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。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）赞助了一个研讨会并促进淀粉样变性相关赠款。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为人所知的方面。目前对淀粉样变性患者心功能不全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浸润心脏并破坏细胞外基质。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沉积在心脏中，在诊断后6个月内表现为充血性心力衰竭、心律失常和死亡。而与其他非轻链蛋白相关的心脏淀粉样变性，即与野生型甲状腺素运载蛋白（TTR）相关的淀粉样变性：老年系统性淀粉样变性（SSA）或突变型甲状腺素运载蛋白（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（MMP）及其抑制剂（TIMP）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门诊随访的一组患者中，我们将确定循环MMP和TIMP水平与心脏重塑之间的关系。在目标1中，我们将检验AL-CMP患者MMP和/或TIMP水平改变并与更不利的结构重塑相关的假设。在目标2中，我们将检验MMP和TIMP水平（基线和治疗后之间）的变化与临床结局、疾病进展（通过超声心动图上的舒张功能障碍确定）和BNP水平相关的假设。我们将在基线、治疗后即刻、出院后3、6和12个月以及需要住院治疗的临床失代偿期测量心脏特异性MMP和TIMP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中轻链沉积的病理生理学提供新的理解。细胞外基质蛋白水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，并允许未来定向治疗干预。 公共卫生相关性：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。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了解最少的方面，因此需要改进检测和治疗。为了响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）赞助了一个研讨会，并正在促进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.