Molecular Imaging of Primary Amyloid Cardiomyopathy

 描述(申请人提供)：原发性轻链淀粉样变性(AL)是最常见的全身性淀粉样变性，由浆细胞癌引起，这是一种血液系统恶性肿瘤。它会导致超过70%的人患有限制性心肌病(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，作为急性-慢性粒细胞白血病的标志，心肌功能障碍显著增加了早期治疗相关的死亡率，主要是心血管死亡，是长期存活率较低的有力预测因子。两种潜在的治疗机制是心肌功能障碍的基础--淀粉样蛋白的机械效应和循环轻链/淀粉样蛋白相互作用的毒性效应--并容易导致AL-CMP患者的心力衰竭、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，人们对AL-CMP发病机制的研究一直受到阻碍。最近的一项突破，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异性和定量成像。此外，我们建议研究临床前证实的人类轻链毒性的三种途径--心肌氧化代谢、氧化应激和冠状动脉微血管功能。我们的中心假设是，心肌18F-florbetapir滞留是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，在改善心肌淀粉样蛋白含量之前，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，我们将量化18F-florbetapir滞留作为急性髓细胞白血病和活动期浆细胞营养不良患者侵袭性心肌疾病的标志，并与患有急性髓细胞白血病和长期血液学缓解的对照组进行比较。在目标2中，我们建议使用先进的成像技术来评估化疗导致的轻链减少对心肌结构、功能和代谢的影响，并确定这些变化的时间进程。CMR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、11C-乙酸酯PET的心肌氧化代谢(Kmono)和冠脉血流储备以及18F-florbetapir成像不仅可以复杂地表征AL-CMP的心肌基质，还可以确定治疗后的变化。这些拟议的研究可能会改变我们目前对AL-CMP的理解，将其理解为一种由被动淀粉样蛋白相关的结构损伤引起的限制性心脏病，而不是由被动和侵袭性因素引起的更复杂的疾病。这些研究的结果可能形成预防和治疗AL-CMP的药物发现计划的基础。

 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.