Advances in Molecular Imaging: Plaque Imaging

Here’s the abstract of a review we published recently in Current Cardiovascular Imaging Reports:-

Recent advances in nuclear plaque imaging aim to achieve noninvasive identification of vulnerable atherosclerotic plaques using positron emission tomography (PET) with 18F-fluorodexoyglucose (FDG) and novel tracers targeting molecular markers of inflammation and other active metabolic processes.

Nuclear imaging of atherosclerosis has been demonstrated in multiple vascular beds, including the carotid, aorta, peripheral and coronary arteries—but significant challenges remain, especially for coronary imaging. The advantage of PET over other molecular imaging modalities is its superior sensitivity, however, low spatial resolution means that images must be co-registered with computed tomography (CT) or magnetic resonance imaging (MRI) for precise anatomical localization of the PET signal.

Such hybrid techniques provide the best hope for early detection of prospective culprit lesions—which may, in the coronary vasculature, appear falsely low-risk using conventional coronary angiography or stress imaging.

Current hot topics in nuclear plaque imaging include the use of FDG-PET for therapeutic monitoring in drug development, identification of imaging biomarkers to evaluate cardiovascular risk, and the development of novel tracers against an array of biologically important markers of atherosclerosis.

The purpose of this article is to review these recent advances in nuclear plaque imaging.

The full article is available here, behind a paywall. I can send reprints as PDFs on request.

Interaction of calcification and inflammation in atherosclerosis

The diagram above seems a logical appraisal of the situation, published recently by Cocker and colleagues.

A proposed schematic staging inflammatory and calcification activity within atherosclerotic lesions with FDG and NaF as imaging biomarkers. During early stages of atherosclerosis, inflammation is the predominant mechanism active within plaque. During these stages, [18F]FDG may be taken up by the lesion. As inflammation peaks, the risk of plaque rupture may increase. Inflammation also contributes toward initiating calcium metabolism within lesions that results in the formation of early calcium deposits. This would be reflected by uptake of both FDG and hydroxyapatite-specific [18F]sodium fluoride (NaF). Once the density of calcium deposits exceeds a certain threshold, it becomes visible with CT. During active calcification, plaque may still be vulnerable. Eventually, the calcification and mineralization processes exceed the inflammatory activity present within plaque, which might be demarcated by only NaF uptake (in the absence of FDG), as well as calcium deposits on CT. Ongoing calcification eventually leads to forming an end- stage stable atheroma that is densely calcified with only evidence for calcium on CT. Model of plaque progression (top bar) is adapted from Koenig and Khuseyinova.

Coronary artery PET imaging with NaF - the debate continues

The paper we published in JACC with colleagues in Edinburgh continues to be discussed. A letter and our reply were recently aired on the JACC website.

It’s certainly true that we don’t fully understand the dynamics of NaF uptake into coronary atherosclerosis. And we are still working on ex-vivo experiments to determine the binding characteristics of the tracer in atherosclerosis, which will likely be similar to that expressed in bone tissue. We do know that the degree of NaF uptake correlates with cardiovascular risk, and there is only a weak relationship between NaF and FDG uptake. So it is likely telling us something different from metabolic activity of the plaque.

Whether it is predictive of future cardiovascular events, can be altered with therapy or is reproducible - time (and lots of research efforts) will tell.

My PhD thesis now online

I just took advantage of Cambridge's online repository service for research documents. I uploaded my PhD thesis from 2003 - 'Imaging atherosclerosis using FDG PET'. In it, I describe the first prospective study if FDG PET for measuring real-time inflammation in the carotid arteries.

Feel free to download it by visiting this page.

Imaging Early Atherosclerosis

My talk at ESC 2012 in Munich is now available for watching via webcast if you're so inclined.

Click here for the webcast page

On my way to ESC 2012

I'm presenting some data about the imaging of early atherosclerosis, at the ESC in Munich this Saturday link to session. The session will be webcast should you be at a loose end.

The heart.org, as always, has a great preview of what to expect from the meeting:

Munich, Germany - This year's European Society of Cardiology (ESC) 2012 Congress is back in Bavaria after a four-year absence. Organizers of the meeting say the line-up of hot-line trials offers a mix of new treatments as well as several seeking to prove once and for all whether certain treatments, used for years, are really the best approach.

In all, this year's program includes 18 hot lines, grouped in three sessions over three days. Among the studies garnering the biggest buzz in the lead-up to the ESC meeting is TRILOGY-ACS, a comparison of prasugrel and clopidogrel in the setting of medically managed unstable angina/NSTEMI.

Read their full preview here.

Hopefully there'll be time for beer and sausages too. And I know from experience that there are some great parks where I can jog for miles.

I'll keep you posted, probably via Twitter

Carotid plaque inflammation predicts early stroke recurrence

This study, just published in the highly respected journal 'Annals of Neurology' lends support to the concept of persisting inflammation, as detected by 18FDG PET, portends early stroke recurrence. In fact, 18FDG uptake was the only factor on multivariate analysis to predict recurrence, out-performing stenosis degree and age. If the SUV was above 2.1, 80% of subjects had recurrent events within 90 days.

What we need now is a prospective study of an FDG PET-guided approach to risk stratification and management compared with standard medical/surgical care.

The SUV value is in the same ballpark as that seen in other PET studies of atherosclerosis, and less than frequently noted in untreated active vasculitis.

