Contrasting effects of ethane-1-hydroxy-1,1-diphosphonate (EHDP) on the regression of two types of dietary-induced atherosclerosis

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Atherosclerosis was induced in White Carneau pigeons by feeding cholesterol either continuously or intermittently during a 14-month period. Animals were then treated daily with either saline, or 0.5 or 2.5 mg EHDP/kg body wt during which time a cholesterol-free “regression” diet was fed. Subgroups of pigeons were studied after four and eight months of treatment. After the progression period, aortas and brachiocephalic arteries of those pigeons that were subjected to intermittent hypercholesterolemia accumulated more cholesterol, were more complicated, and showed a different pattern of lesion regression than arteries in animals continuously hypercholesterolemic. EHDP treatment had no effect on plasma cholesterol, triglyceride, calcium, or phosphorus concentrations. In animals with atherosclerosis induced by intermittent hypercholesterolemia, EHDP treatment resulted in a reduction in intimal plaques in the aorta and brachiocephalic arteries while in animals with atherosclerosis induced by continuous hypercholesterolemia EHDP treatment resulted in more extensive intimal plaques. In animals fed cholesterol intermittently and treated with EHDP, aortic cholesterol concentrations were lower; but animals with atherosclerosis induced by continuous cholesterol feeding and treated with EHDP had higher aortic cholesterol concentrations than controls. Among pigeons with atherosclerosis augmented by intermittent cholesterol feeding, there was increased mineralization during regression and this complication was found to be prevented by EHDP treatment. No effect was seen on collagen concentrations in either the intermittent or the continuous cholesterol fed animals. The beneficial effect of EHDP on the more advanced atherosclerosis in the pigeons fed cholesterol intermittently may be due to an action on lipid-calcium-connective tissue complexes within the atherosclerotic plaque. The opposite effect of EHDP in pigeons with relatively uncomplicated atherosclerosis induced by continuous cholesterol feeding is less easily understood, but a possible role implicating lysosomes is suggested.