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


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.


CONCLUSIONS
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.
Banz
Yara
Y
Department of Clinical Research, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland.
Hess
Otto M
OM
Robson
Simon C
SC
Mettler
Daniel
D
Meier
Pascal
P
Haeberli
André
A
Csizmadia
Eva
E
Korchagina
Elena Y
EY
Bovin
Nicolai V
NV
Rieben
Robert
R
D000818:Animals; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000502:physiology; D003167:Complement Activation; D003402:Creatine Kinase / Q000097:blood; D016264:Dextran Sulfate / Q000627:therapeutic use*; D007150:Immunohistochemistry; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008026:Ligation; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010952:Plasma Substitutes / Q000627:therapeutic use*; D011897:Random Allocation; D013552:Swine; D019210:Troponin I / Q000097:blood
D015415:Biomarkers; D010952:Plasma Substitutes; D019210:Troponin I; D016264:Dextran Sulfate; D003402:Creatine Kinase