Dermatan disulfate (Intimatan) prevents complement-mediated myocardial injury in the human-plasma-perfused rabbit heart

Intimatan (dermatan 4,6-O-disulfate), a heparin cofactor 11 agonist. is a highly sulfated negatively charged semisynthetic polysaccharide. The present study examined the hypothesis that Intimatan reduces complement-mediated myocardial injiuryThe rabbit isolated heart was perfused with 4% normal human plasma (NHP) as a source of complement in the absence or presence of Intimatan (5 muM). Heat-inactivated human plasma (HIHP) was used as a negative control. Previous studies demonstrated that contact of rabbit tissue with human plasma results in activation of the alternative pathway of the human complement system, leading to irreversible myocardial injury. In die presence of NW. left ventricular end-diastolic pressure (LVEDP) was increased significantly to 61.8 +/- 11.7 min H compared to a value of 17.2 +/- 6.1 mm Hg in hearts perfused in the presence of HIHP. Left ventricular developed pressure (LVDP) was reduced significantly upon exposure to NHP, 19.3 +/- 10.2 (NHP) vs. 54.0 +/- 8.0 mm Hg (HIHP). Functional impairment in the presence of NHP was accompanied by a significant release of cardiac troponin I (cTnl-. 131.8 +/- 20.3 ng/ml) as compared to hearts exposed to HIHP (0.8 +/- 0.8). Intimatan treatment improved cardiac function and maintained viability of cardiac myocytes (LVEDP 14.6 +/- 5.6. LVDP 58.0 +/- 8.1 mm Hg and cTnl 6.7 +/- 5.2 ng/ml). Inuntmohistochemical staining demonstrated that Intimatan pretreatment prevented deposition of the human membrane attack complex (MAC) in hearts exposed to NHP. The results indicate that Intimatan, a glycosaminoglycan (GAG), can reduce tissue injury and preserve organ function that otherwise would be compromised during activation of the hurna complement cascade. (C) 2004 Elsevier B.V. All rights reserved.