Occult Small Vessel Cerebrovascular Disease in High Risk Families

小血管脑血管病(SVCD)通常是沉默的，由白色标识 磁共振成像(MRI)上的物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。我们发现流行率显著上升 在一项针对45名看似健康的中年兄弟姐妹的先导性研究中，MRI显示无症状的SVCD(73%) 已知患有早发冠状动脉疾病(CAD)的先证者。兄弟姐妹也接受了 运动铊灌注断层扫描检测隐匿性冠心病。在患有隐匿性冠心病的受试者中，88% 患有室上性心动过速，62%的人在MRI上有明显的室上性心动过速，而没有隐性冠心病的只有5.5% 这些发现。我们发现隐匿性CAD和SVCD共同出现在早产儿CAD家族中 提供了一个研究临床前脑部和脑部小血管疾病模型的机会 心。在临床表现明显的中风和冠心病中，经典的风险因素模型都低估了 事件，表明包括遗传易感性在内的其他因素可能是 供款。此外，脑血管疾病和冠心病都有很强的聚集性 家族，与疾病过程中的基因贡献相一致。至 确定潜在的共享机制衍生生物标记物和与 临床前脑血管疾病和心脏疾病，以及伴随者的贡献 机制特异性基因，我们将利用MRI对SVCD进行流行病学研究 脑白质高信号体积和比率、腔隙性脑梗塞和隐匿性脑白质的测定 CAD采用应力铊心脏断层摄影术。我们已经使用了一个生物学模型 血管疾病选择机制衍生炎症(IL-6、TNF-β、hs-1)的测量 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]， 和传统的血管疾病危险因素。显然，我们将在1000年内检查这些标记 健康的35-75岁的兄弟姐妹，来自记录在案的早产儿CAD家庭。我们还将 使用213个生物学小组来检查遗传变异和SVCD之间的联系- 先前对3000多个单核苷酸多态进行基因分型的衍生候选基因。 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，以利用家庭结构。这样的模式适用于个人 多态效应或单倍型。这项研究将是第一次检查小血管疾病 明显易患冠心病的高危家庭成员的大脑和心脏 心脏病和脑血管疾病。

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.