The majority of myocardial infarctions are caused by atherosclerotic plaque rupture. However, identifying lesions at risk of rupture, so-called vulnerable plaques, is challenging. Most are not flow-limiting Citation[1,2] and will therefore not be detected by conventional stress testing or invasive coronary angiography. Other methods are therefore required to improve the prediction of adverse coronary events.
The presence of calcium in the coronary arteries is pathognomic of atherosclerosis and can be quantified using computed tomography (CT) and the Agatston score. This provides a surrogate of the coronary atherosclerotic burden and offers powerful cardiovascular risk prediction Citation[3], presumably because with an increasing number of plaques, more are likely to be vulnerable.
Vulnerable plaques are known to have certain pathological characteristics, which include inflammation and spotty calcification. Activated macrophages infiltrate the thin fibrous cap, secreting matrix metalloproteinases, which predispose the plaque to rupture Citation[4]. Spotty calcification represents the very earliest stage of the vascular calcific process and is frequently not resolved by CT. Unlike the confluent calcification observed later in the disease process, microcalcification increases wall stress, predisposing the plaque to microfractures and rupture Citation[5–7].
We have recently investigated the feasibility of using PET to image these two processes in the coronary arteries Citation[8]. In a cohort of 119 patients, we performed PET/CT imaging using 18F-fluorodeoxyglucose (18F-FDG) to detect plaque inflammation and 18F-sodium fluoride (18F-NaF) to image calcification. Both tracers are easy to manufacture in modern cyclotrons and are commercially available. 18F-FDG has become well established as a measure of vascular inflammation Citation[9,10], whereas 18F-NaF has been used to image new bone formation, primarily cancer metastases, for 50 years. Fluoride ions exchange with hydroxyl ions in exposed hydroxyapatite, a key structural crystal that is deposited in both bone matrix and in the initial stages of vascular calcium formation. Retrospective data derived from the use of 18F-NaF in cancer imaging have previously suggested that vascular uptake may identify novel or developing regions of arterial calcification Citation[11–13].
In our study results for 18F-FDG were disappointing, being hampered by myocardial uptake from which it was difficult to isolate activity in the coronary arteries. Indeed quantification of 18F-FDG activity was not possible in almost half of the coronary vessel territories examined and, when possible, displayed poor measures of reproducibility. This has also been noted in previous studies Citation[14,15], despite meticulous dietary preparation intended to lower myocardial glucose usage. By contrast, 18F-NaF displayed no myocardial uptake and discrete regions of activity were commonly observed in the coronaries that could be localized to an individual plaque. Quantification was therefore straightforward and measures of reproducibility were excellent. 18F-NaF activity was higher in patients with atherosclerosis compared with those without and rose steadily with progressive disease burden (r2 = 0.652). Patients with atherosclerosis could then be divided into those with and without increased 18F-NaF activity. Those with increased uptake were more likely to have angina, a clinical diagnosis of coronary artery disease, previous major adverse cardiovascular events and prior revascularization. Furthermore, Framingham risk scores were higher in this group. Increased coronary 18F-NaF activity therefore appears to occur in patients with a high-risk profile.
Future directions
Although exciting, this observational study had several limitations, including the fact that it was a substudy of a population recruited to investigate the role of these tracers in calcific aortic valve disease Citation[16]. Further research is therefore required in patients more representative of the population with coronary disease, ideally involving subjects with both stable and unstable presentations. In particular, such studies will need to address several key issues as discussed below.
Histological validation & kinetic modeling
18F-NaF was developed for bone imaging 50 years ago and its kinetics and mechanism of uptake are well established in this tissue Citation[17]. It has been assumed that the mechanism of 18F-NaF uptake is the same in the vasculature as it is in bone and that by detecting regions of exposed hydroxyapatite, 18F-NaF is informing us about vascular calcification activity. However, this remains hypothetical and kinetic modeling and histological studies are required for confirmation.
Kinetic modeling will help establish how 18F-NaF uptake moves from the blood pool into atherosclerotic plaque and should therefore provide insight into the mechanisms underlying plaque activity. Furthermore, it will allow us to determine the optimum tracer circulation time for maximal contrast between the vessel wall and blood pool. Such studies will be challenging to perform in the coronaries, given their size and motion, and the carotid artery may be a better target for dynamic imaging.
