Heart Failure, Diastolic Heart Failure
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGKNO3
Active Comparator
DRUGKCl
Placebo Comparator
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose | Baseline, end of week 1, end of week 2 | Peak oxygen uptake (VO2) defined as the average value obtained during the last 30 seconds of exercise. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Vasodilatory Reserve for Each Dose | Baseline, end of week 1, end of week 2 | Percent change in peak vascular resistance from rest to peak exercise |
| Change in Mitochondrial Oxidative Capacity for Each Dose | Baseline, end of week 1, end of week 2 | Percent change in oxidative capacity (oxyhemoglobin levels) before and after occlusion |
| Change in Aortic Augmentation Index | Baseline, end of week 1, end of week 2 | Percent change in augmentation index, whereas augmentation index at each time point (visit) is defined as the amplitude of the second peak to the first peak of the aortic pulse wave form multiplied by 100: augmentation index = (P2/P1)×100. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Randomized to KNO3 KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated
Active Comparator: Potassium Nitrate | 9 |
| Randomized to KCl KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if tolerating well.
Placebo Comparator: Potassium Chloride | 3 |
| Total | 12 |
Baseline characteristics
| Characteristic | Randomized to KNO3 | Randomized to KCl | Total |
|---|---|---|---|
| Age, Continuous | 62.4 years STANDARD_DEVIATION 5.5 | 62.7 years STANDARD_DEVIATION 8 | 62.5 years STANDARD_DEVIATION 5.8 |
| Body Mass Index, kg/m^2, mean (SD) | 33.4 kg/m^2 STANDARD_DEVIATION 6.3 | 37.4 kg/m^2 STANDARD_DEVIATION 9.9 | 34.4 kg/m^2 STANDARD_DEVIATION 7 |
| Estimated Glomerular Filtration Rate (eGFR) <60 mL/min per 1.73m^2, n (%) | 3 Participants | 1 Participants | 4 Participants |
| Estimated Glomerular Filtration Rate (eGFR), mL/min per 1.73m^2, mean (SD) | 71.0 mL/min per 1.73m^2 STANDARD_DEVIATION 14.1 | 64.7 mL/min per 1.73m^2 STANDARD_DEVIATION 5.9 | 69.4 mL/min per 1.73m^2 STANDARD_DEVIATION 12.6 |
| Hemoglobin, g/dL, mean (SD) | 13.6 g/dL STANDARD_DEVIATION 0.8 | 13.5 g/dL STANDARD_DEVIATION 1 | 13.6 g/dL STANDARD_DEVIATION 0.8 |
| Left atrial volume index, mL/m^2, mean (SD) | 27.20 mL/m^2 STANDARD_DEVIATION 7.87 | 29.38 mL/m^2 STANDARD_DEVIATION 5.33 | 27.74 mL/m^2 STANDARD_DEVIATION 7.15 |
| Left ventricular ejection fraction, %, mean (SD) | 65.84 % (stroke volume/ end-diastolic vol)x100 STANDARD_DEVIATION 7.74 | 59.41 % (stroke volume/ end-diastolic vol)x100 STANDARD_DEVIATION 13.66 | 64.23 % (stroke volume/ end-diastolic vol)x100 STANDARD_DEVIATION 9.27 |
| Left Ventricular (LV) mass,g, mean (SD) | 174.43 g STANDARD_DEVIATION 77.09 | 165.98 g STANDARD_DEVIATION 19.27 | 172.32 g STANDARD_DEVIATION 66.36 |
| Left Ventricular (LV) mass index, g/m^2, mean (SD) | 79.78 g/m^2 STANDARD_DEVIATION 26.01 | 76.18 g/m^2 STANDARD_DEVIATION 7.33 | 78.88 g/m^2 STANDARD_DEVIATION 22.46 |
| Methemoglobin, %, mean (SD) | 1.0 percent of total hemoglobin STANDARD_DEVIATION 0.2 | 1.0 percent of total hemoglobin STANDARD_DEVIATION 0.5 | 1.0 percent of total hemoglobin STANDARD_DEVIATION 0.3 |
| Mitral atrial inflow velocity (E), cm/s, mean (SD) | 70.74 cm/s STANDARD_DEVIATION 20.06 | 88.61 cm/s STANDARD_DEVIATION 21.28 | 75.21 cm/s STANDARD_DEVIATION 20.99 |
| Mitral early inflow velocity (E), cm/s, mean (SD) | 74.53 cm/s STANDARD_DEVIATION 24.75 | 85.73 cm/s STANDARD_DEVIATION 7.04 | 77.33 cm/s STANDARD_DEVIATION 21.91 |
