WISE CVD - Continuation (WISE 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