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Background: Sacubitril/valsartan is a key therapy for heart failure with reduced ejection fraction (HFrEF). However, concerns remain regarding its potential impact on cognitive function since neprilysin inhibition may influence amyloid-β (Aβ) metabolism. This study evaluates the effect of sacubitril/valsartan on plasma biomarkers of neurodegeneration.
Methods: Plasma neuromarkers, i.e. Aβ40, Aβ42, neurofilament light chain (NfL), and total tau (t-tau) were measured at baseline, 3 months, and 1 year after sacubitril/valsartan initiation using the single-molecule array (SIMOA) technology in a HFrEF cohort from a prospective registry with biobank. Comparisons were made for baseline vs. 3 months and baseline vs 1-year follow-up.
Results: A total of 31 HFrEF patients (median age: 61 years, 74% male, NT-proBNP: 2333 pg/ml) were included. Aβ40 increased transiently at 3 months [228.6 pg/ml (Q1-Q3: 157.8-321.1) vs. 138.8 (110.0-202.2), p < 0.001] but remained unchanged at 1 year [215.0 (106.5-290.9), p = 0.052]. Aβ42 remained stable [9.90 (6.67-12.49) and 8.43 (5.57-11.86) vs. 7.84 (6.50-11.02) pg/ml, p = 0.108 and 0.771], resulting in a reduced Aβ42/Aβ40 ratio at both follow-ups [0.039 (0.036-0.049) at 3 months, p < 0.001; 0.048 (0.041-0.060) at 1 year, p = 0.026 vs. 0.055 (0.052-0.061)]. Total tau remained unchanged [1.13 (0.91-1.90) and 1.21 (0.85-1.65) vs. 1.03 (0.82-1.53) pg/ml, p = 0.068 and 0.188], while NfL increased at 1 year [28.3 (16.5-78.6) vs. 22.6 (15.1-46.9) pg/ml, p = 0.013], with no short-term change [25.3 (15.0-51.3), p = 0.502].
Conclusion: Sacubitril/valsartan therapy in HFrEF patients leads to a transient increase in Aβ40 and a sustained reduction in the Aβ42/Aβ40 ratio. Stable t-tau and short-term stable NfL levels provide reassurance regarding the absence of immediate neuronal injury, while an NfL increase observed at 1 year may indicate ongoing heart failure progression rather than direct neurotoxicity. These findings highlight the need for cautious interpretation of the Aβ42/Aβ40 ratio in neurocognitive assessments among patients treated with ARNi. Further studies are warranted to clarify the long-term cognitive implications of sacubitril/valsartan in HFrEF.
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