This study assesses the impact of chronic inorganic nitrate administration on exercise tolerance in a larger trial of participants with heart failure with preserved ejection fraction.
Key Points
Question
Does chronic inorganic nitrate supplementation improve exercise capacity and quality of life in patients with heart failure with preserved ejection fraction (HFpEF)?
Findings
In this randomized clinical trial, potassium nitrate (KNO3) elevated blood nitric oxide metabolites; however, KNO3 did not improve exercise tolerance or quality of life.
Meaning
These results do not support the use of KNO3 in patients with HFpEF.
Abstract
Importance
Nitric oxide deficiency may contribute to exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF). Prior pilot studies have shown improvements in exercise tolerance with single-dose and short-term inorganic nitrate administration.
Objective
To assess the impact of chronic inorganic nitrate administration on exercise tolerance in a larger trial of participants with HFpEF.
Design, Setting, and Participants
This multicenter randomized double-blinded crossover trial was conducted at the University of Pennsylvania, the Philadelphia Veterans Affairs Medical Center, and Northwestern University between October 2016 and July 2022. Participants included patients with symptomatic (New York Heart Association class II/III) HFpEF who had objective signs of elevated left ventricular filling pressures. Image quantification, physiological data modeling and biochemical measurements, unblinding, and statistical analyses were completed in 2024.
Intervention
Potassium nitrate (KNO3) (6 mmol 3 times daily) vs equimolar doses of potassium chloride (KCl) for 6 weeks, each with a 1-week washout in between.
MAIN OUTCOMES AND MEASURES
The coprimary end points included peak oxygen uptake and total work performed during a maximal effort incremental cardiopulmonary exercise test. Secondary end points included the exercise systemic vasodilatory reserve (ie, reduction in systemic vascular resistance with exercise) and quality of life assessed using the Kansas City Cardiomyopathy Questionnaire.
Results
Eighty-four participants were enrolled. Median age was 68 years and 58 participants were women (69.0%). Most participants had NYHA class II disease (69%) with a mean 6-minute walk distance of 335.5 (SD, 97.3) m. Seventy-seven participants received the KNO3 intervention and 74 received the KCl intervention. KNO3 increased trough levels of serum nitric oxide metabolites after 6 weeks (KNO3, 418.4 [SD, 26.9] uM vs KCl, 40.1 [SD, 28.3] uM; P < .001). KNO3 did not improve peak oxygen uptake (KNO3, 10.23 [SD, 0.43] mL/min/kg vs KCl, 10.17 [SD, 0.43] mL/min/kg; P = .73) or total work performed (KNO3, 25.9 [SD, 3.65] kilojoules vs KCl, 23.63 [SD, 3.63] kilojoules; P = .29). KNO3 nitrate did not improve the vasodilatory reserve or quality of life, though it was well-tolerated.
Conclusions and Relevance
In this study, potassium nitrate did not improve aerobic capacity, total work, or quality of life in participants with HFpEF.
Trial Registration
ClinicalTrials.gov Identifier: NCT02840799
Introduction
Impaired nitric oxide (NO) signaling has been described in patients with heart failure with preserved ejection fraction (HFpEF).1 However, efforts at restoring NO bioavailability through organic nitrate supplementation,2 phosphodiesterase type 5 inhibition,3 or stimulation of the soluble guanylate-cyclase receptor have been unsuccessful at improving exercise capacity in this condition.4,5 Alternatively, NO signaling can be increased via inorganic nitrate supplementation. In this complementary pathway, inorganic nitrate is absorbed and subsequently reduced to nitrite by oral commensal bacteria through an enterosalivary circuit. Nitrite is then selectively reduced to NO, preferentially within the context of acidosis and hypoxia, potentially augmenting exercise skeletal muscle oxygen delivery.6 While small short-term trials have demonstrated an improvement in exercise capacity following inorganic nitrate supplementation in patients with HFpEF,7,8,9 the impact of chronic inorganic nitrate supplementation in this condition remains unknown.
