Cerebral and myocardial ischemia, two of the leading causes of morbidity and mortality worldwide, are associated with systemic inflammatory responses that lead to organ injury, shock, and eventually death. HMGB1, a newly appreciated pro-inflammatory cytokine, has been detected in significant concentrations in severe sepsis and hemorrhagic shock, but its relationship to ischemic injury in humans is unknown. In order to determine whether HMGB1 levels are elevated in patients with ischemia, a prospective observational study was performed in subjects with a diagnosis of either acute coronary syndrome or cerebral vascular ischemia (transient ischemic attacks or cerebral vascular accidents). Subjects (n = 13, 69 ± 15.6 yrs.) were enrolled upon presentation to the North Shore LIJ Emergency Department within the first 24 hours of symptom onset. Blood was collected and serum prepared; circulating HMGB1 levels were analyzed by Western blot analysis using previously described methods (Wang et al. Science 1999). Control samples were obtained from healthy age- and sex-matched volunteers (n = 13, 71 ± 15.8 yrs.). Our results indicated that serum HMGB1 levels were significantly elevated in myocardial ischemia subjects as compared with controls (control serum HMGB1 = 10.6 ± 6.5 ng/mL vs. myocardial ischemia serum HMGB1 = 171.1 ± 26.8 ng/mL; p<0.001); serum HMGB1 levels were similarly elevated in cerebral ischemia subjects (control serum HMGB1 = 10.6 ± 6.5 ng/mL vs. cerebral ischemia serum HMGB1 = 194 ± 27.2 ng/mL; p<0.001). [Data presented as mean ± standard error, and analyzed by two-tailed Student's T test.] These results suggest that circulating HMGB1 levels are elevated in human ischemic disease, and that HMGB1 may serve as a serum marker for the early detection of ischemic diseases in humans. Ongoing studies are under way to correlate HMGB1 levels with both disease severity and progression. Supported by NIGMS and GCRC M01RR018535 of the North Shore-LIJ Research Institute. (Figure)
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