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

7.项目摘要/摘要： 二十多年来，女性的心血管疾病(CVD)死亡率一直较高，因为 然而，与男性相比，阻塞性冠状动脉疾病(CAD)在女性中的发病率较低。冠状动脉 血管造影术是诊断梗阻性CAD的金标准，仍然是现代CVD的基石 护理，但它不能识别弥漫性动脉粥样硬化和小血管疾病。这些都可能会导致不利的 心血管事件，包括心力衰竭，由冠状动脉血管运动功能障碍，微血管疾病， 和心肌缺血。因此，即使没有严重梗阻性冠心病的患者也有很高的风险 不良心血管事件。候选人：Viviany Taqueti博士是一位早期的心脏病专家、成像师和内科医生- 马萨诸塞州波士顿布里格姆妇女医院的科学家，长期对血管内皮细胞和 心肌细胞功能和血管炎症。她的目标是成为一名独立的临床研究员。 在利用来自广泛研究设计的成像数据更好地定义缺血性心脏病方面处于领先地位 表型和病理生理学，最终为未来的治疗试验提供信息。此K23应用程序提供了 全面的培训计划，包括结构化的指导(与Marcelo Di Carli博士一起)，一个完善的 咨询委员会(与Paul Ridker博士、Scott所罗门博士和Bairey Merz博士)，以及定制的教学课程 在先进的统计和成像方法方面，这将为塔克蒂博士提供必要的技能 以实现这一目标，并转变为一名成功的独立调查员。环境： 布里格姆妇女医院的心血管成像小组为不同的教职员工提供机会 放射科和医学系中从事基础、临床和人口工作的成员 健康研究，并为跨部门协作提供了独特的环境。BWH是一个世界- 心肌灌注正电子发射断层扫描(PET)成像和非侵入性成像的类别中心 冠脉血流储备(CFR)的量化。重要的是，它的领导层致力于保护塔克蒂博士的 时间用于研究和职业发展活动，并促进她作为独立人士的发展 翻译调查员。Taqueti博士还将获得哈佛大学临床促进会和 翻译科学中心和哈佛大学公共卫生学院。研究综述：目标 这项建议的目的是利用一种新的、非侵入性的冠状动脉血流成像方法来 了解女性和男性在整个解剖CAD谱中心血管疾病结局的机制。冠状动脉 血流储备(CFR)，以充血心肌血流量与静息心肌血流量之比来计算 正电子发射断层扫描(PET)是一种综合的、无创的测量方法 小血管冠心病和心肌缺血，并确定有心血管死亡风险的患者独立于 血管造影疾病严重程度。这对女性尤其重要，在世卫组织中扩散动脉粥样硬化和 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，但通常 未诊断或误诊。然而，CFR受损和不良心血管结局之间的确切关系， 尤其是在没有梗阻性CAD的情况下，人们对此认识不深。我们的中心假设是，过度 接受冠状动脉造影术的女性相对于男性的心血管疾病风险与CFR受损相关 与梗阻性冠心病无关，这种增加的风险可能是由心肌应变增加所介导的 并增加炎症。Taqueti博士将把最先进的分析应用于两个独特和互补的 人群：一项接受PET心肌灌注治疗的患者登记，用于临床评估可疑患者 CAD[CFR注册]；和冠状动脉血流储备中评估心血管炎症的受试者 试验[CIRT-CFR]，NHLBI支持的多中心心血管炎症的辅助研究 减少试验(CIRT)，将测试减轻炎症是否改善稳定的CAD患者的CFR。 具体目标：提出以下具体目标：(1)识别性别之间的关系，CFR 和可疑冠心病患者的血管造影疾病严重程度[CFR注册]；(2)定义 与男性相比，女性的哪种心血管疾病风险与CFR受损有关，而不是阻塞性CAD[CFR 注册]；和(3)确定CFR、心肌劳损和炎症之间的关系在妇女和 冠心病稳定的男性[CIRT-CFR]。通过明确明确CFR对潜在的CVD风险的贡献 具有不同解剖CAD水平的女性和男性，Taqueti博士将获得必要的经验和 未来R01水平研究使用这一功能测量来选择小说对象的初步数据 预防性和治疗性干预，包括使用抗炎、极端血脂的系统治疗- 降血压和神经激素调节剂。提议的翻译目标将有助于定义新的 缺血性心脏病的范例及其对诊断、风险分层和新的开发的启示 一个常见的、认识不佳的临床问题的管理策略，对 妇女健康，美国国立卫生研究院的战略优先事项。

7. PROJECT SUMMARY/ABSTRACT: For over two 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. Coronary angiography is the gold standard for diagnosing obstructive CAD and remains a cornerstone of modern CVD care, but it cannot identify diffuse atherosclerosis and small-vessel disease. These may contribute to adverse CVD events, including heart failure, from resultant coronary vasomotor dysfunction, microvascular disease, and myocardial ischemia. Thus, even patients without significant obstructive CAD may be at high risk for adverse CVD events. CANDIDATE: Dr. Viviany Taqueti is an early career cardiologist, imager, and physician- scientist at Brigham and Women's Hospital in Boston, MA with a longstanding interest in endothelial and cardiomyocyte function and vascular inflammation. Her goal is to become an independent clinical investigator and leader in leveraging imaging data from a breadth of study designs to better define ischemic heart disease phenotypes and pathophysiology, ultimately to inform future therapeutic trials. This K23 application presents a comprehensive training plan including structured mentorship (with Dr. Marcelo Di Carli), a well-developed advisory committee (with Drs. Paul Ridker, Scott Solomon, and Bairey Merz), and a tailored didactic curriculum in advanced statistical and imaging methods, which together will provide Dr. Taqueti with the skills necessary to achieve this goal and transition into a successful independent investigator. ENVIRONMENT: