The causative linkage between hyperbetalipoproteinemia and atherosclerosis is firmly established by a long chain of evidence. The most recent link added to that chain is the evidence from the landmark Lipid Research Clinic intervention trial,'which clearly demonstrated that lowering LDL levels in hypercholesterolemic men significantly reduced their risk of death from coronary artery disease. Since the cholesterol in atherosclerotic lesions derives primarily from the cholesterol in circulating lipoproteins, it is reasonable to conclude that hyperbetalipoproteinemia is causative by virtue of its delivery of that cholesterol to the artery at a high rate. Thus:(1) High LDL levels cause high rates of LDL entry into the artery wall;(2) This leads to high rates of uptake by cells in the artery wall (and/or trapping by extracellular matrix materials);(3) This overloads whatever unloading mechanisms normally operate to prevent accumulation of cholesterol; and,(4) The end result is accelerated atherogenesis. What we have done is simply to restate the lipid infiltration hypothesis of Virchow in slightly modified, contemporary form!

However, the causative linkage could be quite different. High plasma concentrations of LDL have been, with varying degrees of certainty, implicated as contributing to several other processes that may be involved in atherogenesis (TABLE l), as discussed in detail elsewhere,'and there may be still others not yet appreciated. One or more of such factors might be equally relevant or even more relevant to lesion development than the rate of delivery of cholesterol to the tissue. A crucial question is whether the delivery of lipoprotein to and the accumulation of cholesterol in the artery wall is sine qua non for atherogenesis. Certainly cholesterol accumulation is the hallmark of the human lesion and most experimental lesions. Yet, not all experimental lesions are lipid rich. 3 Moreover, even if the chain of causative events were triggered by mechanisms like those listed in TABLE 1, the fact that LDL levels were high during lesion development would probably lead to concurrent lipid accumulation even if it were not an essential factor in the progression of the lesion. Until this issue is completely resolved, we must keep an open mind and explore all possibilities. In the remainder of this paper, however, we confine ourselves to the mechanisms involved in penetration of LDL into the artery wall and its metabolic fate.