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.
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