Association Between Angiotensin Receptor–Neprilysin Inhibition, Cardiovascular Biomarkers, and Cardiac Remodeling in Heart Failure With Reduced Ejection Fraction

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/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

Novel biomarker-driven prognostic models to predict morbidity and mortality in chronic heart failure: the EMPEROR-Reduced trial

“… 13 , 19 It is noteworthy that the lowest quintile for each biomarker identifies thresholds previously identified for risk stratification and cardiac remodelling for both NT-proBNP and hs-cTnT. 18 Given the strong and independent prognostic value of NT-proBNP and hs-cTnT when evaluated individually, a great potential exists in combining both for refining risk prediction in HF.…”

“…17 Similar to NT-proBNP, recent data have linked hs-cTnT concentrations to cardiac remodelling, where the two biomarkers have a unique correlation, with NT-proBNP change preceding that of hs-cTnT. 18 This leads to the hypothesis that increased myocardial stress (reflected in NT-proBNP concentrations) results in subsequent myocardial injury (reflected in hs-cTnT concentrations) ultimately culminating in adverse cardiac remodelling and worse prognosis. 13 , 19 It is noteworthy that the lowest quintile for each biomarker identifies thresholds previously identified for risk stratification and cardiac remodelling for both NT-proBNP and hs-cTnT.…”

Left atrial disease and left atrial reverse remodelling across different stages of heart failure development and progression: a new target for prevention and treatment

“…It has been demonstrated that the significant reduction in circulating NT-proBNP (and high-sensitivity cardiac troponin T) is correlated to the LA volume index reduction among HFrEF patients treated with ARNI. 121 Left atrial reverse remodelling can be considered an active player of the so-called 'complete left-sided reverse remodelling'. 16,48 This concept has been elucidated by trials testing the structural response to cardiac resynchronization therapy (CRT) (Table 4).…”

Molecular mechanisms of sacubitril/valsartan in cardiac remodeling

“…The effectiveness of sacubitril/valsartan therapy in patients with HFrEF has been appraised in many studies. The drug reduced plasma levels of NT-proBNP, high-sensitivity cardiac troponin T (hs-cTnT), and soluble suppressor of tumorigenicity 2 (sST2) in the patients, high levels of which reflect ventricular wall stress and myocardial injury ( Nougué et al, 2019 ; Murphy et al, 2021 ) ( Table 3 ). NT-proBNP level and left ventricular mass are positively correlated, and this fact is useful for identifying patients with cardiac hypertrophy ( Morillas et al, 2008 ; Kahveci et al, 2009 ).…”