Project Abstract
Coronary microvascular dysfunction (CMD) due to changes in the function and structure of coronary
microcirculation in the absence of obstructive coronary artery disease (CAD) is poorly understood, and ischemia
with no obstructive CAD (INOCA) and myocardial infarction with no obstructive CAD (MINOCA) are increasingly
observed in women and men. More than two decades of work has led us to conclude that CMD can lead to heart
failure with preserved ejection fraction (HFpEF). Our findings indicate that risk factor conditions (hypertension,
obesity, dyslipidemia, dysglycemia, estrogen loss) promote a pro-inflammatory, pro-oxidative state, rendering
the coronary microvasculature and myocardium vulnerable to: 1) ischemia, 2) micro-infarction-related myocardial
scar, 3) diffuse fibrosis, 4) adverse LV remodeling. We propose that CMD plays a critical role in a “pre-HFpEF
state”.Despite delineation of HFpEF into specific phenotypes, no effective treatments exist. The current
application will address this therapeutic knowledge gap by investigating CMD-related ischemia as a precursor of
myocellular damage, scar, diffuse fibrosis, and LV diastolic dysfunction (hallmark features of HFpEF). Indeed,
CMD is associated with measurable increases in high sensitivity cardiac troponin (hs-cTnI), and hs-cTnI
elevations predict future HFpEF. Once established, we will be well positioned to aggressively target identified
mechanistic targets in a specific well-characterized at-risk population, with the primary goal of preventing
progression to HFpEF. Our application directly addresses the NHBLI Strategic Vision 4.CQ.05 “How does the
pathobiology that underlies nonobstructive ischemic heart disease and the associated risks for acute coronary
syndrome and early mortality differ between subpopulations, and what are the targets for treatment and
prevention?” We propose the following to address this: Aim 1: Test the hypothesis that CMD-related ischemia
contributes to myocellular damage and impaired ventricular relaxation. CMD will be measured directly, using our
established intracoronary pharmacological vasoactive protocol, in subjects with signs/symptoms of ischemia but
no obstructive CAD perform provocative stress testing while myocardial ischemia will be assessed directly
through invasive simultaneous arterial and coronary sinus/great cardiac vein oxygen tension and lactate
measurements, and continuous ECG’s recordings, while left ventricular function will be directly assessed using
Millar-catheter LV pressure-volume loops and stress-induced myocellular damage will be directly measured by
coronary sinus/great cardiac vein hs-cTnI. Aim 2: Test the hypothesis that CMD-related ischemic myocellular
damage contributes to LV diastolic dysfunction progression. Subjects from Aim 1 will also undergo
comprehensive cardiac magnetic resonance imaging (CMRI) at enrollment and 1-2 years later. We will evaluate
CMRI LV perfusion, myocardial scar, diffuse fibrosis, LV remodeling, and diastolic function. We will leverage the
strengths and resources of our world-renowned proteomics core to establish evidence of chronic myocellular
damage using prospectively repeated ambulatory hs-cTnI determinations. Combining the results of our ongoing
WARRIOR trial (NCT#03417388) results with the current application will identify potential mechanistic treatment
targets of: 1) ischemia/scar, 2) strain/remodeling, and 3) fibrosis/ventricular stiffness, for mechanistically
supported HFpEF prevention clinical trials such as: 1) anti-ischemic/scar therapies (statin/ACE-ARB, alpha-beta
blockers, NO-cyclic GMP), 2) strain/remodeling therapies (sacubitril/valsartan), and/or 3) anti-fibrotic therapies
(galectin 3, peptidyl arginine deiminase type IV inhibitor, stress-activated kinase-1 inhibitor, protein kinase G,
fibroblast growth factor).
