Association between early NLPR3 changes and outcomes after heart failure hospitalization in patients with heart failure and preserved ejection fraction

Background Heart failure (HF) remains a major cause of morbidity and mortality worldwide. HF with preserved ejection fraction (HFpEF) is a heterogeneous syndrome characterized by pathophysiological mechanisms distinct from reduced ejection fraction and is associated with a chronic, low-grade inflammatory state driven by common comorbidities. This inflammatory milieu contributes to myocardial stiffness and vascular dysfunction. Characterizing inflammatory profiles in HFpEF may improve patient stratification and support the development of targeted therapies. Purpose To characterize the inflammatory profile of HFpEF patients and examine the association between early post-discharge changes in systemic inflammatory markers and clinical outcomes, including mortality and HF readmissions. Methods We conducted a prospective cohort study including consecutive patients with HFpEF recently hospitalized for acute HF. The first outpatient visit was performed within the first week after discharge, with blood samples obtained at baseline and at a follow-up visit, approximately one month later. Patients were subsequently followed for HF hospitalizations and all-cause mortality. Inflammatory biomarkers were measured using multiplex immunoassay-based panels. Continuous variables were summarized as mean ± standard deviation or median (P25–P75), and categorical variables as percentages. The independent association between changes in NLPR3 and outcomes was evaluated using joint negative binomial regression models simultaneously modeling HF readmissions and mortality, accounting for outcome correlation through a shared frailty term. Associations were reported as incidence rate ratios (IRR). Results Between October 2022 and July 2024, 219 patients were included (mean age 84 ± 8 years; 53% women). Median baseline LVEF, NT-proBNP and NLPR3 were 60% (48–65), 2600 pg/ml (1203–5795) and 18.1 (9.2–27.8), respectively. At a median of 35 days (28–44) from baseline, the absolute reduction in NLPR3 was 2.9 (−0.8 to 8.6). During a median follow-up of 1.70 years (1.4–2.3), 69 deaths (31.5%) and 128 HF hospitalizations in 82 patients were recorded. Reductions in NLPR3 were greater among patients who remained alive (4.0 vs. 1.2, p = 0.005) and free from readmission (3.5 vs. 1.9, p = 0.047). In multivariable analysis, greater NLPR3 reduction was independently associated with lower risk of mortality (p = 0.001) and recurrent HF hospitalizations (p = 0.036). Conclusion In patients with HFpEF recently hospitalized for acute HF, early post-discharge changes in systemic inflammatory markers were associated with subsequent clinical outcomes. A greater reduction in inflammatory markers during early follow-up was related to lower mortality and fewer HF readmissions. These results highlight the potential value of dynamic inflammatory assessment in HFpEF.Figure 1Figure 2