The hunt for vulnerable plaque has been the holy grail of cardiology for years. The theory driving this mission seems nice and tight. If a cardiologist can detect vulnerable plaque, he or she can undertake some action to treat it and prevent a future myocardial infarction. However, the mission remains a work-in-progress, and the end goals may be off the mark.

The first issue is a good news/bad news fact that relates to detection of vulnerable plaque. The good news is there are multiple imaging modalities with some utility at detecting vulnerable plaque. The bad news? None of them are ideal.

The other challenge relates to the goal. Can one really prevent a future myocardial infarction by detecting vulnerable plaque? According to Armin Arbab-Zadeh, MD, PhD, of the department of medicine, cardiology division at Johns Hopkins University in Baltimore, the answer is no. In a review article (J Am Coll Cardiol 2015; 65:846-55), Zadeh challenges colleagues to drop their focus on vulnerable plaque and instead focus on atherosclerotic disease burden.

Cardiovascular Business unveils the advances and issues regarding imaging vulnerable plaque.

Stable plaque, vulnerable plaque: A brief review

Stable plaque is just that—stable. It typically progresses slowly with each decade of life until symptoms appear, and then a physician attempts to address it as best as he or she can.

In contrast, unstable or vulnerable plaque does not have to become significant to cause problems. It can impinge on the lumen of the vessel and rupture, releasing lipids and igniting the inflammatory process within the vessel as the body tries to heal itself. If the vessel is large enough, a heart attack results.

Thus, the cardiology community is on a quest for a way to identify these vulnerable plaques. Several options are on the table. 

Many arrows in the quiver

“We have so many imaging modalities, and every one of them has plus and negative points,” says Annapoorna S. Kini, MD, from the division of cardiology at Mount Sinai Hospital in New York City.

Intravascular ultrasound (IVUS) has the longest history. For nearly 30 years, IVUS has served as a standard method for cardiovascular imaging. It’s routinely used and readily available in most cath labs. It can image deep into vessels. On the downside, IVUS does not allow assessment of cap thickness, one of the most important features of vulnerable plaque.

Optical coherence tomography (OCT) is a newer imaging modality that provides better imaging resolution than IVUS; OCT proponents suggest the modality can accurately image plaque components and calcium with greater resolution than IVUS. However, OCT cannot image as deeply into the vessel as IVUS, nor does it have decades of randomized study data that IVUS has.

Near-infrared spectral imaging (NIRS) produces a chemogram that quantifies the underlying chemical composition of the vessel wall and displays a probability of lipid core plaque presence using a color-coded scale. But NIRS does not provide information on the depth of lipid, nor does it provide geographic orientation inside the coronary artery.

Experts agree no single modality has emerged as optimal for imaging vulnerable plaque. In fact, it may be a hybrid approach that ultimately meets the goal of imaging vulnerable plaque.

“The combination of IVUS, NIRS, OCT, fluorescence imaging and photoacoustic tomography technology in hybrid catheters will provide new synergistic information,” wrote Pranav M. Patel, MD, from the division of cardiology at the University of California, Irvine in Catheterization and Cardiovascular Interventions online October 20, 2014.

Is hybrid imaging the answer?    

Patel and his colleagues have developed a prototype hybrid OCT-IVUS imaging technique. “Our thought was that combining the two modalities might give us the best of both worlds,” he explains. “What happens if you approach any interventional cardiologist and tell him or her you have three systems? The first is an ultrasound device that looks inside the vessel, but the images have yellow haze and the resolution is not so great. The other system gives you great images, but you can’t image as deeply or identify lipid. The third gives you the features of both. Which will he choose?” asks Patel. Most, if not all, will opt for the hybrid approach.

Early research backs up the merit of this approach.

Patel and his colleagues have reviewed IVUS, OCT and hybrid OCT-IVUS images of autopsy vessels with cardiologists and asked them to identify lipid, vulnerable plaque and calcium. They found cardiologists had a more accurate assessment of plaque when they viewed the hybrid images.

This hybrid approach may address other challenges as well. Speed can be an issue with an IVUS catheter because it’s pulled back slowly, and the physician may be unsure of where he saw the lesion. An OCT catheter tends to be much faster, but localization can be difficult, so there may be multiple passes with a catheter which can result in harm.  A single catheter with the advantages of both OCT and IVUS that localizes the lesion and the catheter may provide a more optimal alternative.

Now, Patel and colleagues need to obtain government approval to use the hybrid technique in humans. “One plus,” says Patel, “is both tools are currently used in humans.”

All for naught?

As researchers focus on imaging tools to detect vulnerable plaque, some acknowledge that the search may not pay off.

“When it comes to vulnerable plaque, we still aren’t sure how to treat when we do identify it,” says Patel. If a cardiologist finds vulnerable plaque, but it doesn’t obstruct the lumen, he may opt for more aggressive medical therapy to prevent the plaque from rupturing. In other cases, he may detect a blockage of 50 percent or more and decide to perform an angiography. Those patients might benefit from the more aggressive therapy.

Zadeh, however, remains unconvinced of the benefits of detecting vulnerable plaque and intervening before it ruptures. “The assumption that one can prevent heart attacks by finding plaque before it ruptures is false. We have very good evidence that these plaques rupture all the time and nothing happens.”

Arbustini et al reviewed pathology data on 77 patients who died of noncardiac causes and 106 with acute coronary syndrome. Among the noncardiac patients, he found nonculprit plaque rupture in 17 percent. The figure rose to 58 percent among acute coronary syndrome patients. “Other studies corroborate these findings,” adds Zadeh. 

