Arterio-venous gradient of active interleukin-18 is associated with diastolic dysfunction: a cross-sectional study

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.

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 h of the procedure. Active IL-18 (aIL-18) and IL-6 concentrations were measured, and associations with echocardiographic and clinical parameters were evaluated. Active interleukin-18-induced fibrotic responses were evaluated in human cardiac fibroblasts.

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 < .01), tricuspid regurgitation pressure gradient (r = 0.29, P = .015), and Heart Failure Association-Pre-test assessment, Echocardiography & natriuretic peptide, Functional testing, Final aetiology (HFA-PEFF) score (r = 0.23, P = .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). Interleukin-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.

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.