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In addition to dyspnea and edema, gastrointestinal discomfort is common among patients with heart failure (HF). Reduced cardiac output can lead to inadequate perfusion of the intestinal mucosa and subsequent impairment of the intestinal barrier. Levosimendan, a novel inotropic agent, binds to cardiac troponin C to enhance calcium sensitivity, activates ATP-dependent potassium channels in cardiomyocytes and vascular smooth muscle cells, exerts positive inotropic and vasodilatory effects, and reduces free radical generation, thereby improving systemic hemodynamics including intestinal circulation. However, clinical evidence regarding its protective effects on the intestinal barrier in HF patients remains limited, and the underlying mechanisms require further clarification. This study aims to investigate whether levosimendan confers protective effects on the intestinal barrier in HF patients and to explore its potential mechanisms.

Network pharmacology was first used to analyze potential mechanisms of levosimendan in treating intestinal barrier dysfunction among HF patients. A total of 62 hospitalized patients with acute exacerbation of HF with reduced ejection fraction (HFrEF) were enrolled based on echocardiographic left ventricular ejection fraction. According to clinical medication regimens, patients were assigned to a conventional treatment group (n=31) or a levosimendan treatment group (n=31). The conventional treatment group received standard anti-HF therapy, while the levosimendan treatment group received levosimendan in addition to standard therapy. Enzyme-linked immunosorbent assays were used to measure plasma levels and changes in the intestinal-barrier proteins zonulin, intestinal fatty acid binding protein (I-FABP), proinflammatory cytokines [interleukin (IL)-17, IL-6, and tumor necrosis factor (TNF)-α], anti-inflammatory cytokine IL-10, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Improvements in cardiac function and gastrointestinal symptoms were evaluated using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Gastrointestinal Symptom Rating Scale (GSRS).

Network pharmacology indicated that the effects of levosimendan on intestinal barrier dysfunction in HF patients may involve inflammation-related pathways such as IL-17 and TNF. Clinically, after treatment, zonulin decreased by 32.94 ng/mL in the levosimendan treatment group versus 15.05 ng/mL in the conventional treatment group (P<0.05). I-FABP decreased by 6.97 pg/mL in the levosimendan treatment group but increased by 35.16 pg/mL in the conventional treatment group (P<0.05). IL-6, IL-17, and TNF-α decreased by 1.11 pg/mL, 1.21 pg/mL, and 2.83 pg/mL, respectively, in the levosimendan treatment group, whereas they increased by 7.68 pg/mL, 0.67 pg/mL, and 2.38 pg/mL in the conventional treatment group (all P<0.05). IL-10 decreased by 24.48 pg/mL in the conventional treatment group but increased by 24.98 pg/mL in the levosimendan treatment group (P<0.05). NT-proBNP increased by 7.35 pg/mL in the conventional treatment group but decreased by 4.73 pg/mL in the levosimendan treatment group (P<0.05). KCCQ scores increased by 0.36 in the conventional treatment group and 1.86 in the levosimendan treatment group, GSRS scores decreased by 1.00 in the conventional treatment group and 2.40 in the levosimendan treatment group, respectively, but the differences were not statistically significant (both P>0.05).

Levosimendan not only improves HF and gastrointestinal symptoms in hospitalized patients with acute exacerbation of HFrEF but also reduces plasma intestinal barrier factor levels. These effects may be associated with decreased plasma proinflammatory cytokines and increased anti-inflammatory cytokines after treatment, potentially involving IL-17 and TNF signaling pathways.