Methods
The KNO3 Compared to KCl on Oxygen UpTake in Heart Failure with Preserved Ejection Fraction (KNO3CK OUT HFpEF) trial was designed to test the impact of chronic potassium nitrate (KNO3) on exercise capacity and quality of life in participants with HFpEF. This was a randomized, double-blinded crossover trial of inorganic nitrate, given as KNO3 6 mmol vs potassium chloride (KCl) 6 mmol 3 times daily. Each interventional phase lasted approximately 6 weeks with a 1-week washout period in between. Participants provided written informed consent prior to participation. The institutional review boards at the respective sites approved the protocol and it was registered at ClinicalTrials.gov (NCT02840799). See Supplement 1 for expanded eMethods.
Inclusion and Exclusion Criteria
Participants had symptomatic HFpEF, a left ventricular ejection fraction (LVEF) more than 50%, and evidence of elevated intracardiac filling pressures. Exclusion criteria included a prior reduced ejection fraction (less than 45%) or alternative causes of exertional intolerance (eg, significant pulmonary or valvular disease).
End Point Assessment
A maximal effort incremental supine cycle ergometer cardiopulmonary exercise test was performed at the end of each interventional phase. The trial’s coprimary end points were the difference in peak oxygen consumption (VO2) and total work performed during the exercise test following KNO3 vs KCl. Secondary end points included quality of life (Kansas City Cardiomyopathy Questionnaire), the exercise systemic vasodilatory reserve, echocardiographic left ventricular systolic and diastolic function, and parameters of pulsatile arterial load. In a subgroup of participants, additional magnetic resonance imaging (MRI) of the lower extremity before and after plantar flexion exercise was performed to explore the effect of KNO3 on skeletal muscle oxidative phosphorylation (SkM OxPhos) capacity.
Exercise Protocol
Participants underwent a maximal effort supine cycle ergometry exercise test with expired gas analysis and exercise echocardiography.7,8,10,11 VO2 consumption and other gas exchange measurements were defined as the average value obtained during the last 30 seconds of exercise.
Creatine Chemical Exchange Saturation Transfer
A subset of participants underwent the MRI assessment of SkM OxPhos at the end of each phase.11 The creatine chemical exchange-saturation transfer protocol estimates intramuscular free creatine generated during exercise by the donation of a high-energy phosphate from phosphocreatine to adenosine diphosphate, yielding free creatine and adenosine triphosphate. During recovery, mitochondria replenish phosphocreatine stores by generating adenosine triphosphate through oxidative phosphorylation, lowering free creatine. Therefore, the half time of creatine recovery is an index of SkM OxPhos.11
Statistical Design
The coprimary exercise end points were peak VO2 (mL/min/kg) and total work performed (kilojoules [kJ]). Linear mixed-effects models assessed treatment effects while controlling for effects of other covariates, such as period, sequence, and a participant-level random-effect term. Least square (LS) means and the standard error from the models are presented in the Tables. Statistical tests with a 2-sided P value <.05 were considered statistically significant. Data were analyzed using SAS version 9.4 (SAS Institute) and R software version 4.3.2 (R Project).
Results
Between October 2016 and July 2022, a total of 84 participants were enrolled in this study (Table 1; eFigure 1 in Supplement 1). The median age of study participants was 68 years, 69% were female, 31% were male, 24% were African American, and 76% were White. Participants were obese with high prevalence of hypertension, diabetes, and obstructive sleep apnea.
