0267: Protective effect of TREM-1 modulation during myocardial infarction in rats

Abstract

Myocardial healing after infarction is hampered by reperfusion injury and ventricular remodeling, partly mediated by detrimental inflammatory responses via Toll-like Receptors (TLRs) signaling. We hypothesized that modulation of the Triggering Receptor Expressed on Myeloid cells-1 (TREM-1), an amplifier of the innate inflammatory response, by the use of a small synthetic peptide, namely LR-12, could improve myocardial injury in a rat model of myocardial infarction. Wistar rats underwent either permanent occlusion of the left coronary artery or transient ischemia for 60 minutes followed by reperfusion. They were randomly assigned to receive LR-12 or vehicle for 5 days. Cardiac function and dimensions were assessed at baseline through positron emission tomography (PET) imaging and 6 weeks after infarction by PET and conductance catheter. Following permanent ischemia, LR-12 treatment significantly reduced ventricular remodeling, as assessed by a lesser increase of end-diastolic volume measured by PET (273±77 vs 198±95 μL; p=0.007), and improved the systolic function: ESPVR (0.98±0.43 vs 1.45±0.49 mmHg.μL-1, p=0.04) or preload recruitable stroke work PRSW (55±23 vs 80±34 mmHg.μL-1, p=0.03). During transient ischemia, LR-12 infusion just before and for 5 days after reperfusion also improved myocardial contractility assessed by conductance catheter (PRSW: 64±25 vs 96±26 mmHg.μL-1, p=0.02; ESPVR 1.00±0.30 vs 1.61±0.69 mmHg.μL-1, p=0.05). Activation of immune response after myocardial infarction is a double-edged sword: mandatory for wound healing, but deleterious during reperfusion injury and ventricular remodeling. Inhibition of TREM-1 with LR-12 does not inhibit inflammation but modulates the amplification of the inflammatory response. LR-12, by inhibiting TREM-1, improves ventricular remodeling and myocardial contractility in different experimental models of myocardial infarction.