A proliferation analysis of arterial neointimal hyperplasia: lessons for antiproliferative restenosis therapies

Abstract

Medial smooth muscle cell proliferation is frequently implicated as the major cause of coronary restenosis. Although antiproliferative agents have shown efficacy in animal studies, they are ineffective in human trials. To better understand these discrepancies, we performed a mathematical kinetic analysis of cellular proliferation in the neointimal hyperplasia of rats, pigs, and patients. A model was derived using a differential expression for proliferation, proportional to the number of cells present. Additional terms were included for inhibition of proliferation proportional to neointimal mass and time. The resulting equation was solved in closed form for the number of cells and proliferation rate. These equations were validated in the rat carotid artery injury model from published data. The model was then applied to the porcine coronary injury model, and then to clinical data obtained from angiographic human studies. Peak cellular proliferative activity in patients occurs at 16 days and continues at lower levels for much longer periods of time. Less than 10 generations of cells are sufficient to develop clinically significant restenosis. Conversely, proliferation rates in the two animal models (rats and pigs) are maximal at roughly 2 and 6 days, respectively, also continuing at low levels for extended time periods. Cell proliferation in restenosis is a highly controlled process, with comparatively few cell generations causing enough neointima for arterial obstruction to occur. Substantial cell kinetic differences occur across species. The rat exhibits high proliferation rates and rapid doubling times compared to patients and pigs, and is thus a highly ‘proliferative’ model. Such differences may be responsible for discrepant animal model and clinical trial results. These data may help determine the timing and strategy of therapy against clinical restenosis.