Table 1. Demographic and Baseline Characteristics by Randomization Groups.
| Parameters | No. (%) | ||
|---|---|---|---|
| Overall (n = 84) | KNO3 first (n = 41) | KCl first (n = 43) | |
| Age, y, median (IQR) | 68.0 (63.0-76.0) | 68.0 (64.0-76.0) | 69 (60.0-75.5) |
| Sex | |||
| Female | 58 (69.0) | 29 (70.7) | 29 (67.4) |
| Male | 26 (31.0) | 12 (29.3) | 14 (32.6) |
| Racea | |||
| African American | 20 (23.8) | 9 (22.0) | 11 (25.6) |
| White | 64 (76.2) | 32 (78.0) | 32 (74.4) |
| Height, cm, mean (SD) | 166.23 (9.52) | 167.06 (9.83) | 165.43 (9.26) |
| Weight, kg, mean (SD) | 99.92 (22.13) | 98.32 (22.76) | 101.46 (21.67) |
| BMI,b mean (SD) | 36.22 (7.88) | 35.26 (7.89) | 37.13 (7.86) |
| Hypertension | 72 (85.7) | 36 (87.8) | 36 (83.7) |
| Diabetes | 38 (45.2) | 17 (41.5) | 21 (48.8) |
| Insulin use | 13 (15.5) | 5 (12.2) | 8 (18.6) |
| Hyperlipidemia | 60 (71.4) | 27 (65.9) | 33 (76.7) |
| Obstructive sleep apnea | 46 (54.8) | 23 (56.1) | 23 (53.5) |
| CPAP use | 34 (40.5) | 17 (41.5) | 17 (39.5) |
| Any arrythmia | 32 (38.1) | 15 (36.6) | 17 (39.5) |
| β-Blocker | 47 (56.0) | 26 (63.4) | 21 (48.8) |
| Calcium-channel blocker | 30 (35.7) | 15 (36.6) | 15 (34.9) |
| ACEi/ARB | 20 (23.8) | 13 (31.7) | 7 (16.3) |
| ARNI | 1 (1.2) | 1 (2.4) | 0 (0) |
| MRA | 21 (25.0) | 12 (29.3) | 9 (20.9) |
| Loop diuretic | 54 (64.3) | 29 (70.7) | 25 (58.1) |
| Thiazide diuretic | 22 (26.2) | 10 (24.4) | 12 (27.9) |
| Statin | 57 (67.9) | 27 (65.9) | 30 (69.8) |
| SGLT2i | 6 (7.1) | 5 (12.2) | 1 (2.3) |
| NYHA class | |||
| II | 58 (69.0) | 33 (80.5) | 25 (58.1) |
| III | 26 (31.0) | 8 (19.5) | 18 (41.9) |
| eGFR, mL/min/1.73m2, mean (SD) | 68.52 (17.73) | 66.37 (16.63) | 70.56 (18.69) |
| Hemoglobin, g/dL, mean (SD) | 13.29 (1.28) | 13.20 (1.42) | 13.37 (1.15) |
| NTproBNP, g/dL, median (IQR) | 110.50 (50.00-253.75) | 114.00 (62.00-293.00) | 96.00 (48.00-238.00) |
| 6-min Walk distance, m, mean (SD) | 335.53 (97.30) | 338.07 (101.52) | 333.11 (94.25) |
| Medial E/e’ ratio, mean (SD) | 13.62 (5.56) | 13.99 (5.79) | 13.27 (5.39) |
Abbreviations: ACEi, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor/neprilysin inhibitor; BMI, body mass index; CPAP, continuous positive airway pressure; eGFR, epidermal growth factor receptor; KCl, potassium chloride; KNO3, potassium nitrate; MRA, mineralocorticoid receptor antagonists; NTproBNP, N-terminal pro b-type natriuretic peptide; NYHA, New York Heart Association; SGLT2i, sodium-glucose cotransporter-2.
Race was self-reported.
Calculated as weight in kilograms divided by height in meters squared.
Serum Nitric Oxide Metabolite Concentrations
Following 6 weeks of KNO3 administration, fasted premedication nitric oxide metabolite levels were 418.44 (SD, 26.9) μM as compared with 40.11 (SD, 28.3) μM after the KCl intervention (P < .001; eTable 1 in Supplement 1).
