Cross-Sectional Plasma Proteomic Phenotypes Associated with Prolonged Intermittent Levosimendan Exposure in Advanced Heart Failure

Abstract

Levosimendan is intermittently administered in selected patients with advanced heart failure, but data on prolonged exposure and associated circulating molecular profiles remain limited. We conducted a retrospective observational study of 41 patients with heart failure with reduced ejection fraction, including eight patients exposed to ≥22 intermittent levosimendan infusions and 33 nonexposed controls followed in the same specialist heart failure setting. Baseline clinical characteristics, follow-up outcomes, and plasma proteomic profiles were assessed using label-free data-independent acquisition mass spectrometry. Patients exposed to prolonged intermittent levosimendan were older and had more advanced heart failure at baseline, including lower left ventricular ejection fraction and higher NT-proBNP concentrations. During clinical follow-up from the first specialist cardiology observation to plasma sampling, cardiovascular hospitalization occurred in 3/8 levosimendan-exposed patients and 1/33 controls, while cardiovascular death occurred in 2/8 and 0/33, respectively; these outcomes are reported descriptively because of baseline imbalance, retrospective treatment allocation, and the small exposed-group size. These outcomes are reported descriptively because of baseline imbalance and the small exposed-group size. Plasma proteomic analysis identified cross-sectional differences between groups. Control patients showed higher representation of immune and inflammatory proteins, whereas levosimendan-exposed patients showed higher abundance of proteins related to antioxidant defense, redox regulation, coagulation/hemostasis, and metabolic adaptation, including GPX3, SELENOP, PROS1, F2, AHSG, and ALDOA. These findings define an exploratory plasma proteomic phenotype associated with prolonged intermittent levosimendan exposure in real-world advanced heart failure. Prospective controlled studies with baseline and serial proteomic sampling are required to determine whether these molecular differences reflect treatment-associated adaptation or underlying clinical differences.