Abstract 15997: Cardioprotective Effects of Intracoronary Administration of 4-Chlorodiazepam in Small and Large Animal Models of Ischemia-Reperfusion
Introduction: The Translocator Protein (TSPO) of the mitochondrial membrane has been recognized as a potential therapeutic target for mitigation of myocardial ischemia-reperfusion injury. Administration of 4-chlorodiazepam (4-CLD), a TSPO ligand, has been shown to confer acute cardioprotective effects in small animals; however, long-term studies and studies in clinically-relevant large animal models are lacking. We investigated a potential cardioprotective effect of intracoronary administration of 4-CLD in small and large animal models of ischemia-reperfusion.
Methods: Acute myocardial infarction (MI) was induced in 38 Wistar rats and 29 farm pigs by ligation of the left anterior descending coronary artery, followed by reperfusion. Animals were randomized to undergo intracoronary infusion of 2 μM 4-CLD or vehicle just prior (pigs) or immediately after (rats) reperfusion. Infarcted rats were euthanized either after 1 hour of reperfusion (for histological assessment of the “no reflow” area) or after 60 days (for serial evaluation of cardiac function and structure by echocardiography and histological assessment of infarct size). Infarcted pigs were euthanized after 2 hours of reperfusion for histological assessment of infarct size and “no reflow” area.
Results: In infarcted rats, intracoronary infusion of 4-CLD resulted in acute reduction of the “no reflow” area and conferred durable long-term structural and functional benefits (reduction in infarct size, decreased end-diastolic and end-systolic volumes, improvement in ejection fraction at 60 days post-MI). In infarcted pigs, intracoronary infusion of 4-CLD was well-tolerated from a hemodynamic standpoint and resulted in acute reduction in infarct size (4-CLD: 78±13% of area at risk vs controls: 89± 10%, p=0.034), reduction in “no reflow” area (4-CLD: 7±5% of area at risk vs controls: 26±12%, p<0.001) and more rapid resolution of ST-segment elevation.
Conclusions: In a rat model of MI, intracoronary administration of 4-CLD attenuated the “no reflow” phenomenon and produced long-term structural and functional benefits. In a porcine model of MI intracoronary administration of 4-CLD did not raise safety concerns and conferred acute cardioprotective effects.
Author Disclosures: C. Kapelios: None. L. Katsaros: None. M. Tsamatsoulis: None. S. Vakrou: None. V. Sousonis: None. S. Sventzouri: None. D. Perrea: None. J. Nanas: None. K. Malliaras: None.
- © 2016 by American Heart Association, Inc.