TIME-COURSE OF CELLULAR PROLIFERATION, INTIMAL HYPERPLASIA, AND REMODELING FOLLOWING ANGIOPLASTY IN MONKEYS WITH ESTABLISHED ATHEROSCLEROSIS - A NONHUMAN PRIMATE MODEL OF RESTENOSIS

Animal models of arterial injury have failed to predict effective ther apy 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 respo nse to angioplasty in atherosclerotic monkeys. Twenty-one cynomolgus m onkeys 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 w as given to label proliferating cells, and iliac arteries were fixed i n situ at physiological pressure (5 or 6 animals at each time point). Comparisons were made between injured and uninjured iliac arteries wit hin each animal. Angioplasty often fractured the intimal plaque and me dia, 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 day s. Proliferation was increased throughout the artery wall at 4 and 7 d ays and later declined to control rates (4 days, injured versus uninju red: 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%). Th e intima thickened markedly from 14 to 28 days, but an increase in EEL generally prevented further loss of the short-term gain in lumen cali ber (28 days, percent of control: intimal area, 342.8 +/- 88.9%; EEL a rea, 150.2 +/- 28.9%; lumen area, 119.3 +/- 21.3%). The response to an gioplasty in atherosclerotic monkeys appears to closely resemble that in humans. Plaque fracture, delayed recoil, intimal hyperplasia, and r emodeling may each be important in determining late lumen caliber. Thi s primate model should prove valuable in defining cellular and biochem ical mediators of human restenosis.