400 The Kinetics of High Mobility Group Box-1 During Acute Coronary Syndromes

Background: Atherosclerosis is a central pathogenic process contributing to coronary artery disease, a major cause of death and disability in developed countries. The formation and rupture of atherosclerotic plaques may be mediated by a late phase pro-inflammatory cytokine (HMGB1), which has been detected within plaques and found to be elevated during ischemic disease processes. Study Objectives: To test the hypothesis that HMGB1 serum levels correlate with disease severity and with other well established inflammatory mediators and biomarkers of cardiac ischemia (TnT, CK-MB) in patients with acute coronary syndromes (ACS). Methods: A prospective pilot cohort study at an 80,000 visit per year suburban university-affiliated Level I emergency department (ED). Inclusion criteria: Adult patients (≥ 18 yrs) admitted through the ED who met ACC/AHA criteria of unstable angina (USA), non-ST elevation myocardial infarction (NSTEMI), or ST elevation myocardial infarction (STEMI). A separate group of healthy controls (no immunosuppression, illicit drug abuse, or chronic medical condition) were also enrolled. Exclusion criteria: Any patient with immunosuppression, illicit drug use, or cocaine-associated chest pain. Study interventions: Control patients had a single blood draw. Patients with ACS had serum drawn upon enrollment and at 6 hour (h), 12h, 24h, 48h, and 72h from ED presentation. Levels of standard cardiac biomarkers (TnT, CK-MB) from blood draws performed for routine patient care were collected from the medical chart. HMGB1 levels were determined using purified recombinant HMGB1 at various dilutions (5, 10, 25 ng) by Western blot analysis with a standard reference curve. Quantity One software (BioRad) was used to digitize Western blots for quantitative analysis. Nonparametric tests were used for statistical analysis. The difference in HMGB1 levels in healthy controls and ACS patients at baseline was analyzed using the Mann-Whitney test. The difference in HMGB1 levels among ACS classification groups (USA/NSTEMI/STEMI) was analyzed using the Kruskal-Wallis test. Results: Thirty study subjects and 8 control subjects were enrolled. The median age of all subjects was 71.5 years, 70% male. There was one mortality in the ACS case groups. There was a significant difference in HMGB1 levels between patients with ACS and healthy controls at baseline with median levels of 9869 ng/mL (95% CI, 9064 - 10673 ng/mL) and 37 ng/mL (95% CI, 17.5 - 66 ng/mL) respectively (p<0.001). At baseline, median values of HMGB1 in the USA, NSTEMI, and STEMI groups were 9754 ng/mL (95% CI, 7264 - 12244 ng/mL), 10550 ng/mL (6706 - 12431 ng/mL), and 11082 ng/mL (7805 - 11344 ng/mL), respectively. At 6h, 12h, and 24h after presentation, median HMGB1 values in patients with ACS were 9443 ng/mL (95% CI, 7281- 11605 ng/mL), 9729 ng/mL (95% CI, 7176 - 12281 ng/mL), 8789 ng/mL (95% CI, 5732 - 11845 ng/mL), respectively. Conclusion: HMGB1 is present in high levels in ACS patients presenting to the ED and correlates well with presence of acute coronary syndromes. This study suggests that HMGB1 may be a potential biomarker for ACS as well as a clinically viable therapeutic target for patients with ACS presenting to the ED within 24 hours of onset due to its persistence in serum over time.