Arterial remodeling after experimental percutaneous injury is highly dependent on adventitial injury and histopathology

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Abstract

Background: The extent and nature of unfavorable geometric remodeling, especially related to the adventitia, has not been studied previously. The purpose of this study was to examine two methods of experimental arterial injury, characterize the extent of remodeling, and determine if remodeling is injury-specific. Methods: Two methods for producing coronary stenoses in pigs were used: heat injury using thermal balloon angioplasty (resulting in adventitial fibrosis), and copper stent implantation (resulting in intense inflammation). Histomorphometric parameters included changes in neointimal thickness (delta neointima) from uninjured to injured sections, and differences in area circumscribed by the internal and external elastic laminas (delta internal elastic lamina area and delta external elastic lamina area, respectively). Remodeling was calculated for each lesion as the enlargement of the external elastic lamina area or internal elastic lamina area for incremental neointimal thickening, expressed as the slopes delta external elastic lamina area/delta neointima and delta internal elastic lamina area/delta neointima. Results: Remodeling indices for the heat lesions were negative (delta internal elastic lamina area/delta neointima=−0.15, delta external elastic lamina area/delta neointima=−0.64) and indicated little remodeling in contrast to copper stent injury (delta internal elastic lamina area/delta neointima=0.95, delta external elastic lamina area/delta neointima=1.20). Conclusions: Remodeling in fibrotic compared to inflammatory lesions differs markedly, and may explain increased restenosis rates observed in thermal balloon angioplasty in patients. This formulation may be useful to study remodeling and restenosis following other interventional technologies.

Introduction

Restenosis after coronary artery percutaneous intervention is multifactorial. While neointimal hyperplasia is frequently cited as a major cause 1, 2, 3, 4, 5, data also suggest that arterial remodeling may play a critical role 6, 7, 8, 9, 10, 11, 12, 13. That this may be true is suggested by the observation that pharmacologic strategies to control this process have failed 14, 15.

In the post-interventional setting, remodeling can be either favorable for maintaining the size of the vessel lumen (where the artery expands to compensate for neointimal thickening), or unfavorable where the vessel either does not expand or constricts, with consequent decrease in lumen size. We hypothesized that differences in remodeling might depend on the adventitial response to injury since the ability of an artery to expand or constrict might rely on the histopathologic nature of the response. We thus studied two types of coronary artery injury in a porcine model that exhibits markedly different adventitial responses, and quantitatively examined the results of subsequent arterial remodeling. Both thermal injury and copper stent implantation have recently been found to produce severe angiographic coronary stenoses in the porcine coronary model [16]. Thermal injury using high temperature balloons results in cell death and adventitial fibrosis, whereas copper stent implantation causes an adventitial response that is highly inflammatory. By inducing two very different adventitial histopathologic responses, we could examine the resulting remodeling effects.

Section snippets

Methods

All studies were approved by the Mayo Foundation Institutional Animal Care and Use Committee. Eighteen arteries from 12 pigs with thermal injury and 13 arteries from 10 pigs with copper stent implantation were studied. Study animals were female swine weighing 22–37 kg fed normal pig chow. To decrease acute closure after injury, premedication with aspirin 650 mg and sustained-release verapamil 120 mg was given the night before the procedure. Pigs were anesthetized with ketamine and xylazine

Heat injured arteries

Mean histopathologic and angiographic stenosis for the heat group was 62±26% and 58±31%, respectively. Table 1 shows data for the remaining parameters. The mean decrease in lumen area between lesion and reference sites (delta lumen) was 1.15±0.83 mm2. Mean delta neointima was 1.10±0.48 mm2 and mean delta internal elastic lamina area was −0.05±0.62 mm2. Mean external elastic lamina area gain (delta external elastic lamina area) was 0.21±0.90 mm2.

Copper stent injured arteries

The average histopathologic stenosis was 80±23%;

Discussion

Remodeling was first described for atherosclerosis in an autopsy study in 1972 of African Masai tribesmen [18]. This study showed coronary artery lumen area was maintained despite voluminous atherosclerotic plaque. Subsequent studies demonstrated similar results 19, 20, 21. Human coronary arteries may demonstrate unfavorable remodeling (vessel contraction) after interventional therapy, as documented by intravascular ultrasound in preliminary reports [9]. Loss of arterial size has been found in

Acknowledgements

This work was supported by a grant from the J. Holden DeHaan Foundation, Naples, FL.

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