Women's Ischemia Syndrome Evaluation (WISE) Pre-HFpEF

The purpose of this study is to examine small vessel disease (a condition in which the small arteries in the heart become narrowed). The investigators want to know how the small vessel disease contributes to pre-HFpEF (a condition with inadequate heart muscle function in the setting of preserved muscle pumping) and to better identify potential treatment for prevention of HFpEF. The main procedures of this study include up to 2 clinic visits (initial visit and a second clinical visit only if participants are unable to complete all research procedures at the initial visit); a 6-week phone interview visit, 4 quarterly follow-up phone interview visits in year 1; year 1 follow up cardiac MRI based on availability and ongoing annual follow-up phone interview visits to track progress. If participants choose to take part in this study, participants direct participation will end after 1 year, participants will then have the option of participating in ongoing annual check-in calls. Participants will be asked to undergo a physical exam and provide a completed medical history; complete a Cardiovascular (or Cardiac) Magnetic Resonance Imaging (CMRI) with contrast agent; complete questionnaires to describe heart symptoms and overall quality of life status; undergo blood draws to provide blood samples for research testing, and allow the study team to have access to medical records.

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. Ischemia with no obstructive CAD (INOCA) and myocardial infarction with no obstructive CAD (MINOCA) are increasingly observed in women and men.

Once established, the investigators 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.

To address this novel hypothesis, the investigators propose the following Specific Aims:

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. In our labs (\>420 patients), \~60% of those tested have evidence for CMD. All subjects will perform provocative stress testing with isometric handgrip - chosen for its unique ability to increase myocardial afterload and myocardial oxygen demand - 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. Left ventricular function will be directly assessed using Millar-catheter LV pressure-volume loops (perfected in our lab over the past 24 months). 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. The investigators will evaluate CMRI LV perfusion, myocardial scar, diffuse fibrosis, LV remodeling, and diastolic function. The investigatorswill 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.

Eligibility Criteria:
Inclusion:

1. 180 symptomatic men and women undergoing invasive coronary angiography for suspected ischemia with no obstructive CAD, defined as ≥50% luminal diameter stenosis in ≥1 epicardial coronary artery.
2. Preserved left ventricular ejection fraction (EF) ≥45%
3. Be \> 18 years old
4. Be able to meet the requirement for a cardiac MRI, which means no metal devices in your chest, no claustrophobia and no angioedema
5. Be competent to give informed consent

Exclusion:

1. Subjects with severe or chronic kidney disease (CKD) with GFR\<405 or acute kidney injury
2. Subjects with allergy to animal dander will be excluded since imaging will be done in BIRI (BIRI scanners are also used to image animals).
3. Subjects who have had four or more prior previous gadolinium contrast scans
4. Allergy/ hypersensitivity to adenosine, gadolinium, aminophylline or regadenoson
5. Second- or third-degree A-V block
6. Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker)
7. Subjects with mild to severe asthma