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

糖尿病周围动脉疾病的多同位素混合 PET/CT 成像

• 批准号: 10586846
• 负责人: Chi Liu
• 金额: $ 83.74万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-19 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586846
• 关键词: 3-Dimensional; Activities of Daily Living; Acute; Albumins; Amputation; Anatomy; Angiography; Arteries; Atherosclerosis; Autonomic Dysfunction; Blood Vessels; Blood flow; Cardiovascular system; Cessation of life; Chronic; Data; Denervation; Development; Diabetes Mellitus; Diabetic Autonomic Neuropathy; Diabetic Foot; Diabetic Neuropathies; Diagnosis; Dose; End stage renal failure; Evaluation; Event; Exercise; Fibrosis; Functional disorder; Heart; Heterogeneity; Hindlimb; Homeostasis; Hybrids; Hyperglycemia; Image; Image Analysis; Ischemia; Isotopes; Label; Legal patent; Limb structure; Lower Extremity; Maps; Medial; Methods; Microspheres; Microvascular Dysfunction; Modeling; Muscle; Muscle denervation procedure; Nerve; Nerve Block; Nervous System; Neuropathy; Norepinephrine; Orthostatic Hypotension; Oryctolagus cuniculus; Outcome; Oxidative Stress Induction; Pain; Pain in lower limb; Patients; Perfusion; Peripheral; Peripheral Nerves; Peripheral arterial disease; Phenotype; Physiologic arteriovenous anastomosis; Physiological; Play; Positron-Emission Tomography; Pre-Clinical Model; Prevalence; Probability; Quality of life; Quantitative Evaluations; Radiolabeled; Registries; Resolution; Rest; Risk; Role; Sclerosis; Severities; Severity of illness; Skeletal Muscle; Smooth Muscle; Stress; Structural defect; Sympathectomy; Sympathetic Nervous System; Technology; Testing; Time; Tissues; Translating; Treatment Cost; Treatment outcome; Vascular calcification; Vascularization; Vasodilation; Vasomotor; Veins; Work; X-Ray Computed Tomography; analog; attenuation; autonomic neuropathy; calcification; cardiovascular risk factor; claudication; clinical application; clinical imaging; comorbidity; critical limb Ischemia; design; diagnostic criteria; endothelial dysfunction; extracellular; foot; high resolution imaging; high risk; hypoperfusion; imaging approach; improved; limb ischemia; mortality; nerve supply; non-invasive imaging; novel; particle; peripheral blood; porcine model; prognostic value; quantitative imaging; radiotracer; response; revascularization surgery; serial imaging; single photon emission computed tomography; treatment pattern; volunteer

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.

糖尿病患者（DM）患有明显的合并症，仍然有高风险， 特别是与自主功能障碍，外周动脉疾病（PAD）和心血管相关的那些 死亡率高2至10倍的并发症。垫子可能表现为压力引起的腿部疼痛 （claurautic）由于血管不足或关键肢体缺血（CLI）作为最严重的表现 下肢垫为特征是下肢缺血性休息疼痛和/或组织损失的存在。这 交感神经系统在脉管系统的正常自动调节中起着至关重要的作用，丧失 血管舒缩控制负责姿势性低血压，但外周的显着增加 神经性糖尿病脚的血流和动静脉分流。因此，同情的神经 增加血流，因为它导致血管舒张和非营养，动脉连接。同情 改造可能对周围动脉造成结构损害，导致动脉内侧变性 平滑肌具有随后的内侧动脉钙化（MAC）的糖尿病神经病的特征。正面 具有82RB的发射断层扫描（PET）成像为高敏性和高分辨率图像提供 绝对流量的量化，而18F标记的去甲肾上腺素类似物（18F-LMI1195）提供了信息 关于同情活动。该项目将优化并应用双同位素（82RB/18F-LMI1195）混合宠物/CT 临床前模型中下肢流动，神经钙化和血管钙化的成像 PAD和DM和PAD的患者。我们提出了两个主动多中心的临床成像子研究 观察性注册表称为范围CLI和肖像，它们旨在表型CLI患者 和laurauration。这些注册机构收集有关治疗模式的观察数据，以及其他 与DM和PAD患者有关的结果。在AIM 1中，我们的混合宠物/CT成像方法将 在存在和不存在急性外周的情况下，使用后肢缺血的猪场模型进行优化 神经阻滞。这些研究将建立评估骨骼肌休息和压力流的方法 流异质性。 AIM 2将应用双同位素PET/CT成像以定量急性和慢性 区域流量和流量储备的变化在下肢区域区域之前和之后 在外围神经支配的慢性兔模型中与MAC的发展有关。在AIM 3中，我们将翻译 DM患者和各种PAD疾病严重程度的这种方法，以评估 下肢的混合PET/CT成像，用于预测MAC的进展，截肢率和主要 不良心血管事件。下肢流量和 与血管钙化成像一起在该项目中开发和应用的神经 表征临界肢体缺血中自主功能障碍的病理生理学，这些信息可能 导致对DM和PAD患者的评估和长期管理的范式变化。