Summary
In reviewing a problem such as atherogenesis in man and animals, it is easy to overemphasize one particular aspect of the pathogenesis and to ignore or discredit other equally well‐substantiated factors. A multitude of atherogenic mechanisms have been advanced in the literature—some reasonably well proven and some quite tentative—but, rather than ignore or arbitrarily reject a number of these concepts, it will be assumed that each is a lesser or greater particle in the complex jigsaw of atherogenesis. A speculative diagram of the interrelationship of various atherogenic and anti‐atherogenic mechanisms is presented in Text‐fig. 4.
In human atherosclerosis the initiating factor appears to be intimal thickening of the artery induced by encrustations of mural thrombus and fine films of fibrin. This mechanism has, however, only been observed on one occasion in spontaneous atherosclerosis of animals. Whether the failure to observe it in mammals and birds is due to insufficient search or whether the pathogenesis of the animal disease is different in this respect from human atherosclerosis is uncertain.
It is postulated that hyperlipaemia and hypertension increase respectively the amount and rate of lipid transport across the arterial wall. From studies on the effects of feeding a cholesterol‐enriched diet to the experimental animal and on the fate of subcutaneously injected cholesterol, it is concluded that accumulation of cholesterol in the tunica intima promotes proliferation of connective tissues, sclerosis and intimal thickening in the arteries in man, other mammals and birds. In man, haemorrhage into the vascularized and thickened tunica intima appears to provoke further organization and thickening. Mechanical strains on the human arterial wall are exaggerated by hypertension and, by inducing reparative changes, contribute to intimal thickening. Such strains are held to be responsible for the severity of atherosclerosis at certain sites of greatest mechanical stress, such as bends, bifurcations and orifices in arteries. Likewise, focal accentuation of experimental atheroma occurs after local application of a variety of physical and chemical insults to the arterial wall.
It is suggested that intimal thickening of the human artery, caused by the three mechanisms of encrustation, lipid accumulation and mechanical stress, precipitates ischaemia of the middle zone of the tunica media. Such ischaemia would interfere with the local synthesis of lipotrophic factors required to transport lipid across the human arterial wall and would lead to further accumulation of lipid in its inner layers. A self‐perpetuating circle would be set up, whereby intimal thickening encourages further mural thrombosis and lipid accumulation which, in turn, lead to further intimal thickening.
In this explanation for the lipid accumulation seen in human atherosclerosis, as much emphasis has been placed on metabolic impairment of the normal outward flow of lipid through the arterial wall as on increased entry of lipid through the endo‐theli...