Occult Small Vessel Cerebrovascular Disease in High Risk Families

小血管脑血管病（SVCD）通常无症状，以白色 磁共振成像（MRI）显示高信号物质和小的局灶性脑梗死。 这些病变使随后中风的风险增加一倍。我们发现， 在一项对45名明显健康的中年兄弟姐妹进行的初步研究中， 已知早发冠状动脉疾病（CAD）的先证者。Sixth也经历了 运动铊灌注断层扫描检测隐匿性CAD。在隐匿性CAD受试者中，88% 有任何SVCD，62%在MRI上有明显的SVCD，而只有5.5%没有隐匿性CAD， 这些发现。我们发现隐匿性CAD和SVCD共同发生在早发CAD家族中 提供了一个研究脑中临床前小血管疾病模型的机会， 心在临床表现的中风和CAD中，经典的风险因素模型低估了 事件，表明其他因素，包括遗传易感性，可能是 贡献。此外，脑血管疾病和CAD在人群中有很强的聚集性。 家庭，与疾病过程的遗传贡献一致。到 确定潜在的共同机制衍生的生物标志物和已知的风险因素， 临床前脑和心脏血管疾病，以及伴随 机制特异性基因，我们将使用MRI对SVCD进行流行病学研究 确定白色高信号体积和比率，腔隙性梗死，以及隐匿性 心脏负荷铊断层扫描的CAD。我们使用了一个生物模型， 血管疾病，以选择机制衍生的炎症（IL-6，TNF-α，hs- CRP、sVCAM-1、sICAM 1和MCP-1）和血栓前因子（派-1、Lp（a）和纤维蛋白原）， 内皮依赖性血管反应性（肱动脉的流动介导的扩张[FMD]， 和传统的血管疾病危险因素。我们将在1000年检查这些标记 健康的35-75岁兄弟姐妹，来自有记录的早发CAD家族。我们还将 使用213个生物学- 衍生的候选基因先前基因分型超过3000单核苷酸多态性。 遗传分析将分别在白人和非洲裔美国人中进行，使用混合 模型分析，以利用家庭结构。这种模式适用于个人 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 在大脑和心脏的高风险家庭成员谁是特别容易受到冠状动脉 心脏病和脑血管病。

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.