Vascular Positron Emission Tomography and Restenosis in Symptomatic Peripheral Arterial Disease

Objectives This study determined whether in vivo positron emission tomography (PET) of arterial inflammation (18F-fluorodeoxyglucose [18F-FDG]) or microcalcification (18F-sodium fluoride [18F-NaF]) could predict restenosis following PTA. Background Restenosis following lower limb percutaneous transluminal angioplasty (PTA) is common, unpredictable, and challenging to treat. Currently, it is impossible to predict which patient will suffer from restenosis following angioplasty. Methods In this prospective observational cohort study, 50 patients with symptomatic peripheral arterial disease underwent 18F-FDG and 18F-NaF PET/computed tomography (CT) imaging of the superficial femoral artery before and 6 weeks after angioplasty. The primary outcome was arterial restenosis at 12 months. Results Forty subjects completed the study protocol with 14 patients (35%) reaching the primary outcome of restenosis. The baseline activities of femoral arterial inflammation (18F-FDG tissue-to-background ratio [TBR] 2.43 [interquartile range (IQR): 2.29 to 2.61] vs. 1.63 [IQR: 1.52 to 1.78]; p < 0.001) and microcalcification (18F-NaF TBR 2.61 [IQR: 2.50 to 2.77] vs. 1.69 [IQR: 1.54 to 1.77]; p < 0.001) were higher in patients who developed restenosis. The predictive value of both 18F-FDG (cut-off TBRmax value of 1.98) and 18F-NaF (cut-off TBRmax value of 2.11) uptake demonstrated excellent discrimination in predicting 1-year restenosis (Kaplan Meier estimator, log-rank p < 0.001). Conclusions Baseline and persistent femoral arterial inflammation and micro-calcification are associated with restenosis following lower limb PTA. For the first time, we describe a method of identifying complex metabolically active plaques and patients at risk of restenosis that has the potential to select patients for intervention and to serve as a biomarker to test novel interventions to prevent restenosis.

L ower limb peripheral arterial disease (PAD) is the third leading cause of atherosclerotic cardiovascular morbidity, following coronary artery disease and stroke (1). PAD is a global problem, affecting more than 200 million people worldwide, and is present in 20% of the population older than the age of 75 years (2). Although 10% of patients with PAD are asymptomatic (2), intermittent claudication is the most common symptom with more se- rates of 40% to 60% at 12 months limit its long-term durability (3,4). Arterial restenosis after PTA is a difficult problem to solve, requiring further attempts at revascularization with associated poorer clinical outcomes and increased cost (5). The mechanisms underlying vascular restenosis are complex but may include inflammation and calcification (6). Currently, we are unable to predict which patients will experience restenosis.
Positron emission tomography (PET) is a clinically available molecular imaging method that produces quantitative images of the distribution of a radiolabelled molecule. Such images can be co-registered with computed tomography (CT) to provide a topographical distribution of activity. 18  1962 for the detection of osteogenic activity (7). More recently, 18 F-NaF has been shown to localize to developing microcalcifications, providing a marker of calcification activity that has been investigated in a range of cardiovascular disorders including aortic stenosis, carotid and coronary atherosclerosis, and abdominal aortic aneurysm disease (8,9).

PET/CT Identifies Restenosis in PAD Patients
See the Supplemental Appendix for further statistical methodology.

RESULTS
A total of 86 patients were identified as eligible for enrollment. Fifty-five patients were eligible for inclusion and 50 patients agreed to participate (Supplemental Table 1). Ten patients did not complete the study protocol because of the following: stenting performed due to a suboptimal PTA (n ¼ 5), patient withdrawal from the study before the 6-week scan (n ¼ 3), and no angioplasty performed because of an unfavorable lesion profile at the time of angioplasty (n ¼ 2). Subsequent results, therefore, refer to the 40 patients who successfully completed the study protocol ( CLINICAL RESTENOSIS. All patients who had anatomic restenosis, re-presented with recurrence of symptoms, before the 12-month duplex scan.

PET/CT Identifies Restenosis in PAD Patients
Symptom recurrence included stable claudication (n ¼ 7), worsening claudication (n ¼ 5), and worsening pain with non-healing ulcer (n ¼ 2). In the norestenosis group, 4 people developed symptoms during follow-up, which was manifest by a deterioration of walking distance.
The predictive value of both 18 F-FDG (with a cutoff TBR max value of 1.98) and 18 F-NaF (with a cut-off TBR max value of 2.11) PET was highly discriminatory for the occurrence of restenosis at 1 year (p < 0.0001, log-rank p < 0.001) (Figure 3). In contrast, there was no difference in the index lesion calcium score between those who did or did not develop restenosis  Mann-Whitney U test used for comparisons. Dots are actual median TBR max values per patient, bars demonstrate median þ interquartile range. **p < 0.001, *p <0.05.
TBR max ¼ target-to-background ratio maximum; other abbreviations as in Figure 1.
Chowdhury et al. The mechanisms associated with vascular restenosis include endothelial denudation, oxidative stress, proliferating macrophages and vascular smooth muscle cells (26), and constrictive arterial wall remodeling (6). Many of these processes will be reflected in uptake of 18  increasing role in the lower limb. These data will require prospective external validation, and the generalizability of the current findings is limited by the modest sample size and single-center setting.

CONCLUSIONS
Noninvasive molecular imaging using 18