January 1, 1910
German chemist Adolf Otto Reinhold Windaus discovered atheromatous arterial lesions (arterial plaques) contain six times as much free cholesterol and 20 times as much esterified cholesterol as do healthy arteries
Über den Gehalt normaler und atheromatöser Aorten an Cholesterin und Cholesterinestern.
In 1910, as part of his pioneering studies of the role of cholesterol in human metabolism, German chemist Adolf Otto Reinhold Windaus discovered atheromatous arterial lesions (arterial plaques) contain six times as much free cholesterol and 20 times as much esterified cholesterol as do healthy arteries (2). Windaus would also later describe the pathways by which cholesterol is converted to vitamin D. For his work, he was awarded the Nobel Prize in chemistry in 1928.
The assumption at the time was, predictably, that the cholesterol in arterial plaques must arise from the cholesterol circulating in the bloodstream. In time, this finding gave rise to Gofman/Keys’ lipid hypothesis, which holds that elevated blood cholesterol concentrations (caused by eating a high-fat diet especially rich in “artery-clogging” saturated fats) drive cholesterol across the arterial lining, a single layer of cells known as the endothelium, and into the subendothelial space, causing the initiation of fatty streaks (Figure 1). These then progress to the development of more advanced atherosclerosis, termed arterial plaques (Figure 2), which among other complications can cause heart attacks and strokes.
Figure 1: This diagram explains the currently accepted theory of how endothelial damage, largely of unknown cause, allows LDL-cholesterol to cross the endothelium and enter a postulated and hypothetical acellular space, the subendothelial space. There, the LDL-cholesterol is taken up by macrophages, causing the development of the earliest form of atherosclerosis, known as the fatty streak. Note that for the atherosclerotic process to happen in this way, the tunica intima must be devoid of all cells other than the single layer of endothelial cells that coat its upper surface, separating it from the blood contained in the lumen of the artery. According to this model, the subendothelial space is essentially a wide-open vacant space waiting expectantly to accommodate these (complex) processes that produce atherosclerosis. Reproduced with additions from reference 4, p. 3.
The finer details in Figure 1 are not critical to the argument. What is important is the way in which the different cellular structures are depicted.
Here, the crucial point is that, according to the currently popular explanation of atherosclerosis (4), until the endothelium is damaged (by currently unknown biological events), allowing the unrestrained entry of LDL-cholesterol, the tunica intima is depicted as a single, thin layer of endothelial cells sitting on top of an acellular space (devoid of cells). This is an important consideration, since the presence of any cells in the subendothelial space must impede the entry of LDL-cholesterol directly from the bloodstream and will hinder the ability of the macrophages to detect and consume the cholesterol, as depicted in Figure 1.
Figure 2 depicts how this model explains the progression of the fatty streak to full-blown atherosclerotic plaque. Note again that the subendothelial space is devoid of cells before the hypothetical endothelial damage allows the free entry of LDL-cholesterol into this conveniently located anatomical space.
Figure 2: This figure shows how the fatty streak (Figure 1) progresses to the atherosclerotic plaque according to the lipid hypothesis. For the lipid hypothesis to be true, until after the initial “injury” to the endothelium has allowed the entrance of blood-derived LDL-cholesterol, the tunica intima must, as shown in this figure and in Figure 1, contain no cells other than the thin layer of endothelial cells on its upper surface. Notice that in this figure, smooth muscle cells (SMC) migrate from the tunica media into the tunica intima to further progress the development of the atherosclerotic plaque. Reproduced with additions from reference 4, p. 8.
In 1910, neither Windaus nor anyone else was aware that cholesterol cannot simply pass through healthy arterial walls, however hard it may be “shoved” (3). Currently, the most popular theory for atherosclerosis is that shown in Figures 1 and 2. This theory holds that the endothelial cells lining the lumen of the artery wall must first be damaged before the passing of cholesterol through the wall can happen. This is termed “endothelial cell dysfunction” (4), but the immediate cause of “endothelial cell dysfunction,” if this is indeed the mechanism, remains shrouded in secrecy even today, 110 years after Windaus’ discovery.
This theory also predicts that cholesterol enters damaged arteries down a concentration gradient, so the degree of a person’s arterial disease can be predicted quite simply as their average blood cholesterol concentration multiplied by the number of years the blood cholesterol concentration has been “elevated” (3, 5).
Also, still unknown then was that atherosclerosis is a patchy disease that selectively targets only specific areas of different arteries. This is exemplified by what happens in the coronary arteries supplying blood to the heart muscle (6).
It also was then unknown that in some populations, there may be advanced atherosclerosis in the cerebral (brain) arteries with minimal involvement of the coronary (heart) arteries (7, 8). In such cases, a person is at greater risk of stroke than heart attack. In other cases, as is more prevalent in the U.S., the opposite applies.