Pharmacological inhibition of the triggering receptor expressed on myeloid cells-1 limits reperfusion injury in a porcine model of myocardial infarction

Abstract

Aims: Limitation of ischemia/reperfusion injury is a major therapeutic target after acute myocardial infarction (AMI). Toll-like receptors are implicated in the inflammatory response that occurs during reperfusion. The triggering receptor expressed on myeloid cells (TREM)-1 acts as an amplifier of the immune response triggered by toll-like receptor engagement. We hypothesized that administration of a TREM-1 inhibitory peptide (LR12) could limit reperfusion injury in a porcine model of AMI.

Methods and results: AMI was induced in 15 adult minipigs by a closed-chest coronary artery occlusion-reperfusion technique. Animals were randomized to receive LR12 or vehicle before reperfusion (LR12 n = 7, vehicle n = 8), and were monitored during 18 h. AMI altered hemodynamics and cardiac function, as illustrated by a drop of mean arterial pressure, cardiac index, cardiac power index, ejection fraction, and real-time pressure-volume loop-derived parameters. TREM-1 inhibition by LR12 significantly improved these dysfunctions (P < 0.03) and limited infarct size, as assessed by lower creatine phosphokinase and troponin I concentrations (P < 0.005). Pulmonary, renal, and hepatic impairments occurred after AMI and were attenuated by LR12 administration as assessed by a better PaO₂ to FiO₂ ratio, a less positive fluid balance, and lower liver enzymes levels (P < 0.05).

Conclusion: Inhibition of the TREM-1 pathway by a synthetic peptide limited myocardial reperfusion injury in a clinically relevant porcine model of AMI.

Keywords: Immune system; Inflammation; Myocardial infarction; Reperfusion.

Figure 1

Experimental timeline. LAD, left anterior descending coronary artery; PBS, phosphate‐buffered saline; MAP, mean arterial pressure; SvO₂, mixed venous oxygen saturation; HR, heart rate; MPAP, mean pulmonary arterial pressure; EDV, end‐diastolic volume; ESV, end‐systolic volume; LVEF, left ventricular ejection fraction; dP/dtmax, pressure development during isovolumic contraction; dP/dtmin, pressure development during isovolumic relaxation; VCO, vena cava occlusion; ESPVR and EDPVR, end‐systolic and end‐diastolic pressure volume relationship; Emax, maximal ventricular elastance; PRSW, preload recruitable stroke work; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CK, creatine phosphokinase.

Figure 2

LR12 improves hemodynamics. Evolution of mean arterial pressure (A), heart rate (B), cardiac index (C), and SvO₂ (D) during the study period. Hemodynamics parameters were improved in LR12‐treated animals as compared with control ones.

Figure 3

LR12 improves cardiac function. Evolution of cardiac power index (A) left ventricular ejection fraction (B), stroke volume (C), stroke work (D), preload recruitable stroke work (E), and pressure‐volume area (F) during the study period. Cardiac dysfunction was attenuated by LR12 treatment.

Figure 4

LR12 improves remote organ dysfunction and limit infarct size. Evolution of creatine phosphokinase (A), and troponin I plasma concentration (B), fluid balance (C), and PaO₂ to FiO₂ ratio (D) during the study period. Myocardial infarction was associated with impaired renal function, outlined by highly positive fluid balance, and altered gas exchange. These dysfunctions were corrected by LR12 administration. Moreover, LR12 limited infarct size, as assessed by lower creatine phosphokinase and troponin I levels throughout the study period.