Plaque Attack: Options Evolve for Imaging Coronaries and Carotids, but Link With Hard Outcomes Remains Elusive

PRAGUE, Czech Republic—How newer atherosclerosis imaging tests can be used to pinpoint the risk of future cardiovascular events remains one of the hottest areas of cardiac research, but the relative importance of plaque burden versus plaque vulnerability remains unresolved.

In a dedicated session at the 2017 European Atherosclerosis Society meeting last week, speakers argued the relative merits of 3-D ultrasound, CT angiography, and positron emission tomography/magnetic resonance (PET/MR) for imaging coronary and carotid disease.

3-D Ultrasound ‘Ticks All the Boxes’

“As we start to move beyond the coronary vessels, [we] acknowledge that IVUS at best is a very good research tool, . . . but nobody seriously thinks that this is going to have a significant role in the clinical detection of disease and triage of patients on a wide scale phenomenon,” said presenter Stephen Nicholls, MBBS, PhD (University of Adelaide, Australia), explaining the potential role for 3-D ultrasound as a noninvasive method for measuring plaque volume. “Clearly there’s going to be a lot more interest in how we can use noninvasive approaches and if there are opportunities to use ultrasound to do that. This has been a field that has been really gaining momentum for a number of decades now.”

For imaging of carotid arteries, he noted, there has been a push to move away from focusing on longitudinal, two-dimensional measurements of intima-media thickness (IMT) to a more systematic approach of measuring plaque volume in a cross-sectional manner, one that’s “very similar to the approach we've used with coronary IVUS,” albeit more complicated.

“We've seen a number of groups now generate analytical approaches that have enabled them to apply that cross-sectional analysis across a number of equidistant images throughout the length of the vessel to be able to generate volume,” Nicholls added. “That’s been an important move forward in this field.”

Measurement variability with a volumetric approach appears to be “much less” than with measuring IMT and individual plaques, he said. “In fact, the greater the disease burden, the much lower the variability appears to be. Certainly, it may have its greatest bang for its buck in patients who have a much larger amount of plaque in the carotid arteries.”

[3-D ultrasound] may have its greatest bang for its buck in patients who have a much larger amount of plaque in the carotid arteries. Stephen Nicholls

Reviewing the literature, Nicholls explained that carotid ultrasound can potentially be used to look at plaque characteristics in addition to overall burden. “Measuring the texture within the plaque may give us some insight into potential differences in plaque character and therefore cardiovascular risk,” he said.

Additionally, using 3-D ultrasound in a serial fashion enables imagers to measure plaque volume over time and hence capture the effect of therapies on these changes, which “may be a useful tool moving forward,” he said.

But to move the field of 3-D ultrasound along, Nicholls said, very high quality images and expertise will be required. “Where you have great sonographers, I suspect this is going to be a valuable tool in your clinic,” he predicted.

Whether this technique will “be able to proliferate to other centers” remains to be determined, Nicholls concluded. 3-D ultrasound “ticks all the boxes” in that it is noninvasive, can be applied quickly and in a mobile fashion, and is inexpensive, he continued. But “are the changes that we see on serial imaging of a significant magnitude to support a role in individual models in your patients? We don’t know.”

There’s also the question of what degree of plaque volume determined by 3-D ultrasound is relevant for predicting hard events. Session Chair and EAS President Lale Tokgözoğlu, MD (Hacettepe University, Ankara, Turkey), asked Nicholls how he would define significant atherosclerosis given the new dyslipidemia guidelines, which suggest that subclinical imaging is important for these high-risk patients. “Is it one plaque over 60%, or is it a lot of small plaques adding up to a lot of burden?” she asked.

Acknowledging that there is no current right answer, Nicholls said he likes what the guidelines were trying to do, but thinks that they perhaps “have gotten one step ahead of themselves.

“Many of us in this room certainly will be faced with not necessarily doing this test ourselves and having to manage the issue, but often the patients have had the test ordered by somebody else and they were referred to you,” he continued. “In an evidence-free zone, it’s hard to know what to do. We do need larger, prospective studies that really show that by doing the imaging, it changes what we do and ultimately changes the outcomes. Then, only at that point can we then reliably inform the guidelines beyond what we've already seen.”

CT Angiography Advances in Assessing Plaque Severity

Indeed, the next speaker in the session, Jason Tarkin, MBBS, PhD (Barts Heart Centre, London, England), said that while there are “many good tests to diagnose atherosclerosis, . . . risk prediction remains a significant challenge. Most coronary events occur in people without prior knowledge of their underlying condition.”

Moreover, a number of studies have shown that while the features of high-risk plaques are important to know, “we know most high risk plaques don’t cause clinical events,” he said.

As such, Tarkin sees CT angiography as playing a bigger role in risk prediction when used as a serial test to track plaque progression over time, he explained.

Its “major strength” is excellent sensitivity and negative predictive value to exclude significant stenoses in patients with low-to-moderate risk, Tarkin said. “It's also demonstrated reasonable specificity to detect significant disease in symptomatic patients when evaluated in clinical trials.”

Additionally, “the natural history of the disease is also changing because of preventive health measures and increased statin usage, potentially making individual high-risk plaque identification even less important,” Tarkin said. “This raises the question: should we focus on plaque burden instead, and shift focus toward identification of vulnerable patients rather than vulnerable plaques?”

