Isoeffect curves for radiation-induced cardiomyopathy in the dog.

Canine hearts were irradiated with a range of total doses given in 2, 3, or 4 Gy per fraction. Echocardiography was done before irradiation and at 3 and 6 months after irradiation. Histologic analyses were done of tissues taken at necropsy 6 months after irradiation. The percentage vascular component in the ventricles decreased with increasing total doses. The connective tissue component increased at lower doses and then decreased at higher doses. There was more fibroblastic proliferation and collagen production in the lower dose range and there may have been more cell killing by the higher doses. There was some evidence of myocardial hypertrophy at higher doses, which would have caused an apparent decrease in the connective tissue component. In either case, surviving fibroblasts would be expected to continue proliferating and producing collagen. At longer time intervals after irradiation the connective tissue component would likely continue to increase as observed clinically. That increase would be proportional to dose, but might not be closely related to initial killing of fibroblasts. Many factors such as changes in blood supply, continued loss of myocardium, and other stresses on the heart could influence the degree of fibrosis at later times. A relationship of response to cell killing appeared to exist based on alpha/beta ratios that were less than 3 Gy whether determined at the mid-range or for the greatest response of vasculoconnective tissues. Alpha/beta ratios ranged from 2.7 to 5 Gy for increases in diastolic wall thickness of the left ventricle at 3 and 6 months after irradiation. The low alpha/beta ratios reflect relatively steep isoeffect curves and have important implications for use of coarser fractionation schedules for treatment volumes that include the heart. The risk of cardiac damage could be significantly increased.