High mobility group box 1 predicts mortality and systemic organ dysfunction in cardiology intensive care patients

High mobility group box 1 (HMGB1) is a prototypical danger-associated molecular pattern (DAMP) released from stressed or necrotic cells, driving systemic inflammation and organ dysfunction. Elevated HMGB1 levels have been linked to poor outcomes in sepsis and general intensive care populations. However, its prognostic role in specialised cardiology intensive care units (ICU) and its direct impact on circulating immune cells remain insufficiently understood.

To determine whether HMGB1 concentrations at ICU admission predict mortality and systemic organ dysfunction in patients treated for acute cardiovascular disease, and to explore translational mechanisms of HMGB1-driven immune cell dysfunction in vitro.

Plasma HMGB1 levels were measured on admission in 219 consecutive patients admitted to a cardiology ICU. Patients were stratified by median values and into tertiles of HMGB1 concentrations (T1: <4.1; T2: 4.1–7.0; T3: >7.0 ng/mL). Survival was analysed using Kaplan–Meier curves with log-rank testing. Receiver operating characteristic (ROC) analysis evaluated the predictive capacity of HMGB1 for ICU mortality. Correlations with clinical and biochemical parameters of organ dysfunction were assessed by Pearson’s correlation coefficients. For translational analysis, peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured for 48 hours with pooled serum from ICU patients or control serum. Nuclear HMGB1 localisation was analysed by immunofluorescence, and apoptosis was quantified by Annexin V staining using flow cytometry (Attune NxT).

Median HMGB1 levels were significantly higher in non-survivors compared with survivors (9.3 ng/mL vs. 6.0 ng/mL, p < 0.01). Patients in the highest tertile (T3) had substantially reduced ICU survival compared with those in the lowest tertile (T1). HMGB1 predicted ICU mortality with an area under the ROC curve (AUC) of 0.67 (95% CI: 0.60–0.75). Elevated HMGB1 was significantly associated with lactate (r = 0.55) and markers of liver dysfunction including bilirubin (r = 0.32), fibrinogen (r = -0.25), and thrombocyte count (r = -0.30), but showed no associations with age, sex, or underlying cardiac diagnosis. In translational experiments, PBMCs exposed to ICU serum displayed reduced nuclear HMGB1 compared with control serum and exhibited a significant increase in Annexin V-positive apoptotic cells after 48 hours of stimulation.

In patients admitted to a cardiology ICU, elevated HMGB1 levels on admission were independently associated with increased mortality and systemic organ dysfunction, particularly hepatic injury. Complementary in vitro experiments demonstrated that ICU serum drives HMGB1 nuclear depletion and immune cell apoptosis, supporting a mechanistic role for HMGB1 in circulating immune dysfunction. These findings highlight HMGB1 both as a prognostic biomarker and as a potential therapeutic target in acute cardiovascular critical illness.