This study will test whether pharmacologic agents that may improve mitochondrial function and energy fuel metabolism [Empagliflozin (Empa)], with and without additional supplements that increase perfusion and fatty acid oxidation [Potassium Nitrate (KNO3)], improve submaximal exercise endurance and skeletal muscle oxidative phosphorylation capacity (SkM OxPhos) in participants with Heart Failure with Preserved Ejection Fraction (HFpEF).

This study will test whether Empagliflozin (Empa), with and without Potassium Nitrate (KNO3), improves submaximal exercise endurance, skeletal muscle oxidative phosphorylation capacity (SkM OxPhos), intramuscular perfusion, and changes in the skeletal muscle metabolome, proteome, and respiration in participants with Heart Failure with Preserved Ejection Fraction (HFpEF).

Inclusion:

1. NYHA Class II-III symptoms 2. Left ventricular ejection fraction >= 50% 3. Stable medical condition for at least 2 weeks, as per investigator judgment 4. Prior or current evidence for elevated filling pressures, as evidenced by at least one of the following:

a. Mitral early (E)/septal tissue annular (e') velocity ratio > 8, in the context of a septal e' velocity <=7 cm/s or a lateral e' <= 10 cm/s, 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: Women of childbearing potential will undergo a urine pregnancy test during the screening visit.

3. Treatment with organic nitrates or phosphodiesterase inhibitors that cannot be interrupted

4. Uncontrolled atrial fibrillation, as defined by a resting atrial fibrillation 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 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 will also be grounds for exclusion

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)

    - Exercise-induced regional wall motion abnormalities on the echocardiographic assessment during the baseline maximal effort cardiopulmonary exercise test will also be exclusionary

15. Left ventricular ejection fraction < 45% on a prior echocardiogram or cardiac MRI, unless the reduced LVEF occurred within the context of an uncontrolled supraventricular arrhythmia, with return of a normal ejection fraction following treatment of the arrhythmia

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

17. eGFR < 30 mL/min/1.73m2.

18. Methemoglobin > 5%

19. Serum potassium > 5.0 mEq/L on baseline testing

20. Type I Diabetes

21. History of ketoacidosis

22. Current use of, or prior intolerance to, an SGLT2i

23. Ongoing maintenance of a 'Ketogenic Diet' (low carbohydrate, high fat)

24. Allergy to beets

25. Severe right ventricular dysfunction

26. Baseline resting seated systolic blood pressure > 180 mmHg or < 100 mmHg

27. Persistently low or high seated blood pressure or orthostatic blood pressure response to the transition from supine to standing (>20 mmHg reduction in systolic blood pressure 2-3 minutes after standing, or a fall in SBP to < 90 mmHg) at the baseline visit

28. Active participation in another study that utilizes an investigational agent (observational studies/registries allowed)

29. Any condition that, in the opinion of the investigator, may interfere with the completion/performance of the study. This may include comorbid or psychiatric conditions that may impede successful completion of the protocol, or logistical concerns (e.g., inability to travel to the exercise unit).

Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be maintained indefinitely in an electronic database. This will not include the participant's contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by clinical sites and by the research staff will be secured and password protected. At the end of the study, all study databases will be de-identified and archived.

If any data or samples are shared with collaborators at UPenn or elsewhere, only de-identified samples/data will be given, without any linking information.

All personnel will be masked except for the IDS pharmacist dispensing the drugs.