Cardiac Imaging
Future of CVI: It’s all about
plaque
Identification of vulnerable lesions, not
‘rusty pipes,’ could become cornerstone of preventive
cardiology
By Catherine
Carrington
Think of a pump fed by a network of pipes so rusty and corroded that only a
trickle of fluid finds its way through the constricted core, until finally the
pump seizes up and stops working. That’s how scientists once viewed the
cardiovascular system and its most extreme example of deferred maintenance, the
heart attack.
Today, we know the picture is far more complex. Most heart attacks
aren’t caused by a slow, occlusive build-up of atherosclerotic
“rust,” but rather by the sudden rupture of weakened plaque silently
festering with inflammation [Fig. 1]. What’s more alarming,
rupture-prone plaque seldom narrows the coronary “pipes” much or
interferes with blood flow, and that makes it undetectable by conventional
diagnostic methods.
“The microanatomic characteristics of plaque composition may be more
important than the severity of the stenosis in the angiogram,” said Dr.
Pedro Moreno, who directs the catheterization laboratory at the Veterans Affairs
Medical Center in Lexington, KY. “Unfortunately, regular angiography is not
able to detect this lesion.”
That realization is changing the face of cardiovascular imaging.
Characterizing plaque has become the relentless focus of nearly every form of
cardiovascular imaging. It is fueling research not only in MR, CT, ultrasound,
and nuclear medicine, but also in novel invasive approaches that exploit the
potential of light, heat, and chemistry to distinguish stable, calcified plaque
from soft, vulnerable lesions that are filled with fat and inflammatory cells
and encased by only a thin, fibrous cap.
From The Outside In
Noninvasive methods of plaque characterization are especially appealing, and
MR brings certain advantages to the task. Its spatial resolution, though not as
impressive as that of its invasive competitors, lets it image plaques smaller
than 1 mm. It can create both two- and three-dimensional images. And it is also
capable of quickly assessing atherosclerosis throughout the body, a key strength
in gauging the risk not only of heart attack but also of stroke, which can
result from plaque rupture in the carotid arteries and aorta.
“It’s very important to have an imaging modality that can assess
this disease in a systemic fashion,” said Zahi Fayad, Ph.D., who directs
cardiovascular imaging physics and research at Mount Sinai Medical Center in New
York City.
MR differentiates components in the plaque through natural tissue contrast
arising from differences in chemical composition. Each of the four main
components of plaque—calcium, lipid, the fibrous cap, and
thrombus—scripts a different signature on the MR sequences used to image
it. From this information, it may be possible to predict which plaques are
stable and which are vulnerable to rupture.
Calcium, for example, has very little water and few protons, so it looks
hypointense on T1-weighted imaging and very hypointense on both proton-density
and T2-weighted imaging. A plaque’s threatening lipid core, by comparison,
appears very hyperintense on T1-weighted imaging, hyperintense on proton-density
imaging, and very hypointense on T2-weighted imaging. The fibrous cap looks
isointense or hyperintense with all three imaging sequences, while the
appearance of thrombus is variable.
Though MR leads noninvasive plaque evaluation, CT can add important details
to the picture, and preliminary research suggests it may, in the future, offer
information on plaque composition as well.
When information from MR and CT is pieced together, it will offer valuable
insight into vessel wall pathology, experts predict.
“I believe that we will have noninvasive techniques mastered in the next
three to five years,” said Dr. Tom Brady, who directs the cardiac imaging
program at Massachusetts General Hospital in Boston. “When people go into
the cath lab in 2007 or even earlier, they will have not just the
‘lumenogram’ provided by conventional angiography, but a map of wall
thickness, plaque volume, lipid volume, and calcium volume displayed for the
cardiologist.”
The View From Within
Despite the advantages of noninvasive imaging, the most accurate way to
characterize plaque so far appears to be up close and personal. MR researchers
know this and are working on invasive and interventional MR technologies. Fayad
and his colleagues, as well as researchers at Johns Hopkins Hospital in
Baltimore, are testing the potential of high-resolution intravascular MR coils
mounted inside of catheter guidewires, for example.
Invasive MR faces competition from a number of novel invasive techniques that
are vying to establish their scientific validity.
“Our information regarding the atherosclerotic plaque largely comes from
cross sections obtained at autopsy,” said Dr. E. Murat Tuzcu, who directs
the intravascular ultrasound laboratory at the Cleveland Clinic. “All of us
are trying to get a glimpse of the action when the patient is living and awake.
Down the line, I think we will rely less on taking care of patients after a
catastrophe than on trying to prevent it.”
Of the invasive approaches, intravascular ultrasound (IVUS) has the longest
track record and is often cited as the imaging gold standard for plaque
identification, offering tomographic images that visualize many of the
characteristics defined by pathologists at autopsy.
