Sean P Murphy1, Margaret F Prescott2, Alan S Maisel3, Javed Butler4, Ileana L Piña5, G Michael Felker6, Jonathan H Ward2, Kristin M Williamson2, Alexander Camacho1, Ritvik R Kandanelly1, Scott D Solomon7, James L Januzzi8. 1. Massachusetts General Hospital, Boston, MA. 2. Novartis Pharmaceuticals, East Hanover, NJ. 3. University of California, San Diego School of Medicine, San Diego, CA. 4. University of Mississippi Medical Center, Jackson, MS. 5. Detroit Medical Center, Detroit, MI. 6. Duke University Medical Center and Duke Clinical Research Institute, Durham, NC. 7. Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA. 8. Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA; Baim Institute for Clinical Research, Boston, MA.
Abstract
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/m2, 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.
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/m2, 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.
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