Occult Small Vessel Cerebrovascular Disease in High Risk Families

高危家庭中的隐匿性小血管脑血管病

• 批准号: 8013515
• 负责人: Paul Alan Nyquist
• 金额: $ 60.32万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013515
• 关键词: African American; Age; Arteries; Atherosclerosis; Basal Ganglia; Biological Markers; Biological Models; Biological Process; Blood Pressure; Blood Vessels; Body mass index; Brain; CCL2 gene; Candidate Disease Gene; Cardiac; Cerebrovascular Disorders; Cognitive deficits; Communities; Coronary; Coronary Arteriosclerosis; Coronary artery; Coronary heart disease; Data; Diffuse; Dilatation - action; Disease; Elderly; Endothelium; Epidemiologic Studies; Epidemiology; Event; Exercise; Family; Family history of; Family member; Fibrinogen; Functional disorder; Future; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Glucose; Haplotypes; Health; Heart; Image; Individual; Infarction; Inflammation; Inflammatory; Interleukin-6; Lesion; Lipids; Lipoprotein (a); Magnetic Resonance Imaging; Measurement; Measures; Mediating; Modeling; Motion; Perfusion; Persons; Pilot Projects; Plasminogen Activator Inhibitor 1; Population; Predisposition; Prevalence; Process; Race; Radionuclide Imaging; Recording of previous events; Risk; Risk Factors; Sampling; Siblings; Single Nucleotide Polymorphism; Stress; Stroke; Study models; TNF gene; Thalamic structure; Thallium; Thallium Myocardial Perfusion Imaging Stress Test; Thrombosis; Trees; Vascular Diseases; Weight; base; brachial artery; brain volume; cardiovascular risk factor; cerebrovascular; cigarette smoking; design; disease phenotype; disorder risk; family structure; genetic analysis; genetic profiling; genetic variant; high risk; inflammatory marker; middle age; population based; pre-clinical; premature; proband; respiratory; sex; tomography; trait; vascular endothelial dysfunction; vascular inflammation; white matter

DESCRIPTION (provided by applicant): Small vessel cerebrovascular disease (SVCD) is generally silent and is identified by white matter hyperintensities and small focal brain infarcts on magnetic resonance imaging (MRI). These lesions double the risk of subsequent stroke. We found a markedly increased prevalence of silent SVCD (73%) on MRI in a pilot study of 45 apparently healthy middle-aged siblings of probands with known premature coronary artery disease (CAD). Siblings also underwent exercise thallium perfusion tomography to detect occult CAD. Of subjects with occult CAD, 88% had any SVCD, and 62% had significant SVCD on MRI, while only 5.5% without occult CAD had these findings. Our discovery that occult CAD and SVCD co-occur in premature CAD families provides an opportunity to study models for pre-clinical small vessel disease in the brain and heart. In both clinically manifest strokes and CAD, classical risk factor models underestimate incident events, suggesting that other factors, including genetic susceptibility, may be contributory. In addition, there is strong clustering of both cerebrovascular disease and CAD in families, consistent with a genetic contribution to the disease process. To determine potential shared mechanism-derived biomarkers and known risk factors related to pre-clinical vascular disease in the brain and the heart, and the contribution of attendant mechanism-specific genes, we will conduct an epidemiologic study of SVCD using MRI determination of white matter hyperintensity volumes and ratios, and lacunar infarcts, and occult CAD using stress thallium tomography of the heart. We have used a biological model of vascular disease to select measurements of mechanism-derived inflammatory (IL-6, TNF-a, hs-CRP, sVCAM-1, sICAM1, and MCP-1) and prothrombotic factors (PAI-1, Lp(a) and fibrinogen), endothelium dependent vascular reactivity (flow mediated dilatation [FMD] of the brachial artery, and traditional vascular disease risk factors. We will examine these markers in 1000 apparently healthy 35-75 year old siblings from families with documented premature CAD. We will also examine associations between genetic variants and SVCD using a panel of 213 biologically derived candidate genes previously genotyped for over 3000 single nucleotide polymorphisms. Genetic analyses will be performed separately in whites and African Americans using mixed model analysis to leverage family structures. Such models accommodate individual polymorphism effects or haplotypes. This study will be the first to examine small vessel disease in the brain and the heart in high risk family members who are notably susceptible to coronary heart disease and cerebrovascular disease. PUBLIC HEALTH RELEVANCE This study will focus on the occurrence of vascular disease in the heart and brain and is designed to examine new epidemiologic models of atherosclerosis that include mechanisms such as inflammation, thrombosis and vascular function. It is also focused on the genes that may increase the susceptibility to small vessel disease in high risk families with a history of disease.

描述（由申请人提供）：小血管脑血管疾病（SVCD）通常是静音的，并通过白质高强度和磁共振成像（MRI）的小局灶性脑梗塞来鉴定。这些病变是随后中风的风险。我们发现，在一项针对45个具有已知早期冠状动脉疾病（CAD）的探针中显然健康的中老年兄弟姐妹（CAD）的预示率研究中，MRI的无声SVCD的患病率显着增加。兄弟姐妹还进行了运动灌注断层扫描，以检测神秘的CAD。在具有神秘CAD的受试者中，有88％的受试者具有任何SVCD，而62％的受试者对MRI有明显的SVCD，而只有5.5％没有隐性CAD 这些发现。我们发现，过早的CAD家族中神秘的CAD和SVCD共发生为研究大脑和心脏中临床前小血管疾病的模型提供了机会。在临床表现的中风和CAD中，经典风险因素模型低估了事件事件，这表明其他因素（包括遗传易感性）可能是贡献的。此外，家庭中脑血管疾病和CAD都有很强的聚类，这与对疾病过程的遗传贡献一致。 To determine potential shared mechanism-derived biomarkers and known risk factors related to pre-clinical vascular disease in the brain and the heart, and the contribution of attendant mechanism-specific genes, we will conduct an epidemiologic study of SVCD using MRI determination of white matter hyperintensity volumes and ratios, and lacunar infarcts, and occult CAD using stress thallium tomography of the heart.我们使用了一个生物学模型 血管疾病以选择机制衍生的炎症性测量（IL-6，TNF-A，HS-CRP，SVCAM-1，SICAM1和MCP-1）和促血栓形成因子（PAI-1，LP（A）和纤维蛋白原），依赖性血管反应性（流动性均匀疾病）[FMD]的风险因素[FMD]，依赖于Endphium依赖的血管反应性。检查有1000个健康的35-75岁的兄弟姐妹，这些兄弟姐妹的兄弟姐妹还将使用213个以前在生物统治的模型中进行分析的模型，并使用213种生物介绍的候选人来检查遗传变异和SVCD之间的关联可容纳单个多态性效应或单倍型。公共卫生相关性 这项研究将着重于心脏和大脑中血管疾病的发生，并旨在检查动脉粥样硬化的新流行病学模型，包括炎症，血栓形成和血管功能等机制。它还集中在可能增加具有疾病史的高风险家庭中小血管疾病的易感性的基因上。