Multi-isotope Hybrid PET/CT Imaging of Peripheral Artery Disease in Diabetes

Patients with diabetes mellitus (DM) remain at high risk for the development of significant co-morbidities, specifically those associated with autonomic dysfunction, peripheral artery disease (PAD), and cardiovascular complications with a 2 to 10-fold higher mortality rate. PAD may manifest as stress induced leg pain (claudication) due to vascular insufficiency or critical limb ischemia (CLI) as the most severe manifestation of lower extremity PAD characterized by lower limb ischemic rest pain and/or the presence of tissue loss. The sympathetic nervous system plays a critical role in the normal autoregulation of the vasculature, and loss of vasomotor control is responsible for postural hypotension but also for the remarkable increase of peripheral blood flow and arteriovenous shunting in the neuropathic diabetic foot. Therefore, sympathetic denervation increases blood flow, as it results in vasodilation and non-nutritive, arterio-venous shunting. Sympathetic denervation may cause structural damage to peripheral arteries resulting in degeneration of arterial medial smooth muscle with subsequent medial artery calcification (MAC) a feature of diabetic neuropathy. Positron emission tomography (PET) imaging with 82Rb provides high-sensitivity and high-resolution images for quantification of absolute flow, while a 18F-labeled norepinephrine analog (18F-LMI1195) provides information about sympathetic activity. This project will optimize and apply dual isotope (82Rb/18F-LMI1195) hybrid PET/CT imaging for evaluation of lower extremity flow and denervation and vascular calcification in pre-clinical models of PAD and in patients with DM and PAD. We propose a clinical imaging sub-studies of two active multi-center observational registry called SCOPE-CLI and PORTRAIT, which were designed to phenotype patients with CLI and claudication, respectively. These registries collect observational data on treatment patterns, and other outcomes that are relevant to patients with DM and PAD. In Aim 1, our hybrid PET/CT imaging approach will be optimized using a porcine model of hindlimb ischemia in the presence and absence of an acute peripheral nerve block. These studies will establish methods for evaluation of skeletal muscle rest and stress flow and flow heterogeneity. Aim 2 will apply dual isotope PET/CT imaging for quantification of acute and chronic changes in regional flow and flow reserve before and after regional denervation of the lower extremities in relation to development of MAC in a chronic rabbit model of peripheral denervation. In Aim 3 we will translate this approach to patients with DM and a spectrum of PAD disease severity to evaluate the prognostic value of hybrid PET/CT imaging of lower extremity for predicting progression of MAC, rates of amputation, and major adverse cardiovascular events. The proposed multi-isotope PET/CT imaging of lower extremity flow and innervation developed and applied in this project in conjunction with imaging of vascular calcifications will characterize the pathophysiology of autonomic dysfunction in critical limb ischemia and this information may lead to a paradigm change in the evaluation and long-term management of patients with DM and PAD.