Inorganic NItrate and EXercise Performance in Heart Failure (iNIX-HF): Dose Response

The purpose of this study is to do the work that is necessary and sufficient for setting up an appropriate multi-center, randomized clinical trial (RCT) of a new therapy for heart failure: inorganic nitrate. The investigators will first determine the effects and palatability of \~12.8mmol KNO3 (an oral pill) as compared to the roughly equivalent amount of nitrate in 2 beetroot juice (BRJ) Sports Shots (by James White Drinks). Next, the investigators will determine the effects of inorganic nitrate (KNO3 in an oral pill format) on blood pressure, blood nitrate levels, breath nitric oxide (NO) levels, and exercise performance in a dose-response study. Third, the investigators will perform a small phase II chronic treatment study that will allow them to determine the best primary endpoint and the numbers of patients the investigators will need to study in the large, multi-center RCT to follow this project. In the small study and in the RCT to follow, the investigators will determine whether inorganic nitrate can improve aerobic exercise capacity, muscle power, and speed of muscle contraction, and lessen the effort of breathing during exercise.

1. Subjects will be patients with Heart Failure (HF).
2. All subjects will be consented.
3. All subjects will give permission for the investigators to review their medical records.
4. After consenting to participate, subjects will be instructed to refrain from spitting or the use of an antibacterial mouthwash, antacids, proton pump inhibitors, or chewing gum during the morning of each clinic visit.
5. Subjects will have a physical examination.
6. Subjects will undergo transthoracic echocardiographic imaging at rest (unless they had this performed within the past 6 months).
7. Subjects will be asked to undergo a mouth swab for bacterial DNA analyses.
8. Subjects will be asked to answer questionnaires regarding their medical health (basic health questionnaire, Minnesota living with heart failure questionnaire, a combined fatigue questionnaire.
9. Dose visit 1: Subjects will receive 2 capsules containing either 10 or 20 mmol of potassium nitrate (KNO3).
10. Before and at 3 hourly time points after receiving the KNO3, subjects will undergo phlebotomy for plasma nitrite levels, will have their blood pressure measured, and will blow into a small machine to assess the amount of nitric oxide in their breath.
11. Exercise Test 1: Subjects will complete measurements of leg muscle power by doing knee extension exercises on a dynamometer (a device that measures voluntary muscle force production while controlling the speed of movement).
12. Exercise Test 2: Subjects complete a measurement of peak aerobic capacity (VO2peak) while walking on a treadmill and breathing into a mouthpiece. Blood pressure, heart rate and heart rhythm will be monitored during this test.
13. Subjects will undergo a 7 d washout period.
14. Dose visit 2: Subjects will receive 2 capsules containing either 10 or 20 mmol of KNO3 (whichever dose they did not receive at dose visit 1). They will repeat the same assessments listed above in 10, 11, and 12.

Eligibility Criteria:
Inclusion Criteria:

1. Sex: females and males
2. Age: at least 18 years and less than 75 years
3. Diagnosis of heart failure with reduced ejection fraction (NYHA II-IV)
4. Ejection fraction \<45% as determined on an imaging study within 12 mo of enrollment
5. Stable medical therapy - defined by no addition or removal (or change of more than 100%) of the following: beta-adrenergic blockade, angiotensin converting enzyme (ACE) inhibitors, or angiotensin receptor blocker (ARB or aldosterone antagonists) for 30 days prior to enrolment

Exclusion Criteria:

1. "Vulnerable populations" as defined by the U.S. Department of Health and Human Services, such as prisoners and children
2. Pharmacologic, organic nitrate therapy within the last 3 months
3. Major orthopedic, psychiatric, neurological, or other conditions that would impair performance of the exercise tests in this study
4. Atrial fibrillation/flutter
5. Estimated glomerular filtration rate \< 50 ml/min on most recent clinical laboratories
6. Systolic blood pressure \< 95 mmHg or \>180 mmHg at consent
7. Diastolic blood pressure \<40 mmHg or \>100 mmHg at consent
8. Previous adverse reaction to nitrates necessitating withdrawal of therapy
9. Treatment with phosphodiesterase inhibitors within the last 3 months (patient must also be willing to not take them for the duration of the trial).
10. Ejection fraction \> 45%
11. Primary hypertrophic cardiomyopathy
12. Infiltrative cardiomyopathy (e.g., amyloid)
13. Active myocarditis
14. Complex congenital heart disease
15. Active collagen vascular disease
16. Active angina/ischemia from epicardial coronary disease
17. Percutaneous coronary intervention, new bi-ventricular pacing, or coronary artery bypass grafting within the past 3 months
18. More than mild mitral or aortic stenosis
19. Valvular heart disease with severe regurgitation of any valve.
20. Acute or chronic severe liver disease as evidenced by encephalopathy, international normalized ratio (INR) \>1.7 without anticoagulation therapy, or variceal bleeding
21. Patients requiring exogenous oxygen at rest or for exercise
22. Terminal disease (other than heart failure) with expected survival \< 1 y
23. Enrollment in another therapeutic trial during the period of the study
24. Pregnancy