Evaluation of multimeric tyrosine-O-sulfate as a cytoprotectant in an in vivo model of acute myocardial infarction in pigs.

Abstract

OBJECTIVES:

Intracoronary administration of glycosaminoglycan analogs, including the complement inhibitor dextran sulfate, attenuates myocardial ischemia/reperfusion injury (I/R injury). However, dextran sulfate has a distinct anticoagulatory effect, possibly limiting its use in specific situations in vivo. We therefore developed multimeric tyrosine sulfate (sTyr-PAA), a novel, minimally anticoagulatory, fully synthetic non-carbohydrate-containing polyacrylamide conjugate, for in vivo testing in an acute closed-chest porcine model of acute myocardial infarction.

METHODS:

Following balloon occlusion of the left anterior descending artery just after the first diagonal branch (60-minute ischemia), sTyr-PAA (approx. 10 mg/kg bodyweight, fraction with strongest complement-inhibitory and minimal anticoagulatory properties, n = 11) or phosphate-buffered saline (controls, n = 9) was administered intracoronarily into ischemic myocardium prior to 120 min of reperfusion.

RESULTS:

sTyr-PAA significantly reduced infarct size (from 61.0 ± 12.0% of the ischemic area at risk to 39.4 ± 17.0%), plasma creatine kinase, local complement deposition and tissue factor upregulation, without affecting systemic coagulation. Protection was associated with significantly reduced myocardial neutrophil extravasation and translated into a significant improvement of ejection fraction and left ventricular enddiastolic pressure.

CONCLUSIONS:

sTyr-PAA protected significantly against myocardial I/R injury without substantially affecting systemic coagulation. Local intravascular sTyr-PAA administration may prove advantageous in situations where bleeding complications are likely or are to be avoided at all costs.

• Authors: Yara Banz, Otto M Hess, Pascal Meier, Elena Y Korchagina, Elena A Gordeeva, Simon C Robson, Thusitha Gajanayake, Eva Csizmadia, Daniel Mettler, André Haeberli, Nicolai V Bovin, Robert Rieben
• Journal: Cardiology (Cardiology) Vol. 121 Issue 1 Pg. 59-70 ( 2012) ISSN: 1421-9751 [Electronic] Switzerland
• PMID: 22398380 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 S. Karger AG, Basel.

Chemical References

• Anticoagulants
• Complement Inactivating Agents
• tyrosine O-sulfate
• Tyrosine
• Thromboplastin

Topics

• Animals
• Anticoagulants (pharmacology)
• Complement Inactivating Agents (pharmacology)
• Complement Pathway, Classical (drug effects)
• Cytoprotection (drug effects)
• Dose-Response Relationship, Drug
• Granulocytes (pathology)
• Hemodynamics (drug effects)
• Myocardial Infarction (complications, immunology)
• Myocardial Reperfusion
• Myocardial Reperfusion Injury (immunology, pathology, prevention & control)
• Neutrophils (pathology)
• Sus scrofa
• Thromboplastin (metabolism)
• Tyrosine (analogs & derivatives, pharmacology)
• Ventricular Fibrillation (chemically induced)