MECHANISMS OF CORONARY ARTERY DISEASE IN HIGH RISK FAMILIES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究将严格比较用于亚临床CAD检测的功能测试（运动灌注SPECT）和用于检测早发CAD患者的30-59岁同胞的高风险无症状人群中冠状动脉钙化的解剖测试（螺旋CT）的病理生理学特征。 患者将接受使用两种方法筛查隐匿性CAD，并且所有在任何一种（运动诱导的缺血或钙评分> 100）上异常的患者将提供心导管插入术，其将包括定量冠状动脉造影术，通过冠状动脉内乙酰胆碱评估内皮功能，以及通过血管内超声（IVUS）测量选定冠状动脉中的斑块体积和成分。 这项研究将集中在运动性缺血伴低钙评分和高钙评分无缺血的个体中隐匿性CAD的病理生理学。 这两种测试之间的差异测量了潜在的不同生物学途径。 将进行分析，以确定哪些生物风险因素可以解释斑块钙化的变化（包括脂质水平和亚类、Lp（a）、糖尿病、血栓形成因素、促炎细胞因子，以及重要的是，参与钙调节的那些因素和骨调节蛋白）。 在接受心导管插入术的同胞中，将进行分析，以确定冠状动脉管腔扩张的严重程度或程度、心外膜或微血管内皮功能障碍的存在或IVUS斑块的钙含量体积是否可以解释两种筛选试验之间的不一致性。 可能影响组织钙化的几个候选基因的多态性将作为测试不一致性的可能解释进行检查。 这将是第一个全面的研究，以确定独特的生物学和遗传因素相关的隐匿性冠状动脉疾病的检测灌注成像和超快CT。 本研究的结果将为快速传播技术的适当临床应用和对高风险无症状人群中临床前CAD机制的理解提供强有力的科学依据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This study will rigorously compare the pathophysiological features of a functional test for subclinical CAD detection (exercise perfusion SPECT) and an anatomical test to detect coronary artery calcification (helical CT) in a high risk asymptomatic population of 30-59 year old siblings of people with premature CAD. Siblings will undergo screening for occult CAD using both methods and all who are abnormal on either (exercise-induced ischemia or calcium score > 100) will be offered cardiac catheterization, which will include quantitative coronary angiography, assessment of endothelial function by intracoronary acetylcholine, and measurement of plaque volume and composition in a selected coronary artery by intravascular ultrasound (IVUS). The study will focus on the pathophysiology of occult CAD among individuals who have exercise ischemia with low calcium scores and others who have high calcium scores without ischemia. Discrepancies between these two tests measure potentially different biological pathways. Analyses will be done to determine which biological risk factors can account for variation in plaque calcification (including lipid levels and subclasses, Lp(a), diabetes, thrombotic factors, pro-inflammatory cytokines, and importantly, those factors involved in calcium regulation, and bone regulatory proteins). In those siblings undergoing cardiac catheterization, analyses will be done to determine whether the severity or extent of coronary luminal narrowings, the presence of epicardial or microvascular endothelial dysfunction, or the volume of calcium content of plaque by IVUS can account for discordances between the two screening tests. Polymorphisms in several candidate genes that may affect tissue calcification will be examined as a possible explanation for test discordance. This will be the first comprehensive study to define the unique biological and genetic factors related to occult coronary disease as detected by both perfusion imaging and ultrafast CT. The results of this study will provide a strong scientific underpinning to appropriate clinical application of rapidly disseminating technology and understanding of the mechanisms of preclinical CAD in high risk asymptomatic populations.