Inflammatory and Genetic Determinants of Functional Status in HFpEF: The Role of Circulating IL-6 and IL6 Polymorphisms

Background/Objectives: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome characterized by systemic inflammation and impaired functional capacity. Interleukin-6 (IL-6) is implicated in HFpEF pathophysiology, but the influence of IL6 genetic variability on its clinical impact remains unclear. This study investigated the associations of circulating IL-6, IL6 polymorphisms, and functional severity in HFpEF. Methods: This single-center observational study included 110 clinically stable HFpEF patients. Clinical, laboratory, and functional data, including C-reactive protein (CRP), IL-6 serum levels were collected. The neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio were calculated from complete blood count, while IL6 polymorphisms rs1800795 and rs1818879 were genotyped using TaqMan assays. Functional status was assessed using NYHA classification, the six-minute walk test (6MWT), and the Borg dyspnea scale. Results: Among carriers of the rs1800795 G/C+C/C genotype, elevated IL-6 was associated with higher odds of advanced symptoms (NYHA III; OR = 6.08, 95% CI 1.45–25.45, p = 0.014) and reduced exercise capacity (6MWT; OR = 6.55, 95% CI 1.60–26.72, p = 0.009). The combined effect of elevated IL-6 levels and the rs1800795 genotype was also associated with greater dyspnea burden, as assessed by the Borg scale (OR = 1.17, 95% CI 1.02–1.34, p = 0.029). In multivariable analysis, the NYHA and 6MWT models additionally retained NLR as an independent predictor, while the Borg model included advanced age, pulmonary hypertension, and the combined effect of elevated IL-6 levels and the rs1800795 genotype. Conclusions: The observed combined effect of elevated IL-6 levels and the rs1800795 genotype on symptom burden and functional impairment suggests that combined inflammatory and genetic profiling may improve severity assessment in HFpEF.