Cardiopulmonary Exercise Testing
Participants reached a peak respiratory exchange ratio of 1.09, indicative of exhaustive effort. Contrary to the hypothesis, inorganic nitrate did not improve peak VO2 (KNO3, 10.23 [SD, 0.43] mL/kg/min vs KCl, 10.17 [SD, 0.43] mL/kg/min; P = .73) or total work performed (KNO3, 25.9 [SD, 3.65] kJ vs KCl, 23.63 [SD, 3.63] kJ; P = .29; Table 2, eTable 2 in Supplement 1, and Figure).
Table 2. Effect of Potassium Nitrate (KNO3) on Cardiopulmonary Exercise Testing Metrics.
| End points | LS mean (SE) | Estimated difference between KNO3 and KCl (95% CI) | P value | |
|---|---|---|---|---|
| KNO3 | KCl | |||
| Resting | ||||
| Peak exercise total NOm levels, uM | 534.07 (38.41) | 45.08 (41.36) | 488.99 (375.61-602.38) | <.001 |
| VO2, L/min | 0.28 (0.01) | 0.26 (0.01) | 0.01 (0.00-0.03) | .12 |
| VO2, mL/kg/min | 2.81 (0.08) | 2.71 (0.08) | 0.1 (−0.05 to 0.25) | .17 |
| RER | 0.86 (0.01) | 0.88 (0.01) | −0.01 (−0.04 to 0.02) | .36 |
| Systolic blood pressure, mm Hg | 130.05 (2.1) | 130.21 (2.12) | −0.16 (−4.92 to 4.6) | .95 |
| Diastolic blood pressure, mm Hg | 74.07 (1.16) | 72.58 (1.17) | 1.49 (−0.79 to 3.78) | .20 |
| Mean arterial pressure, mm Hg | 96.43 (1.35) | 95.66 (1.36) | 0.78 (−2.05 to 3.6) | .59 |
| Heart rate, bpm | 70.45 (1.49) | 69.04 (1.47) | 1.41 (−0.78 to 3.59) | .20 |
| Stroke volume, mL | 81.12 (2.12) | 79.51 (2.12) | 1.61 (−1.20 to 4.42) | .26 |
| Cardiac output, L/min | 5.12 (0.14) | 4.94 (0.14) | 0.18 (−0.02 to 0.38) | .08 |
| AVO2 diff, mL O2/dL of blood | 5.55 (0.2) | 5.57 (0.2) | −0.03 (−0.36 to 0.31) | .88 |
| Total peripheral resistance, Wood units | 19.71 (0.62) | 20.57 (0.63) | −0.86 (−2.05 to 0.33) | .15 |
| Ventilatory threshold | ||||
| Ventilatory threshold, L/min | 0.73 (0.02) | 0.75 (0.02) | −0.02 (−0.05 to 0.01) | .22 |
| Ventilatory threshold, mL/min/kg | 7.58 (0.28) | 7.83 (0.28) | −0.24 (−0.55 to 0.07) | .12 |
| Peak exercise | ||||
| Exercise time, min | 8.98 (0.69) | 8.83 (0.69) | 0.15 (−0.51 to 0.81) | .65 |
| VO2, L/min | 0.99 (0.04) | 0.98 (0.04) | 0.01 (−0.03 to 0.05) | .68 |
| VO2, mL/kg/min | 10.23 (0.43) | 10.17 (0.43) | 0.06 (−0.32 to 0.45) | .73 |
| Mean arterial pressure, mm Hg | 122.5 (2.3) | 127.6 (2.28) | −5.10 (−10.00 to −0.20) | .04 |
| Work rate, watts | 62.43 (5.5) | 60.33 (5.49) | 2.11 (−3.05 to 7.26) | .42 |
| Total work performed, kJ | 25.9 (3.65) | 23.63 (3.63) | 2.27 (−1.98 to 6.51) | .29 |
| Net efficiency: total work performed/total oxygen consumed during exercise, kJ/L O2 | 4.14 (0.28) | 3.84 (0.28) | 0.30 (−0.32 to 0.92) | .33 |
| RER | 1.09 (0.02) | 1.09 (0.02) | 0.00 (−0.03 to 0.02) | .78 |
| Systolic blood pressure, mm Hg | 182.47 (4.01) | 189.64 (3.98) | −7.17 (−15.92 to 1.57) | .11 |
| Diastolic blood pressure, mm Hg | 82.5 (2.11) | 86.23 (2.09) | −3.73 (−8.20 to 0.74) | .10 |
