PET Imaging Technique Finds Plaques 'Ripe for Rupture'

November 11, 2013

EDINBURGH, SCOTLAND — Positron-emission tomography (PET) can identify recently ruptured atherosclerotic plaques or those at risk of rupture in patients using the metabolic tracer 18F-sodium fluoride (18F-NaF), suggests a small prospective observational study[1].

Focal uptake of the tracer in the coronaries "informs about calcification activity, which is believed to be a healing response to intense plaque inflammation," according to the study's lead author, Dr Nikhil V Joshi (University of Edinburgh, Scotland). It was seen in the culprit artery of >90% of the group's patients with recent acute MI and in more than a third of those with stable coronary disease, he explained to heartwire .

Plaques with concentrations of increased tracer uptake showed features linked to rupture risk (positive remodeling, microcalcification, large necrotic core) at coronary computed tomography (CT) and intravascular ultrasound (IVUS), those findings supported by carotid endarterectomy tissue histology.

"18F-NaF therefore holds considerable promise as a noninvasive means of identifying the vulnerable plaque and therefore in pinpointing high-risk vulnerable patients at risk of myocardial infarction," according to Joshi, who said his emailed comments also contained input from the study's two senior authors, Dr Marc R Dweck and Prof David E Newby (University of Edinburgh). Their study was published online November 10, 2013 in the Lancet.

It builds on years of earlier work by different research teams, using different imaging modalities, attempting to image plaque based on vulnerability to rupture.

And even more research is needed to determine whether patients with high-risk plaques at imaging actually have a higher risk of MIs, Joshi said. "If this is established, then this technique might fundamentally alter the way we assess coronary disease, moving us away from the current paradigm based on lesion severity and ischemia to one based on plaque metabolism and vulnerability."

He and his colleagues propose that the technique "could, for example, permit the identification of the vulnerable patient with single or multiple high-risk or silently ruptured plaques, providing an opportunity to treat and modify their risk to prevent future adverse cardiovascular events."

In their patients with stable disease, Joshi said, most lesions with enhanced 18F-NaF uptake "were nonobstructive, but it will be interesting to assess this relationship in more depth in future studies. It may be that interventional strategies [will] prove more effective if they are targeted to the metabolically active lesions identified by 18F-NaF."

"Now That We Can, Should We?"

A commentary accompanying the Joshi et al report was circumspect but ultimately upbeat about its implications[2]. "Now that we can detect plaque rupture, should we?" ask Dr Gregory S Thomas (University of California, Irvine) and Dr Reka A Haraszti (University of Massachusetts Medical School, Worcester).

Much more research is needed before the technique should enter practice, they agreed. "Just because a plaque at risk for rupture can be identified does not mean that we know what to do with this information." However, the ability to image and possibly measure plaques at high rupture risk "creates a new world of opportunity for the investigation of pharmacological and device therapy."

The current study "is indeed a step forward," according to Dr Jagat Narula (Mount Sinai School of Medicine, New York, NY). Preceding studies have shown that microcalcification by 18F-NaF imaging, like coronary calcium scores by CT, highlight the presence of atherosclerosis, he explained in an email to heartwire . In those studies, however, it was "intriguing" that the location of calcium by CT didn't always correspond to regions of microcalcification by 18F-NaF imaging. "The current study clarifies the discrepancy, [in that 18F-NaF] targets the nascent process [of coronary calcification] and probably represents the process of necrotic-core enlargement."

Because expanding necrotic cores and increasing inflammation are the two most important noninvasively discernible substrates for plaque vulnerability, Narula said, "if proved in prospective investigation, fluoride imaging may constitute the most logical imaging strategy for detection of relatively high-risk plaques."

18F-NaF vs 18F-FDG

The current study looked at 40 patients with acute MI, with or without ST-segment elevation, and 40 others with stable angina, who underwent elective coronary angiography. All also underwent coronary CT and PET, the latter using two separate metabolic tracers, 18F-NaF and 18F-fluorodeoxyglucose (18F-FDG). Stable-angina patients also underwent coronary IVUS. Endarterectomy specimens came from nine other patients who had symptomatic carotid disease.

In patients undergoing PET an average of six days after MI, uptake of 18F-NaF was 34% higher in culprit lesions than the maximum value anywhere else in the coronary vessels (p<0.0001). "By contrast, coronary 18F-FDG uptake was commonly obscured by myocardial uptake and where discernible, there were no differences between culprit and nonculprit plaques," according to the group.

Focal 18F-NaF uptake that was associated with a preponderance of IVUS features indicating high rupture risk, including positive remodeling (p=0.0004), microcalcification (p=0.002), and necrotic core (p=0.001), was seen in 18 stable-angina patients (45%).

18F-NaF PET Sees "Angry Plaques"

As Joshi explained, 18F-NaF PET and coronary CT with calcium scoring provide different information about coronary calcification. "Calcium scoring tells us about macroscopic calcium that has already been formed in the artery. It is an excellent surrogate for plaque burden and predictor of events, presumably on the basis that the more plaque you have the more likely you are to have a high-risk one. However, calcium scoring cannot tell us whether the calcium formed recently or indeed many years ago, when any inflammation is likely to have burned out," he said.

"By contrast, 18F-NaF tells us about ongoing calcification activity and is therefore much more closely aligned to the processes of necrotic inflammation. As a consequence, it has the ability to identify angry plaques in need of healing and therefore those with an increased tendency to rupture."

All that "provides a strong rationale to suggest that 18F-NaF might provide further improvements to the prediction of cardiovascular risk over and above coronary calcium scoring."

Calcium scoring is more practical than 18F-NaF PET imaging but shows only the presence of disease, observed Narula. It doesn't identify lesions that are "ripe" for rupture. "Plaque vulnerability may only become clinically relevant if prospective studies demonstrate that we are able to detect those that are on the verge of rupture and if they also demonstrate that intervention is lifesaving."

According to Joshi, if the technique is confirmed to identify patients at high risk for MI, "then we would need to carefully consider which patients would benefit from scanning." It probably wouldn't be used for initial screening, given its cost and radiation exposure to the patient. "However, 18F-NaF PET could be used to provide further prognostic information in patients already known to be at risk, perhaps those with high calcium scores or patients who have just sustained a myocardial infarction or [who are] about to undergo major vascular surgery where we know subsequent MI rates are high."

The study was funded by the Chief Scientist Office Scotland and British Heart Foundation. Joshi, Dwerck, and Newby declared no conflicts of interest; disclosures for the coauthors are listed in the paper. Narula is editor in chief of the Journal of the American College of Cardiology: Cardiovascular Imaging. Thomas and Haraszti declare no conflicts of interest.

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