Payman Zamani

Rationale:: Nitrate-rich beetroot juice has been shown to improve exercise capacity in heart failure with preserved ejection fraction, but studies using pharmacological preparations of inorganic nitrate are lacking. Objectives:: To determine (1) the dose–response effect of potassium nitrate (KNO ₃ ) on exercise capacity; (2) the population-specific pharmacokinetic and safety profile of KNO ₃ in heart failure with preserved ejection fraction. Methods and Results:: We randomized 12 subjects with heart failure with preserved ejection fraction to oral KNO ₃ (n=9) or potassium chloride (n=3). Subjects received 6 mmol twice daily during week 1, followed by 6 mmol thrice daily during week 2. Supine cycle ergometry was performed at baseline (visit 1) and after each week (visits 2 and 3). Quality of life was assessed with the Kansas City Cardiomyopathy Questionnaire. The primary efficacy outcome, peak O ₂ -uptake, did not significantly improve ( P =0.13). Exploratory outcomes included exercise duration and quality of life. Exercise duration increased significantly with KNO ₃ (visit 1: 9.87, 95% confidence interval [CI] 9.31–10.43 minutes; visit 2: 10.73, 95% CI 10.13–11.33 minute; visit 3: 11.61, 95% CI 11.05–12.17 minutes; P =0.002). Improvements in the Kansas City Cardiomyopathy Questionnaire 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 KNO ₃ . Pronounced elevations in trough levels of nitric oxide metabolites occurred with KNO ₃ (visit 2: 199.5, 95% CI 98.7–300.2 μmol/L; visit 3: 471.8, 95% CI 377.8–565.8 μmol/L) versus baseline (visit 1: 38.0, 95% CI 0.00–132.0 μmol/L; P 3 did not lead to clinically significant hypotension or methemoglobinemia. After 6 mmol of KNO ₃ , systolic blood pressure was reduced by a maximum of 17.9 (95% CI −28.3 to −7.6) mm Hg 3.75 hours later. Peak nitric oxide metabolites concentrations were 259.3 (95% CI 176.2–342.4) μmol/L 3.5 hours after ingestion, and the median half-life was 73.0 (interquartile range 33.4–232.0) minutes. Conclusions:: KNO ₃ is potentially well tolerated and improves exercise duration and quality of life in heart failure with preserved ejection fraction. This study reinforces the efficacy of KNO ₃ and suggests that larger randomized trials are warranted. Clinical Trial Registration : URL: http://www.clinicaltrials.gov . Unique identifier: NCT02256345

Arterial load is composed of resistive and various pulsatile components, but their relative contributions to left ventricular (LV) remodeling in the general population are unknown. We studied 4145 participants enrolled in the Multi-Ethnic Study of Atherosclerosis, who underwent cardiac MRI and radial arterial tonometry. We computed systemic vascular resistance (SVR=mean arterial pressure/cardiac output) and indices of pulsatile load including total arterial compliance (TAC, approximated as stroke volume/central pulse pressure), forward wave amplitude ( P _f ), and reflected wave amplitude ( P _b ). TAC and SVR were adjusted for body surface area to allow for appropriate sex comparisons. We performed allometric adjustment of LV mass for body size and sex and computed standardized regression coefficients (β) for each measure of arterial load. In multivariable regression models that adjusted for multiple confounders, SVR (β=0.08; P P P _b (β=0.73; P P _f (β=−0.23; P =0.001) were significant independent predictors of LV mass. Conversely, TAC (β=−0.43; P P P _f (β=−0.18; P =0.004) were independently associated with the LV wall/LV cavity volume ratio. Women demonstrated greater pulsatile load than men, as evidenced by a lower indexed TAC (0.89 versus 1.04 mL/mm Hg per square meter; P 2 ; P <0.0001). In conclusion, various components of arterial load differentially associate with LV hypertrophy and concentric remodeling. Women demonstrated greater pulsatile load than men. For both LV mass and the LV wall/LV cavity volume ratio, the loading sequence (ie, early load versus late load) is an important determinant of LV response to arterial load.