Transcriptional Upregulation of Leukemia Inhibitory Factor in Peripheral Blood of Patients with Heart Failure and Its Association with Inflammatory and Myocardial Stress Biomarkers

Background: Heart failure (HF) is a complex clinical syndrome characterized by sustained inflammatory activation, oxidative stress, and extensive alterations in gene regulation. Leukemia inhibitory factor (LIF), a pleiotropic cytokine belonging to the interleukin-6 (IL-6) superfamily, mediates cellular stress signaling through the glycoprotein 130 (gp130) receptor complex. Although previous investigations have predominantly examined LIF expression in experimental animal models or endomyocardial biopsies, clinical evidence regarding peripheral blood LIF gene expression in human HF remains limited. This study aimed to investigate peripheral blood LIF transcript levels in a South Indian cohort and evaluate its diagnostic performance and potential utility as a complementary transcriptional biomarker within a multimarker framework. Methods: In this hospital-based case–control study, 150 patients with clinically confirmed stable HF and 150 age- and sex-matched healthy controls were enrolled across cardiac centers in Kerala, India. Peripheral blood LIF messenger RNA (mRNA) expression was quantified by reverse transcription quantitative polymerase chain reaction (RT-qPCR) using the 2−ΔΔCt relative quantification method normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Circulating concentrations of established cardiac stress, inflammatory, oxidative stress, and myocardial remodeling biomarkers—specifically N-terminal pro-B-type natriuretic peptide (NT-proBNP), interleukin-6 (IL-6), malondialdehyde (MDA), and soluble suppression of tumorigenicity 2 (sST2)—were determined by enzyme-linked immunosorbent assay (ELISA). Diagnostic accuracy was evaluated using receiver operating characteristic (ROC) curves, and independent associations were assessed via sequential multivariable logistic regression models. Results: Peripheral blood LIF gene expression was significantly upregulated in patients with HF compared with healthy controls (mean fold change: 2.1 ± 1.2 vs. 1.1 ± 0.2, p < 0.01). Circulating levels of NT-proBNP, IL-6, sST2, and MDA were also significantly elevated in HF cases (all p < 0.01). ROC curve analysis demonstrated robust diagnostic accuracy for LIF gene expression, with an area under the curve (AUC) of 0.784 (95% CI: 0.732–0.836), achieving a sensitivity of 58%, an exceptional specificity of 98%, and a positive likelihood ratio of 29.0. Bivariate analysis revealed significant positive correlations between LIF expression and NT-proBNP (ρ = 0.5146, p < 0.001), IL-6 (ρ = 0.4425, p < 0.001), sST2 (ρ = 0.5321, p < 0.001), and MDA (ρ = 0.4371, p < 0.001). In binary logistic regression, LIF expression exhibited a powerful unadjusted association with HF (Model 1: OR = 15.123, 95% CI: 6.300–36.303, p < 0.01) that persisted after adjusting for age, sex, and body mass index (Model 2: OR = 6.220, p < 0.01) and hypertension (Model 3: OR = 3.248, p = 0.014). However, upon full adjustment for circulating NT-proBNP, IL-6, MDA, and sST2 (Model 4), the association was attenuated to non-significance (adjusted OR = 0.625, 95% CI: 0.202–1.935, p = 0.415). Conclusions: Peripheral blood LIF gene expression is markedly elevated in patients with HF and correlates with established biomarkers of myocardial wall stress, systemic inflammation, lipid peroxidation, and cardiac fibrosis. The loss of independent predictive significance upon comprehensive multivariable adjustment indicates that peripheral LIF transcription reflects shared biological and signaling variance within the broader gp130 cytokine and myocardial stress cascade. Consequently, peripheral LIF mRNA expression serves as a valuable complementary molecular indicator for disease phenotyping rather than an isolated standalone diagnostic biomarker.