Hsieh_2025_Can.J.Cardiol__

BACKGROUND: Modulating parasympathetic activity through vagal pathways represents a promising but underexplored strategy in heart failure (HF) treatment. Cholinesterase inhibitors (ChEIs), which enhance cholinergic tone by preventing acetylcholine degradation, have shown therapeutic value in patients with HF. This study investigates the association between ChEI use and clinical outcomes in patients with HF with preserved ejection fraction (HFpEF). METHODS: We performed a retrospective cohort study using a multi-institutional database spanning July 2002 to December 2022. HFpEF was defined as left ventricular ejection fraction >50% and an H2FPEF score <=6. Following 1:2 propensity score matching, primary endpoints included all-cause and cardiovascular mortality, with HF hospitalization as a secondary endpoint over a 5-year follow-up. Echocardiographic parameters were compared between ChEI users and matched nonusers. RESULTS: Among 11,862 HFpEF patients, 516 received ChEIs. After matching, 1,242 patients (414 ChEI users, 828 nonusers; mean age 80.8 years; 64% female) were included in the analysis. ChEI use was associated with significantly lower all-cause mortality (hazard ratio [HR] 0.45, 95% CI 0.36-0.57, p<0.001), cardiovascular mortality (HR 0.41, 95% CI 0.26-0.65, p<0.001), and HF hospitalization (HR 0.52, 95% CI 0.34-0.80, p=0.003). Echocardiographic follow-up showed a lower incidence of elevated left ventricular filling pressure (E/e' <=13) in ChEI users compared to nonusers (43.4% vs. 65.1%, p=0.010). CONCLUSIONS: ChEI therapy in HFpEF is associated with significant reductions in mortality and HF hospitalizations, alongside improved left ventricular filling pressure. These findings support further prospective trials to explore ChEIs as a potential therapeutic strategy in HFpEF.