WISE CVD - Continuation (WISE HFpEF)
WISE CVD - Continuation (WISE HFpEF)
The Women's Ischemia Study Evaluation (WISE), a cohort study of over 1000 women, has made
 many contributions to the understanding of cardiovascular disease. A milestone acknowledged
 in the 2011 AHA Herrick Lecture is the role of Coronary Microvascular Dysfunction (CMD) in
 women with symptoms/signs of ischemia without obstructive coronary artery disease (CAD).
 While in 1996, CMD was considered "an imaging artifact", in 2013, it is a widely accepted as
 a pathophysiologic process requiring systematic cohesive scientific pursuit. CMD is
 prevalent, associated with adverse clinical outcomes, poor quality of life and healthcare
 costs rivaling obstructive CAD. There are 2-3 million US women with CMD, and 100,000 new
 cases projected annually placing CMD prevalence, morbidity and costs higher than all female
 reproductive cancers combined.

 Among women with ischemia, preserved ejection fraction and no obstructive CAD, it has been
 observed that there are relatively more new onset heart failure (HF) hospitalizations than
 nonfatal myocardial infarction (MI). It has been hypothesized that CMD contributes to left
 ventricular (LV) diastolic dysfunction and subsequent heart failure with preserved ejection
 fraction (HFpEF). Preliminary data further suggests that left ventricular diastolic
 dysfunction is linked to CMD via a mechanism of augmentation and/or perpetuation by
 cardiomyocyte fat accumulation. HFpEF is prevalent in women and older men, but poorly
 understood. Mechanistic understanding is critical to HFpEF intervention and guideline
 development.

 The study hypotheses are as follows:

 1. Risk factor conditions (hypertension, dyslipidemia, dysglycemia, loss of estrogen)
 promote an inflammatory and pro-oxidative state making the microvasculature vulnerable;

 2. Vulnerable coronary microvasculature becomes dysregulated (sympathetic nervous system
 activation, endothelial dysfunction, changes in vascular smooth muscle activation,
 spasm) causing repeated episodes of transient ischemia;

 3. Repeated ischemia-reperfusion episodes facilitate preconditioning with preservation of
 cardiomyocyte contractile and microvascular function against ischemic injury;

 4. Ischemia-reperfusion and preconditioning lead to cardiomyocyte fat accumulation and
 relaxation impairment resulting in diastolic dysfunction and heart failure with
 preserved ejection fraction (HFpEF).
The current application will study new cohorts of women and men with the following specific
 aims:

 Specific Aim 1: LV diastolic dysfunction is linked to CMD. Sub-Aim 1: LV diastolic
 dysfunction and CMD are linked via the mechanism of cardiomyocyte fat accumulation.

 Specific Aim 2: Comprehensive noninvasive Cardiac Magnetic Resonance Imaging (CMRI) that
 includes LV diastolic function is linked with invasive measures of LV diastolic function and
 can optimize diagnosis of CMD.

 Sub-Aim 2: Coronary Magnetic Resonance Angiography (CMRA) can exclude obstructive CAD in CMD.

 Specific Aim 3: Add completely de-identified data sharing to prepare for future large
 precision medicine research and to advance precision medicine initiative.

 Exploratory Aim: Blood proteomic and metabolomics biomarkers of extracellular matrix
 remodeling and fibrosis combined with ischemia measures will predict HFpEF.

 In this prospective, cohort design study, investigators intend to enroll 220 new subjects
 including 120 symptomatic women undergoing invasive coronary angiography for suspected
 ischemia with no obstructive coronary artery disease (CAD) defined as ≥50% luminal diameter
 stenosis in ≥1 epicardial coronary artery and 100 women and men hospitalized for Heart
 Failure with preserved Ejection Fraction (HFpEF) defined by the European Society of
 Cardiology (ESC) criteria who have not yet undergone coronary angiography.

 New and existing samples and longer term follow-up will be analyzed in an exploratory fashion
 looking for potential HFpEF biomarkers for pilot data purposes.

 After baseline evaluation, the n=120 cohort will undergo noninvasive high resolution,
 comprehensive CMRI imaging, invasive angiography, coronary reactivity testing and rest-stress
 Millar pressure-volume measurement. Handgrip, mild leg exercise, and brief Valsalva Maneuver
 will be conducted during CMRI and Millar pressure-volume assessment to characterize cardiac
 response to stress. Lastly, these patients will also undergo MR Coronary Angiography, for
 validation purposes against gold-standard angiography.

 The cohort of 100 women and men with HFpEF admitted to the hospital who have not yet
 undergone coronary angiography will also undergo CMRI (with stress), including MR coronary
 angiography (CMRA) and noninvasive computed coronary tomographic angiography (CCTA)(CSMC
 only).