Should we focus on plaque burden instead, and shift focus toward identification of vulnerable patients rather than vulnerable plaques? Jason Tarkin

Because of advances in the field, it’s clear that “CT coronary angiography is no longer just the gatekeeper to invasive angiography,” he concluded. “It can provide important information on anatomical stenosis severity, but also [on] plaque morphology, plaque burden, and functional ischemia. Ultimately this information can be used to identify vulnerable patients with high-risk plaques and high-burden disease.”

Following his presentation, Tokgözoğlu asked Tarkin the same question she’d asked Nicholls earlier about how best to link significant atherosclerosis with clinical events. Currently, “we mainly focus on stenosis severity” when viewing CT angiograms, he responded. “But clearly other factors are important, which is why the guidelines have included assessments of plaque vulnerability. And clearly if you're thinking about prediction of long-term events, plaque burden is the most important.”

So is looking at the disease from a “comprehensive point of view,” Tarkin said. “Taken together, the advantage of CT over some of the other invasive techniques is that you can have multiple assessments of disease severity, which together have a greater chance of predicting outcomes than any single assessment.”

Tokgözoğlu also asked about radiation safety with CT angiography, given that in the past, high radiation dose was seen as an Achilles’ heel of this approach.

“Radiation has dramatically decreased,” Tarkin responded, adding that “you can get good diagnostic images” today with doses comparable to those of chest x-rays.

PET/MR Almost Ready for Prime Time

The third presenter, Marc Dweck, MBBS, PhD (University of Edinburgh, Scotland), focused on the role of PET/MR. This approach, he acknowledged, has a little bit further to go in terms of refinement in the coronary and carotid artery imaging space, “but nevertheless holds very great potential.”

On top of looking at both plaque burden and characteristics, PET/MR imaging can “take things a step further” and also look at disease activity at very low radiation doses, he explained. “If we combine that information, I think we’ve got a much better chance of providing really accurate models of risk prediction for our patients.”

The benefits of MR imaging alone in the carotid arteries, “are already well established,” he said. “It has become the gold standard for assessing these vessels based on very detailed angiographic images and also soft tissue characterization.” The same is “not quite true” for coronary imaging, Dweck continued, “but it is catching up. We are able now to get pretty robust images of these vessels.”

In his mind, MR images of carotid arteries are better than those achieved with 3-D ultrasound, although the technology does not “have the same advantages of portability and of ease.”

As for PET, “the idea is you develop a tracer used to target a biological process you’re interested in. In principle, you can target any process that you like” with the right tracer, Dweck explained. There has been “great growth” in the field of tracers for coronary imaging in the past 5 years, but right now there are only three main ones in use, he added.

Because PET imaging doesn’t provide “huge amounts of anatomical information,” Dweck said they have traditionally fused the images with a CT scan to pinpoint the location of the disease activity. “This type of imaging is really going to let us understand more fully how systemic diseases at multiple different spots in the body are related.”

Combining PET and MR together is really where things get interesting, he commented, as it could make it so that the patient only has to undergo one scan instead of two, with the “key advantage” being lower radiation. “That opens up a whole range of different imaging studies where we can suddenly do imaging at different time points . . . so we can track disease activity with time and also potentially use different tracers to better look at their interplay in these complex conditions,” he said.

Also, because PET/MR scans are “as repeatable” as PET/CT scans, “we don’t need many patients if we want to design a trial to demonstrate the effects of a new drug,” Dweck said. “So we can do phase III trials relatively inexpensively.”

PET/CT imaging is already being done in some institutions, and Dweck admitted to being able to “get very nice images of the heart” with it. “But the radiation dose is not insignificant, and I think the prize of us working in the field of PET/MR is if we can get the sequences as good as PET/CT,” he said, “then PET/MR is always going to be the winner because we are not going have the high radiation doses that limit PET/CT.”

The prize of us working in the field of PET/MR is if we can get the sequences as good as PET/CT, then PET/MR is always going to be the winner because we are not going have the high radiation doses. Mark Dweck 

By contrast, PET/MR is not widely available and is “quite expensive,” he concluded. “So you need a good reason to do it. But the low radiation really . . . allows you to do some studies that are pretty interesting from a pathophysiological point of view.”

There is more work to be done and plenty of “room for optimization,” Dweck acknowledged. “But there are lots of groups around the world working on this, and I think it will move forward quickly over the next few years.”

‘The Right Test for the Question at Hand’

Contacted by TCTMD, James Rudd PhD (University of Cambridge, England), summed up the field by saying that certain tests, including CTA, are well-suited to the clinical setting, while others—for example, PET-scans (potentially in combination with tests that deliver anatomical specificity)—will likely remain research tools.

As to whether the focus should be on plaque burden or plaque characteristics, Rudd said having the “right test for the question at hand is crucial.” Tests to determine plaque burden—particularly if they are radiation free—have wide clinical applicability and can be used to prompt initiative of drug and lifestyle interventions, he said. By contrast, vulnerable-plaque imaging, particularly in the research setting, can potentially help establish drug efficacy, hone event prediction, and illuminate the biology of heart disease, Rudd concluded.