Arterio-Venous Gradient of Active Interleukin-18 Is Associated with Diastolic Dysfunction: A Cross-Sectional Study

Abstract Aims Diastolic dysfunction is a key determinant of symptoms and prognosis in heart failure (HF). Interleukin (IL)-18 and IL-6 are key inflammatory cytokines in HF; however, their local activation within the cardiopulmonary circulation and relevance to diastolic dysfunction remain unclear. This exploratory study investigated associations between arterio-venous (A/V) cytokine gradients and diastolic dysfunction. Methods Eighty-seven patients undergoing diagnostic cardiac catheterization were enrolled. Paired arterial samples from the left ventricle (LV) or ascending aorta and peripheral venous samples were obtained simultaneously or within 24 hours of the procedure. Active IL-18 (aIL-18) and IL-6 concentrations were measured, and associations with echocardiographic and clinical parameters were evaluated. aIL-18-induced fibrotic responses were evaluated in human cardiac fibroblasts (HCFs). Results The cohort exhibited impaired myocardial relaxation (septal e′: 5.3 ± 2.0 cm/s) and preserved ejection fraction (57.4 ± 11.8%). The aIL-18 A/V ratio correlated with average E/e′ (r = 0.31, p 0.01), tricuspid regurgitation pressure gradient (r = 0.29, p = 0.015), and HFA-PEFF score (r = 0.23, p = 0.034). Correlations between the aIL-18 A/V ratio and E/e′ were more pronounced in non-diabetic patients and in those with elevated LV filling pressure (average E/e′ ≥15). IL-6 correlated with albuminuria and pulmonary function; however, no synergistic interaction with aIL-18 was observed. In vitro, aIL-18 stimulated fibroblast proliferation and collagen synthesis. Conclusions The aIL-18 A/V ratio correlated with markers of diastolic dysfunction, particularly in patients with increased filling pressure. These exploratory findings indicate an association between local IL-18 gradients and diastolic dysfunction, warranting further investigation.