Molecular Imaging of Primary Amyloid Cardiomyopathy

原发性淀粉样心肌病的分子影像

• 批准号: 9124197
• 负责人: Sharmila Dorbala
• 金额: $ 87.28万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9124197
• 关键词: Acetates; Address; Affinity; Aggressive course; Amyloid; Amyloid Fibrils; Amyloid deposition; Amyloidosis; Animal Model; Arrhythmia; Binding; Biological Markers; Blood flow; Cardiac; Cardiomyopathies; Cardiovascular system; Cell Respiration; Cessation of life; Clinical Research; Complex; Coronary; Data; Deposition; Development; Diagnosis; Disease; Disease remission; Early treatment; F2-Isoprostanes; Foundations; Goals; Heart Diseases; Heart failure; Hematologic Neoplasms; Human; Image; Individual; Infiltration; Infusion procedures; Knowledge; Left; Left Ventricular Mass; Life; Light; Light-Chain Immunoglobulins; Magnetic Resonance Imaging; Malignant neoplasm of lung; Mechanics; Metabolism; Microvascular Dysfunction; Mitochondria; Myocardial; Myocardial dysfunction; Myocardium; Oxidative Stress; PET/CT scan; Pathogenesis; Pathogenicity; Pathway interactions; Peroxonitrite; Plasma Cell Neoplasm; Positron-Emission Tomography; Recovery; Rest; Restrictive Cardiomyopathy; Risk Marker; Role; Serum; Serum Markers; Staging; Stress; Structure; Sudden Death; Techniques; Testing; Thick; Time; Toxic effect; Tracer; Ventricular; Woman; Work; amyloid imaging; base; chemotherapy; clinically significant; drug discovery; extracellular; human data; imaging modality; improved; in vivo; indexing; light effects; men; molecular imaging; mortality; novel; novel strategies; novel therapeutics; preclinical study; prevent; primary amyloidosis of light chain type; pro-brain natriuretic peptide (1-76); programs; public health relevance; quantitative imaging; response; uptake

 DESCRIPTION (provided by applicant): Primary light chain amyloidosis (AL) is the most common systemic amyloidosis, resulting from a plasma cell dyscrasia, a hematological malignancy. It causes a restrictive cardiomyopathy (AL-CMP) in over 70% of individuals. AL-CMP is as lethal as stage 4 lung cancer and more lethal than any other form of restrictive heart disease; if untreated, the mortality rate is 50% within 18 months. Moreover, myocardial dysfunction, the hallmark of AL-CMP, significantly increases early treatment related mortality, predominantly cardiovascular death, and is a powerful predictor of poor long-term survival. Two potentially treatable mechanisms underlie myocardial dysfunction-mechanical effects of amyloid and toxic effects from circulating light chain/ amyloid interactions-and predispose to heart failure, arrhythmias, and sudden death in individuals with AL-CMP. Until now, efforts to determine the mechanisms of AL-CMP have been hampered by a lack of animal models and the limitations of noninvasive techniques to directly image myocardial amyloid. A recent breakthrough, 18F- florbetapir PET/CT, has provided for the first time specific and quantitative imaging of myocardial amyloid including toxic amyloid protofibrils. Furthermore, we propose to investigate three pre-clinically proven pathways of light chain toxicity in humans-myocardial oxidative metabolism, oxidative stress, and coronary microvascular function. Our central hypotheses are that myocardial 18F-florbetapir retention is a biomarker for aggressiveness of AL-CMP and that effective chemotherapy will, by reducing circulating light chains, decrease aggressiveness of AL-CMP and improve oxidative stress, myocardial oxidative metabolism, microvascular function and contractile function, prior to an improvement in myocardial amyloid content. In Aim 1, we will quantify myocardial 18F-florbetapir retention as a marker of aggressive myocardial disease in individuals with AL-CMP and active plasma cell dyscrasia compared to control individuals with AL-CMP and long-term hematological remission. In Aim 2, we propose, using advanced imaging, to assess the effects of light chain reduction due to chemotherapy on myocardial structure, function, and metabolism and define the time course of these changes. Serial ECV and strain imaging by CMR, serum F2-isoprostanes and peroxynitrite levels, myocardial oxidative metabolism (Kmono) and coronary flow reserve by 11C-acetate PET, and 18F-florbetapir imaging will not only intricately characterize the myocardial substrate in AL-CMP, but also identify changes in response to therapy. The proposed studies offer the potential to transform our current understanding of AL- CMP as a restrictive heart disease caused by passive amyloid-related architectural damage to that of a more complex disorder resulting from both passive and aggressive factors. The results of these studies may form the foundation for drug discovery programs to prevent and cure AL-CMP.

 描述（由适用提供）：原发性轻链淀粉样变性（AL）是最常见的全身性淀粉样变性，由血浆细胞性诊所（一种血液学恶性肿瘤）产生。它导致超过70％的个体中的限制性心肌病（AL-CMP）。 Al-CMP与4期肺癌一样致命，比任何其他形式的限制性心脏病都更致命。如果未经治疗，死亡率在18个月内为50％。此外，心肌功能障碍（AL-CMP的标志）显着提高了早期治疗相关的死亡率，主要是心血管死亡，并且是长期生存不良的有力预测指标。淀粉样蛋白和毒性作用是循环轻链/淀粉样蛋白相互作用以及倾向于心力衰竭，心律不齐，心律不齐和肌肉疾病的两种潜在可治疗的机制，其淀粉样蛋白和毒性作用是淀粉样蛋白和毒性作用的基础。到目前为止，缺乏动物模型以及无创技术的局限性来确定AL-CMP的机制的努力受到阻碍，以直接成像心肌淀粉样蛋白。最近的突破，18f- Florbetapir PET/CT，首次提供了包括有毒淀粉样原纤维在内的心肌淀粉样蛋白的特定和定量成像。此外，我们建议研究人类心肌氧化代谢，氧化应激和冠状动脉微血管功能的三种轻链毒性途径。我们的中心假设是，心肌18F氯二肽保留率是AL-CMP侵略性的生物标志物，有效的化学疗法将通过减少循环光链，降低Al-CMP的攻击性并改善氧化应激的攻击性，改善氧化应激，在氧化型的氧化应激，心肌氧化性代谢性，微血管性功能和合同功能，并改善了Ammy in nimy in Mysy in Myyy insy in Myyy ryy insy romy in Myyy。在AIM 1中，与患有AL-CMP和长期血液学缓解的个体相比，我们将在AL-CMP和活动性浆细胞性障碍患者中定量心肌18F叶绿素保留为攻击性心肌疾病的标志。在AIM 2中，我们建议使用高级成像来评估由于化学疗法对心肌结构，功能和代谢而引起的轻链减少的影响，并定义这些变化的时间过程。通过CMR，血清F2-异丙烷和过氧亚硝酸盐水平，心肌氧化物代谢（Knono）和冠状动脉流量储备的连续ECV和应变成像，以及18F氯贝氏PET的冠状动脉流量储备以及18F氯酸酯的成像不仅会在Al-CMP中鉴定出质量变化，还将精心鉴定出心肌的特征。拟议的研究提供了潜力，可以改变我们对AL-CMP的当前理解是由被动淀粉样蛋白相关的建筑损害引起的限制性心脏病，造成了由被动和侵略性因素引起的更复杂的疾病。这些研究的结果可能构成了预防和治愈CMP的药物发现计划的基础。