Allylamine cardiotoxicity: I. Sequence of pathologic events

Allylamine, given to adult male rats in drinking water at a concentration of 0.005, 0.05, or 0.1% for 21-104 days, caused dose-dependent myocardial and vascular lesions, although no consistent histopathologic changes were observed in other organs. Treated animals also demonstrated decreased weight gain and diminished fluid consumption which were dose dependent. An "H₂O match" experiment in which control rats were given amounts of water equivalent to the decreased volume of fluid ingested by animals given 0.1% allylamine indicated that dehydration alone does not cause the degree of decreased weight gain or the cardiovascular lesions observed in allylamine-treated animals. When animals given 0.1% allylamine were sacrificed at appropriate intervals, acute myocardial lesions were observed as early as 4 days, and progressive fibrous lesions consistently developed by 21 days. The myocardial lesion began as small areas of multifocal subendocardial myocardial necrosis; extension of necrosis continued and was followed by fibrosis which, when extensive, resulted in an apical aneurysmal scar which frequently was grossly evident. Vascular arterial lesions consisting of medial thickening and hyalinization occurred predominantly within scarred areas but were not observed before 21 days of allylamine consumption. Coronary arteries were studied by morphometry in rats given 0.1% allylamine for 21 days; these studies indicated that a subtle medial hypertrophy occurs in medium and large sized vessels in hearts which do not display an evident morphologic vascular lesion. Serum creatine phosphokinase activity in rats given allylamine rose sporadically with occasional four-to fivefold increases in individual animals, most likely reflecting this focal and progressive necrotizing process of the myocardium. When a single dose of allylamine (50, 100, or 150 mg/kg) was given by gavage, acute morphologic myocardial lesions were observed 24 hr later at the two higher but not the lowest dose; serum creatine phosphokinase activity appeared elevated at the lower dose levels. These studies demonstrate that myocardial necrosis and fibrosis begin in the first few days of allylamine consumption and precede significant morphologic vascular lesions.