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European Heart Journal Advance Access published online on July 29, 2005
European Heart Journal, doi:10.1093/eurheartj/ehi421
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European Heart Journal © The European Society of Cardiology 2005; all rights reserved
Received February 10, 2005
Revised June 3, 2005
Accepted June 27, 2005

Preclinical research

Locally targeted cytoprotection with dextran sulfate attenuates experimental porcine myocardial ischaemia/reperfusion injury

Yara Banz 1, Otto M. Hess 2, Simon C. Robson 3, Daniel Mettler 1, Pascal Meier 2, André Haeberli 1, Eva Csizmadia 3, Elena Y. Korchagina 4, Nicolai V. Bovin 4, and Robert Rieben 1*

1 Department of Clinical Research, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland
2 Department of Cardiology, Swiss Cardiovascular Center, University Hospital, Bern, Switzerland
3 Beth Israel Deaconess Medical Center, Harvard University, Boston, MA, USA
4 Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia

* To whom correspondence should be addressed.
Robert Rieben, E-mail: robert.rieben{at}dkf.unibe.ch


  Abstract

Aims Intravascular inflammatory events during ischaemia/reperfusion injury following coronary angioplasty alter and denudate the endothelium of its natural anticoagulant heparan sulfate proteoglycan (HSPG) layer, contributing to myocardial tissue damage. We propose that locally targeted cytoprotection of ischaemic myocardium with the glycosaminoglycan analogue dextran sulfate (DXS, MW 5000) may protect damaged tissue from reperfusion injury by functional restoration of HSPG.

Methods and results In a closed chest porcine model of acute myocardial ischaemia/reperfusion injury (60 min ischaemia, 120 min reperfusion), DXS was administered intracoronarily into the area at risk 5 min prior to reperfusion. Despite similar areas at risk in both groups (39 ± 8% and 42 ± 9% of left ventricular mass), DXS significantly decreased myocardial infarct size from 61 ± 12% of the area at risk for vehicle controls to 39 ± 14%. Cardioprotection correlated with reduced cardiac enzyme release creatine kinase (CK-MB, troponin-I). DXS abrogated myocardial complement deposition and substantially decreased vascular expression of pro-coagulant tissue factor in ischaemic myocardium. DXS binding, detected using fluorescein-labelled agent, localized to ischaemically damaged blood vessels/myocardium and correlated with reduced vascular staining of HSPG.

Conclusion The significant cardioprotection obtained through targeted cytoprotection of ischaemic tissue prior to reperfusion in this model of acute myocardial infarction suggests a possible role for the local modulation of vascular inflammation by glycosaminoglycan analogues as a novel therapy to reduce reperfusion injury.

Keywords: Ischaemia reperfusion injury; Dextran sulfate; Cytoprotection; Endothelium.
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