This study provides a counterpart to the MRI one I published here yesterday.

Any thoughts?

Atherosclerotic plaque imaging - past, present, and future

Dr. Alistair Lindsay hosts a round table from the British Cardiovascular Society Conference in Manchester, on the topic of atherosclerotic plaque imaging; past, present, and future.

He is joined by:

• Matthias Nahrendorf, Center for Systems Biology, Harvard University
• Farouc Jaffer, Center for Molecular Imaging Research, Harvard University
• James Rudd, Division of Cardiovascular Medicine, University of Cambridge
• Robin Choudhury, Department of Cardiovascular Medicine, University of Oxford

Click here to listen.

See also:
Webcasts from all the sessions at the British Cardiovascular Society Conference 2012

Click here to watch.

Scientists develop new technique that could improve heart attack prediction

From left to right, CT, PET and combined PET/CT images of the heart arteries. The areas in white on the left and right panels demonstrate calcification of the arteries, whilst the orange spots on the middle and right panels demonstrate actively calcifying areas of atherosclerosis. These have accumulated significant amounts of NaF, and we believe that these areas represent high-risk areas for future heart attacks. Further work is, of course, needed to prove this hypothesis.

Building on work pioneered in Cambridge 10 years ago, scientists have developed a new imaging approach that could help improve how doctors predict a patient’s risk of having a heart attack.

The British Heart Foundation (BHF) funded project, a collaboration between scientists from the Universities of Cambridge and Edinburgh, is the first to demonstrate the potential of combined PET and CT imaging to highlight the disease processes causing heart attacks directly within the coronary arteries.

The research, published last week in the Journal of the American College of Cardiology (JACC), involved imaging over 100 people with a CT calcium scan to measure the amount of calcified or hardened plaques in their coronary arteries. This is a standard test, which is commonly used to predict heart attack risk but cannot distinguish calcium that has been there for some time from calcium that is actively building up.

The patients were also injected with two contrast agents that show up on PET imaging scans, and which can be used to track various metabolic pathways in the body. One of these tracers, 18F-sodium fluoride (18F-NaF), is a molecule taken up by cells in which active calcification is occurring. The 18F-NaF can then be visualised and quantified during a PET scan.

The researchers wanted to see if they could identify patients with active, ongoing calcification because these patients may be at higher risk of heart attack than patients in whom the calcium developed a long time ago. The results showed that increased 18F-NaF activity could be observed in specific coronary artery plaques in patients who had many other high-risk markers of cardiovascular disease.

Dr James Rudd, HEFCE Senior Lecturer at the Department of Medicine and joint senior author of the paper, said:

Our results show, for the first time, that certain areas of atherosclerosis within the coronary arteries, previously thought to be inert, are actually highly active and have the potential to cause heart attack. Once identified, they might be targeted with drug therapy more effectively.

Additionally, we might be able to improve our ability to predict an individual person’s future risk of heart attack using this fairly straightforward imaging test in selected people.

This research exploits longstanding scientific links between my research team in Cambridge and Professor Newby’s in Edinburgh, with core support from the Cambridge NIHR Biomedical Research Centre, HEFCE and the British Heart Foundation.

Dr Marc Dweck, lead author on the research paper and a BHF Clinical Research Fellow at the University of Edinburgh, said:

Predicting heart attacks is very difficult and the methods we’ve got now are good but not perfect. Our new technique holds a lot of promise as a means of improving heart attack prediction although further ongoing work is needed before it becomes routine clinical practice.

If we can identify patients at high risk of a heart attack earlier, we can then use intensive drug treatments, and perhaps procedures such as stents, to reduce the chances of them having a heart attack.

Dr Shannon Amoils, Research Advisor at the (BHF), which funded the study, said:

For decades cardiologists have been looking for ways to detect the high-risk plaques found in coronary arteries that could rupture to cause a heart attack, but it’s been difficult to develop a suitable imaging test that can focus in on these small vessels.

This research is a technical tour de force as it allows us to assess active calcification happening right in the problem area – inside the wall of the coronary arteries and this active calcification may correlate with a higher risk of a heart attack.

There are nearly 2.7 million people living with coronary heart disease (CHD) in the UK and it kills 88,000 people each year. Most of these deaths are caused by a heart attack. Each year there are around 124,000 heart attacks in the UK.

Non-invasive imaging of atherosclerosis review in EHJ

A very comprehensive review from an eminent group of authors appeared in EHJ recently.

Non-invasive anatomic and functional imaging of vascular inflammation and unstable plaque

It covers:

1. Pathobiology of plaque, including lipid accumulation, oxidation, inflammation, matrix breakdown, apoptosis and calcification (both macro- and micro-).

2. Imaging techniques PET, SPECT, CT, MRI and ultrasound

There were some interesting comments on the increasing use of FDG PET imaging for detection of inflammation in atherosclerosis : -

Despite these attractions, some issues require resolution before embracing FDG uptake in this regard. Firstly, only limited prospective data correlate FDG uptake, or changes in FDG uptake, with cardiovascular events or altered rates of such complications,42 and we eagerly await the results of larger prospective cohort studies, such as the High Risk Plaque Initiative and BioImage studies."

"In this regard, nuclear agents that image hypoxia, already in use in oncology, may be
useful in imaging atherosclerosis, as hypoxic conditions may prevail in the core of lesions."

I quite agree on point 1 and keep watching this space for point 2!