Novel Insights into the Pathogenesis of Light Chain Cardiac Amyloidosis

对轻链心脏淀粉样变性发病机制的新见解

基本信息

批准号：
8011456
负责人：
Flora Sam
金额：
$ 24.38万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-04 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8011456
关键词：
Affect Amyloid Amyloid Fibrils Amyloidosis Arrhythmia Biological Markers Biological Preservation Blood Boston Cardiac Cardiac Myocytes Cessation of life Clinic Clinical Clinical Trials Congestive Heart Failure Data Deposition Detection Diagnosis Disease Progression Echocardiography Educational workshop Extracellular Matrix Functional disorder Future Gelatinase A Gelatinase B Grant Heart Heart Transplantation Heart failure Hospitalization Hospitals Housing Infiltration Interstitial Collagenase Lead Light Light-Chain Immunoglobulins Matrix Metalloproteinases Measures Medical center Myocardial dysfunction Outcome Pathogenesis Pathologic Patients Pattern Play Prealbumin Prevention Proteins Rare Diseases Research Research Priority Risk Role Sampling Stratification Stress Testing Therapeutic Intervention Time Tissue Inhibitor of Metalloproteinase-1 Tissues United States National Institutes of Health Universities Work body system cohort follow-up improved inhibitor/antagonist insight mutant new therapeutic target novel outcome forecast prevent programs public health relevance repository response tissue inhibitor of metalloproteinase 4

项目摘要

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.

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) 主办了一次研讨会并推广淀粉样变性相关的拨款。淀粉样蛋白原纤维引起的组织损伤机制代表了淀粉样蛋白病理生理学中最重要和最不为人所知的方面。目前对淀粉样变性心脏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心脏中淀粉样蛋白浸润并伴有细胞外基质破坏。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沉积所致，表现为充血性心力衰竭、心律失常，甚至诊断后 6 个月内死亡。而心脏淀粉样变性则与其他非轻链蛋白相关，即与野生型转甲状腺素蛋白（TTR）相关的淀粉样变性：老年系统性淀粉样变性（SSA）或突变型转甲状腺素蛋白（ATTR）； AL-CMP 患者的预后极其糟糕。我们的中心假设是细胞外基质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诊所跟踪的一组患者中，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，我们将测试以下假设：AL-CMP 患者中 MMP 和/或 TIMP 水平发生改变，并且与更不利的结构重塑相关。在目标 2 中，我们将测试以下假设：MMP 和 TIMP 水平（基线和治疗后之间）的变化与临床结果、疾病进展（由超声心动图上的舒张功能障碍确定）和 BNP 水平相关。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认识。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，并允许未来的定向治疗干预。公众健康相关性：系统性淀粉样变性是一种罕见疾病，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最不为人所知的方面，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) 主办了一个研讨会，并正在推广与淀粉样变性相关的拨款，因此淀粉样变性被认为是一种高危疾病。优先考虑该领域的研究。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adiponectin modulates oxidative stress-induced autophagy in cardiomyocytes.

脂联素调节心肌细胞中氧化应激诱导的自噬。

DOI：
发表时间：
2013
期刊：
影响因子：
3.7
作者：
Essick, Eric E;Wilson, Richard M;Pimentel, David R;Shimano, Masayuki;Baid, Simoni;Ouchi, Noriyuki;Sam, Flora
通讯作者：
Sam, Flora

What can adiponectin say about left ventricular function?

脂联素对左心室功能有何影响？

DOI：
发表时间：
2010-03
期刊：
影响因子：
0
作者：
Sam, Flora;Walsh, Kenneth
通讯作者：
Walsh, Kenneth

State hospitals, academic medicine and the decline of health care in South Africa - a cry of support from those who have left for those who stay.

南非的公立医院、学术医学和医疗保健的衰落——离开的人对留下来的人发出支持的呼声。

DOI：
发表时间：
2010-01-29
期刊：
影响因子：
0
作者：
Don;Karas, Andreas;Chetty, Vasudhevan T;Davidson, Howard K;Gottschalk, Raymond;Rabiner, Eugenii A;Sam, Flora;Sommerville, Garth P;Swartz, Jina;Viljoen, Adie
通讯作者：
Viljoen, Adie

Circulating matrix metalloproteinases and tissue inhibitors of metalloproteinases in cardiac amyloidosis.

心脏淀粉样变性中的循环基质金属蛋白酶和金属蛋白酶的组织抑制剂。

DOI：
发表时间：
2013-03-12
期刊：
影响因子：
5.4
作者：
Tanaka, Komei;Essick, Eric E;Doros, Gheorghe;Tanriverdi, Kahraman;Connors, Lawreen H;Seldin, David C;Sam, Flora
通讯作者：
Sam, Flora

Oxidative stress and autophagy in cardiac disease, neurological disorders, aging and cancer.

心脏病、神经系统疾病、衰老和癌症中的氧化应激和自噬。