Novel Insights into the Pathogenesis of Light Chain Cardiac Amyloidosis

描述（由申请人提供）：系统性淀粉样变性是一种罕见的疾病，影响许多器官系统，其中最具破坏性和致命性的是心脏。为了回应美国众议院拨款委员会关于淀粉样变性需要进一步研究的声明，罕见病办公室（NIH）赞助了一个研讨会，并促进了淀粉样变性相关的资助。淀粉样蛋白原纤维引起的组织损伤机制是淀粉样蛋白病理生理学中最重要和最不了解的方面。目前对淀粉样变性心功能障碍和心肌损伤的机制了解有限，需要改进检测和治疗。心脏淀粉样变性的特点是淀粉样蛋白在心脏内浸润并破坏细胞外基质。系统性淀粉样变累及心脏（AL-CMP）是由于免疫球蛋白轻链蛋白沉积在心脏，表现为充血性心力衰竭、心律失常和诊断后6个月内死亡。而心脏淀粉样变性与其他非轻链蛋白相关，即与野生型甲状腺转蛋白（TTR）相关的淀粉样变性：老年性系统性淀粉样变性（SSA）或突变型甲状腺转蛋白（ATTR）；AL-CMP患者的预后异常差。我们的中心假设是细胞外基质的蛋白水解活性的决定因素，基质金属蛋白酶（MMPs）及其抑制剂（TIMPs）具有不同的模式，并有助于AL-CMP的发病机制。在波士顿医学中心淀粉样蛋白诊所随访的一组患者中，我们将确定循环MMP和TIMP水平与心脏重塑之间的关系。在Aim 1中，我们将验证AL-CMP患者中MMP和/或TIMP水平发生改变并与更多不良结构重构相关的假设。在Aim 2中，我们将检验MMP和TIMP水平的变化（在基线和治疗后）与临床结果、疾病进展（由超声心动图舒张功能障碍确定）和BNP水平相关的假设。我们将在基线、治疗后立即、出院后3、6和12个月以及需要住院治疗的临床失代偿期间测量心脏特异性MMP和TIMP水平。这些研究将为以累及心脏为特征的系统性淀粉样变性轻链沉积的病理生理学提供新的认识。细胞外基质蛋白水解激活可能在心脏受损伤的功能和临床表现中发挥重要作用，并允许未来的直接治疗干预。

DESCRIPTION (provided by applicant): Systemic amyloidosis is a rare disease that affects many organ systems, the most devastating and lethal of which is cardiac involvement. In response to statements from the U.S. House of Representatives Appropriations Committee on the need for additional research on amyloidosis, the Office of Rare Diseases (NIH) sponsored a workshop and the promotion of amyloidosis-related grants. Mechanisms of tissue damage caused by amyloid fibrils represents the most important and least understood aspect of amyloid pathophysiology. The current understanding of the mechanisms of cardiac dysfunction and myocardial damage in amyloidosis is limited and improved detection and treatment is needed. Cardiac amyloidosis is characterized by amyloid infiltration in the heart with disruption of the extracellular matrix. Systemic amyloidosis featuring cardiac involvement (AL-CMP) is due to immunoglobulin light chain protein deposition in the heart that manifests with congestive heart failure, arrhythmias and death within 6 months of diagnosis. While cardiac amyloidosis related to other non-light chain proteins i.e. amyloidosis associated with wild-type transthyretin (TTR): the senile systemic amyloidosis (SSA) or a mutant transthyretin (ATTR); the prognosis for patients with AL-CMP is inordinately worse. Our central hypothesis is that determinants of the proteolytic activity of the extracellular matrix, the matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) have distinct patterns and contribute to the pathogenesis of AL-CMP. In a cohort of patients that have been followed at the Amyloid Clinic at Boston Medical Center, we will determine the relationship between circulating MMP and TIMP levels and cardiac remodeling. In Aim 1, we will test the hypotheses that MMP and/or TIMP levels are altered in AL-CMP patients and are associated with more adverse structural remodeling. In Aim 2, we will test the hypotheses that change in MMP and TIMP levels (between baseline and post-therapy) are associated with clinical outcomes, disease progression (as determined by diastolic dysfunction on echocardiography) and BNP levels. We will measure cardiac specific MMP and TIMP levels at baseline, immediately post-therapy and 3, 6, and 12 months after discharge from the hospital and during periods of clinical decompensation that require hospitalization. These studies will provide new understanding into the pathophysiology of light chain deposition in systemic amyloidosis featuring cardiac involvement. Extracellular matrix proteolytic activation may play an important role in the functional and clinical manifestations of cardiac involvement and allow for future directed therapeutic interventions. PUBLIC HEALTH RELEVANCE: Systemic amyloidosis is a rare disease that affects many organ systems, the most devastating and lethal of which is cardiac involvement. Cardiac involvement and its resultant dysfunction is the least understood aspect of amyloid pathophysiology, therefore improved detection and treatment is needed. In response to statements from the U.S. House of Representatives Appropriations Committee on the need for additional research in amyloidosis, the Office of Rare Diseases (NIH) sponsored a workshop and is promoting amyloidosis-related grants and as a result amyloidosis is considered to be a high priority for research in the field.