862 
ANATOMY AND PATHOLOGY 
rather ' wly as is the case in man. Even after 
a yeai the mild diet the swine will have rela- 
tively few small lesions. With the severe diet le- 
sions progress much more rapidly; and after a 
year on the diet there will be near occlusion of 
many coronary arteries. The rapidity with 
which the lesions progress can be increased 
even more if some form of physical injury to 
arteries is given in addition to the hypercholes- 
terolemic diet. For example, if deep x-irradia- 
tion is given to the coronary arteries of hyper- 
cholesterolemic swine, even in doses that 
produce no significant morphologic changes by 
themselves, the rapidity of growth of lesions 
will be greatly increased. We have done this in 
conjunction with both the moderate and the se- 
vere diet ; and occlusive lesions develop in 4 to 5 
months with associated myocardial infarction 
and often "sudden death," which we have 
shown to be due to ventricular fibrillation in 
many instances. 
The morphologic features of the atheroscler- 
otic lesions as seen by light and electron micro- 
scopy are basically similar in swine fed the mild, 
moderate, or severe diet with or without x-irra- 
diation. As in man, there is excessive accumula- 
tion of modified smooth muscle cells (SMC) in 
the intima and inner media.^ Many of the SMC 
in the lesions are filled with lipid droplets, and 
these cells usually show variable degrees of de- 
generative changes. Some cells in the lesions are 
so packed with lipid and so degenerate as to 
make absolute identification virtually impossi- 
ble. This has led to a minor controversy among 
morphologists as to whether they originate as 
SMC or as macrophages. The distinction is 
probably not important, since the modified SMC 
in lesions appear to carry out many functions 
other than contraction. For example, lesions 
usually contain a great deal of collagen, and yet 
recognizable fibroblasts are seldom if ever pres- 
ent. The SMC can apparently synthesize colla- 
gen, elastic tissue, and perhaps many other pro- 
teins. 
In earlier studies of atherosclerotic lesions in 
swine fed only the mild diet we have shown an 
increased rate of deoxyribonucleic acid (DNA) 
synthesis resulting from an increased number 
of cells synthesizing DNA at any one time.^* 
As might be expected, oxygen consumption is 
increased along with the increase in DNA 
synthesis.^ We have developed methods for sep- 
arating mitochondria from arterial tissue so 
that respiratory control can be studied in 
vitro.^ Mitochondrial activity of aortic intima- 
media preparations from swine with substan- 
tial atherosclerotic lesions appear to be similar 
to those from controls.'' Thus significantly in- 
creased uncoupling of oxidative phosphoryla- 
tion, which one investigator has suggested oc- 
curs in arteries of atherosclerotic rabbits,^ does 
not appear to be a feature of disturbed arterial 
metabolism in atherosclerotic swine. We have 
also carried out studies of protein synthesis in 
arteries with early lesions and the rate appears 
to be considerably increased.^ 
The conclusion to draw from the above stud- 
ies of metabolism in arteries of swine with 
early atherosclerotic lesions is that overall met- 
abolic activity, including DNA and protein syn- 
thesis, is enhanced. This is consistent with the 
great increase in SMC, collagen, and elastic tis- 
sue associated with the development of lesions. 
The increased oxygen uptake seems to indicate 
that the lesions do not result from oxygen dep- 
rivation as has been suggested for human le- 
sions by some investigators in the past. 
Along with the overall rise in metabolic activ- 
ity is an apparent increase in the rate of degen- 
eration and death of cells in the lesions. 
This conclusion has to be based only on light 
and electron microscopy observations, since 
biochemical methods for detecting and quanti- 
tating the degenerative aspects have not been 
perfected. Current studies on activities of lyso- 
somal enzymes in arteries by several laborato- 
ries, including our own, may provide new 
information on the degenerative factors in 
atherosclerosis. 
The significance of greater metabolic activity 
in arteries with early atherosclerotic lesions is 
difficult to assess. Clearly, when cells proliferate 
excessively, there must be an accompanying in- 
crease in energy production, and this requires a 
greater consumption of either glucose or oxygen 
or both. This tells us nothing about cause and 
effect. We decided that study of metabolic 
changes that occurred in the arteries of choles- 
terol-fed swine prior to the development of 
gross lesions might provide more readily inter- 
