Soluble urokinase plasminogen activator receptor and outcomes in HFpEF: A TOPCAT ancillary study

Abstract

Aims: Inflammation is postulated to be a key pathogenic mechanism in heart failure with preserved ejection fraction (HFpEF). Soluble urokinase plasminogen activator receptor (suPAR), a regulator of innate immune activity, is associated with incident heart failure; however, its role in HFpEF remains unclear. We aimed to elucidate the role of suPAR in HFpEF outcomes.

Methods: In this secondary analysis of the TOPCAT trial's North American cohort, suPAR was measured at baseline and 1 year in a subset of patients with HFpEF (n = 406) treated with either spironolactone or placebo. We assessed the association between suPAR levels and adverse outcomes, whether spironolactone influenced suPAR levels and whether the association between spironolactone and outcomes is dependent on suPAR levels. The primary outcome was a composite of cardiovascular death, cardiac arrest or hospitalization for heart failure management.

Results: The mean age of participants was 69.5 years, and 46.6% were female. After a median follow-up of 2.9 years, 19.9% experienced the primary outcome event. The 5-year cumulative incidence of the primary outcome in the highest tertile of suPAR (>3.93 ng/mL) was 44%, compared with 14% in the lowest tertile (≤2.94 ng/mL) (P = 0.001). Spironolactone did not significantly change suPAR levels at 1 year, nor was its effect on outcomes modified by baseline suPAR (P for interaction = 0.6). In multivariable analysis, each doubling of baseline suPAR levels was associated with nearly twofold increased risk of the primary outcome, independent of traditional risk factors and natriuretic peptide (NP) levels (HR 1.94 [95% CI 1.33-2.83]). suPAR's risk discrimination ability was superior and additive to that of NP.

Conclusions: While suPAR levels independently predict poor outcomes in HFpEF patients, spironolactone does not modulate this inflammatory pathway. The findings suggest that suPAR represents a stable inflammatory biomarker in HFpEF, highlighting the need for further evaluation of targeted anti-inflammatory strategies in this population.

Keywords: biomarkers; cardiovascular outcomes; heart failure with preserved ejection fraction; inflammation; soluble urokinase plasminogen activator receptor; spironolactone.

Figure 1

Median change in suPAR levels by treatment arm (placebo versus spironolactone). The boxplot displays the median (IQR) change in suPAR (ng/mL) for placebo (blue) and spironolactone (orange). The P‐value indicates the statistical difference between groups using the Wilcoxon rank sum test.

Figure 2

Kaplan–Meier plots illustrating the cumulative incidence of the primary outcome based on baseline tertiles of suPAR across the 5‐year period. The log‐rank test was used to test for significance between tertiles, with significance indicated by a P‐value of <0.05. suPAR, soluble urokinase plasminogen activator receptor. Primary outcome, composite of death from a cardiovascular cause, aborted cardiac arrest or heart failure hospitalization.

Figure 3

Sensitivity analysis among subgroups for the association of baseline suPAR (log‐base 2) and the primary outcome. Models are adjusted for age, race, sex, hypertension, diabetes, BMI, smoking history and history of cardiovascular disease The interaction P‐value was significant at a level of <0.05.

Figure 4

Effect of natriuretic peptides on the primary outcome, stratified by high and low suPAR levels (cutoff 3 ng/mL). The model is adjusted for age, sex, race, eGFR, hypertension, diabetes, smoking, history of cardiovascular disease and BMI.