Overview

This study will test whether pharmacologic agents that increase perfusion [Potassium Nitrate (KNO3)], with and without additional supplements that may improve mitochondrial function [Propionyl-L-Carnitine (PLC) and Nicotinamide Riboside (NR)], improve submaximal exercise endurance and skeletal muscle oxidative phosphorylation capacity (SkM OxPhos) in participants with Heart Failure with Preserved Ejection Fraction (HFpEF).

Eligibility

Inclusion Criteria:

1. NYHA Class II-III symptoms
2. Left ventricular ejection fraction >= 50%
3. Stable medical therapy for at least 1 month
4. Prior or current evidence for elevated filling pressures as follows:
   1. Mitral early (E)/mitral septal tissue annular (e') velocity ratio > 8, in the context of a septal e' velocity <=7, in addition to one of the following: i. Large left atrium (LA volume index > 34 mL/m2) ii. Chronic loop diuretic use for control of symptoms iii. Elevated natriuretic peptides within the past year (e.g. NTproBNP > 125 pg/mL in sinus rhythm or > 375 pg/mL if in atrial fibrillation) b. Mitral E/e' ratio > 14 at rest or during exercise c. Elevated invasively-determined filling pressures previously (resting left ventricular end-diastolic pressure >= 16 mm Hg or pulmonary capillary wedge pressure >= 15 mmHg; or PCWP/LVEDP >= 25 mmHg with exercise) d. Prior episode of acute heart failure requiring IV diuretics

Exclusion Criteria:

1. Age <18 years old
2. Pregnancy:
3. Treatment with organic nitrates or phosphodiesterase inhibitors that cannot be interrupted
4. Uncontrolled atrial fibrillation, as defined by a resting heart rate > 100 beats per minute at the time of the baseline assessment
5. Hemoglobin < 10 g/dL
6. Subject inability/unwillingness to exercise
7. Moderate or greater left sided valvular disease (mitral regurgitation, aortic stenosis, aortic regurgitation), mild or greater mitral stenosis, severe right-sided valvular disease
8. Known hypertrophic, infiltrative, or inflammatory cardiomyopathy
9. Clinically significant pericardial disease, as per investigator judgment
10. Current angina due to clinically significant epicardial coronary disease, as per investigator judgment
11. Acute coronary syndrome or coronary intervention within the past 2 months
12. Primary pulmonary artery hypertension (WHO Group 1 Pulmonary Arterial Hypertension)
13. Clinically significant lung disease as defined by: Chronic Obstructive Pulmonary Disease meeting Stage III or greater GOLD criteria (FEV1<50%), treatment with oral steroids within the past 6 months for an exacerbation of obstructive lung disease, current use of supplemental oxygen aside from nocturnal oxygen for the treatment of obstructive sleep apnea, desaturation to <90% on the baseline maximal effort cardiopulmonary exercise test
14. Clinically-significant ischemia, as per investigator's judgement, on stress testing without either (1) subsequent revascularization, (2) an angiogram demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator judgment; (3) a follow-up 'negative' stress test, particularly when using a more specific technique (i.e., a negative perfusion imaging test following a 'positive' ECG stress test)
15. Left ventricular ejection fraction < 45% on a prior echocardiogram or cardiac MRI
16. Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x ULN, Albumin < 3.0 g/dL)
17. eGFR < 30 mL/min/1.73m^2
18. Methemoglobin > 5%
19. Serum potassium > 5.0 mEq/L
20. Severe right ventricular dysfunction
21. Baseline resting seated systolic blood pressure > 180 mmHg or < 100 mmHg
22. Orthostatic blood pressure response to the transition from supine to standing (>20 mmHg reduction in systolic blood pressure 2-3 minutes after standing)
23. Active participation in another study that utilizes an investigational agent (observational studies/registries allowed)
24. Any condition that, in the opinion of the investigator, will interfere with the performance and completion of the study.
25. Contraindications to MRI