Early warning - non-invasive imaging technique using PET radioisotopes

31 October 2014



Coronary plaque rupture and subsequent acute myocardial infarction are a major cause of death worldwide, but anticipating cases successfully is a problem. Dr Nikhil Joshi from the University of Edinburgh discusses a new inexpensive and non-invasive imaging technique using PET radioisotopes that might prove to be the solution.


Medical Imaging Technology: How do atherosclerotic plaques form, and what happens when they rupture?

Nikhil Joshi: Atherosclerosis is a systemic disease that is thought to be initiated by wear and tear within the arterial wall, which results in endothelial cell damage. Subsequently, over many decades, lipids and inflammatory molecules are deposited within the inner layer of the vessel.

Atherosclerosis usually only manifests in advanced stages. Several risk factors have been implicated in accelerated progression of the atherosclerotic plaque disease, including family history, smoking and increased cholesterol.

Myocardial infarction and stroke are the two most common clinical consequences of atherosclerosis. Normally, the lipid-rich core of the plaque is protected from the lumen by a fibrous cap, but in this instance the cap thinning and subsequently rupturing exposes the lipid core contents to free- flowing blood, leading to clot formation within the vessel, which cuts off the blood supply.

"The ability to identify vulnerable coronary atherosclerotic plaques non-invasively allows us first to identify patients at the highest risk of myocardial infarction, and then to make an aggressive medical intervention."

The heart muscle is then deprived of essential oxygen and nutrients and this results in an attack. Similarly, when this phenomenon occurs within the carotid arteries, it could cause a stroke.

Why is prediction of plaque rupture so difficult?

The ability to identify unstable plaque has been long thought to be the holy grail of cardiology: most of the plaques that subsequently rupture - the so-called 'vulnerable plaques' - are non-flow limiting, and so tend to be missed by more conventional techniques, such as coronary angiography and stress testing.

However, these high-risk vulnerable plaques do have pathological features, and can therefore be identified. Typical characteristics of a vulnerable plaque include a thin, fibrous cap, a large necrotic core, a positively remodelled vessel, spotty calcification and inflammation. All these features are potential targets for identification of high-risk vulnerable plaques.

Our understanding of this area has improved vastly in the last few years, but the plaques that will go on to rupture and cause an attack remain a mystery.

What we do know, though, is that the final step of plaque rupture involves a bursting of the fibrous plaque and the subsequent escape of the plaque contents, which react with the platelets to occlude the vessel.

With modern imaging techniques such as intracoronary imaging, visualising a plaque's contents and fibrous cap is possible. Furthermore, techniques such as CT angiography, PET/CT and MRI allow further anatomical and metabolic assessment within a plaque.

With modern invasive and non-invasive techniques, the race to identify the high-risk plaques that are likely to rupture is truly on.

How did the idea for the research come about?

Well, interestingly, this was a bit of good luck. We were working with another project using 18F-fluoride PET imaging on patients with aortic stenosis. Coincidentally, one of our patients had sustained a heart attack about a week prior to the test and we were pleasantly surprised to find that the very bit of the coronary artery that had caused the attack was lighting up on the PET CT scan. On this basis we planned a prospective study to look at this further, and that's how it all started.

What is the significance of the two radioactive tracers used in the research?

We used positron emission tomography (PET), a non-invasive technique that allows study of biochemical processes within small structures such as coronary arteries. This data can be superimposed on precise anatomical CT images.

The high-risk atherosclerotic plaques have several important features, and we choose to target inflammation and calcification with 18F-fluorodeoxyglucose and 18F-fluoride respectively.

The most commonly used tracer in oncological imaging in clinical practice is 18F-fluorodeoxyglucose. FDG is a glucose analogue that has been shown to correlate historically with vascular macrophage burden, and it has become a widely used measure of vascular inflammation in the carotids and aorta. However, there only a few reports of variable uptake in the coronary arteries. From our previous experience, the myocardial uptake of 18F-FDG makes it difficult to assess signal within the coronary arteries.

Since this was reported by other research groups, we decided to prospectively evaluate this. Moreover, this tracer also allows accurate assessment of signal within the aorta, and we were also interested in studying the difference in signal between patients with and without heart attacks.

