Time Course of Cellular Proliferation, Intimal Hyperplasia, and Remodeling Following Angioplasty in Monkeys With Established Atherosclerosis

Abstract

Animal models of arterial injury have failed to predict effective therapy to prevent restenosis in humans. While this may relate to species differences in the control of smooth muscle cell growth, many studies have used nonatherosclerotic animals, thereby failing to consider the importance of atherosclerosis in the response to injury. In an attempt to model human restenosis more accurately, we characterized the response to angioplasty in atherosclerotic monkeys. Twenty-one cynomolgus monkeys were fed an atherogenic diet for 36 months (plasma cholesterol, 12 +/- 1 mmol/L [470 +/- 23 mg/dL]). Angioplasty was then performed in the left iliac artery. After 4, 7, 14, or 28 days, bromodeoxyuridine was given to label proliferating cells, and iliac arteries were fixed in situ at physiological pressure (5 or 6 animals at each time point). Comparisons were made between injured and uninjured iliac arteries within each animal. Angioplasty often fractured the intimal plaque and media, transiently increasing lumen caliber (4 days: lumen area, 232.5 +/- 80.3% of control) and artery size as reflected by external elastic lamina area (EEL). EEL and lumen caliber returned to baseline by 7 days. Proliferation was increased throughout the artery wall at 4 and 7 days and later declined to control rates (4 days, injured versus uninjured: adventitia, 45.0 +/- 6.2% versus 16.3 +/- 7.2%; media, 8.6 +/- 2.6% versus 0.6 +/- 0.1%; intima, 16.0 +/- 5.6% versus 7.8 +/- 3.1%). The intima thickened markedly from 14 to 28 days, but an increase in EEL generally prevented further loss of the short-term gain in lumen caliber (28 days, percent of control: intimal area, 342.8 +/- 88.9%; EEL area, 150.2 +/- 28.9%; lumen area, 119.3 +/- 21.3%). The response to angioplasty in atherosclerotic monkeys appears to closely resemble that in humans. Plaque fracture, delayed recoil, intimal hyperplasia, and remodeling may each be important in determining late lumen caliber. This primate model should prove valuable in defining cellular and biochemical mediators of human restenosis.

Preclinical Models of Restenosis and Their Application in the Evaluation of Drug-Eluting Stent Systems

“…11,155 Studies that have been conducted to date in normal and atherosclerotic nonhuman primate models have provided valuable insight with regard to vascular responses to injurious stimuli, atherosclerosis, and the influence of genetics on vascular pathophysiology. 30,57,192 Nonetheless, the paucity of studies in nonhuman primate models utilizing either balloon angioplasty or stent implantation and the relative inconsistencies among studies are further shortcomings. 64,186 Model Selection, Application, and Limitations Each preclinical model of ISR has a unique set of attributes, assumptions, and limitations.…”

Downregulation of cyclin-dependent kinase 2 activity and cyclin A promoter activity in vascular smooth muscle cells by p27(KIP1), an inhibitor of neointima formation in the rat carotid artery.

“…Although the occurrence of restenosis in ‫ف‬ 20-55% of patients after clinically successful revascularization remains the major limitation to percutaneous transluminal coronary angioplasty (6)(7)(8)(9)(10)(11), no clinical trials have yet demonstrated convincing effects in reducing the incidence of restenosis (12)(13)(14). Previous studies using several models of angioplasty have demonstrated a rapid proliferative response of VSMCs in the media, followed by a second peak of proliferation in the neointima, which then declines to basal levels by 2-4 wk after angioplasty (15)(16)(17)(18). While the contribution of several cell cycle control genes and growth stimulatory genes to VSMC growth has been well established (19)(20)(21)(22)(23)(24)(25)(26)(27)(28), the endogenous factors underlying the reestablishment of the quiescent phenotype in VSMCs after angioplasty are largely unknown.…”

Temporary placement of a paclitaxel or rapamycin-eluting stent is effective to reduce stenting induced inflammatory reaction and scaring in benign cardia stricture models

“…Several studies have investigated the pathological mechanisms of arterial stenosis in recent years (17)(18)(19). Currently, most of the drugs used in eluting stents aim to inhibit the inflammatory reaction, or reduce cell proliferation and fibrosis to prevent lumen stenosis (11,12).…”