Neurodegeneration is strongly linked to heart failure severity and outcomes: framing the cardiocerebral syndrome

ABSTRACT Background and Objectives Cognitive impairment is prevalent in patients with heart failure with reduced ejection fraction (HFrEF), affecting self-care and outcomes. Novel blood-based biomarkers have emerged as potential diagnostic tools for neurodegeneration. This study aimed to assess neurodegeneration in HFrEF by measuring neurofilament light chain (NfL), total tau (t-tau), amyloid-beta 42 (Aβ42), and 40 (Aβ40) in a large, well-characterised cohort. Methods The study included 470 HFrEF patients from a biobank-linked prospective registry at the Medical University of Vienna. High-sensitivity single-molecule assays were used for measurement. Unplanned hospitalisations and all-cause death were recorded as outcome parameters. Results All markers, but not the Aβ42/Aβ40 ratio, correlated with heart failure (HF) severity, i.e. NTproBNP and NYHA class, comorbidity burden and were significantly associated with all-cause death and HF-hospitalisations [crude HR for 1-log unit increase (95%CI): 4.44 (3.02-6.53), 5.04 (2.97-8-58), 3.90 (2.27-6.72) and 5.14 (2.84-9.32) for all-cause death and 2.48 (1.60-3.85), 3.44 (1.95-6.04), 3.13 (1.84-5.34) and 3.48 (1.93-6.27) for HHF, p<0.001 for all]. These markers remained significant after adjustment in multivariate models including NT-proBNP. NfL and t-tau showed the highest prognostic ability in the receiver operating characteristic analysis [AUC: 0.72, 0.68, 0.66, 0.67 for NfL, t-tau, Aβ40 and Aβ42, respectively]. The performance of NfL was comparable to that of NT-proBNP [C-index: 0.70 vs 0.72, p=0.225]. Conclusions Neurodegeneration is directly interwoven with the progression of HF. Biomarkers, particularly NfL, may help identify patients profiting from detailed neurological workups. Further research is necessary to test if early diagnosis or optimised HFrEF treatment can preserve cognitive function.