This study will be performed to determine the safety, tolerability, and dose-response to inorganic nitrate on exercise capacity in HFpEF. There are two primary goals for this study:

1. Determine the population-specific pharmacokinetics and dose of KNO3 that can be safely given to subjects with HFpEF.
2. Determine if there is a dose-response effect of nitrate supplementation on exercise capacity, evidenced by peak oxygen consumption (peak VO2), and physiologic adaptations to exercise.

This study randomized subjects to either placebo (n=3) or KNO3 (n=9) given a sequential dosing regimen: 6 mmol twice daily for 1 week followed by dose escalation to 6 mmol thrice daily for 1 week). Although a primary goal of the study was to assess the safety of KNO3 and within-group changes in various end points in KNO3-treated subjects, a small number of placebo-treated (PB, n=3) subjects were included only to assess for any potential training effect on repeated exercise and Kansas City Cardiomyopathy Questionnaire (KCCQ) measurements. Potassium chloride, given in equivalent doses, was used as the PB to account for differences in blood pressure or flow that could be attributed to potassium.

The study was initially designed to be single-blinded to allow the principal investigator to be aware of arm allocation because of potential concerns for methemoglobinemia with drug administration. One investigator, who was the primary investigator responsible for supervising all visits and measurements during the study, remained blinded to treatment allocation throughout the entirety of the study. All physiological and imaging data were analyzed in a double-blind manner.

Inclusion Criteria:

1. NYHA Class II-III symptoms.
2. LV EF > 50%.
3. Stable medical therapy for at least 1 month.
4. Evidence of significant diastolic dysfunction, meeting the European Society of Echocardiography criteria for HFpEF.

Exclusion Criteria

1. Any rhythm other than sinus with native conduction.
2. Inability to exercise.
3. Moderate or greater valvular disease.
4. Hypertrophic, infiltrative, or inflammatory cardiomyopathy.
5. Pericardial disease.
6. Current angina.
7. Acute coronary syndrome or coronary intervention within the past 2 months.
8. Primary pulmonary arteriopathy.
9. Clinically significant lung disease.
10. Ischemia on stress testing without subsequent revascularization.
11. Treatment with phosphodiesterase inhibitors that cannot be withheld.
12. Treatment with organic nitrates or allopurinol.
13. Significant liver disease impacting synthetic function or volume control.
14. Poor echocardiographic windows.
15. eGFR < 30 mL/min/m2 or Cr >2.5.
16. Current smoking.
17. Alcohol dependency.
18. History of Barret's esophagus.
19. G6PD deficiency
20. Methemoglobinemia - baseline methemoglobin level >3% prior to any study medication.

Adverse events were collected at every visit. There are a total of three visits that are 1 week apart.

All adverse events were non serious so they are reported under Other Adverse Events

• Small sample size
• Serial blood draws, which caused a decrease in hemoglobin concentration, which may have constrained the increase in VO2,peak and reduced the magnitude of the improvement in exercise capacity and quality of life.