Relationships Among Regional Arterial Inflammation, Calcification, Risk Factors, and Biomarkers

Abstract

Background Fluorodeoxyglucose positron emission tomography (FDG PET) imaging of atherosclerosis has been used to quantify plaque inflammation and to measure the effect of plaque stabilizing drugs. Here we explore how atherosclerotic plaque inflammation varies across arterial territories and how it relates to arterial calcification. We also test the hypotheses that the degree of local arterial inflammation measured by PET is correlated with the extent of systemic inflammation and presence of risk factors for vascular disease. Methods and Results Forty-one subjects underwent vascular PET/CT imaging with FDG. All had either vascular disease or multiple risk factors for it. Forty subjects underwent carotid imaging, twenty-seven underwent aortic, twenty-four iliac and thirteen femoral imaging. Thirty-three subjects had a panel of biomarkers analyzed. We found strong associations between FDG uptake in neighboring arteries (left vs. right carotid r=0.91, p<0.001, ascending aorta vs. aortic arch r=0.88, p<0.001). Calcification and inflammation rarely overlapped within arteries – carotid artery FDG uptake vs. calcium score r=−0.42, p=0.03). Carotid artery FDG uptake was greater in those with a history of coronary artery disease (target to background ratio (TBR) 1.83 vs. 1.61, p<0.01), and in males vs. females (TBR 1.83 vs. 1.63, p<0.05). Similar findings were also noted in the aorta and iliac arteries. Subjects with the highest levels of FDG uptake also had the greatest concentrations of inflammatory biomarkers: descending aorta TBR vs. matrix metalloproteinase 3 (MMP 3): r=0.53, p=0.01 and carotid TBR vs. MMP 9: r=0.50, p=0.01. Non-significant positive trends were seen between FDG uptake and levels of interleukin 18, fibrinogen and C-reactive protein. Finally, we found that the atheroprotective biomarker adiponectin was negatively correlated with the degree of arterial inflammation in the descending aorta: r=−0.49, p=0.03). Conclusions This study shows that FDG PET imaging can increase our knowledge of how atherosclerotic plaque inflammation relates to calcification, serum biomarkers and vascular risk factors. Plaque inflammation and calcification rarely overlap, supporting the theory that calcification represents a late, burnt-out stage of atherosclerosis. Inflammation in one arterial territory is associated with inflammation elsewhere, and the degree of local arterial inflammation is reflected in the blood levels of several circulating biomarkers. We suggest that FDG PET imaging could be used as a surrogate marker of both atherosclerotic disease activity and drug effectiveness. Prospective, event driven studies are now underway to determine the role of this technique in clinical risk prediction.

Vascular imaging with positron emission tomography

“…Aortic plaque inflammation has been well described in clinical FDG-PET imaging studies [54,81]. Recent studies have extended this work into the area of abdominal aortic aneurysm, to determine whether inflammation might be a predictor of rapid aneurysm expansion or heightened rupture risk.…”

“…This has proved important in the search for quantitative measures of inflammation that can be used to test the impact of new therapies. Uptake may be widespread [44,54], although especially affecting the carotid arteries and proximal aorta (Figs 1 and 2). This is consistent with the hypothesis that atherosclerosis is a generalized inflammatory condition.…”

“…Vascular FDG uptake seems to be greater in those subjects with pre-existing metabolic syndrome [44], more than 1 cardiovascular risk factor [54], a history of coronary artery disease or diabetes [54,61]. It rarely co-localizes with vascular calcification [54,62], an independent risk factor for cardiovascular events, perhaps because calcification tends to occur late in the course of the disease, with inflammation earlier.…”

“…It rarely co-localizes with vascular calcification [54,62], an independent risk factor for cardiovascular events, perhaps because calcification tends to occur late in the course of the disease, with inflammation earlier. Arterial uptake in one vascular region correlates strongly with its anatomical pair, and more strongly with neighbouring regions than more distally.…”

“…Plaques with high-risk features on MRI (large lipid core [49] or intraplaque haemorrhage [63]) or ultrasound [64,65] (echolucency) have higher FDG than more stable phenotypes. Aortic uptake has been shown to correlate with circulating biomarkers matrix metalloproteases 1, 3 and 9 [54,66], and an inverse correlation has been reported with the atheroprotective biomarkers adiponectin and plasminogen activator inhibitor 1 [54,66]. There are mixed results when comparisons are made between the circulating biomarker of inflammation C-reactive protein (CRP) and FDG uptake.…”