Abstract 3194: Imaging Matrix Metalloproteinase Activity in Atherosclerotic Plaque of Diabetic, Hyperlipidemic Swine
Background- Matrix metalloproteinases (MMP) are secreted by macrophages in atheroscle-rotic lesions and have been implicated in the destruction of connective tissue essential for plaque stability. We tested the hypothesis that active MMPs could be non-invasively detected in the arterial vasculature on SPECT images using a Tc99m-labeled broad spectrum matrix metalloproteinase inhibitor (MPI) in a large animal model of accelerated atherosclerosis, the diabetic, hyperlipidemic pig.
Methods- Castrated male Yorkshire pigs (n=5), each weighing 19 +/− 2 kg were treated with streptozotocin (50mg/kg) for 3 days. The pigs were fed a daily diet of 1.5% cholesterol and 15% lard. Fasting blood sugar and cholesterol levels were monitored. At 5.5 +/− 1 month, they were injected with 837 +/−42 MBq of Tc99m-MPI and were imaged 228 +/−50 minutes later on a Philips Precedence-16P scanner. The pigs were immediately sacrificed. The coronaries, aorta, innominate, carotids and iliacs were excised for pathology and imaged ex vivo en block. Quantitative analysis of SPECT images was done by ROI analysis on a Philips Jet Stream workstation.
Results- The pigs had fasting blood glucoses of 354 +/−95 mg/dl and total cholesterols of 395 +/−156 mg/dl. SPECT images showed Tc99m-MPI uptake, reported as % of injected dose, in the aortic root (0.18 +/− 0.04), in the arch (0.17 +/−0.06) and in the descending aorta (0.14 +/− 0.05) in all 5 pigs and in the innominate artery (0.004 +/− 0.05) in 3 of 5 pigs. No tracer uptake was seen in the coronaries. The % of injected dose was similar in ex vivo images of the aortic root (0.18 +/− 0.6), of the arch (0.20 +/− 0.09), of the descending aorta (0.12 +/− 0.06) in all pigs and of the innominate artery (0.06 +/− 0.04) in 4/5 pigs. In vivo % injected dose correlated significantly (R2=0.6, p<0.001) with ex vivo % injected dose. On pathology minimal atherosclerotic changes were seen in the coronaries. Fatty streaks with lipid-laden macrophages were seen in the aortae.
Conclusions- In these pigs atherosclerosis at 5.5 months was not advanced; nevertheless MMP activation can be detected non-invasively by Tc99m-MPI in AHA Type 1 and 2 lesions.