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Adjunctive selectin blockade successfully reduces infarct size beyond thrombolysis in the electrolytic canine
M J Silver1, J M Sutton, S Hook
1Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Cardiology, Cleveland Clinic Foundation, OH 44195, USA.
Insights
Selectin blockade with CY 1503 significantly reduced myocardial infarct size and neutrophil infiltration in a canine model of ischemia-reperfusion injury. This adjunctive therapy enhances thrombolysis by mitigating inflammatory responses post-reperfusion.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Inflammation Biology
Background:
- Ischemia-reperfusion injury contributes to myocardial damage after thrombolytic therapy.
- Neutrophil infiltration, a key inflammatory response, exacerbates this injury.
- Selectins are adhesion molecules crucial for neutrophil migration to injured tissues.
Purpose of the Study:
- To evaluate the efficacy of a selectin blocker, CY 1503, as an adjunct to thrombolysis.
- To determine if CY 1503 can reduce myocardial infarct size by interfering with ischemia-reperfusion-induced inflammation.
- To assess the impact of selectin blockade on neutrophil infiltration in a canine model.
Main Methods:
- An electrolytic canine model was used to induce coronary artery occlusion and subsequent reperfusion.
- Dogs received recombinant tissue-type plasminogen activator (rTPA) with either placebo or CY 1503.
- Infarct size, myocardial myeloperoxidase activity (a marker of neutrophil infiltration), and reperfusion arrhythmias were measured post-reperfusion.
Main Results:
- CY 1503 treatment resulted in a significant 69% reduction in infarct size compared to placebo.
- Myeloperoxidase activity was markedly reduced in the CY 1503 group, indicating decreased neutrophil infiltration.
- No significant difference in reperfusion arrhythmias was observed between the groups.
Conclusions:
- Selectin blockade with CY 1503 is an effective adjunctive therapy to thrombolysis for reducing myocardial infarct size.
- Neutrophils are potent mediators of ischemia-reperfusion injury, and their infiltration can be targeted to limit damage.
- These findings support the potential of selectin blockade in managing myocardial ischemia-reperfusion injury.
Background:
An adjunctive pharmacological strategy to thrombolytic therapy that is tailored to limit reperfusion injury after thrombolysis could further maximize the unquestioned benefit of restoring flow to ischemic myocardium. Ischemia-reperfusion injury exhibits features characteristic of an acute inflammatory response, including the rapid activation and infiltration of neutrophils. The initial process of neutrophil migration from the circulation to injured tissue is modulated by a group of adhesion molecules called selectins. The purpose of the present study was to assess the efficacy of a selectin blocker (CY 1503) given as an adjunct to thrombolytic therapy to interfere with the inflammatory response after ischemia-reperfusion and subsequently reduce myocardial infarct size in the electrolytic canine model.
Methods And Results:
A fully occlusive thrombus was formed in the left circumflex coronary artery by electrolytic injury in 20 anesthetized open-chest dogs. After occlusion, an infusion of 1 mg/kg recombinant tissue-type plasminogen activator (rTPA) was administered over 20 minutes with either a bolus of placebo or the selectin blocker CY 1503 (40 mg/kg). At the onset of reperfusion, 20 micrograms/kg per minute rTPA was administered for 1 hour to prevent reocclusion. After 1 hour of reperfusion, infarct size, myocardial myeloperoxidase activity, and reperfusion arrhythmias were measured. In CY 1503-treated dogs, there was a significant 69% reduction in infarct size when expressed as a percentage of the area at risk (6.7 +/- 8.4% versus 21.8 +/- 13.6%; P = .008) and a marked reduction in myeloperoxidase activity (0.014 +/- 0.009 versus 0.0370 +/- 0.025 U/min per gram; P = .02) compared with the placebo group. There was no difference between the groups in the occurrence of reperfusion arrhythmias.
Conclusions:
Selectin blockade as an adjunct to rTPA-mediated thrombolysis significantly reduces infarct size and myocardial neutrophil infiltration well beyond thrombolysis alone in the electrolytic canine model. These data suggest that selectin blockade is extremely effective at reducing ischemia-reperfusion injury and myocardial infarct size in this model and that the neutrophil is a potent mediator of ischemia-reperfusion injury.