RESUMEN
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 (KNO3) on exercise capacity; (2) the population-specific pharmacokinetic and safety profile of KNO3 in heart failure with preserved ejection fraction. METHODS AND RESULTS: We randomized 12 subjects with heart failure with preserved ejection fraction to oral KNO3 (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 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% 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 KNO3. Pronounced elevations in trough levels of nitric oxide metabolites occurred with KNO3 (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<0.001). KNO3 did not lead to clinically significant hypotension or methemoglobinemia. After 6 mmol of KNO3, 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: KNO3 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 KNO3 and suggests that larger randomized trials are warranted. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02256345.
Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Nitratos/farmacocinética , Compuestos de Potasio/farmacocinética , Volumen Sistólico , Anciano , Ejercicio Físico , Femenino , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/rehabilitación , Humanos , Masculino , Persona de Mediana Edad , Nitratos/efectos adversos , Compuestos de Potasio/efectos adversos , Calidad de VidaRESUMEN
BACKGROUND: Stable plasma nitric oxide (NO) metabolites (NOM), composed predominantly of nitrate and nitrite, are attractive biomarkers of NO bioavailability. NOM levels integrate the influence of NO-synthase-derived NO production/metabolism, dietary intake of inorganic nitrate/nitrite, and clearance of NOM. Furthermore, nitrate and nitrite, the most abundant NOM, can be reduced to NO via the nitrate-nitrite-NO pathway. METHODS AND RESULTS: We compared serum NOM among subjects without heart failure (n=126), subjects with heart failure and preserved ejection fraction (HFpEF; n=43), and subjects with heart failure and reduced ejection fraction (HFrEF; n=32). LV mass and extracellular volume fraction were measured with cardiac MRI. Plasma NOM levels were measured after reduction to NO via reaction with vanadium (III)/hydrochloric acid. Subjects with HFpEF demonstrated significantly lower unadjusted levels of NOM (8.0 µmol/L; 95% CI 6.2-10.4 µmol/L; ANOVA P=0.013) than subjects without HF (12.0 µmol/L; 95% CI 10.4-13.9 µmol/L) or those with HFrEF (13.5 µmol/L; 95% CI 9.7-18.9 µmol/L). There were no significant differences in NOM between subjects with HFrEF and subjects without HF. In a multivariable model that adjusted for age, sex, race, diabetes mellitus, body mass index, current smoking, systolic blood pressure, and glomerular filtration rate, HFpEF remained a predictor of lower NOM (ß=-0.43; P=0.013). NOM did not correlate with LV mass, or LV diffuse fibrosis. CONCLUSIONS: HFpEF, but not HFrEF, is associated with reduced plasma NOM, suggesting greater endothelial dysfunction, enhanced clearance, or deficient dietary ingestion of inorganic nitrate. Our findings may underlie the salutary effects of inorganic nitrate supplementation demonstrated in recent clinical trials in HFpEF.
Asunto(s)
Insuficiencia Cardíaca/sangre , Hipertrofia Ventricular Izquierda/sangre , Óxido Nítrico/sangre , Remodelación Ventricular , Anciano , Estudios de Casos y Controles , Femenino , Fibrosis , Corazón/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Miocardio/patología , Óxido Nítrico/metabolismo , Tamaño de los Órganos , Estudios Prospectivos , Volumen Sistólico , Estados Unidos , United States Department of Veterans AffairsRESUMEN
BACKGROUND: The utility of longitudinal, circumferential, and radial strain and strain rate in determining prognosis in chronic heart failure is not well established. METHODS AND RESULTS: In 416 patients with chronic systolic heart failure, we performed speckle-tracking analyses of left ventricular longitudinal, circumferential, and radial strain and strain rate on archived echocardiography images (30 frames per second). Cox regression models were used to determine the associations between strain and strain rate and risk of all-cause mortality, cardiac transplantation, and ventricular-assist device placement. The area under the time-dependent ROC curve (AUC) was also calculated at 1 year and 5 years. Over a maximum follow-up of 8.9 years, there were 138 events (33.2%). In unadjusted models, all strain and strain rate parameters were associated with adverse outcomes (P<0.001). In multivariable models, all parameters with the exception of radial strain rate (P=0.11) remained independently associated, with patients in the lowest tertile of strain or strain rate parameter having a ≈ 2-fold increased risk of adverse outcomes compared with the reference group (P<0.05). Addition of strain to ejection fraction (EF) led to a significantly improved AUC at 1 year (0.697 versus 0.633, P=0.032) and 5 years (0.700 versus 0.638, P=0.001). In contrast, strain rate did not provide incremental prognostic value to EF alone. CONCLUSIONS: Longitudinal and circumferential strain and strain rate, and radial strain are associated with chronic heart failure prognosis. Strain provides incremental value to EF in the prediction of adverse outcomes, and with additional study may be a clinically relevant prognostic tool.