Acute perioperative stress-induced increase of plaque volume and vulnerability in apolipoprotein E-deficient mice is amenable to statin treatment and IL-6-inhibition

Abstract

Myocardial infarction and stroke are frequent after surgical procedures and consume a considerable amount of benefit of surgical therapy. Perioperative stress, induced by surgery, is composed of hemodynamic and inflammatory reactions. The effects of perioperative stress on atherosclerotic plaques are ill-defined. Murine models to investigate the influence of perioperative stress on plaque stability and rupture are not available. We developed a model to investigate the influence of perioperative stress on plaque growth and stability by exposing apolipoprotein E-deficient mice, fed a high cholesterol diet for 7 weeks, to a double hit consisting of 30 minutes of laparotomy combined with a substantial blood loss (20% body weight; 400µl). The innominate artery was harvested 72 hours after the intervention. Control groups were sham and baseline controls. Interleukin-6 (IL-6) and Serum Amyloid A plasma levels were determined. Plaque load VSMC- and macrophage-content were quantified. Plaque stability was assessed using the Stary score and frequency of signs of plaque rupture. High-dose atorvastatin (80 mg/kg body weight/day) was administered for 6 days starting 3 days prior to double hit. A single dose of an IL-6-neutralizing antibody or the fusion protein sgp130-Fc selectively targeting IL-6 trans-signaling was subcutaneously injected. IL-6 plasma levels increased peaking at 6h after the intervention. SAA levels peaked at 24 hours (n=4, p<0.01). Plaque volume increased significantly with the double hit compared to sham (n=8, p<0.01). More plaques were scored as complex or bearing signs of rupture after the double hit compared to sham (n=5-8, p<0.05). Relative VSMC and macrophage content remained unchanged. IL-6-inhibition or atorvastatin, but not blocking of IL-6 trans-signaling, significantly decreased plaque volume and complexity (n=8, p<0.01), Using this model, researchers will be able to further investigate the pathophysiology of perioperative plaque stability, which can result in myocardial infarction, and additionally, to test potential protective strategies.