Histological studies will allow colocalization of 18F-NaF activity with plaque components, and will investigate relationships between tracer uptake and immunohistochemical markers of calcification. Once more, these studies may prove difficult in the coronary arteries due to the difficulties in obtaining tissue samples. However, carotid atheroma explanted at endarterectomy is readily available, and so validation may again be easier in this tissue.
Finally, although we have established that the interobserver variability of coronary 18F-NaF measurements is good, the test/retest repeatability has not been established. This is an important measure in the assessment of any novel imaging technique. Favorable repeatability would also provide estimates of sample sizes required if the technique were to be used as a surrogate end point in clinical trials of novel antiatherosclerosis therapies.
What is the trigger to calcification in the coronary arteries?
The most interesting question that this area of research raises is what the stimulus to coronary calcification might be. Calcification in the body generally occurs as a healing response to injury. Perhaps the best-recognized example is tuberculosis, where calcification effectively walls off intense regions of inflammation. We believe that calcification activity in the coronaries is also likely to be a healing response, perhaps to an intensely inflamed necrotic core or to plaque rupture events. Theoretically, therefore, 18F-NaF holds potential as a means of identifying high-risk plaque acting as both a surrogate of intense plaque inflammation and the microcalcification that develops in response.
To address this hypothesis, we need to characterize the composition of those plaques displaying increased 18F-NaF activity. CT coronary angiography is appealing in this regard, because it can be performed at the time of the PET scan and can identify microcalcification and characterize plaque morphology. However, virtual histology intravascular ultrasound has the potential to give us even more detail. This invasive technique has been extensively validated against histology and is able to quantify the necrotic core, micro and confluent calcification, as well as fibrous and fibrofatty tissue in the plaque. In addition, it can identify thin-cap fibroatheromata, high-risk morphological lesions that have been associated with future coronary events Citation[18]. Finally, optical coherence tomography is an alternative invasive technique that may provide useful information particularly in the detection of subclinical plaque ruptures.
ECG & respiratory gating
Coronary arterial imaging is subject to both cardiac motion and the respiratory motion of the chest, limiting the precision with which the PET signal can be localized to individual plaque. However, modern PET scanners are capable of ECG gating, so that images can be created from counts acquired in diastole when the heart is stationary. Furthermore, techniques exist that can model and correct for respiratory motion, with the potential to create an even more precise PET signal Citation[19], although partial volume effects may ultimately limit precise colocalization within components of individual plaques.
Longitudinal & prospective follow studies
By identifying metabolically active calcific plaque, there is a hope that 18F-NaF PET may refine the prognostic capability of coronary calcium scoring. This is supported by evidence that progression of calcium scores offers more powerful risk prediction than scoring at a single time point Citation[20,21]. However, establishing 18F-NaF as a useful predictor of cardiovascular risk will require multicenter prospective trials in a variety of different patient groups. Extensive validation is required before such trials can be considered and given the expense of PET, these will prove costly. Finally given that 18F-NaF PET also involves exposure to ionising radiation, it will have to demonstrate considerable superiority in risk prediction over and above cardiovascular risk scores and alternative noninvasive imaging modalities if it is to become a useful clinical tool.
Conclusion
In summary, 18F-NaF PET is a feasible and potentially reproducible method for studying calcification activity in the coronary arteries. Further assessment is required in more representative populations with coronary disease, but it has the potential to provide key insights into the role that calcification plays in the progression of atherosclerosis. Furthermore, it holds promise as a noninvasive means of identifying vulnerable plaque and may yet provide a surrogate end point for trials of novel antiatherosclerotic therapies. There is much to be done before this technique can be considered ready for clinical practice; nevertheless, further work is eagerly anticipated.
Financial & competing interests disclosure
MR Dweck is supported by a British Heart Foundation Clinical PhD Training Fellowship (FS/10/026). DE Newby is supported by the British Heart Foundation. JHF Rudd is supported by HEFCE, the British Heart Foundation and the Cambridge NIHR Biomedical Research Centre. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Related Research Data
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