lipid-rich regions of plaque into subregions of
cholesterol, cholesteryl ester, and phospholipids and (2) a
single MR contrast weighting may not be enough to identify these
regions. For example, the hypointensive region of lipid mixtures with
low cholesteryl ester content had similar signal intensity as water in
the T1W image (Fig 5a) but was darker than water in the PDW image (Fig 5d). In addition, this region may contain more free
cholesterol than its neighboring hyperintensive region.
Further studies will be needed to correlate the differences of MR
signal from lipid-rich regions of plaques to the differences of lipid
contents and to compare the signal features of lipid-rich regions with
those of other tissues of atherosclerotic plaques, especially fibrous
plaque and intraplaque hemorrhage.
In summary, this study shows that among individual lipids,
triglycerides, which constitute 6% of the plaque, have
strong signals in all three MR contrast weightings at body temperature.
Hydrated phospholipids, typified by sphingomyelin and
L--lecithin, also have high MR signal intensities. In
contrast, cholesterol and cholesteryl esters have very low
MR signal at body temperature. Because the MR signals of aortic media
are intermediate in intensity, it may be possible to distinguish both
high-MR-intensity triglycerides and phospholipids and
low-intensity cholesterol and cholesteryl esters in
arterial tissue. Further, the marked regional
heterogeneity of MR signals seen in lipid mixtures that
simulate plaque lipid proportions suggests that it may be possible not
only to determine the total lipid content of plaques but also to get
some idea of the relative proportions of different lipid types within
an individual plaque. It will be important for future studies to
determine whether these observations can be confirmed by careful
correlation of MR images with histological examination
of human atherosclerotic lesions. If this is the case, this technique
may have the exciting potential of allowing the detection of lipid-rich
as opposed to lipid-poor plaques in vivo to confirm whether these
lipid-rich plaques are indeed at higher risk of subsequent rupture and
to follow serially the response of such plaques to interventions such
as lipid-lowering or antioxidant therapy.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We gratefully acknowledge the support of the Whitaker Foundation and the John Locke, Jr, Charitable Foundation of Seattle, Wash. We thank Jason Lingel and Marilyn Osterman for assistance in manuscript preparation.
Received December 29, 1995; accepted October 25, 1996.
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