Insulin‐like growth factor I reduces atherosclerosis in Rapacz pigs

Abstract

Cardiovascular disease is the leading cause of mortality in the Western world and its manifestations result in large part from atherosclerotic lesion development and destabilization. We have reported previously that administration of insulin-like growth factor I (IGF-1) reduced atherosclerosis in the murine model. To test the effect of IGF-1 on human-like atherosclerosis we injected 50 ug/kg recombinant human IGF-1 or saline (control) (n=9/group) into high-fat diet fed Rapacz familial hypercholesterolemic (FH) swine for 6 months. We quantified vessel volume, atherosclerotic burden (% of volume of atherosclerotic plaque + media per vessel volume), lumen volume and assessed plaque phenotype in coronary arteries using intravascular ultrasound (IVUS) at time 0 and after 3 and 6 months on the diet. IGF-1-injected pigs had on average 2.6-fold increase in total plasma IGF-1 (ELISA, p<0.001 vs. control pigs). Pigs in the IGF-1 and control group gradually gained weight over the time of experiment, however pigs in the IGF-1 group had a larger increase in BW compared to controls at 6 months (IGF-1, 60.6±7.4% increase vs. saline, 44.3±4.0% increase, p<0.05) consistent with growth-stimulating effects of IGF-1. Pigs in both groups had a gradual increase in vessel volume in the right coronary artery (RCA), left anterior descending artery (LAD) and left circumflex artery (LCX) with time as quantified by serial IVUS. However, IGF-1-injected pigs had a larger increase in vessel volume after 3 and 6 months compared to controls suggesting vascular hypertrophy. The atherosclerotic burden was increased in RCA, LAD and LCX in both groups after 3 and 6 months of injections compared to the pre-injection time point. We found a significant reduction in atherosclerotic burden in RCA and LAD in IGF-1 group compared to control at 6 months’ time-point (RCA: IGF-1, 203±13%, vs. control, 244±8; LAD: IGF-1, 200±6%, vs. control, 228±11%). The lumen volume of coronaries was decreased in both groups, however, coronaries in IGF-1-injected pigs had on average 24±3% larger lumen volume compared to control pigs at 6 months’ time-point. We used virtual histology (VH) post-IVUS image processing to assess plaque composition and to classify plaque sub-types. Pigs in both groups had a progressive increase in plaque calcification, necrotic core area, fibrous plaque and fibro-fatty plaque area. IGF-1 did not significantly change plaque composition. In summary, we report that IGF-1 increased pig BW, and total volume of coronaries suggesting hypertrophy and these data are consistent with growth-stimulating effects of IGF-1. We found a significant reduction in atherosclerotic burden and increase in lumen volume in coronaries in the IGF-1 group after 6 months of injections consistent with an anti-atherosclerotic effect of IGF-1. Our data support the feasibility of using IGF-1 as an anti-atherogenic therapy.