 This will provide understanding of a non-cath-lab based population regarding links between
 CMD, diastolic function and HFpEF, and will result in data to test the hypothesis that
 coronary MRA can exclude obstructive CAD and diagnose CMD without ionizing radiation.
 Proteomic and metabolomics biomarker assays in the (n=567) subjects with no obstructive CAD
 (Exploratory Aim) will be performed.
Inclusion Criteria:

 For the new cohort n=120 women undergoing coronary angiography:

 -  Symptomatic angina or anginal equivalent

 -  Age ≥ 18

 -  Participant is willing to give written informed consent

 For the cohort n=100 women and men hospitalized for HFpEF (defined by ESC guidelines):

 -  Age ≥ 18

 -  Signs and symptoms of heart failure

 -  Preserved ejection fraction, left ventricular ejection fraction (LVEF) ≥45% prior to
 study entry.

 -  Structural evidence of cardiovascular abnormalities: elevated brain naturetic peptide,
 evidence of abnormal filling or relaxation, left ventricular hypertrophy, or an
 increased left atrial size

 -  Evidence of elevated filling pressures: LVEDP or PCWP at rest > 15 mmHg and/or with
 exercise ≥25 mmHg, exercise E/e' >13, elevated BNP, or use of diuretic

 -  Participant is willing to give written informed consent

 Exclusion Criteria:

 For the new cohort n=120 women undergoing invasive coronary angiography:

 -  Obstructive CAD ≥ 50% luminal diameter stenosis in ≥ 1 epicardial coronary artery

 -  STEMI within 3-7 days post MI, or Acute coronary syndrome/NSTEMI with with symptoms or
 signs of acute myocardial ischemia within the last 12 to 24 hours prior to the
 research procedure, as outlined in ACC/AHA guidelines.

 -  Primary valvular heart disease clearly indicating the need for valve repair or
 replacement

 -  Patients with concurrent cardiogenic shock or requiring inotropic or intra-aortic
 balloon support or LVEF<45%

 -  Prior or planned percutaneous coronary intervention or coronary artery bypass grafting
 for obstructive coronary atherosclerosis

 -  Non-cardiac illness with a life expectancy < four years

 -  Unable to give informed consent

 -  Chest pain which has an alternative non-ischemic etiology, i.e. pericarditis,
 pulmonary embolism, pleurisy, pneumonia, esophageal spasm, etc.

 -  Contraindications to CMRI, such as internal cardiac defibrillator, untreatable
 claustrophobia or known angioedema

 -  Contraindications to adenosine or regadenoson including severe COPD and asthma

 -  End stage renal or liver disease

 -  Women with intermediate coronary stenoses (>20% but <50% luminal diameter stenosis
 assessed visually at the time of angiography) will undergo clinically indicated
 fractional flow reserve (FFR) based on the judgment of the operator; those determined
 to have flow-obstructing stenosis will be excluded.

 -  Documented allergy to gadolinium

 For the new cohort n=100 women and men hospitalized for HFpEF:

 -  Current LVEF <45%

 -  STEMI within 3-7 days post MI, or Acute coronary syndrome/NSTEMI with with symptoms or
 signs of acute myocardial ischemia within the last 12 to 24 hours prior to the
 research procedure, as outlined in ACC/AHA guidelines.

 -  Acute coronary syndrome (defined by ACC/AHA guidelines, including MI) within 3 months
 of entry. Patients who have had an MI or other event within the 6 months prior to
 entry unless an echo measurement performed after the event confirms a LVEF ≥45%.

 -  Primary valvular heart disease (moderate regurgitation or>mild stenosis), primary
 cardiomyopathies (hypertrophic, infiltrative or restrictive), constrictive
 pericarditis, high-output heart failure, and right ventricular myopathies)

 -  Patients with concurrent cardiogenic shock or requiring inotropic or intra-aortic
 balloon support or current acute decompensated HF requiring therapy including due to
 trauma, infection.

 -  Alternative reason for shortness of breath such as: significant pulmonary disease or
 severe COPD, hemoglobin (Hgb) <10 g/dl, or body mass index (BMI) > 40 kg/m2.

 -  Systolic blood pressure (SBP) ≥ 180 mmHg at entry, or SBP >150 mmHg and <180 mmHg at
 entry unless the patient is receiving 3 or more antihypertensive drugs.

 -  Prior or planned percutaneous coronary intervention or coronary artery bypass grafting
 for obstructive coronary atherosclerosis

 -  Non-cardiac illness with a life expectancy < four years

 -  Unable to give informed consent

 -  Contraindications to CMRI, such as internal cardiac defibrillator, untreatable
 claustrophobia or known angioedema

 -  Contraindications to adenosine or regadenoson including severe COPD and asthma.

 -  Obstructive stenoses (≥50% luminal diameter stenosis assessed visually at the time of
 research CTA) will be excluded from further analyses. Subjects with obstructive or
 borderline obstructive coronary CTA stenoses will be referred to their clinicians for
 further clinical care and clinical decision making. End stage renal or liver disease