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.

8. PROJECT NARRATIVE/PUBLIC HEALTH RELEVANCE: For over two decades, case fatality rates for cardiovascular disease (CVD) in the US have been higher for women as compared with men. Yet paradoxically, obstructive coronary artery disease (CAD)—the kind which is visible on coronary angiography and for which revascularization with angioplasty or bypass is indicated—is less prevalent in women. This study will utilize a novel, noninvasive imaging method of quantifying coronary blood flow (and blood flow reserve) to test if: (1) excess cardiovascular disease risk in women relative to men who are referred for coronary angiography is at least partly mediated by impaired coronary flow reserve, even in the absence of obstructive CAD, and (2) impaired flow reserve is associated with increased heart strain and inflammation.