With IVUS, plaque is characterized according to the degree of echogenicity in
comparison with normal adventitia. Soft, lipid-filled plaque is less echogenic,
and calcified plaque demonstrates a bright echo and acoustic shadow. But Tuzcu
cautioned that ultrasound is limited in the details provided.
“Ultrasound gray-scale pictures do not always represent faithfully the
histologic changes,” he said. “On the other hand, intravascular
ultrasound is very accurate in determining the location of plaque and whether it
is eccentric or concentric.”
One of the most promising new technologies is optical coherence tomography
(OCT). This is akin to IVUS but measures back-reflected infrared light rather
than sound. It is a high-speed technology whose simple fiber optics are
incorporated into existing arterial catheters. Its key advantage over IVUS and
many other techniques is an extremely high resolution, 4 to 20 mm.
“That’s up to 25 times higher than anything in clinical
medicine,” said Dr. Mark Brezinski, a researcher at Brigham and
Women’s Hospital in Boston.
This means that while IVUS may detect plaque, OCT can visualize its makeup in
detail, including the layers of intima the plaque has invaded and the thickness
of its fibrous cap—a key in assessing the risk of rupture [Fig.
2]. A fibrous cap that is less than 65 mm thick is considered to be at high
risk for rupture, according to pathologist Renu Virmani of the Armed Forces
Institute of Pathology in Washington, DC.
Human trials of OCT are expected to begin in late summer, said David Kolstad,
marketing vice president of LightLab Imaging, a company founded by Brezinski and
others to commercialize OCT technology.
A Biopsy With Light
At the University of Kentucky, researchers are testing the potential of
near-infrared (NIR) spectroscopy to go beyond creating an image of plaque and,
instead, provide information on its chemical and molecular structure.
When plaque is illuminated by halogen or laser light from a fiber-optic probe
tuned to the NIR wavelength, some of the light is absorbed by the plaque, but
most is scattered back. Once captured by a receptor, scattered photonic energy
is dissected into different wavelengths.
“We have these absorbent peaks that usually are produced by combinations
of fundamental bonds, like carbon-hydrogen, carbon-carbon, and carbon-oxygen.
These bonds actually stretch with light and induce these peaks,” said
Moreno, an assistant professor at the University of Kentucky, where the research
is being conducted.
The technique has demonstrated high sensitivity and specificity for
identifying vulnerable plaque in laboratory and animal studies. Moreno expects
to begin human studies by the end of this year. Down the road, researchers are
planning to conduct a 1000-patient trial to gauge how successful NIR
spectroscopy is in predicting clinical outcomes, not just in patients at risk
for plaque rupture but also for a related condition known as plaque erosion.
Erosion is a thrombotic process in which the plaque appears more stable than
it really is. The plaque is not filled with lipid and the fibrous cap remains
intact. The endothelium is worn away, however, exposing the intima to blood.
Erosion is believed to account for 40% to 50% of plaque thrombosis, particularly
in young women and smokers.
“We will follow those patients that we thought had stable plaques,”
Moreno said. “Some of these patients will evolve with an acute syndrome,
and the NIR signal could be analyzed retrospectively to finally detect a plaque
that is not only vulnerable for disruption but also vulnerable for erosion and
thrombosis.”
Hot Plaque
Inflammation plays a key role in the destabilization of plaque. The coronary
arteries don’t have pain fibers, and both swelling and redness can have
many other causes, according to Dr. S. Ward Casscells III, cardiology chief at
the University of Texas Health Science Center in Houston.
“Fortunately, heat remains a valid sign of inflammation in the
coronaries—and the heat is more than anyone might have predicted,”
Casscells said.
Casscells and his colleagues have analyzed arterial specimens immediately
after surgical removal and noted temperature increases in the plaque of up to
2ºC. Heat variation in plaque is correlated most closely with the number
and activity of inflammatory cells and the thinness of the fibrous cap. A thick
cap acts as an insulator, but a thin cap places inflammatory cells close to the
lumen.
To measure the heat generated by inflamed plaque, Dr. Morteza Naghavi,
Casscell’s colleague at UT, has led the development of an intravascular
thermography catheter equipped with infrared fibers [Fig.
3]. Researchers in Greece have developed a similar device and have
demonstrated striking differences in the temperature of plaque between patients
with stable angina and those with unstable angina or myocardial infarction.
In the future, such catheters may also be used to treat thrombosis-prone
lesions—ironically, by heating them even more.
“If you raise the temperature a little bit higher to 41° or 42°C
(106° to 108°F), you see that the inflammatory cells, the macrophages,
preferentially undergo apoptosis,” Casscells said. “Presumably this is
a good thing, since these are the cells that eat through the cap and cause the
thrombosis.”
Ms. Carrington is a medical writer in Vallejo,
CA.
