Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia.

Abstract

Restenosis after successful PTCA remains a major problem limiting the efficacy of the procedure. The pathophysiologic mechanism of restenosis has been enigmatic so far, but accumulated evidence strongly suggests that intimal hyperplasia is the major mechanism. Based on current understanding of the process of intimal hyperplasia, one unifying concept may be that there are at least two major local biologic determinants influencing this process, lesion characteristics and regional flow dynamics. Lesion characteristics include the plaque structure and the quantity of smooth muscle. These may provide the anatomic substrate that determines the extent of injury and the degree of smooth muscle cell proliferation. The amount of smooth muscle cells in the stenotic lesion activated by injury to undergo proliferation may determine the eventual bulk of the restenotic lesion. In addition, low wall shear stress could promote intimal hyperplasia and cause structural change of vessels to decrease the lumen, whereas high wall shear stress exerts the opposite effects. Intimal hyperplasia after balloon injury is a complex process involving platelets, growth factors, endothelial cells, smooth muscle cells, mechanical injury, wall shear stress, and probably other unknown factors. Platelets not only contribute growth factors such as PDGF but also cause organized thrombus. Different growth factors may be involved in initiating smooth muscle cell proliferation and may come from many different sources, including smooth muscle cells, endothelial cells, and macrophages. Intact confluent endothelial cells may produce heparin sulfates and inhibit intimal proliferation; however, regenerating endothelial cells may have the opposite effect. Thus, the proliferative potential of smooth muscle cells, endothelial recovery, extent of injury, wall shear stress, and other unknown factors may all influence this process. Based on these concepts concerning the biology of restenosis, some research directions concerning potential forms of therapy are proposed.

Flow affects development of intimal hyperplasia after arterial injury in rats.

“…Atherosclerotic plaques, intimal hyperplasia after angioplasty, and vein graft thickening are all increased in areas of low shear. 9 - 18 The purpose of this study was to examine the effect of shear in a well-established model of intimal hyperplasia after balloon catheter injury of the rat common carotid artery. 19 - 21 Flow through the injured artery was altered by ligation of the opposite common carotid artery (increased flow) or of the ipsilateral internal carotid artery (decreased flow).…”

Berberine suppresses MEK/ERK-dependent Egr-1 signaling pathway and inhibits vascular smooth muscle cell regrowth after in vitro mechanical injury

“…However, restenosis after angioplasty is still a major limitation [1][2][3]. Restenosis occurs in approximately 30-40% of patients after balloon angioplasty and in between 20 and 30% of patients following coronary stenting [4,5].…”

“…Injury induces medial and then intima cell cycle reentry, following a wave of immediate early gene expression [1,6]. Cells undergo either cell proliferation, migration or both, with subsequent synthesis of extracellular matrix and collagen resulting in neointimal formation [1][2][3].…”

Radiation therapy to prevent coronary artery restenosis

“…The gradual development of the concept that restenosis was the end-result of an uncontrolled proliferation of tissue at the injury site laid the groundwork for radiation being tested in this area. 13,14,15,16 In vitro studies had demonstrated the inhibition of proliferation of arterial smooth muscle cells (SMC's) and fibroblasts as well as decreased collagen synthesis by fibroblasts. 17,18,19 The development of the porcine overstretch balloon injury model of restenosis has provided an excellent model in which to evaluate new therapies since as radiation.…”