Radiotracer-Based Imaging for Quantitative Assessment of Skeletal Muscle Perfusion in Peripheral Artery Disease

PROJECT SUMMARY Patients with lower extremity peripheral artery disease (PAD) are at increased risk of lifestyle limiting claudication, ulceration, amputation, and death. Despite this knowledge, an ongoing challenge for the vascular community is the lack of a standard non-invasive test for quantifying regional abnormalities in skeletal muscle perfusion in PAD. Our laboratory has been at the forefront of translating nuclear perfusion imaging techniques to patients with PAD and demonstrated the potential prognostic value of these methods for prediciting clinical outcomes. Specifically, in the prior funding period of this award, we clinically translated a single photon emission computed tomography (SPECT)/CT imaging approach from pigs with limb ischemia to patients with PAD and demonstrated that SPECT/CT perfusion imaging measures were repeatable in patients, detected regional abnormalities in resting perfusion of the lower extremities, assessed perfusion defects that corresponded with the level of future amputation, and quantified revascularization-induced regional improvements in relative perfusion that were associated with risk of amputation after endovascular therapy. We then developed and validated a dynamic positron emission tomography (PET) perfusion imaging approach using fluorine-18 (18F)-sodium fluoride (NaF), a radionuclide traditionally used for molecular imaging of bone and vascular microcalcification. Dynamic 18F-NaF PET imaging revealed utility for quantifying regional, absolute measures of muscle perfusion (i.e., ml/min/100g) in pigs and PAD patients with limb ischemia that coincided with microvascular remodeling in pig skeletal muscle and symptom severity in PAD patients. The goal of this proposal is to leverage the novel PET perfusion imaging method developed in the prior funding period to optimize regional evaluation of absolute measures of skeletal muscle perfusion in PAD patients undergoing endovascular revascularization. To accomplish this goal, in Aim 1, we will validate dynamic 18F- NaF PET perfusion imaging as an approach for monitoring ischemia-induced alterations in skeletal muscle morphology and mitochondrial function using a newly developed porcine model of chronic limb-threatening ischemia (CLTI). In Aim 2, we will establish a healthy clinical database for 18F-NaF PET perfusion measures and compare these perfusion measures to standard indices of macro- and microvascular disease in patients with PAD. In Aim 3, we will quantify absolute changes in regional calf muscle perfusion in response to revascularization procedures in patients with PAD using dynamic PET imaging, and evaluate the relationship between regional perfusion responses and clinical outcomes. These studies are designed to pre-clinically validate the utility of dynamic PET perfusion imaging for evaluating adverse remodeling of skeletal muscle and test the clinical efficacy of this method for monitoring regional responses to endovascular treatment and predicting clinical outcomes.