ARTERIOSCLEROSIS IN MAN, OTHER MAMMALS AND BIRDS*
Authors: ADAMS C. W. M. 
Published: January 2008

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‐thelium from the blood. Conversely, in experimental atheroma produced by feeding cholesterol, the accumulation of lipid in the artery appears to be a result of gross overloading of an otherwise intact system for lipid transport in the arterial wall.

Hyperlipaemia has the other important atherogenic role of accelerating fibrin deposition over the arterial wall and, at the same time, inhibiting serum fibrinolytic activity. Experimental evidence suggests that hyperlipaemia with high levels of triglyceride promotes thrombosis, presumably by increasing platelet adhesiveness and the coagulability of the blood. Some hormones act against hyperlipaemia either by increasing the catabolic breakdown and excretion of lipid or by diverting metabolites away from lipid synthesis towards protein and carbohydrate metabolism. Excess lipid can also be eliminated from plasma and tissue by the action of clearing factor or lipo‐lytic systems. Acid mucopolysaccharide—a component of these clearing systems—is synthesized in the atherosclerotic plaque and may, thus, contribute towards the local degradation of atheroma lipids.

It can be argued, however, that it is not hyperlipaemia that is directly responsible for the deposition of lipid in human and animal arteries but, rather, an associated instability of the suspension of lipid in plasma and tissue fluid. Such instability may result from a deficiency of phospholipid and an excess of hydrophobic triglycerides, cholesterol and cholesterol esters in the β‐lipoprotein molecule and other vehicles for lipid transport. Hydrophilic surface‐active agents, such as phospholipid and the detergents Tritons and Tweens, appear to stabilize lipoprotein and shift the partition of lipids away from the arterial wall towards plasma. Furthermore, the arterial wall in both man and the experimental animal reacts to lipid infiltration by synthesis of phospholipid, in an apparent endeavour to stabilize infiltrated lipoprotein and to disperse precipitated lipid.