Effect of KNO3 Compared to KCl on Oxygen UpTake in Heart Failure With Preserved Ejection Fraction (KNO3CK OUT HFPEF)

Approximately 50% of heart failure patients exhibit preserved left ventricular (LV) ejection
fraction (EF), and therefore have HF with preserved EF (HFpEF). There are currently no proven
effective pharmacologic interventions. Exercise intolerance with reduced aerobic capacity is
the hallmark of HFpEF and greatly impairs quality of life (QOL). During exercise, blood
vessels within active muscle vasodilator, increasing perfusion to the muscle bed. Nitric
oxide is a chief mediator of this process. Inorganic nitrate can ultimately be converted to
nitric oxide. This conversion occurs preferentially at the site of exercising muscle,
allowing for vasodilation to occur, hence increasing blood flow to the working muscle.
Preliminary data suggest that inorganic nitrate improves exercise tolerance in HFpEF. The
investigator will aim to test this hypothesis in a larger group.

Inclusion Criteria:

1. Adults aged 18-90 years of age

2. A diagnosis of heart failure with NYHA Class II-III symptoms

3. LV ejection fraction >50% during baseline echocardiography

4. Stable medical therapy: no addition/removal/changes in antihypertensive medications,
or beta-blockers in the preceding 30 days

5. Elevated filling pressures as evidenced by at least 1 of the following:

1. Mitral E/e' ratio > 8 (either lateral or septal), with low e' velocity (septal
e'<7 cm/sec or lateral e'< 10 cm/sec), in addition to one of the following:

i Enlarged left atrium (LA volume index >34 ml/m2) ii Chronic loop diuretic use
for control of symptoms iii Elevated natriuretic peptides (BNP levels >100 ng/L
or NT-proBNP levels >300 ng/L)

2. Mitral E/e' ratio > 14 (either lateral or septal)

3. Elevated invasively-determined filling pressures previously (resting LVEDP>16
mmHg or mean pulmonary capillary wedge pressure [PCWP] > 12 mmHg; or
PCWP/LVEDP≥25 mmHg with exercise)

4. Acute heart failure decompensation requiring IV diuretics

Exclusion Criteria:

1. Supine systolic blood pressure <100 mm Hg

2. Pregnancy: Women of childbearing potential will undergo a pregnancy test during the
screening visit

3. Orthostatic hypotension defined as >20 mm Hg decrease in systolic blood pressure 3-5
minutes following the transition from the supine to standing position

4. Uncontrolled atrial fibrillation, as defined by a resting heart rate>100 beats per
minute

5. Hemoglobin < 10 g/dL

6. Inability/unwillingness to exercise

7. Moderate or greater left sided valvular disease (mitral regurgitation, aortic
stenosis, aortic regurgitation), any degree of mitral stenosis, severe right-sided
valvular disease, or presence of a prosthetic valve in the mitral position

8. Hypertrophic, infiltrative, or inflammatory cardiomyopathy

9. Clinically significant pericardial disease, as per investigator judgement.

10. Current angina

11. Acute coronary syndrome or coronary intervention within the past 2 months

12. Primary pulmonary arteriopathy

13. Clinically significant lung disease as defined by: Chronic Obstructive Pulmonary
Disease meeting Stage III or greater GOLD criteria, treatment with oral steroids
within the past 6 months for an exacerbation of obstructive lung disease, or the use
of daytime supplemental oxygen

14. Ischemia on stress testing without either (1) subsequent revascularization, or; (2) a
subsequent angiogram demonstrating the absence of clinically significant epicardial
coronary artery disease, as per investigator judgement.

15. Left ventricular ejection fraction <45% in any prior echocardiogram or cardiac MRI,
unless this was in the setting of uncontrolled atrial fibrillation.

16. Treatment with phosphodiesterase inhibitors that cannot be withheld

17. Treatment with organic nitrates

18. Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x
ULN, Albumin <3.0 g/dL)

19. eGFR < 30 mL/min/1.73m2

20. G6PD deficiency. In males of African, Asian or Mediterranean decent, this will be
formally evaluated by enzyme testing prior to drug administration. A negative
screening test for G6PD will be required in these subjects for inclusion in the study.
If a quantitative test is being performed, a clinically significant reduction in G6PD
activity (<60% of normal) will exclude subjects.

21. Methemoglobinemia - baseline methemoglobin level >5%

22. Serum K>5.0 mEq/L

23. Severe right ventricular dysfunction

24. Any medical condition that, in the opinion of the investigator, will interfere with
the safe completion of the study.

25. Contraindications to MRI (except as noted below), including the presence of a
pacemaker, metal implants, claustrophobia, or that have known medical conditions which
can be exacerbated by stress such as anxiety or panic attacks. Inability to lie flat
in the MRI scanner for 90 minutes is also an exclusion criterion.