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: 7583750
• 负责人: Paul Alan Nyquist
• 金额: $ 61.11万
• 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/7583750
• 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; 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; Thalamic structure; Thallium; Thallium Myocardial Perfusion Imaging Stress Test; Thrombosis; Trees; Vascular Diseases; Weight; base; brachial artery; brain volume; cardiovascular risk factor; 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; public health relevance; 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）：小血管脑血管病（SVCD）通常是无声的，在磁共振成像（MRI）上通过白质高信号和小局灶性脑梗死来识别。这些病变使随后中风的风险增加一倍。我们在一项对45名患有过早冠状动脉疾病（CAD）的先显健康的中年兄弟姐妹进行的初步研究中发现，MRI上无症状SVCD的患病率明显增加（73%）。兄弟姐妹也接受了运动铊灌注断层扫描以检测隐匿性CAD。隐匿性CAD的受试者中，88%的人有SVCD， 62%的人MRI上有明显的SVCD，而没有隐匿性CAD的只有5.5%