Neointimal proliferation in canine coronary arteries. A model of restenosis permitting local and continuous drug delivery.

BACKGROUND: A number of experimental preparations have been used to elucidate the pathophysiology of restenosis after percutaneous transluminal coronary angioplasty; however, few models have been advanced that address restenosis in coronary arteries, and none provides an effective means of continuous local drug delivery. In this report, we describe a model of restenosis in coronary arteries with the provision for local, continuous delivery of cytotoxic and/or anti-proliferative agents. EXPERIMENTAL DESIGN: An ameroid constrictor was placed on the left circumflex coronary artery of 17 normocholesterolemic dogs. One month later, after substantial collateral development had ensued, a segment of the left circumflex coronary artery distal to the ameroid was mechanically compressed using surgical forceps for 10 (N = 4), 15 (N = 4), 20 (N = 2), or 30 minutes (N = 5). In two dogs, an indwelling left circumflex catheter and implanted pump maintained a continuous infusion of saline at the injury site. In addition, the pump side port provided transcutaneous access for serial, selective coronary arteriography. The animals were maintained on a normal diet, without cholesterol or fat supplementation. RESULTS: Three weeks after vascular injury, significant neointimal proliferation was observed in all dogs that was morphologically similar to the proliferation seen after percutaneous transluminal coronary angioplasty in human coronary arteries. The extent of neointimal formation was linearly related to the duration of injury: neointimal/medial area ratios were 0.35 +/- 0.10, 0.46 +/- 0.10, 0.58 +/- 0.03, and 1.16 +/- 0.26 (mean +/- SE) after 10, 15, 20, and 30 minutes of mechanical compression injury, respectively. CONCLUSIONS: This model produces striking neointimal proliferation in the coronary arteries of normocholesterolemic dogs, morphologically similar to that seen in human coronary restenosis specimens. The model appears suitable to test the efficacy of agents with the potential to inhibit neointimal formation, providing continuous intracoronary drug delivery, as well as transcutaneous access for serial, selective arteriography.