Novel Technologies to Identify Preclinical Coronary Disease in High Risk Families

描述（由申请人提供）： 挑战领域总结，05年比较有效性研究（CER）：挑战主题NHLBI-05-HL-104* 降低中度风险和无症状患者的心血管风险。我们的项目名为“识别高危家庭中临床前冠心病的新技术”。“其主要目的是比较创新的冠状动脉成像技术与标准成像方法在高危人群中检测非常早期的冠状动脉疾病，但没有症状或临床冠状动脉疾病事件。冠状动脉粥样硬化早在临床冠心病（CAD）之前就开始了。如果可以在临床前阶段准确识别隐匿性CAD及其程度，则可以测试可能减轻CAD事件的靶向强化预防性治疗。在这项研究中，我们将应用一个比较有效性的研究范式，以一个易感人群的无症状的一级成人亲属的人与已知的过早CAD，所有容易识别的家族史，CAD的风险是一般人群的2-5倍。我们在一项前瞻性家族研究中对约3000名个体进行了广泛的基因分型，GeneSTAR（动脉粥样硬化风险的遗传决定因素）。这项拟议的挑战补助金研究的目标是使用比较有效性研究模型推进个性化预防医学。我们将比较CT CAC和MDCTA在识别潜在临床前CAD受试者方面的相对有效性，这些受试者将代表强化预防性治疗的适当目标。我们的主要目的是：（1）在GeneSTAR研究中，对1000名22 - 75岁的明显健康的兄弟姐妹和已知早发CAD先证者（< 60岁）的成年后代进行MDCTA评估钙化和非钙化冠状动脉斑块的程度，以及冠状动脉钙评分（CAC）。(2)确定传统风险因素（Frachial Global Risk Score）和hsCRP与结果的关系，以确定患有显著临床前CAD的人的最佳识别，以及（3）确定增加已知的CAD遗传风险变体是否改善CT或MDCTA受试者的选择。数据将用于斑块体积的一般参考值，并确定MDCTA作为后续一级预防试验中跟踪治疗反应性的方法的价值。目标也是创造就业机会和更快地推进科学。我们计划通过创造2个新的工作岗位，支持2-4个其他人，并通过提供资金来留住现有职位的人来实现这一目标。我们的工作也是基于这样一个原则，即该项目应产生数据，为随后的随访和更大规模的一级预防临床试验提供数据。每年约翰霍普金斯研究所直接在马里兰州产生约100亿美元的经济活动，比2002年产生的70亿美元增加了43%，相当于今天该州经济中的每24美元。2008年，约翰霍普金斯机构提供了45，000个工作岗位，自2002年以来每年创造700个新工作岗位。约翰霍普金斯学院直接和间接地为马里兰州提供了10万多个工作岗位，是该州每29个工作岗位中的一个。仅在巴尔的摩市，约翰霍普金斯大学就直接和间接提供了6万个工作岗位，占该市所有就业岗位的16.7%。此应用程序将创建或保留至少7-10个工作岗位，包括2个直接新的全职员工。 公共卫生相关性： 这项拟议的挑战补助金研究的目标是使用比较有效性研究模型来比较两种观察冠状动脉斑块的方法的相对有效性，以推进个性化预防医学。目的是识别潜在临床前CAD受试者，这些受试者将代表强化预防性治疗的适当目标。

DESCRIPTION (provided by applicant): Summary Challenge Area, 05 Comparative Effectiveness Research (CER): Challenge Topic NHLBI-05-HL-104* Reducing Cardiovascular Risk in Moderate-Risk and Asymptomatic Patients." Our project is entitled "Novel Technologies to Identify Preclinical Coronary Disease in High Risk Families." Its prime purpose is to compare an innovative coronary artery imaging technology with a standard imaging method in the detection of very early coronary disease in people who are at high risk but who have not had symptoms or a clinical coronary disease event. Coronary atherogenesis begins well before manifest clinical coronary disease (CAD). If occult CAD and its extent could be accurately identified during the preclinical phase, targeted intensive preventive therapies could be tested that may mitigate CAD events. In this study we will apply a comparative effectiveness research paradigm to a susceptible population of asymptomatic first degree adult relatives of persons with known premature CAD, all easily identifiable by family history, with a CAD risk that is 2-5 times that of the general population. We have extensive genotyping in ~3000 individuals in a prospective family study, GeneSTAR (Genetic Determinants of Atherosclerosis Risk). The goal of this proposed challenge grant study is to advance personalized preventive medicine using a comparative effectiveness research model. We will compare the relative effectiveness of CT CAC and MDCTA for identifying subjects with latent preclinical CAD who would represent appropriate targets for intensive preventive therapies. Our primary specific aims are to (1) evaluate both (the extent of calcified and noncalcified coronary plaque using MDCTA, and coronary calcium score (CAC) in 1000 22 to 75 year old apparently healthy siblings and adult offspring of probands with known premature CAD (< 60 years of age) from the GeneSTAR study. (2) determine the relationship of traditional risk factors (Framingham Global Risk Score), and hsCRP to outcomes to determine the optimal identification of persons with significant preclinical CAD, and (3) determine whether the addition of known genetic risk variants for CAD improve selection of subjects for CT or MDCTA. Data will be used to general reference values for plaque volumes and to determine the value of MDCTA as a method to track responsiveness to therapy in a subsequent primary prevention trial. The goal is also to create jobs and advance science more quickly. We plan to do this by creating 2 new jobs, supporting 2-4 others, and by providing funds to retain people in their current positions. Our work is also predicated on the tenet that the project should yield data that will provide for subsequent follow-up and for a larger primary prevention clinical trial. Every year The Johns Hopkins Institutions directly generate about $10 billion in economic activity in the State of Maryland, a 43% increase from the $7 billion generated in 2002 and the equivalent of one of every twenty-four dollars in the state's economy today. In 2008, Johns Hopkins Institutions provided 45,000 jobs and created 700 new jobs each year since 2002. Directly and indirectly Johns Hopkins Institutions support more than 100,000 jobs in Maryland, one of every 29 in the state. In Baltimore City alone Johns Hopkins directly and indirectly supports 60,000 jobs, or 16.7% of all City employment. This application will create or retain at least 7-10 jobs, including 2 direct new full-time employees. Public Health Relevance: The goal of this proposed challenge grant study is to advance personalized preventive medicine using a comparative effectiveness research model to compare the relative effectiveness two methods for looking at coronary artery plaque. The purpose is to identify subjects with latent preclinical CAD who would represent appropriate targets for intensive preventive therapies.