Novel Insights into the Pathogenesis of Light Chain Cardiac Amyloidosis

描述(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受累。为了回应美国众议院拨款委员会关于需要对淀粉样变进行更多研究的声明，罕见疾病办公室(NIH)赞助了一次研讨会，并促进了与淀粉样变相关的赠款。淀粉样蛋白纤维引起组织损伤的机制是淀粉样蛋白病理生理学中最重要也是最不为人所知的方面。目前对淀粉样变性的心功能障碍和心肌损伤机制的了解有限，需要改进检测和治疗。心脏淀粉样变性的特征是淀粉样蛋白在心脏内的渗透和细胞外基质的破坏。以心脏受累为特征的系统性淀粉样变性(AL-CMP)是由于免疫球蛋白轻链蛋白在心脏中沉积，表现为充血性心力衰竭、心律失常和6个月内死亡。而心脏淀粉样变性与其他非轻链蛋白相关，如与野生型转甲状腺蛋白相关的淀粉样变性：老年性系统性淀粉样变性(SSA)或突变型转甲状腺蛋白(ATTR)；AL-CMP患者的预后异常差。我们的中心假设是，细胞外基质、基质金属蛋白酶(MMPs)及其抑制物(TIMPs)的蛋白分解活性的决定因素具有不同的模式，并在AL-CMP的发病机制中起作用。在波士顿医学中心淀粉样蛋白诊所跟踪调查的一组患者中，我们将确定循环中基质金属蛋白酶和组织基质金属蛋白酶水平与心脏重构之间的关系。在目标1中，我们将检验以下假设：在AL-CMP患者中，基质金属蛋白酶和/或TIMP水平发生改变，并与更不利的结构重建相关。在目标2中，我们将检验这样的假设，即基质金属蛋白酶和组织金属蛋白酶水平的变化(在治疗前和治疗后之间)与临床结果、疾病进展(由超声心动图上的舒张期功能障碍确定)和脑钠素水平有关。我们将在基线、治疗后即刻、出院后3个月、6个月和12个月以及需要住院的临床失代偿期测量心脏特异性基质金属蛋白酶和组织金属蛋白酶水平。这些研究将为以心脏受累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理解。细胞外基质蛋白分解激活可能在心脏受累的功能和临床表现中发挥重要作用，并为未来的定向治疗干预提供依据。 公共卫生相关性：系统性淀粉样变性是一种影响许多器官系统的罕见疾病，其中最具破坏性和致命性的是心脏受累。心脏受累及其导致的功能障碍是淀粉样蛋白病理生理学中最不了解的方面，因此需要改进检测和治疗。为了回应美国众议院拨款委员会关于需要对淀粉样变性进行更多研究的声明，罕见疾病办公室(NIH)赞助了一次研讨会，并正在推动与淀粉样变性相关的赠款，因此，淀粉样变性被认为是该领域研究的高度优先事项。

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.