Occult Small Vessel Cerebrovascular Disease in High Risk Families

描述(申请人提供)：小血管脑血管病(SVCD)一般无症状，在磁共振成像(MRI)上表现为脑白质高信号和小灶性脑梗塞。这些损伤会使随后中风的风险增加一倍。我们在一项初步研究中发现，在45名明显健康的中年兄弟姐妹的已知早发冠状动脉疾病(CAD)先证者中，静止性SVCD的患病率在MRI上显著增加(73%)。他们的兄弟姐妹也接受了运动铊灌注断层扫描，以检测隐匿性CAD。在患有隐性冠心病的受试者中，88%的人在MRI上有任何SVCD，62%的人有明显的SVCD，而没有隐性CAD的人中只有5.5%有 这些发现。我们的发现，隐匿性CAD和SVCD共同出现在早产儿CAD家族中，这为研究临床前脑和心脏小血管疾病的模型提供了机会。在临床表现明显的中风和冠心病中，经典的风险因素模型低估了事件的发生，这表明包括遗传易感性在内的其他因素可能起到了作用。此外，脑血管疾病和冠心病在家族中都有很强的聚集性，这与疾病过程中的基因贡献是一致的。为了确定潜在的共同机制衍生的生物标记物和与临床前心血管疾病相关的已知危险因素，以及伴随的机制特异性基因的贡献，我们将进行一项SVCD的流行病学研究，使用MRI测定脑白质高信号体积和比率，以及腔隙梗死，以及使用心脏应力铊断层扫描进行隐匿性CAD。我们已经使用了一个生物学模型 选择机制衍生炎症(IL-6、TNF-a、hs-CRP、sVCAM-1、sICAM-1和MCP-1)和血栓前因子(PAI-1、Lp(A)和纤维蛋白原)、内皮依赖性血管反应性(血流介导的肱动脉扩张[FMD])和传统血管疾病危险因素的测量方法。我们将在1000名明显健康的35-75岁的兄弟姐妹中检测这些标记物，这些兄弟姐妹来自有记录的早产儿CAD家族。我们还将使用一组213个生物衍生的候选基因来检查遗传变异和SVCD之间的关联，这些候选基因之前对3000多个单核苷酸多态进行了基因分型。基因分析将在白人和非裔美国人中分别进行，使用混合模型分析来利用家庭结构。这样的模型适应了个体多态效应或单倍型。这项研究将首次对明显易患冠心病和脑血管疾病的高危家庭成员的大脑和心脏小血管疾病进行检查。公共卫生相关性 这项研究将侧重于心脏和大脑中血管疾病的发生，旨在检查动脉粥样硬化的新流行病学模型，其中包括炎症、血栓形成和血管功能等机制。它还侧重于可能增加有疾病病史的高危家庭中小血管疾病易感性的基因。

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.