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Molecular Imaging of Primary Amyloid Cardiomyopathy

原发性淀粉样心肌病的分子影像

基本信息

批准号：
9124197
负责人：
Sharmila Dorbala
金额：
$ 87.28万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9124197
关键词：
Acetates Address Affinity Aggressive course Amyloid Amyloid Fibrils Amyloid deposition Amyloidosis Animal Model Arrhythmia Binding Biological Markers Blood flow Cardiac Cardiomyopathies Cardiovascular system Cell Respiration Cessation of life Clinical Research Complex Coronary Data Deposition Development Diagnosis Disease Disease remission Early treatment F2-Isoprostanes Foundations Goals Heart Diseases Heart failure Hematologic Neoplasms Human Image Individual Infiltration Infusion procedures Knowledge Left Left Ventricular Mass Life Light Light-Chain Immunoglobulins Magnetic Resonance Imaging Malignant neoplasm of lung Mechanics Metabolism Microvascular Dysfunction Mitochondria Myocardial Myocardial dysfunction Myocardium Oxidative Stress PET/CT scan Pathogenesis Pathogenicity Pathway interactions Peroxonitrite Plasma Cell Neoplasm Positron-Emission Tomography Recovery Rest Restrictive Cardiomyopathy Risk Marker Role Serum Serum Markers Staging Stress Structure Sudden Death Techniques Testing Thick Time Toxic effect Tracer Ventricular Woman Work amyloid imaging base chemotherapy clinically significant drug discovery extracellular human data imaging modality improved in vivo indexing light effects men molecular imaging mortality novel novel strategies novel therapeutics preclinical study prevent primary amyloidosis of light chain type pro-brain natriuretic peptide (1-76)programs public health relevance quantitative imaging response uptake

项目摘要

DESCRIPTION (provided by applicant): Primary light chain amyloidosis (AL) is the most common systemic amyloidosis, resulting from a plasma cell dyscrasia, a hematological malignancy. It causes a restrictive cardiomyopathy (AL-CMP) in over 70% of individuals. AL-CMP is as lethal as stage 4 lung cancer and more lethal than any other form of restrictive heart disease; if untreated, the mortality rate is 50% within 18 months. Moreover, myocardial dysfunction, the hallmark of AL-CMP, significantly increases early treatment related mortality, predominantly cardiovascular death, and is a powerful predictor of poor long-term survival. Two potentially treatable mechanisms underlie myocardial dysfunction-mechanical effects of amyloid and toxic effects from circulating light chain/ amyloid interactions-and predispose to heart failure, arrhythmias, and sudden death in individuals with AL-CMP. Until now, efforts to determine the mechanisms of AL-CMP have been hampered by a lack of animal models and the limitations of noninvasive techniques to directly image myocardial amyloid. A recent breakthrough, 18F- florbetapir PET/CT, has provided for the first time specific and quantitative imaging of myocardial amyloid including toxic amyloid protofibrils. Furthermore, we propose to investigate three pre-clinically proven pathways of light chain toxicity in humans-myocardial oxidative metabolism, oxidative stress, and coronary microvascular function. Our central hypotheses are that myocardial 18F-florbetapir retention is a biomarker for aggressiveness of AL-CMP and that effective chemotherapy will, by reducing circulating light chains, decrease aggressiveness of AL-CMP and improve oxidative stress, myocardial oxidative metabolism, microvascular function and contractile function, prior to an improvement in myocardial amyloid content. In Aim 1, we will quantify myocardial 18F-florbetapir retention as a marker of aggressive myocardial disease in individuals with AL-CMP and active plasma cell dyscrasia compared to control individuals with AL-CMP and long-term hematological remission. In Aim 2, we propose, using advanced imaging, to assess the effects of light chain reduction due to chemotherapy on myocardial structure, function, and metabolism and define the time course of these changes. Serial ECV and strain imaging by CMR, serum F2-isoprostanes and peroxynitrite levels, myocardial oxidative metabolism (Kmono) and coronary flow reserve by 11C-acetate PET, and 18F-florbetapir imaging will not only intricately characterize the myocardial substrate in AL-CMP, but also identify changes in response to therapy. The proposed studies offer the potential to transform our current understanding of AL- CMP as a restrictive heart disease caused by passive amyloid-related architectural damage to that of a more complex disorder resulting from both passive and aggressive factors. The results of these studies may form the foundation for drug discovery programs to prevent and cure AL-CMP.