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 (DM) 患者仍然面临发生重大并发症的高风险， 特别是与自主神经功能障碍、外周动脉疾病 (PAD) 和心血管疾病相关的疾病 并发症的死亡率高出 2 至 10 倍。 PAD 可能表现为压力引起的腿部疼痛 由于血管功能不全或严重肢体缺血 (CLI) 导致的（跛行）是最严重的表现 下肢 PAD 的特征是下肢缺血性静息痛和/或存在组织损失。这 交感神经系统在脉管系统的正常自动调节和丧失 血管舒缩控制不仅是导致体位性低血压的原因，而且也是导致外周血压显着增加的原因。 神经性糖尿病足的血流和动静脉分流。因此，去交感神经支配 增加血流量，因为它会导致血管舒张和非营养性动静脉分流。富有同情心 去神经术可能会对周围动脉造成结构性损伤，导致动脉内侧变性 平滑肌随后出现内侧动脉钙化（MAC），这是糖尿病神经病变的一个特征。正电子 82Rb 发射断层扫描 (PET) 成像可提供高灵敏度和高分辨率图像 绝对流量的量化，而 18F 标记的去甲肾上腺素类似物 (18F-LMI1195) 提供信息 关于交感神经活动。该项目将优化和应用双同位素（82Rb/18F-LMI1195）混合PET/CT 用于评估临床前模型中下肢血流、去神经支配和血管钙化的成像 PAD 以及 DM 和 PAD 患者。我们提出了两个活跃的多中心的临床影像子研究 名为 SCOPE-CLI 和 PORTRAIT 的观察登记系统，旨在对 CLI 患者进行表型分析 和跛行，分别。这些登记处收集有关治疗模式的观察数据以及其他 与 DM 和 PAD 患者相关的结果。在目标 1 中，我们的混合 PET/CT 成像方法将 使用猪后肢缺血模型在存在和不存在急性外周血的情况下进行优化 神经阻滞。这些研究将建立评估骨骼肌休息和应力流的方法 流动异质性。目标 2 将应用双同位素 PET/CT 成像来量化急性和慢性疾病 下肢区域去神经术前后区域血流和血流储备的变化 与慢性兔外周去神经支配模型中 MAC 发展的关系。在目标 3 中我们将翻译 这种方法对 DM 患者和一系列 PAD 疾病严重程度来评估预后价值 下肢混合 PET/CT 成像可预测 MAC 进展、截肢率和严重程度 不良心血管事件。所提出的下肢血流和下肢血流多同位素 PET/CT 成像 在该项目中开发和应用的神经支配与血管钙化成像相结合将 描述严重肢体缺血时自主神经功能障碍的病理生理学特征，该信息可能 导致 DM 和 PAD 患者的评估和长期管理发生范式变化。