Administrative Supplement to Coronary Flow Reserve to Assess Hidden Risk: Focus on Women, Heart Failure, and Inflammation

7.项目总结/摘要： 博士Viviany Taqueti是美国布里格姆妇女医院的一名早期职业心脏病专家和内科医生， 波士顿，长期以来对内皮和心肌细胞功能以及血管炎症感兴趣。她 我的目标是成为一名领先的临床研究者，使用功能性成像生物标志物提供创新的 炎症和缺血交叉点临床结果研究的机制见解，以提供信息 未来的治疗试验她的K23奖与要求的行政补充提出了一个全面的 职业发展计划，包括详细的培训建议，结构化的指导，完善的 咨询委员会，和明确的机构支持，这将共同为Taqueti博士提供 提供必要的支持，以便顺利过渡为独立调查员。20多年来，每年 女性的心血管疾病（CVD）死亡率高于男性， 冠状动脉疾病（CAD）在女性中较不普遍。因此，即使患者没有明显的梗阻性疾病， CAD可能是不良CVD事件的高风险。正在进行的K23研究的目标是利用 量化冠状动脉血流量以了解CVD机制的新兴非侵入性成像方法 所有解剖学CAD谱中女性和男性的结局。冠状动脉血流储备（CFR），计算方法为 通过正电子发射非侵入性定量的充血与静息心肌血流量的比率 断层扫描（PET）是大血管和小血管CAD和心肌梗死的综合非侵入性测量方法。 缺血，并独立于血管造影疾病的严重程度，识别有CVD死亡风险的患者。这 可能对女性尤其重要，因为女性弥漫性动脉粥样硬化和微血管功能障碍可能 导致心血管疾病的结果，特别是心力衰竭，但往往未被诊断。我们的核心假设是， CFR受损介导女性相对于男性的CVD风险增加，这种风险增加可能与 增加心肌张力和增加炎症。塔奎蒂博士正在运用最先进的分析技术 2个互补人群（CFR登记研究和CIRT-CFR，NHLBI申办的辅助研究） 多中心心血管炎症减轻试验），以解决以下具体目标：（1）确定 可疑冠心病患者性别、CFR与冠心病斑块严重程度关系 [CFR登记研究]，（2）定义CVD风险（尤其是心力衰竭事件）与 与CAD无关，女性相对于男性的CFR受损[CFR登记]，以及（3）定义 女性和男性稳定型CAD患者CFR、心肌应变和炎症之间的关系[CIRT- CFR]。这个早期职业发展奖的结果将（1）定义CFR对隐性CVD的贡献 不同程度解剖学CAD的女性和男性的风险，（2）阐明微血管功能障碍的作用 心力衰竭中的炎症，（3）改善风险评估，为未来的预防和治疗提供信息 研究，和（4）作为一个理想的车辆博士Taqueti过渡到一个独立的研究者。

7. PROJECT SUMMARY/ABSTRACT: Dr. Viviany Taqueti is an early career cardiologist and physician-scientist at Brigham and Women's Hospital in Boston with a longstanding interest in endothelial and cardiomyocyte function and vascular inflammation. Her goal is to become a leading clinical investigator using functional imaging biomarkers to provide innovative mechanistic insights to clinical outcome studies at the intersection of inflammation and ischemia to inform future therapeutic trials. Her K23 award with requested administrative supplement present a comprehensive career development plan, including a detailed training proposal, structured mentorship, a well-developed advisory committee, and unequivocal institutional support, which together will provide Dr. Taqueti with the necessary support to transition successfully into an independent investigator. For over 2 decades, the annual cardiovascular disease (CVD) mortality rate has been higher for women as compared to men, yet obstructive coronary artery disease (CAD) is less prevalent in women. Thus, even patients without significant obstructive CAD may be at high risk for adverse CVD events. The objective of the ongoing K23 research is to utilize an emerging, noninvasive imaging method of quantifying coronary blood flow to understand mechanisms of CVD outcomes in women and men across the anatomic CAD spectrum. Coronary flow reserve (CFR), calculated as the ratio of hyperemic to rest myocardial blood flow as quantified noninvasively by positron emission tomography (PET), is an integrated noninvasive measure of large and small vessel CAD and myocardial ischemia, and identifies patients at risk for CVD death independently of angiographic disease severity. This may be especially important for women, in who diffuse atherosclerosis and microvascular dysfunction likely contribute to CVD outcomes, especially heart failure, but are often undiagnosed. Our central hypothesis is that impaired CFR mediates excess CVD risk in women relative to men, and that this increased risk may be related to increased myocardial strain and increased inflammation. Dr. Taqueti is applying state of the art analyses to 2 complementary populations (CFR-Registry and CIRT-CFR, an ancillary study of the NHLBI sponsored multicenter Cardiovascular Inflammation Reduction Trial) to address the following specific aims: (1) To identify the relationship between sex, CFR and CAD plaque severity in symptomatic patients with suspected CAD [CFR Registry], (2) To define the extent to which CVD risk (especially heart failure events) is associated with impaired CFR in women relative to men, independently of CAD [CFR Registry], and (3) To define the relationship between CFR, myocardial strain, and inflammation in women and men with stable CAD [CIRT- CFR]. The results of this early career development award will (1) define the contribution of CFR to hidden CVD risk in women and men with varying levels of anatomic CAD, (2) clarify the role of microvascular dysfunction and inflammation in heart failure, (3) improve risk assessment to inform future preventive and therapeutic studies, and (4) serve as an ideal vehicle for Dr. Taqueti to transition to an independent investigator.