Elevated Macrophage Migration Inhibitory Factor 1 Is Associated with Left and Right Ventricular Systolic Dysfunction in Heart Failure with Reduced Ejection Fraction

<b>Background/Objectives</b>: Low-grade systemic inflammation, characteristic of heart failure (HF), is a nonspecific inflammatory syndrome that affects the entire body. Macrophage migration inhibitory factor 1 (MIF-1) is a pro-inflammatory cytokine, a key mediator of the innate immune response, and may serve as a potential biomarker of monocyte homing and activation in HF with reduced and mildly reduced ejection fraction (HFrEF, HFmrEF). <b>Methods</b>: We evaluated 70 hemodynamically stable patients with left ventricular EF (LVEF) < 50% by means of echocardiography and blood sampling. <b>Results</b>: We report significant correlations between MIF-1, LVEF (r = -0.33, <i>p</i> = 0.005), LV global longitudinal strain (LVGLS, r = 0.41, <i>p</i> = 0.0004), and tricuspid annular plane systolic excursion (TAPSE, r = -0.37, <i>p</i> = 0.001). MIF-1 levels in HFrEF patients were relatively higher, but not significantly different from those observed in HFmrEF. MIF-1 showed significant associations with TAPSE to systolic pulmonary artery pressure ratio (TAPSE/sPAP, <i>p</i> < 0.0001). Also, patients with TAPSE/sPAP < 0.40 mm/mmHg had significantly higher levels of MIF-1 (<i>p</i> = 0.009). Moreover, ischemic cardiomyopathy (ICM) was more frequent in patients with MIF-1 concentrations above 520 pg/mL (57.1% MIF-1^hi vs. 28.6% MIF-1^lo, <i>p</i> = 0.029). In terms of congestion, MIF-1 showed significant associations with the presence of peripheral edema (<i>p</i> = 0.007), but none was found with self-reported dyspnea (<i>p</i> = 0.307) and New York Heart Association (NYHA) class (<i>p</i> = 0.486). Also, no relationship was reported with N-terminal pro-B-type natriuretic peptide concentrations (NT-proBNP, r = 0.14, <i>p</i> = 0.263). However, the six-minute walk distance was greater in individuals in the MIF-1^lo group when compared to those in the MIF-1^hi group (404.0 ± 127.4 vs. 324.8 ± 124.1 m, <i>p</i> = 0.010). <b>Conclusions</b>: Beyond identifying inflammatory biomarkers related to disease severity, linking MIF-1 to various pathophysiological mechanisms may highlight the active involvement of the monocyte-macrophage system in HF. This system holds notable significance in congestion-related conditions, acting as a major source of reactive oxygen species that perpetuate inflammation.