| Heart rate, bpm | 115.9 (2.88) | 114.24 (2.85) | 1.66 (−1.73 to 5.05) | .33 |
| Stroke volume, mL | 82.71 (2.39) | 83.46 (2.36) | −0.75 (−4.46 to 2.96) | .69 |
| Cardiac output, L/min | 8.93 (0.3) | 8.81 (0.29) | 0.12 (−0.37 to 0.61) | .62 |
| AVO2 difference, mL O2/dL of blood | 11.6 (0.49) | 11.73 (0.48) | −0.13 (−0.85 to 0.58) | .71 |
| Total peripheral resistance, Wood units | 15.14 (0.68) | 15.64 (0.67) | −0.50 (−1.50 to 0.49) | .31 |
| VE/VCO2 slope | 31.36 (0.99) | 31.87 (0.99) | −0.51 (−2.28 to 1.27) | .56 |
| Vasodilatory reserve, % | −23.11 (3.3) | −22.02 (3.18) | −1.09 (−9.5 to 7.32) | .80 |
| Change in CO/VO2 | 5.71 (0.45) | 5.95 (0.43) | −0.24 (−1.15 to 0.67) | .60 |
Abbreviations: AVO2, arteriovenous oxygen; CO, carbon dioxide production; KCl, potassium chloride; kJ, kilojoules; LS, least squares; NOm, nitric oxide metabolite; O2, oxygen; RER, respiratory exchange ratio; SE, standard error; VE/VCO2, ventilation to carbon dioxide production ratio; VO2, peak oxygen consumption.
Figure. Effect of Potassium Nitrate (KNO3) on the Coprimary End Points: Peak Oxygen Consumption (VO2) and Total Work Performed During a Maximal Effort Incremental Cardiopulmonary Exercise Test.
KCl indicates potassium chloride; kJ, kilojoule; O2, oxygen.
Quality of Life
The Kansas City Cardiomyopathy Questionnaire Overall Summary Score was not altered by KNO3 (eTable 3 in Supplement 1).
Resting Echocardiography
The left ventricular end-systolic volume was lower after KNO3 and the end-diastolic volume tended to be lower (eTable 4 in Supplement 1). Accordingly, LVEF tended to be slightly higher following KNO3 (KNO3, 61.6 [SD, 0.5%] vs KCl, 60.9 [SD, 0.5%]; P = .07).
Resting and Exercise Hemodynamics
Neither resting nor orthostatic blood pressure were different between phases (eTable 5 in Supplement 1). In general, KNO3 did not alter metrics of pulsatile arterial load (eTable 6 in Supplement 1). The vasodilatory reserve was unaffected by KNO3; however, the mean arterial pressure at peak exercise was lower (KNO3, 122.5 [SD, 2.3] mm Hg vs KCl, 127.6 [SD, 2.3] mm Hg; P = .04).
MRI Substudy: SkM OxPhos
KNO3 did not alter SkM OxPhos on MRI results (n = 18; eTable 7 in Supplement 1).
Tolerability of KNO3 and Adverse Effects
There were no significant differences in kidney function, potassium, or methemoglobin levels between interventions (eTable 1 in Supplement 1). Adverse events were generally minor, with gastrointestinal adverse effects occurring most commonly (eTable 8 and eTable 9 in Supplement 1).
Prespecified Exploratory Subgroups
The study team investigated whether KNO3 exerted differential effects by sex, self-reported African-American vs White race, diabetes status, hemoglobin less than 13.3 g/dL, and calcium channel blocker use. No evidence for heterogeneity, with respect to the coprimary end points, in any subgroup was found (eFigure 2 in Supplement 1).
