Pharmacokinetics and Pharmacodynamics of Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction

Abstract

Rationale Nitrate-rich beetroot juice has been shown to improve exercise capacity in Heart Failure with Preserved Ejection Fraction (HFpEF), but studies using pharmacologic preparations of inorganic nitrate are lacking. Objectives To determine: (1) the dose-response effect of potassium nitrate (KNO3) on exercise capacity; (2) the population-specific pharmacokinetic and safety profile of KNO3 in HFpEF. Methods and Results We randomized 12 subjects with HFpEF to oral KNO3 (n=9) or potassium chloride (KCl, n=3). Subjects received 6mmol twice-daily during Week-1, followed by 6mmol thrice-daily during Week-2. Supine cycle ergometry was performed at baseline (Visit 1) and after each week (Visits 2&3). Quality of life (QOL) was assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ). The primary efficacy outcome, peak O2-uptake, did not significantly improve (P=0.13). Exploratory outcomes included exercise duration and quality of life. Exercise duration increased significantly with KNO3 (Visit 1: 9.87 [95%CI=9.31–10.43]; Visit 2: 10.73 [95%CI=10.13–11.33]; Visit 3: 11.61 [95%CI=11.05–12.17] minutes, P=0.002). Improvements in the KCCQ total symptom (Visit 1: 58.0 [95%CI=52.5–63.5], Visit 2: 66.8 [95%CI=61.3–72.3]; Visit 3: 70.8 [95%CI=65.3–76.3], P=0.016) and functional status scores (Visit 1: 62.2 [95%CI=58.5–66.0], Visit 2: 68.6 [95%CI=64.9–72.3], Visit 3: 71.1 [95%CI=67.3–74.8]; P=0.01) were seen after KNO3. Pronounced elevations in trough levels of nitric oxide metabolites (NOm) occurred with KNO3 (Visit 2: 199.5 [95%CI=98.7–300.2]; Visit 3: 471.8 [95%CI=377.8–565.8]) versus baseline (Visit 1: 38.0 [95%CI=0.00–132.0] μM; P<0.001). KNO3 did not lead to clinically-significant hypotension or methemoglobinemia. Following 6 mmol of KNO3, systolic blood pressure was reduced by a maximum of 17.9 (95%CI −28.3-[−7.6]) mmHg 3.75 hours later. Peak NOm concentrations were 259.3 (95%CI 176.2–342.4) μM 3.5 hours after ingestion, and the median half-life was 73.0 (IQR 33.4–232.0) minutes. Conclusions KNO3 is potentially well-tolerated and improves exercise duration and QOL in HFpEF. This study reinforces the efficacy of KNO3 and suggests that larger randomized trials are warranted. ClinicalTrials.gov NCT02256345; https://www.clinicaltrials.gov/ct2/show/NCT02256345

Deep Phenotyping of Systemic Arterial Hemodynamics in HFpEF (Part 2): Clinical and Therapeutic Considerations

“…In both trials, organic nitrates were poorly tolerated. This is in sharp contrast with available studies which consistently suggest a favorable effect of inorganic nitrate/nitrite on exercise capacity or various hemodynamic parameters [100–102, 110 –114]. …”

INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction)

“…53 Orally administered inorganic nitrate, which is converted to active molecule nitrite, has been shown to improve exercise duration and systemic vascular function when administered as a single dose or with repeated doses over 1-2 weeks in patients with HFpEF. 54-56 …”

Impaired skeletal muscle performance as a consequence of random functional capillary rarefaction can be restored with overload‐dependent angiogenesis

“…Future benefits of deciphering this relationship may include modifying existing treatments (Zamani et al 2017) to recover impaired exercise tolerance in microvascular disease. We therefore studied how muscle function and blood flow were affected by acute and chronic reductions in the number of functional (perfused) capillaries, and how the angiogenic response to mechanical overload (Degens et al 1992;Zhou et al 1998;Egginton et al 2011;Ballak et al 2016) was affected by an underlying constrained microcirculation in otherwise healthy tissue.…”