IMPORTANCE In patients with heart failure and reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan reduces N-terminal pro-b-type natriuretic peptide (NT-proBNP) concentrations. The effect of sacubitril-valsartan on cardiac remodeling is uncertain. OBJECTIVE To determine whether NT-proBNP changes in patients with HFrEF treated with sacubitril-valsartan correlate with changes in measures of cardiac volume and function. DESIGN, SETTING, AND PARTICIPANTS Prospective, 12-month, single-group, open-label study of patients with HFrEF enrolled in 78 outpatient sites in the United States. Sacubitril-valsartan was initiated and the dose adjusted. Enrollment commenced on October 25, 2016, and follow-up was completed on October 22, 2018. EXPOSURES NT-proBNP concentrations among patients treated with sacubitril-valsartan. MAIN OUTCOMES AND MEASURES The primary outcome was the correlation between changes in log 2-NT-proBNP concentrations and left ventricular (LV) EF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e′) at 12 months. RESULTS Among 794 patients (mean age, 65.1 years; 226 women [28.5%]; mean LVEF = 28.2%), 654 (82.4%) completed the study. The median NT-proBNP concentration at baseline was 816 pg/mL (interquartile range [IQR], 332-1822) and 455 pg/mL (IQR, 153-1090) at 12 months (difference, P < .001). At 12 months, the change in log 2-NT-proBNP concentration was correlated with changes in LVEF

BACKGROUND-Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target. METHODS-We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR.

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Background : Sacubitril/valsartan (S/V) treatment is associated with reverse cardiac remodeling and reductions in biomarkers reflecting ventricular wall stress and myocardial injury, such as N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT) and soluble suppressor of tumorigenicity-2 (sST2). How longitudinal changes in these biomarkers analyzed collectively are associated with cardiac remodeling in patients with heart failure with reduced ejection fraction (HFrEF) treated with S/V is uncertain. Methods : In a prospective study of S/V in patients with HFrEF, this pre-specified exploratory analysis included patients with serially collected biomarkers and echocardiographic measures of cardiac remodeling through 12 months of treatment. A multivariate Latent Growth Curve model assessed associations between simultaneous changes in biomarkers and left ventricular ejection fraction (LVEF) and left atrial volume index (LAVi). Results : 715 out of 794 total study participants were included (mean age 65 years, 73% male). Mean baseline LVEF and LAVi were 29% and 40 ml/m 2 , respectively. Adjusted geometric mean baseline concentrations for biomarkers included NT-proBNP of 649 pg/ml, hs-cTnT of 15.9 ng/L and sST2 of 24.7 ng/ml. Following initiation of S/V, circulating concentrations of NT-proBNP, hs-cTnT and sST2 significantly decreased within 30 days and remained significantly different than baseline at all subsequent timepoints. From baseline to month 12, decreases in adjusted biomarker concentrations averaged -27.9% (95% CI: -35.1% to -20.7%; p<.001) for NT-proBNP; -6.7% (95% CI: -8.8% to -4.7%; p<.001) for hs-cTnT; and -1.6% (95% CI: -2.9% to -0.4%; p<.001) for sST2. NT-proBNP concentrations were predictive of later changes in hs-cTnT. The magnitude of reductions in NT-proBNP and hs-cTnT concentrations associated with improvements in LVEF and LAVi. There was no association between changes in sST2 and changes in other measures. Conclusions : Following initiation of S/V, NT-proBNP, hs-cTnT and sST2 concentrations decreased significantly. Longitudinal changes in NT-proBNP and hs-cTnT together associated with LA and LV reverse remodeling. Registration : URL: ClinicalTrials.gov; Unique Identifier: NCT02887183