These studies show that vulnerable plaque is part of the natural history of plaque. The plaque grows, ruptures early in the process and then heals. After its ruptures two to three times, high-grade stenosis results. Many of these vulnerable plaques lose their characteristics (primarily the thin fibrous cap); the cap thickens and the plaque becomes fibrous. 

“This means finding a plaque prone to rupture doesn’t have the meaning we have ascribed to it,” says Zadeh, who cautions against overdiagnosis and overtreatment, pointing to a second issue—the sensitivity of the various modalities used to detect vulnerable plaque is not optimal.

A clinical scenario illustrates the pitfalls of imaging vulnerable plaque. Suppose a cardiologist detects vulnerable plaque in a 58-year-old male. The physician stents the plaque, aiming to prevent rupture and myocardial infarction. But, according to Zadeh, this approach does not balance the risks and benefits of stenting and potential infarction. Because these plaques rupture all of the time and nothing happens, the patient faces more risk with stenting than from the vulnerable plaque.

“This is very strongly supported by data showing we don’t reduce myocardial infarction or mortality by stenting. Many of the plaques that cardiologists stent are probably vulnerable plaques, but there isn’t a hint of evidence that they are reducing death,” says Zadeh.

He encourages his colleagues to take a broader view, reminding them that the more plaque a patient has the higher the risk for rupture. “We have to get away from focusing on the individual plaque and focus on the entire plaque burden.”

This larger picture of plaque burden can be imaged by CT angiography and indirectly by calcium scoring.  

Where now?

Researchers, including Patel and others, continue to refine tools to detect vulnerable plaque. It’s an admirable quest, but likely one that should be paired with appropriate clinical action. If the plaque can be accurately detected, how should the cardiologist respond? Can he or she intervene and actually prevent rupture and myocardial infarction? That remains to be seen. Another issue is that sensitivity of the various modalities used to detect vulnerable plaque is not optimal.

Molecular imaging and vulnerable plaque: Is there a role for 18F-fluoride PET?

One of the imaging techniques that could play a role in detecting vulnerable plaque is PET. Philips Adamson, MD, from the Centre for Cardiovascular Science at University of Edinburgh, and colleagues undertook a prospective clinical trial to compare 18F-fluoride PET and 18F-fluorodeoxyglucose (18F-FDG) for the identification of vulnerable coronary plaques. Results were published in Cardiovasc Design Ther 2015;5(2):150-155.

Pathophysiological processes, including inflammation and microcalcification, are key components of vulnerable plaque that have proven elusive to capture non-invasively. Imaging these components could help physicians identify vulnerable plaque and patients at increased risk for myocardial infarction.

According to Adamson, 18F-FDG is not a suitable tracer for imaging the coronary arteries because of intense uptake in the myocardium which obscures the coronary signal and limits plaque analysis.

18F-fluoride, in contrast, provides excellent signal-to-background activity in the coronary arteries and holds potential as a marker of microcalcification and high-risk plaque.

Adamson’s study comprised three patient cohorts. In the first—a group of 40 patients with acute myocardial infarction—the researchers compared 18F-fluoride tissue-to-background ratio (TBR) of culprit and non-culprit lesions. They defined positive plaques as those with a TBRmax >25 percent higher than the reference lesion. They observed increased 18F-fluoride in the culprit plaque of 37 of 40 patients. They were unable to accurately assess plaque on 18F-FDG imaging in more than half of the patients.

Next, they investigated the prospective value of 18F-fluoride. They completed 18F-fluoride and 18F-FDG PET/CT studies in 40 patients with clinically stable coronary disease scheduled for elective i nvasive coronary angiography. Patients also underwent IVUS imaging of plaques with normal and increased tracer uptake. A total of 18 patients had areas of increased 18F-fluoride uptake, and these plaques demonstrated multiple high-risk features on IVUS, according to the researchers.

“This provides further evidence to support 18F-fluoride PET as a marker of increased cardiovascular risk and also raises the possibility that the myocardial injury detected in these patients might relate to sub-clinical plaque rupture,” wrote Adamson et al.

In contrast, 18F-FDG images were largely uninterpretable due to myocardial spillover.

In the final arm of the study, the researchers attempted pathological confirmation that 18F-fluoride uptake is increased in plaques with high-risk features. They removed nine carotid specimens from patients with symptomatic carotid artery disease undergoing carotid endarterectomy. The specimens were imaged with 18F-fluoride PET and analyzed histologically. The researchers found tracer uptake localized to regions of plaque rupture, and they noted increased calcification staining and links to high-risk features, including inflammation and cell death.

“This study has demonstrated the potential that 18F-fluoride PET/CT holds in detecting ruptured and high-risk plaques in the coronary arteries,” wrote Adamson et al.

They suggest the next steps include larger prospective trials of 18F-fluoride imaging to determine whether the tracer can be used to detect plaque susceptible to rupture. Two studies currently underway could shed provide additional date.

The Prediction of Recurrent Events with 18F-fluoride to Identify Ruptured and High-Risk Coronary Artery Plaques in Patients with Myocardial Infarction (PRE18FFIR) will follow 700 high-risk patients for two years. The goal is to determine whether or not PET imaging can identify patients who ultimately infarct and predict progression of coronary artery disease.

The Dual Antiplatelet Therapy to Inhibit Coronary Artherosclerosis and Myocardial Injury in Patients with Necrotic High-risk Coronary Plaque Disease (DIAMOND) is set to examine the link between 18F-fluoride uptake and high sensitivity troponin concentrations. The study also aims to determine if potent antiplatelet therapy can be employed to modify troponin concentrations. 

The researchers concluded by re-asserting the potential value of 18F-fluoride PET and suggested it could play a role in identifying patients and tailoring treatment.