Abstract
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is recognized as an aging-related clinical syndrome with high mortality, from which systemic inflammation could represent a primary culprit. Thus, this study aimed to evaluate the association between the lymphocyte-to-monocyte ratio (LMR), a systemic inflammation marker, and clinical outcomes, and to explore the mediation effect of the LMR in the relationship between age and mortality for HFpEF. METHODS: Participants in the Real-world Data of Cardiometabolic ProtEcTion trial (RED-CARPET) trial were categorized into tertiles based on the recorded LMRs. We employed Cox regression analyses to explore the relationship between the LMR and mortality, as well as mediation analyses to determine whether the LMR serves as a mediator between aging and mortality. RESULTS: A total of 1274 inpatients with HFpEF were enrolled between May 2015 and December 2023. After a median follow-up period of 4.9 years, there were 166 recorded deaths, of which 82 were due to cardiovascular causes. In the third model, each one-unit increase in standard deviation (SD) for age was correlated with a 1.98-fold increase in the risk of overall mortality (95% confidence interval (CI), 1.66-2.35) and a 1.73-fold increase in the risk of death due to cardiovascular disease (95% CI, 1.36-2.21). Compared to patients in the first tertile of the LMR, those in the third tertile exhibited a lower risk of death (hazard ratio (HR) 0.42; 95% CI (0.27-0.65)) and cardiovascular death (HR 0.23; 95% CI (0.12-0.46)). Mediation analyses indicated that the LMR partially mediated the relationship between age and cardiovascular mortality in patients with HFpEF, with a mediation proportion of 17.9% (95% CI (7.2%-36%); p < 0.001). CONCLUSIONS: The LMR may serve as a marker for mortality and is implicated in the mediation of age-related cardiovascular death in patients with HFpEF. This study offers a cost-effective predictor for HFpEF and suggests potential mechanisms related to immunosenescence and inflammation-related aging (inflamm-aging).