Abstract

A proposal to account for the inter-relationships between established risk factors and cardiovascular disease is presented. In this concept, the critical substance is prostaglandin (PG) E1 which is a vasodilator, an inhibitor of platelet aggregation, an inhibitor of cholesterol and collagen biosynthesis and an inhibitor of smooth muscle proliferation. PGE1 biosynthesis is enhanced by the essential fatty acid, linoleic acid, by the platelet aggregating agent thromboxane (TX) A2, by cholesterol and by melatonin. These factors may participate in a negative feedback control loop. As a result of the operation of this loop, any tendency for PGE1 levels to fall is followed by increased cholesterol and TXA2 biosynthesis, and enhanced platelet aggregation, vasoconstriction, smooth muscle proliferation and collagen biosynthesis. Enhancement of PGE1 biosynthesis will have the opposite effects. Factors known to increase PGE1 biosynthesis include essential fatty acids, vitamin C, ethanol, pyridoxine, zinc and probably niacin, all of which are known to have some protective effects against cardiovascular disease. The hypothesis predicts that lowering of cholesterol biosynthesis by any method other than enhanced PGE1 formation, while reducing the risk of cardiovascular disease, will increase the risk of other disorders. The hypothesis suggest new approaches to treatment and new ways of combining existing treatments. Colchicine, which at low concentrations may imitate and action of melatonin, has particularly interesting possibilities. Colchicine and related compounds have already been shown to have potent cholesterol- lowering and anti-atherogenic actions in both humans and animals.