Discussion
In this double-blinded, crossover randomized clinical trial, we tested whether KNO3, as compared with KCl, improved peak VO2 and total work performed among participants with HFpEF. Contrary to our hypothesis, KNO3 did not improve these end points. Prespecified secondary end points, including quality of life, the vasodilatory reserve, and metrics of arterial pulsatile load (eg, wave reflections), were also not impacted by KNO3.
Limitations
Several explanations for these neutral findings exist. Multiple abnormalities in oxygen transport may coexist within a single patient with HFpEF,12 suggesting that several interventions targeting multiple abnormalities may need to be administered concurrently to improve exercise capacity. Perhaps this explains why aerobic exercise training, and its pleiotropic effects, is the only known intervention to date that consistently improves exercise capacity in patients with HFpEF.13 Second, compensatory mechanisms may have been activated by chronic inorganic nitrate administration, neutralizing any potential short-term benefits. Indeed, the lack of efficacy of chronically administered inorganic nitrite,14 despite positive physiologic effects of single-dose administration,15 suggests that counterregulatory adaptations may neutralize the benefits of inorganic nitrate/nitrite with chronic administration in patients with HFpEF. However, we note that chronic administration of both inorganic nitrate (in this study) and inorganic nitrite (prior work) lowered exercise blood pressure, suggesting that some biologic effects persist.14
Conclusions
In this randomized crossover trial, chronic KNO3 administration did not improve exercise capacity or quality of life, as compared with KCl among participants with HFpEF.
eMethods. Expanded eMethods
eResults. Expanded eResults
eFigure 1. CONSORT Diagram
eFigure 2. Effect of KNO3 on peak VO2 (A), total work performed (B) and KCCQ overall summary score (C) in pre-specified subgroups
eTable 1. Trough, Post Drug, and Peak Exercise NO Metabolite Levels, and Safety Lab Information
eTable 2. Effect of KNO3 on key trial endpoints calculated based on data from participants who underwent both treatments (KCl and KNO3)
eTable 3. Effect of KNO3 on KCCQ Quality of Life
eTable 4. Effect of KNO3 on Resting Echocardiographic Endpoints
eTable 5. Orthostatic blood pressure measurements 3-minutes after standing
eTable 6. Effect of KNO3 on Arterial Hemodynamics and Late Systolic LV Wall Stress
eTable 7. Effect of KNO3 on CrCEST MRI Skeletal Muscle Oxidative Phosphorylation Capacity (n=18)
eTable 8. Adverse Events
eTable 9. Adverse Events classified by organ system
eTable 10. Comparison of the KNO3CK-OUT Enrolled Participants with Other HFpEF Trials that Utilized Exercise Endpoints
eReferences
Study protocol
Data sharing statement
References
- 1.Paulus WJ, Zile MR. From systemic inflammation to myocardial fibrosis: the heart failure with preserved ejection fraction paradigm revisited. Circ Res. 2021;128(10):1451-1467. doi: 10.1161/CIRCRESAHA.121.318159 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Redfield MM, Anstrom KJ, Levine JA, et al. ; NHLBI Heart Failure Clinical Research Network . Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med. 2015;373(24):2314-2324. doi: 10.1056/NEJMoa1510774 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Redfield MM, Chen HH, Borlaug BA, et al. ; RELAX Trial . Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309(12):1268-1277. doi: 10.1001/jama.2013.2024 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Armstrong PW, Lam CSP, Anstrom KJ, et al. ; VITALITY-HFpEF Study Group . Effect of vericiguat vs placebo on quality of life in patients with heart failure and preserved ejection fraction: the VITALITY-HFpEF randomized clinical trial. JAMA. 2020;324(15):1512-1521. doi: 10.1001/jama.2020.15922 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Udelson JE, Lewis GD, Shah SJ, et al. Effect of praliciguat on peak rate of oxygen consumption in patients with heart failure with preserved ejection fraction: the CAPACITY HFpEF randomized clinical trial. JAMA. 2020;324(15):1522-1531. doi: 10.1001/jama.2020.16641 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Cosby K, Partovi KS, Crawford JH, et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. 2003;9(12):1498-1505. doi: 10.1038/nm954 [DOI] [PubMed] [Google Scholar]
