Morphologic characteristics of lesion formation and time course of smooth muscle cell proliferation in a porcine proliferative restenosis model

Abstract

Objectives: This study was performed to define the evolution of lesion morphology and its relation to thrombus formation and smooth muscle cell proliferation after experimental coronary stent placement.

Background: Restenosis after percutaneous revascularization may develop because of thrombus accumulation and smooth muscle cell proliferation. In animal models of restenosis, thrombus may assume a significant role in neointimal formation by providing an absorbable matrix into which smooth muscle cells proliferate.

Methods: Twenty-eight oversized stents were placed in the coronary arteries of 23 juvenile domestic pigs. The histologic degree of vessel injury, lesion morphometry and smooth muscle cell proliferation measured by immunolocalization with a monoclonal antibody to proliferating cell nuclear antigen (PCNA) were assessed at 24 h and 7, 14 and 28 days after stent placement.

Results: The area of thrombus was minimal at 24 h ([mean +/- SE] 0.44 +/- 0.12 mm2). Neointimal area at 7 days (0.72 +/- 0.20 mm2) was similar to the area of thrombus, followed by a significant increase at 14 days (3.15 +/- 0.39 mm2) and 28 days (3.30 +/- 0.28 mm2) (p < 0.0036, 24 h and 7 days vs. 14 and 28 days). At 14 and 28 days, neointimal thickness correlated with the histologic degree of vessel injury (p < 0.003). In arteries with severe injury, the increase in neointimal thickness is accounted for by replacement of the damaged media. The smooth muscle cell proliferation index was 18.6 +/- 3.5% at 7 days compared with 9.6 +/- 1.3% by 14 days (p = 0.0247) and declined to 1.1 +/- 0.97% by 28 days (p < 0.008, 7 and 14 days vs. 28 days).

Conclusions: Early thrombus formation is minimal, and thrombus accounts for a small portion of subsequent neointimal formation. Smooth muscle cell proliferation and matrix formation are the major factors relating to neointimal formation in this proliferative model of restenosis. The evolution of neointimal formation after coronary stenting shows maximal smooth muscle cell proliferation at 7 days, with a decline to low levels by 28 days. Therefore, these data may be useful for developing effective therapies for restenosis.