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（由申请方提供）：原发性轻链淀粉样变性（AL）是最常见的系统性淀粉样变性，由浆细胞恶液质（一种血液恶性肿瘤）引起。它会导致超过70%的个体发生限制性心肌病（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更致命;如果不治疗，18个月内的死亡率为50%。此外，心肌功能障碍，AL-CMP的标志，显著增加早期治疗相关的死亡率，主要是心血管死亡，是长期生存不良的有力预测因子。两种潜在的可治疗的机制是心肌功能障碍的基础-淀粉样蛋白的机械作用和循环轻链/淀粉样蛋白相互作用的毒性作用-并使AL-CMP患者易患心力衰竭、心律失常和猝死。到目前为止，由于缺乏动物模型和直接成像心肌淀粉样蛋白的非侵入性技术的局限性，确定AL-CMP机制的努力受到阻碍。最近的一项突破，18F-氟倍他匹PET/CT，首次提供了心肌淀粉样蛋白（包括毒性淀粉样蛋白原纤维）的特异性和定量成像。此外，我们建议调查三个临床前证明轻链毒性在人类心肌氧化代谢，氧化应激和冠状动脉微血管功能的途径。我们的中心假设是，心肌18F-florbetapir潴留是AL-CMP侵袭性的生物标志物，有效的化疗将通过减少循环轻链，降低AL-CMP的侵袭性，并在心肌淀粉样蛋白含量改善之前改善氧化应激、心肌氧化代谢、微血管功能和收缩功能。在目标1中，我们将定量心肌18F-氟倍他匹潴留作为AL-CMP和活动性浆细胞恶液质个体与AL-CMP和长期血液学缓解的对照个体相比的侵袭性心肌疾病的标志物。在目标2中，我们提出，使用先进的成像技术，以评估轻链减少由于化疗对心肌结构，功能和代谢的影响，并确定这些变化的时间过程。通过CMR进行的连续ECV和应变成像、血清F2-异前列腺素和过氧亚硝酸盐水平、通过11 C-乙酸PET进行的心肌氧化代谢（Kmono）和冠状动脉血流储备以及18 F-florbetapir成像不仅可以复杂地表征AL-CMP中的心肌基质，还可以识别对治疗反应的变化。拟议的研究提供了将我们目前对AL-CMP的理解从被动淀粉样蛋白相关结构损伤引起的限制性心脏病转变为被动和侵袭性因素引起的更复杂疾病的可能性。这些研究的结果可能为预防和治疗AL-CMP的药物发现计划奠定基础。