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
基本信息
- 批准号:8121801
- 负责人:
- 金额:$ 7.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:African AmericanAgeArteriesAtherosclerosisBasal GangliaBiological MarkersBiological ModelsBiological ProcessBlood PressureBlood VesselsBody mass indexBrainCCL2 geneCandidate Disease GeneCardiacCerebrovascular DisordersCognitive deficitsCommunitiesCoronaryCoronary ArteriosclerosisCoronary arteryCoronary heart diseaseDataDiffuseDilatation - actionDiseaseElderlyEndotheliumEpidemiologic StudiesEpidemiologyEventExerciseFamilyFamily history ofFamily memberFibrinogenFunctional disorderFutureGenesGeneticGenetic PolymorphismGenetic Predisposition to DiseaseGenotypeGlucoseHaplotypesHeartImageIndividualInfarctionInflammationInflammatoryInterleukin-6LesionLipidsLipoprotein (a)Magnetic Resonance ImagingMeasurementMeasuresMediatingModelingMotionPerfusionPersonsPilot ProjectsPlasminogen Activator Inhibitor 1PopulationPredispositionPrevalenceProcessRaceRadionuclide ImagingRecording of previous eventsRiskRisk FactorsSamplingSiblingsSingle Nucleotide PolymorphismStressStrokeStudy modelsThalamic structureThalliumThallium Myocardial Perfusion Imaging Stress TestThrombosisTreesVascular DiseasesWeightbasebrachial arterybrain volumecardiovascular risk factorcigarette smokingdesigndisease phenotypedisorder riskfamily structuregenetic analysisgenetic profilinggenetic varianthigh riskinflammatory markermiddle agepopulation basedpre-clinicalprematureprobandpublic health relevancerespiratorysextomographytraitvascular endothelial dysfunctionvascular inflammationwhite matter
项目摘要
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(由申请方提供):小血管脑血管病(SVCD)通常无症状,通过磁共振成像(MRI)上的白色高信号和小的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名明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的患病率显著增加(73%),这些兄弟姐妹都是已知的早发性冠状动脉疾病(CAD)先证者。Sixtian还接受了运动铊灌注断层扫描,以检测隐匿性CAD。在患有隐匿性CAD的受试者中,88%有任何SVCD,62%在MRI上有显著的SVCD,而只有5.5%没有隐匿性CAD,
这些发现。我们的发现,隐匿性CAD和SVCD共同发生在过早CAD家庭提供了一个机会,研究模型的临床前小血管疾病的大脑和心脏。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,可能是促成因素。此外,在家族中,脑血管病和CAD都有很强的聚集性,这与遗传对疾病过程的贡献一致。为了确定潜在的共享机制衍生的生物标志物和已知的与脑和心脏临床前血管疾病相关的风险因素,以及伴随的机制特异性基因的贡献,我们将使用MRI确定白色物质高信号体积和比率,腔隙性梗死和隐匿性CAD进行SVCD的流行病学研究,使用负荷铊心脏断层扫描。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])和传统血管疾病风险因子的测量。我们将在1000名明显健康的35-75岁的兄弟姐妹中检查这些标记物,这些兄弟姐妹来自有记录的早发CAD家族。我们还将研究遗传变异和SVCD之间的关联,使用一组213个生物来源的候选基因,以前基因分型超过3000个单核苷酸多态性。将使用混合模型分析在白人和非裔美国人中单独进行遗传分析,以利用家庭结构。这样的模型适应个体多态性效应或单倍型。这项研究将是第一个检查脑和心脏小血管疾病的高危家庭成员谁是特别容易患冠心病和脑血管疾病。公共卫生相关性
这项研究将重点关注心脏和大脑血管疾病的发生,旨在研究动脉粥样硬化的新流行病学模型,包括炎症,血栓形成和血管功能等机制。它还关注可能增加具有疾病史的高风险家庭对小血管疾病易感性的基因。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Paul Alan Nyquist其他文献
Paul Alan Nyquist的其他文献
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{{ truncateString('Paul Alan Nyquist', 18)}}的其他基金
Vascular Contributors to Blood Brain Barrier Permeability and Regional White Matter Hyperintensity Progression in Young Asymptomatic People
血管对年轻无症状人群血脑屏障通透性和局部白质高信号进展的影响
- 批准号:
10501246 - 财政年份:2022
- 资助金额:
$ 7.87万 - 项目类别:
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:
8013515 - 财政年份:2009
- 资助金额:
$ 7.87万 - 项目类别:
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 - 财政年份:2009
- 资助金额:
$ 7.87万 - 项目类别:
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 - 财政年份:2009
- 资助金额:
$ 7.87万 - 项目类别:
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
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8401554 - 财政年份:2009
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有脑血管疾病风险的患者群体中的无症状中风
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