Abstract 4371237: Imaging Sympathetic Stress in Peripheral Artery Disease: Insights from Preclinical Models

Abstract

Background: Peripheral artery disease (PAD) portends significant morbidity (immobility, limb amputation, life-threatening infections, etc) and an up to 10-fold greater mortality, yet remains a largely ill-defined and poorly characterized disease. Lower extremity ischemia in PAD patients may lead to heightened sympathetic activity, stress, which may be imageable with novel high-resolution sympathetic radiotracers like 18 F-labeled fluorobenguanane ( 18 F-FBBG), a norepinephrine analogue. The ability to image ischemic stress may have diagnostic/prognostic implications for PAD patients. Methods/Approach: Sympathetic activity was evaluated in calf muscles in a rabbit model of hindlimb ischemia using 18 F-FBBG. New Zealand rabbits (n=6) underwent 2D angiography, contrast CT angiography, and 18 F-FBBG PET/CT 50-60 minutes post-injection on a high-resolution PET scanner (NX, United Imaging) with 18 F-FBBG PET uptake expressed as mean SUVs ( Figures 1 and 2 ). The animals were then euthanized at 5, 14, or 28 days post right femoral artery ligation. Calf muscles were then gamma well-counted for 18 F-FBBG activity ( Table 1 ). 18 F-FBBG uptake in ischemic (I) and non-ischemic (NI) muscles was related to relative percentage of type I or slow twitch oxidative fibers. Results: In the calf the ischemic soleus (a muscle with up to 90% type I fiber content compared to all other calf muscles being ≤20%) demonstrated significant uptake of 18 F-FBBG (I/NI median: 1.089, IQR: 0.137, p =0.031) an observation which trended with 18 F-FBBG uptake on PET-imaging (R=0.98, p =0.003, Table 1 and Figures 1 and 2 ). Further, 18 F-FBBG uptake trended with type I fiber content especially in the most acute, 5 day, timepoint in the calf (R=-0.62, p =0.022) with the greatest average I/NI uptake of all calf muscles, excluding the outlier, being the 5-day soleus. Conclusions: The most oxygen-dependent muscle, the soleus, demonstrates a significant and imageable uptake of the novel sympathetic tracer 18 F-FBBG under acute and chronic ischemic conditions ( Table 1, Figures 1 and 2 ). This suggests, that the ischemic stress response of skeletal muscle may relate to extent of type I fiber content and potentially the reliance on oxygen during acute ischemia, although less evident at chronic timepoints.