We have known about 18F-fluoride as a bone tracer for the last four decades, and have recently described sodium fluoride (18F-NaF) as a marker for calcification activity. It acts by binding to hydroxyapatite, a key structural component laid down in earliest stages of calcium formation.

We reported its uptake in the coronary arteries, in patients with aortic stenosis, but wanted to prospectively evaluate its utility in patients with stable and unstable coronary disease.

How does this work differ to conventional diagnosis of coronary plaques?

With 18F-fluoride you have a completely novel, non-invasive imaging approach to investigating coronary artery disease. Current methods predominantly revolve around the detection of ischemia, or assessment of the severity of coronary luminal stenosis. While both of these predict risk, treatment methods targeted at ischemia have consistently failed to reduce rates of myocardial infarction, or death.

18F-NaF PET is different - it looks instead at the metabolic activity of coronary plaques, localising to lesions that have caused myocardial infarction and in stable patients to plaques with multiple high-risk features for rupture.

Further studies are now required to investigate whether patients with high-risk lesions go on to have an increased incidence of myocardial infarction.

If this is established, this technique might alter the way we assess coronary disease, moving us away from a paradigm based on lesion severity and ischemia to one founded upon plaque metabolism and vulnerability.

What were the results? Did they confirm your hypothesis?

We assessed a number of patients with myocardial infarction using 18F-fluoride PET combined with computed tomography (CT) imaging. Increased 18F-fluoride uptake was observed at the exact site of culprit plaque rupture in 93% of these patients. Analysis of atherosclerotic plaques obtained from subjects undergoing carotid endarterectomy following a stroke or transient ischaemic attack confirmed increased 18F-fluoride uptake at the site of macroscopic plaque rupture that histologically localised to regions of increased calcification activity, necrosis and inflammation.

"Being able to identify unstable plaques has been long thought to be the holy grail of cardiology: most of the plaques that rupture are non-flow limiting, and so are missed by conventional techniques."

Interestingly, 38% of those with stable angina also had coronary 18F-fluoride uptake that localised to plaques with multiple high-risk features on intravascular ultrasound imaging, such as positive remodelling, microcalcification, and increased necrotic core.

We started out with the hypothesis that both these tracers would be able to identify high-risk plaques within the coronary arteries. With 18F-fluoride, we demonstrated that it was taken up by high-risk, as well as ruptured, plaques.

The results were not so encouraging for 18F-FDG: this was primarily due to intense myocardial uptake obscuring assessment within the coronaries.

What are the implications of the study for medical science?

Our study represents a step change in our scientific understanding of atherosclerosis, in particular the mechanisms underlying the calcification process. We already know that CT coronary calcium scoring is one of the most powerful predictors for cardiovascular events.

However, unlike established macrocalcification visible on CT, 18F-fluoride uptake identifies actively calcifying atherosclerotic plaques that, similar to the caseating granulomata associated with tuberculosis, occurs as a healing response to intense inflammation, either within the necrotic core, or related to the plaque rupture event itself.

Inflamed lesions are at the highest risk of rupturing, so therefore there is an extremely clear rationale for why 18F-fluoride uptake should predict myocardial infarction, and why this technique also has important potential clinical applications.

The ability to identify vulnerable coronary atherosclerotic plaques non-invasively is really exciting, as it allows us first to identify patients at the highest risk of myocardial infarction and then to step in with aggressive medical or interventional strategies in an attempt to prevent those events occurring. Through the expansion in oncological imaging, PET technology is now widely available.

Moreover, the ease of manufacture and commercial availability of 18F-fluoride means that this approach is now readily translatable into the clinic. Large-scale prospective studies are now required to confirm that 18F-fluoride PET can identify such vulnerable patients, and which strategies can be used to avoid myocardial infarction.

However, if this is established then 18F-fluoride PET is likely to fundamentally alter the way we assess and treat coronary artery disease, moving us away from the current paradigm, which is based on lesion severity and ischemia, to one based on plaque metabolism and vulnerability.

Dr Nikhil Joshi is a specialist registrar/research fellow in cardiology at the University of Edinburgh. His primary research interests are cardiac PET, CT coronary angiogram and intravascular ultrasound. He is looking at using these advanced techniques to identify unstable coronary plaques.
If doctors can spot vulnerable coronary atherosclerotic plaques early on, they will be able to intervene in order to take steps towards averting dangerous cardiovascular situations.


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