- 7.Zamani P, Rawat D, Shiva-Kumar P, et al. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation. 2015;131(4):371-380. doi: 10.1161/CIRCULATIONAHA.114.012957 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Zamani P, Tan V, Soto-Calderon H, et al. Pharmacokinetics and pharmacodynamics of inorganic nitrate in heart failure with preserved ejection fraction. Circ Res. 2017;120(7):1151-1161. doi: 10.1161/CIRCRESAHA.116.309832 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Eggebeen J, Kim-Shapiro DB, Haykowsky M, et al. One week of daily dosing with beetroot juice improves submaximal endurance and blood pressure in older patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2016;4(6):428-437. doi: 10.1016/j.jchf.2015.12.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Zamani P, Proto EA, Mazurek JA, et al. Peripheral determinants of oxygen utilization in heart failure with preserved ejection fraction: central role of adiposity. JACC Basic Transl Sci. 2020;5(3):211-225. doi: 10.1016/j.jacbts.2020.01.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Zamani P, Proto EA, Wilson N, et al. Multimodality assessment of heart failure with preserved ejection fraction skeletal muscle reveals differences in the machinery of energy fuel metabolism. ESC Heart Fail. 2021;8(4):2698-2712. doi: 10.1002/ehf2.13329 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Houstis NE, Eisman AS, Pappagianopoulos PP, et al. Exercise intolerance in heart failure with preserved ejection fraction: diagnosing and ranking its causes using personalized O2 pathway analysis. Circulation. 2018;137(2):148-161. doi: 10.1161/CIRCULATIONAHA.117.029058 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Sachdev V, Sharma K, Keteyian SJ, et al. ; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and American College of Cardiology . Supervised exercise training for chronic heart failure with preserved ejection fraction: a scientific statement from the American Heart Association and American College of Cardiology. Circulation. 2023;147(16):e699-e715. doi: 10.1161/CIR.0000000000001122 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Borlaug BA, Anstrom KJ, Lewis GD, et al. ; National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network . Effect of inorganic nitrite vs placebo on exercise capacity among patients with heart failure with preserved ejection fraction: the INDIE-HFpEF randomized clinical trial. JAMA. 2018;320(17):1764-1773. doi: 10.1001/jama.2018.14852 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Borlaug BA, Melenovsky V, Koepp KE. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction. Circ Res. 2016;119(7):880-886. doi: 10.1161/CIRCRESAHA.116.309184 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods. Expanded eMethods
eResults. Expanded eResults
eFigure 1. CONSORT Diagram
eFigure 2. Effect of KNO3 on peak VO2 (A), total work performed (B) and KCCQ overall summary score (C) in pre-specified subgroups
eTable 1. Trough, Post Drug, and Peak Exercise NO Metabolite Levels, and Safety Lab Information
eTable 2. Effect of KNO3 on key trial endpoints calculated based on data from participants who underwent both treatments (KCl and KNO3)
eTable 3. Effect of KNO3 on KCCQ Quality of Life
eTable 4. Effect of KNO3 on Resting Echocardiographic Endpoints
eTable 5. Orthostatic blood pressure measurements 3-minutes after standing
eTable 6. Effect of KNO3 on Arterial Hemodynamics and Late Systolic LV Wall Stress
eTable 7. Effect of KNO3 on CrCEST MRI Skeletal Muscle Oxidative Phosphorylation Capacity (n=18)
eTable 8. Adverse Events
eTable 9. Adverse Events classified by organ system
eTable 10. Comparison of the KNO3CK-OUT Enrolled Participants with Other HFpEF Trials that Utilized Exercise Endpoints
eReferences
Study protocol
Data sharing statement
