Potassium Nitrate for HFpEF Lacks Benefit for Exercise Capacity, Quality of Life

Chronic administration of potassium nitrate (KNO3) led to no improvements in exercise capacity or quality of life, compared with potassium chloride (KCl), for patients with heart failure with preserved ejection fraction (HFpEF), according to new research.1

The multicenter randomized double-blinded crossover trial, conducted between October 2016 and July 2022, found no rise in peak oxygen uptake or total work performed after potassium nitrate administration, and no additional effect on quality of life while remaining well tolerated.

“Contrary to our hypothesis, [potassium nitrate] did not improve these endpoints,” wrote the investigative team, led by Julio A. Chirinos, MD, PhD, Perelman Center for Advanced Medicine, University of Pennsylvania. “Prespecified secondary endpoints, including quality of life, the vasodilatory reserve, and metrics of arterial pulsatile load (eg, wave reflections), were also not impacted by [potasisum nitrate].”

Populations with HFpEF have reported impaired nitric oxide (NO) signaling, but efforts to restore bioavailability through organic nitrate supplementation are typically unsuccessful in benefiting exercise capacity.2 Inorganic nitrate supplementation can potentially benefit NO signaling and augment exercise skeletal muscle oxygen delivery.

Short-term data have demonstrated the potential for exercise capacity improvement after inorganic nitrate supplementation in HFpEF, but the impact of chronic use on the condition is still not well understood.3 Chirinos and colleagues designed an assessment of the effect of chronic inorganic nitrate administration on exercise tolerance and quality of life in the KNO3 Compared to KCl on Oxygen UpTake in Heart Failure with Preserved Ejection Fraction (KNO3CK OUT HFpEF) trial.1

Conducted at the University of Pennsylvania, the Philadelphia Veterans Affairs Medical Center, and Northwestern University, between October 2016 and July 2022, participants with symptomatic (New York Heart Association [NYHA] Class II/III) HFpEF and a left ventricular ejection fraction (LVEF) ≥50% were included for analysis.

The enrolled study population (n = 84) received potassium nitrate (6 mmol 3 times daily) or equimolar doses of potassium chloride for 6 weeks, with a 1-week washout in between each dose. Co-primary endpoints were peak oxygen uptake and total work performed, followed by secondary endpoints, including the exercise systemic vasodilatory reserve and quality of life by the Kansas City Cardiomyopathy Questionnaire.

Participants had a mean age of 68 years, 69% were female, 31% were male, 24% were African American, and 76% were White. All participants were obese and had a high prevalence of hypertension, diabetes, and obstructive sleep apnea.

Upon analysis, after 6 weeks of potassium nitrate administration, fasted premedication nitric oxide metabolite levels were 418.44 µm, compared with 40.11 µm after the potassium chloride intervention (P <.001). Participants achieved a peak respiratory exchange ratio of 1.09, but inorganic nitrate did not improve peak oxygen capacity (KNO3, 10.23 mL/kg/min vs. KCI, 10.17 mL/kg/min; P = .73) or total work performed (KNO3, 25.9 kJ vs. KCI, 23.63; P = .29).

Notability, the quality of life in patients with HFpEF was not altered or improved by potassium nitrate according to the Kansas City Cardiomyopathy Questionnaire Overall Summary Score. The left ventricular end-systolic volume was lower after potassium nitrate, with the LVEF slightly higher (KNO3, 61.6 vs. KCI, 60.9; P = .07).

Data on resting and exercise hemodynamics revealed resting and orthostatic blood pressure were not different between phases and potassium nitrate did not change any metrics of pulsatile arterial load. Notably, the vasodilatory reserve was unaffected by potassium nitrate, but the mean arterial pressure at peak exercise was lower (KNO3, 122.5 mmHg vs. KCl, 127.6 mmHg; P = .04).

Overall, safety data found no significant differences in kidney function, potassium, or methemoglobin levels between potassium nitrate and potassium chloride interventions, with gastrointestinal adverse effects occurring most commonly.

Chirinos and colleagues noted these neutral findings could be due to abnormalities in oxygen transport in a patient with HFpEF, citing the pleiotropic effects of aerobic exercise training in improving capacity. In addition, the team noted the potential difference between chronic vs. short-term neutralizing the effect of inorganic nitrate administration.

“Multiple abnormalities in oxygen transport may coexist within a single patient with HFpEF, suggesting that several interventions targeting multiple abnormalities may need to be administered concurrently to improve exercise capacity,” they wrote. “...Indeed, the lack of efficacy of chronically administered inorganic nitrite, despite positive physiologic effects of single-dose administration, suggests that counterregulatory adaptations may neutralize the benefits of inorganic nitrate/nitrite with chronic administration in patients with HFpEF.”

References

1. Zamani P, Shah SJ, Cohen JB, et al. Potassium Nitrate in Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial. JAMA Cardiol. Published online December 18, 2024. doi:10.1001/jamacardio.2024.4417
2. 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
3. Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2015;373(24):2314-2324. doi:10.1056/NEJMoa1510774