Vulnerable plaques identified visually by computed-tomography (CT) angiography
are more likely to result in a subsequent acute coronary syndrome during
follow-up, a new study has shown [1]. Identifying these unstable coronary
plaques, which have areas of low attenuation and have undergone positive
remodeling, could be used to aggressively treat patients who are at higher risk
for future events, according to researchers.

"Our data suggest that once a patient is identified to be at risk of having an
adverse event on the basis of traditional clinical, biochemical, and biomarker
risk profiles, imaging may help identify those at greater risk of acute coronary
events," write lead investigator Dr Sadako Motoyama (Fujita Health University
School of Medicine, Toyoake, Japan) and colleagues in the June 30, 2009 issue of
the Journal of the American College of Cardiology.

Speaking with heartwire , Dr Renu Virmani (Cardiovascular Pathology Institute,
Gaithersburg, MD), one of the study investigators, said the results show for the
first time that high-risk, vulnerable lesions, characterized previously in
pathologic studies, are able to identify patients with future symptoms, and this
moves the field forward by a "big step."

"This is just the beginning, but it is a good beginning," she said. "It is the
first study we have showing us that we can actually identify these lesions and
that these are the lesions that are going to produce symptoms in patients.
Before that, it's all been a theory. We were able to say these are vulnerable
plaques, and we should watch and worry about them, but we had no way of showing
these were the ones that would go on to produce symptoms."

More Than 1000 Patients Assessed by CTA

To determine whether the characteristics of atherosclerotic lesions were
associated with future acute coronary syndromes, the researchers analyzed the
lesions based on the presence of positive vessel remodeling and low-attenuation
plaques. Virmani explained that these two characteristics, along with a necrotic
core, are thought to be associated with subsequent plaque rupture.

Among the 1059 patients who underwent CT angiography, 45 patients had coronary
plaques that had undergone positive remodeling and were classified as low
attenuation. After more than two years of follow-up, 10 patients, 22.2%, with
both characteristics of vulnerable plaque developed an acute coronary syndrome.
On the other hand, just one of the 27 patients with only one feature, either low
attenuation or positive remodeling, developed symptoms, while only 0.5% of the
820 patients without any features of vulnerable plaque developed an acute
coronary syndrome.

In a multivariable regression analysis, the presence of low-attenuation plaque
or positive remodeling was associated with a 23-fold increase in the risk of an
acute coronary syndrome (hazard ratio 22.8; 95% CI 6.9-75.2; p<0.001).

Virmani told heartwire that it is not always easy to identify low-attenuation
plaque and that there are those who doubt whether visualizing these softer
plaques can be done reliably, although the technology is improving. On the
horizon are better imaging modalities, including 320-detector-row CT scanners
that improve resolution, as well as machines that limit the amount of radiation
exposure.

Systemic vs Focal Disease

Commenting on the results of the study for heartwire , Dr Steven Nissen
(Cleveland Clinic, OH) said he was skeptical of the results and the
vulnerable-plaque hypothesis, in general. In a recent editorial in the Journal
of the American College of Cardiology: Cardiovascular Imaging, Nissen said that
many diagnostic techniques designed to detect vulnerable plaques, including
thermography, virtual histology, and optical coherence tomography, among others,
have promised much but delivered little [2].

Last week, noted Nissen, a CT-angiography study, reported by heartwire , showed
that the technology was unable to reliably identify the functional significance
of coronary lesions in patients with stable angina and atypical chest pain. To
now suggest that CT angiography can identify plaques at risk for rupture is
"asking an awful lot from this technology." Also, he said the investigators did
not show that the lesion of the coronary artery identified by CT angiography as
vulnerable is responsible for the acute coronary syndrome.

"They don't close the loop," said Nissen. "We don't find out that the site that
had positive remodeling and low attenuation is the site where the plaque
ruptured. Without that, this becomes much more speculative."

In general, Nissen said that he believes the vulnerable-plaque approach is the
wrong approach because atherosclerosis is a systemic disease, and if anything is
likely to predict outcomes, it's a systemic, not focal, marker. Virmani, on the
other hand, strenuously disagrees, telling heartwire that Nissen is "missing the
boat" regarding these high-risk focal lesions because evidence shows that
patients with coronary events have a focal thrombus formation.

"If you look at acute-myocardial-infarction patients, it occurs in one vessel,
in the proximal areas," said Virmani. "Why? Those are the most prone areas.
That's where we need to concentrate. His [Nissen's] idea of concentrating on
systemic factors, such as LDL cholesterol, diabetes--yes, absolutely, but those
are the patients that then have focal lesions. I don't deny that you need
hypercholesterolemia for a patient to have focal lesions, but in the patients
that are high risk, they do develop them at focal spots."

Did Anybody See My Stolen Horse?

In an editorial accompanying the published study, Dr Eugene Braunwald (Harvard
Medical School, Boston, MA) adopts the middle road, hailing the study by
Motoyama and colleagues as a landmark trial, while acknowledging the current
limitations in the detection of vulnerable plaque [3].

Braunwald notes that widespread clinical application of CT angiography to
characterize coronary lesions at risk for future rupture, which he aptly
describes as "locking the barn before the horse is stolen," will require more
potent measures for the prevention of plaque rupture than are currently
available. Dual antiplatelet therapy, possible stenting, or more potent
anti-inflammatory drugs are just some of the possibilities, writes Braunwald.

"Nobody is saying we need to start treating these patients," adds Virmani.
"Start treating them systemically, just as Dr Braunwald points out in his
editorial. Right now, we don't know how to treat these patients. We might need
to think of different therapies. Some patients might need anti-inflammatory
drugs, or some might need stents, but we won't know until we learn how these
lesions behave prospectively."

Dr Mario Garcia (Mount Sinai School of Medicine, New York) told heartwire that
low-attenuation plaques with positive remodeling are features identified as
characteristics of thin-cap, lipid-rich plaques in intravascular ultrasound
(IVUS) correlative studies. He added that while the present study identifies a
novel imaging biomarker as a powerful predictor of future ACS, there remain
unanswered questions, particularly whether the predictive accuracy of CT is
superior to established serum biomarkers such as high-sensitivity C-reactive
protein (CRP) and whether the same predictive utility could be extrapolated to
asymptomatic subjects at risk.

In addition, like Braunwald and Nissen, Garcia says trials are needed to
determine the optimal treatment strategy to follow--for example, intensive
medical therapy vs prophylactic PCI--once these "high-risk features" are
identified in a patient.