The Cardiovascular Imaging Group at Brigham and Women's Hospital offers exposure to a diverse range of faculty members in the Departments of Radiology and Medicine who are engaged in basic, clinical, and population health research, and provides a unique environment for cross-departmental collaborations. BWH is a world- class center for myocardial perfusion positron emission tomography (PET) imaging and noninvasive quantification of coronary flow reserve (CFR). Importantly, its leadership is dedicated to protecting Dr. Taqueti's time for research and career development activities, and to foster her development as an independent translational investigator. Dr. Taqueti will also have access to resources at the Harvard Catalyst Clinical and Translational Science Center and the Harvard School of Public Health. RESEARCH SUMMARY: The objective of this proposal is to utilize a novel, 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 is especially important for women, in who diffuse atherosclerosis and microvascular dysfunction likely contribute to CVD outcomes, especially heart failure, but are often undiagnosed or misdiagnosed. Yet the exact relationship between impaired CFR and adverse CVD outcomes, particularly in the absence of obstructive CAD, is not well understood. Our central hypothesis is that excess CVD risk in women relative to men referred for coronary angiography is associated with impaired CFR independently of obstructive CAD, and that this increased risk may be mediated by increased myocardial strain and increased inflammation. Dr. Taqueti will apply state of the art analyses to two unique and complementary populations: a registry of patients undergoing PET myocardial perfusion for clinical evaluation of suspected CAD [CFR Registry]; and subjects from the Coronary Flow Reserve to Assess Cardiovascular Inflammation trial [CIRT-CFR], an ancillary study of the NHLBI sponsored multicenter Cardiovascular Inflammation Reduction Trial (CIRT) which will test whether reducing inflammation in stable CAD patients improves CFR. SPECIFIC AIMS: The following specific aims are proposed: (1) To identify the relationship between sex, CFR and angiographic disease severity in patients with suspected CAD [CFR Registry]; (2) To define the extent to which CVD risk in women relative to men is associated with impaired CFR, not obstructive CAD [CFR Registry]; and (3) To define the relationship between CFR, myocardial strain, and inflammation in women and men with stable CAD [CIRT-CFR]. By clarifying definitively the contribution of CFR to hidden CVD risk in women and men with varying levels of anatomic CAD, Dr. Taqueti will acquire the requisite experience and preliminary data for future R01-level studies employing this functional measure to select subjects for novel preventative and therapeutic interventions, including systemic therapy with anti-inflammatory, extreme lipid- lowering, and neurohormonal modulating agents. The proposed translational aims will help to define a new paradigm of ischemic heart disease with implications for diagnosis, risk stratification, and development of novel management strategies for a common, poorly recognized clinical problem with a disproportionate impact on women's health, an NIH strategic priority.