| New York Heart Association Heart failure classification (NYHA Class) n (%) Class II | 8 Participants | 2 Participants | 10 Participants |
| New York Heart Association Heart failure classification (NYHA Class) n (%) Class III | 1 Participants | 1 Participants | 2 Participants |
| N-terminal pro-brain natriuretic peptide (NT-proBNP), pg/ml, mean (SD) | 108.3 pg/ml STANDARD_DEVIATION 94.7 | 119 pg/ml STANDARD_DEVIATION 87 | 111 pg/ml STANDARD_DEVIATION 89 |
| Number of Hypertensive Participants, n(%) | 9 Participants | 3 Participants | 12 Participants |
| Number of Obese Participants, n(%) | 5 Participants | 3 Participants | 8 Participants |
| Number of Participants onACEI/ARB, n (%) | 7 Participants | 2 Participants | 9 Participants |
| Number of Participants on Beta-blockers, n (%) | 7 Participants | 2 Participants | 9 Participants |
| Number of Participants on Calcium-channel blockers, n (%) | 3 Participants | 1 Participants | 4 Participants |
| Number of Participants on Loop diuretics, n (%) | 7 Participants | 2 Participants | 9 Participants |
| Number of Participants on Mineralocorticoid receptor antagonists, n (%) | 2 Participants | 1 Participants | 3 Participants |
| Number of Participants on Statin, n (%) | 5 Participants | 2 Participants | 7 Participants |
| Number of Participants on Thiazide diuretic, n (%) | 3 Participants | 1 Participants | 4 Participants |
| Number of Participants with Coronary Artery Disease, n (%) | 3 Participants | 1 Participants | 4 Participants |
| Number of Participants with Current Continuous Positive Airway Pressure (CPAP) use, n (%) | 2 Participants | 3 Participants | 5 Participants |
| Number of Participants with Diabetes Mellitus, n (%) | 5 Participants | 2 Participants | 7 Participants |
| Number of Participants with high N-terminal pro-brain natriuretic peptide (NT-proBNP), pg/ml, n (%) | 3 Participants | 2 Participants | 5 Participants |
| Number of Participants with History of atrial fibrillation, n (%) | 0 Participants | 1 Participants | 1 Participants |
| Number of Participants with Hyperlipidemia, n (%) | 7 Participants | 3 Participants | 10 Participants |
| Number of Participants with Obstructive lung disease, n (%) | 2 Participants | 1 Participants | 3 Participants |
| Number of Participants with Obstructive sleep apnea, n (%) | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Race, n (%) Black | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Race, n (%) Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race, n (%) White | 5 Participants | 3 Participants | 8 Participants |
| Relative wall thickness, mean (SD) | 0.47 ratio STANDARD_DEVIATION 0.09 | 0.46 ratio STANDARD_DEVIATION 0.09 | 0.47 ratio STANDARD_DEVIATION 0.09 |
| Septal E/e' ratio, mean (SD) | 10.70 ratio STANDARD_DEVIATION 3.76 | 9.60 ratio STANDARD_DEVIATION 2.39 | 10.42 ratio STANDARD_DEVIATION 3.4 |
| Septal tissue doppler early velocity (e'), mm/s, mean (SD) | 70.64 mm/s STANDARD_DEVIATION 12.45 | 93.71 mm/s STANDARD_DEVIATION 28.65 | 76.41 mm/s STANDARD_DEVIATION 19.26 |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 3 |
| other Total, other adverse events | 5 / 9 | 1 / 3 |
| serious Total, serious adverse events | 0 / 9 | 0 / 3 |
Outcome results
Primary
Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose
Peak oxygen uptake (VO2) defined as the average value obtained during the last 30 seconds of exercise.
