We prospectively evaluated 41 subjects with either risk factors for, or established atherosclerosis using FDG PET/CT as a surrogate marker of vascular inflammation. Previous studies have established that the degree of arterial uptake of FDG correlates strongly with macrophage infiltration in two different animal models of disease5, 18
and in patients with symptomatic carotid atherosclerosis4, 6
. Tahara and colleagues highlighted the ability of FDG PET to track atherosclerotic inflammation reduction resulting from a modest dose of simvastatin8
, and similar results were noted in an animal model of atherosclerosis10
. Most recently, it has been shown that arterial FDG PET imaging is capable of reporting on the reduction of vascular inflammation resulting from cardiovascular risk factor modification over a one year period9
. These intervention studies have set the stage for the use of FDG PET imaging as a potential surrogate marker for evaluating drug efficacy, analogous to its use in cancer therapy trials16
The current study shows how FDG PET imaging can extend our insight into the disease process of atherosclerosis. Here we have shown that the presence of inflammation in one arterial territory is highly predictive of inflammation in others. This finding suggests a form of systemic arterial activation. There seems to be some degree of regionality however, because inflammation across neighboring territories is more correlated than inflammation across arterial areas more anatomically remote from each other.
Supporting this theory of systemic activation, we also noted that the degree of arterial FDG uptake was associated with blood levels of several systemic inflammatory biomarkers, including those from the matrix metalloproteinase family, and strong trends amongst both the interleukin group and CRP. A previous study demonstrated a link between carotid FDG uptake and level of MMP 1 in a group of patients with carotid disease awaiting surgery19
. We found no association in our population with this particular MMP, but did observe moderately strong correlations between FDG uptake and levels of both MMP 3 and MMP 9, which, along with MMP 1, have been implicated in plaque rupture20–22
. Over-expression of MMP 9 in ApoE knockout mice leads to rapid plaque destabilization23
, highlighting the key role of these macrophage-secreted enzymes. One particular advantage of FDG PET atheroma imaging over measurement of circulating biomarkers is the ability to pinpoint a particular arterial segment as being inflamed, allowing it to be targeted for treatment. Wu et al demonstrated that arteries that were most highly inflamed on FDG PET prior to carotid intervention had the greatest release of harmful MMP 1 during the procedure19
We noted a modest relationship between arterial FDG uptake and serum CRP levels. Some previous publications have demonstrated positive correlations between FDG uptake and CRP, whilst others have not demonstrated any sort of relationship4, 8, 19, 24
. Therefore, although this biomarker can help to refine the risk of future cardiovascular events at a population level25
, its role in individual subjects is not yet certain.
The lack of a relationship between arterial inflammation and serum LDL levels, and the inverse relationships between arterial inflammation and the biomarkers adiponectin and PAI-1 are interesting. Adiponectin is known to act as a brake on inflammation in both healthy individuals and those with vascular disease26, 27
, so it is intriguing that in those with the highest levels of this hormone, there were the lowest degrees of FDG arterial uptake. Serpins such as PAI-1 have pro- or anti-inflammatory actions, depending on the degree of vascular activation28
. Other groups have previously noted no relationship between FDG uptake and LDL level8, 9, 29
, and it may be that oxidised LDL levels are more important in determining the amount of artery inflammation than LDL.
In this study inflammation and calcification within arteries rarely overlapped. This has been previously suggested30
; but in a retrospective study of cancer patients where the degree of inflammation was not numerically quantified. Our finding supports the view that plaques of different age might coexist in arteries, with episodes of inflammation leading to rupture events and having an end stage of calcification.
The observation that males have greater arterial FDG uptake than females suggests that atherosclerotic plaques in males may be more highly inflamed, perhaps providing a pathological link for their higher rate of cardiovascular events. Higher FDG uptake in the carotid and iliac arteries of patients with a prior history of CAD reinforces the global nature of atherosclerotic disease, whereas in patients with a history of cigarette smoking, FDG uptake was only increased in the iliac arteries. It is well known that iliac artery disease is common amongst smokers31
, and this result suggests a site-specific nature of the response to certain risk factors.
The fact that the small number of diabetic subjects in our study did not have higher FDG uptake than non-diabetics may be due to effective medical therapy in our study group, or to the competitive effect of hyperglycemia on FDG uptake. Some diabetic medications, such as glitazones, have been shown to have anti-inflammatory actions32
while metformin has been associated with a decreased risk of future cardiovascular events in obese type 2 diabetic patients33
. It is therefore plausible that taking these medications could reduce the degree of arterial inflammation detected by PET imaging. Since we excluded patients with high blood glucose from the study, it is unlikely that significant competition between FDG and glucose would explain the lack of difference. Furthermore, it seems that FDG uptake into inflammatory lesions may be less sensitive to elevated serum glucose levels than tumour cells34
Our study did not show an association of statin use and FDG uptake, in contrast to other work8
. This is most likely due to the small sample size in our non-statin subgroup (as shown in , 88.8% of the subjects were taking statins).