Targeting Pulsatile Load to Increase Exercise Capacity and Quality of Life After Aortic Valve Replacement for Severe Aortic Stenosis (PULSE AS)

This is a randomized double-blind crossover clinical trial, in which 22 subjects who
underwent transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS) three
or more months prior to enrollment will receive the following 2 interventions, in randomized
order: (1) Potassium nitrate (KNO3), at a dose of 12-18 mmol/d by mouth for 4 weeks, or; (2)
Potassium chloride (KCl), at a dose of 12-18 mmol/d by mouth for 4 weeks. A 1-week washout
period will be introduced between the 2 interventions. The purpose of the trial is to test
the safety of KNO3 and its efficacy on a number of clinical and physiologic endpoints in
subjects who underwent TAVR for severe AS.

Inclusion Criteria:

1. Adults aged 50-90 years of age

2. Diagnosis of severe aortic stenosis prior to aortic valve repair

3. Successful trancatheter aortic valve repair via transfemoral procedural approach or
successful surgical aortic valve repair at least three months prior to enrollment

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

Exclusion Criteria

1. Supine systolic blood pressure (SBP) < 100 mmHg OR supine diastolic blood pressure
(DBP) <60 mmHg

2. Poorly controlled hypertension, as defined as SBP > 160 mmHg OR DBP > 100 mmHg

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

4. Atrial fibrillation within the prior 8 weeks before enrollment

5. Inability/unwillingness to exercise

6. Moderate or greater mitral regurgitation or aortic/peri-valvular regurgitation, any
degree of mitral stenosis, severe right-sided valvular disease, or presence of a
mitral prosthetic valve.

7. Moderate or severe patient prosthesis mismatch, as defined by Effective Orifice Area
Index < 0.85 cm2/m2

8. Hypertrophic, infiltrative, or inflammatory cardiomyopathy

9. Pericardial disease

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 subsequent revascularization (during the screening
visit)

15. Treatment with phosphodiesterase inhibitors that cannot be withheld

16. Treatment with organic nitrates

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

18. eGFR < 30 mL/min/1.73 m2

19. G6PD deficiency. For males of African, Asian or Mediterranean decent, this will be
evaluated prior to drug administration. A qualitative test positive for deficiency or
a quantitative test with clinically significant G6PD deficiency (<60% of normal
activity) will prompt exclusion from the trial (prior to drug administration).

20. History of methemoglobinemia or methemoglobin level >5% at baseline visit

21. Serum K>5.0 mEq/L

22. Severe right ventricular dysfunction.

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