Time frame: Baseline, end of week 1, end of week 2
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Randomized to KNO3 | Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose | Baseline Viist | 1.16 L/min |
| Randomized to KNO3 | Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose | End of week 1 visit | 1.20 L/min |
| Randomized to KNO3 | Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose | End of week 2 visit | 1.20 L/min |
| Randomized to KCl | Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose | Baseline Viist | 1.49 L/min |
| Randomized to KCl | Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose | End of week 1 visit | 1.44 L/min |
| Randomized to KCl | Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose | End of week 2 visit | 1.44 L/min |
Secondary
Change in Aortic Augmentation Index
Percent change in augmentation index, whereas augmentation index at each time point (visit) is defined as the amplitude of the second peak to the first peak of the aortic pulse wave form multiplied by 100: augmentation index = (P2/P1)×100.
Time frame: Baseline, end of week 1, end of week 2
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Randomized to KNO3 | Change in Aortic Augmentation Index | Baseline visit | 3.0 Percent change in augumentation index |
| Randomized to KNO3 | Change in Aortic Augmentation Index | End of week 1 visit | -5.4 Percent change in augumentation index |
| Randomized to KNO3 | Change in Aortic Augmentation Index | End of week 2 visit | -7.1 Percent change in augumentation index |
| Randomized to KCl | Change in Aortic Augmentation Index | Baseline visit | -2.3 Percent change in augumentation index |
| Randomized to KCl | Change in Aortic Augmentation Index | End of week 1 visit | -11.9 Percent change in augumentation index |
| Randomized to KCl | Change in Aortic Augmentation Index | End of week 2 visit | -0.2 Percent change in augumentation index |
Secondary
Change in Mitochondrial Oxidative Capacity for Each Dose
Percent change in oxidative capacity (oxyhemoglobin levels) before and after occlusion
Time frame: Baseline, end of week 1, end of week 2
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Randomized to KNO3 | Change in Mitochondrial Oxidative Capacity for Each Dose | Baseline | 63.2 Percent change in oxidative capacity |
| Randomized to KNO3 | Change in Mitochondrial Oxidative Capacity for Each Dose | End of Week 2 visit | 62.2 Percent change in oxidative capacity |
| Randomized to KNO3 | Change in Mitochondrial Oxidative Capacity for Each Dose | End of week 1 visit | 59.2 Percent change in oxidative capacity |
| Randomized to KCl | Change in Mitochondrial Oxidative Capacity for Each Dose | End of week 1 visit | 110.4 Percent change in oxidative capacity |
| Randomized to KCl | Change in Mitochondrial Oxidative Capacity for Each Dose | End of Week 2 visit | 45.4 Percent change in oxidative capacity |
| Randomized to KCl | Change in Mitochondrial Oxidative Capacity for Each Dose | Baseline | 106.5 Percent change in oxidative capacity |
Secondary
Change in Vasodilatory Reserve for Each Dose
Percent change in peak vascular resistance from rest to peak exercise
Time frame: Baseline, end of week 1, end of week 2
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Randomized to KNO3 | Change in Vasodilatory Reserve for Each Dose | Baseline | -25.6 %change in peak vascular resistance |
| Randomized to KNO3 | Change in Vasodilatory Reserve for Each Dose | End of week 1 visit | -27.1 %change in peak vascular resistance |
| Randomized to KNO3 | Change in Vasodilatory Reserve for Each Dose | End of week 2 visit | -34.2 %change in peak vascular resistance |
| Randomized to KCl | Change in Vasodilatory Reserve for Each Dose | Baseline | -25.8 %change in peak vascular resistance |
| Randomized to KCl | Change in Vasodilatory Reserve for Each Dose | End of week 1 visit | -30.6 %change in peak vascular resistance |
| Randomized to KCl | Change in Vasodilatory Reserve for Each Dose | End of week 2 visit | -20.0 %change in peak vascular resistance |