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

• 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
• 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

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）：全身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是心脏参与。为了回应美国众议院拨款委员会关于淀粉样蛋白病的其他研究的拨款委员会，稀有疾病办公室（NIH）赞助了一个研讨会和促进与淀粉样蛋白相关的赠款的促进。由淀粉样蛋白原纤维引起的组织损伤机制代表了淀粉样病理生理学的最重要，最不理知识的方面。当前对淀粉样变性中心脏功能障碍和心肌损伤机制的理解是有限的，需要改善检测和治疗。心脏淀粉样变性的特征是心脏中的淀粉样蛋白浸润，并破坏细胞外基质。具有心脏参与的全身性淀粉样变性（AL-CMP）是由于心脏中免疫球蛋白轻链蛋白沉积引起的，其在诊断后6个月内表现出充血性心力衰竭，心律不齐和死亡。而与其他非光链蛋白相关的心脏淀粉样变性，即与野生型经胸蛋白（TTR）相关的淀粉样蛋白：衰老的全身性淀粉样变性（SSA）或突变的经胸蛋白酶（ATTR）； al-CMP患者的预后差异更糟。我们的中心假设是，细胞外基质，基质金属蛋白酶（MMP）及其抑制剂（TIMP）的蛋白水解活性的决定因素具有不同的模式，并有助于Al-CMP的发病机理。在波士顿医疗中心淀粉样蛋白诊所的一系列患者中，我们将确定循环MMP与TIMP水平与心脏重塑之间的关系。在AIM 1中，我们将测试AL-CMP患者MMP和/或TIMP水平改变的假设，并且与更不良的结构重塑有关。在AIM 2中，我们将测试MMP和TIMP水平变化（基线和治疗后）的假设与临床结局，疾病进展（通过超声心动图上的舒张功能障碍确定）和BNP水平有关。我们将在基线，治疗后立即测量心脏特异性的MMP和TIMP水平，以及从医院出院后的3、6和12个月以及需要住院的临床代偿交易期间。这些研究将为系统性淀粉样变性中的轻链沉积的病理生理提供新的理解，具有心脏参与。细胞外基质蛋白水解活化可能在心脏受累的功能和临床表现中起重要作用，并允许将来有针对性的治疗干预措施。 公共卫生相关性：全身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是心脏参与。心脏受累及其由此产生的功能障碍是淀粉样病理生理学的知识最少，因此需要改善检测和治疗。为了回应美国众议院拨款委员会在淀粉样蛋白病的其他研究中的拨款委员会时，稀有疾病（NIH）的办公室赞助了一个研讨会，并且正在促进与淀粉样变性相关的补助金，因此，淀粉样蛋白病被认为是该领域研究的高度优先级。

项目成果

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

• DOI: 10.4161/oxim.3.3.12106
• 发表时间: 2010-05
• 期刊: Oxidative medicine and cellular longevity
• 作者: Essick EE;Sam F
• 通讯作者: Sam F

Adiponectin modulates oxidative stress-induced autophagy in cardiomyocytes.

• DOI: 10.1371/journal.pone.0068697
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Essick EE;Wilson RM;Pimentel DR;Shimano M;Baid S;Ouchi N;Sam F
• 通讯作者: Sam F

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

• DOI: 10.1161/jaha.112.005868
• 发表时间: 2013-03-12
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Tanaka K;Essick EE;Doros G;Tanriverdi K;Connors LH;Seldin DC;Sam F
• 通讯作者: Sam F

What can adiponectin say about left ventricular function?

脂联素对左心室功能有何影响？

• DOI: 10.1136/hrt.2009.178590
• 发表时间: 2010
• 期刊: Heart (British Cardiac Society)
• 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: 10.7196/samj.3966
• 发表时间: 2010
• 期刊: South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde
• 作者: Don-Wauchope,AndrewC;Karas,Andreas;Chetty,VasudhevanT;Davidson,HowardK;Gottschalk,Raymond;Rabiner,EugeniiA;Sam,Flora;Sommerville,GarthP;Swartz,Jina;Viljoen,Adie
• 通讯作者: Viljoen,Adie