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: 8209067
• 负责人: Paul Alan Nyquist
• 金额: $ 60.1万
• 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/8209067
• 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; 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

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 the 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-¿, 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.

小血管脑血管疾病（SVCD）通常是沉默的，白色鉴定 物质高强度和小型局灶性大脑在磁共振成像（MRI）上发出。 这些病变是随后中风的风险。我们发现患病率明显增加 在一项针对45个看似健康的中年兄弟姐妹的试点研究中，MRI的无声SVCD（73％） 患有已知过早冠状动脉疾病（CAD）的概率。兄弟姐妹也接受了 运动tallium灌注断层扫描以检测神秘的CAD。具有神秘CAD的受试者，88％ 有任何SVCD，而62％的MRI有明显的SVCD，而只有5.5％没有神秘的CAD 这些发现。我们发现，在过早的CAD家庭中，神秘的CAD和SVCD共同发生 提供了研究大脑前临床前小血管疾病模型的机会 心。在临床表现和CAD中，经典风险因素模型低估了 事件事件，表明其他因素，包括遗传敏感性，可能是 贡献。此外，脑血管疾病和CAD都有很强的聚类 家庭，与对疾病过程的遗传贡献一致。到 确定潜在的共享机制衍生的生物标志物和已知风险因素 大脑和心脏的临床前血管疾病以及服务员的贡献 机理特异性基因，我们将使用MRI对SVCD进行流行病学研究 确定白质高强度的体积和比率以及lacunar Infacts和cocult CAD使用心脏的压力thallium断层扫描。我们使用了一个生物学模型 血管疾病以选择机理衍生炎症的测量（IL-6，TNF-¿，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）， 依赖内皮的血管反应性（肱动脉的流动介导扩张[FMD]， 和传统的血管疾病危险因素。我们显然将在1000中检查这些标记 健康的35-75岁的兄弟姐妹，来自有记录的早产CAD的家庭。我们也会 使用213个生物学 - 先前针对3000多个单核苷酸多态性的衍生候选基因。 遗传分析将在白人和非裔美国人中分别进行 模型分析以利用家庭结构。这样的模型可容纳个人 多态性效应或单倍型。这项研究将是第一个检查小血管疾病的研究 在大脑和高风险家庭成员的心脏中，他们特别容易受到冠状动脉的影响 心脏病和脑血管疾病。