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Abstract

Our understanding of coronary artery disease risk and the atherosclerotic process has changed greatly in recent years. For example, it is now known that angiographically apparent coronary artery plaque is not the major cause of myocardial infarction (MI). Rather, it is unstable, soft plaque that cannot be seen angiographically that is prone to rupture and result in infarction. Also important are changes in vascular reactivity resulting from diet. Cholesterol levels by themselves reveal little about a patient's coronary artery disease risk. Most infarctions occur in patients who have normal total cholesterol levels. At-risk patients can be identified using the ratio of total-to-high-density lipoprotein (HDL) cholesterol levels. The ratio of triglyceride to HDL cholesterol levels is also important. Simple steps to assess patients' risk in practice are outlined. Primary prevention trials demonstrate that coronary artery disease risk can be lowered dramatically with diet and drug therapy.

Figure 5 shows the progression of atherosclerosis with further lipid accumulation in the deep layers of the tunica intima. It also depicts the addition of macrophages in the latter stages — Grade 3 — of the progression of atherosclerosis.

Figure 5: This figure shows the further progression of atherosclerosis from Grade 2 fatty streak to Grade 3 PIT with foam cells. It shows lipid accumulation increases in the deep layers of the tunica intima (central column of panels) with the addition of macrophages (column of panels on the right). The column of panels on the left shows the histological changes corresponding with this lipid accumulation in the deep layers of the tunica intima. Reproduced from Figure 6 in reference 10.

Figures 4 and 5 clearly establish that cholesterol circulating within arteries cannot explain why the atherosclerotic plaque begins to develop deep within the highly cellular tunica intima, far removed from where LDL-cholesterol is circulating in the bloodstream.

The sole conclusion must be that Keys’ lipid hypothesis cannot explain these findings. Hence, these findings disprove the essential foundations on which Keys’ theories are based.

The second critical finding reported by Nakashima and colleagues already in 2007 (13) and essentially forgotten until its rediscovery by Subbotin (10, 11) is the initial deposition of lipid material in the walls of arteries affected by atherosclerosis. This occurs in the deep layers of the tunica intima. These layers are separated from the endothelial cell layer by numerous layers of smooth muscle cells (Figure 4).

Figure 4: The panels on the left (panels a, d, and g) show the histological evolution of the fatty streaks in arteries of different subjects dying from different causes. The middle panels (b, e, and h) show the site at which lipid (staining red) begins to accumulate. Note especially in panel h that the main site of accumulation is in the deep layers of the tunica intima, close to the internal elastic lamina. The panels on the right (panels c, f, and i) are stained to detect the presence of macrophages. The panels show that despite some degree of lipid accumulation (panels e and h), there is no evidence for the invasion of macrophages. Figures 1 and 2 require that an invasion by macrophages into the (non-existent) subendothelial space is essential for the development of atherosclerosis. Reproduced from Figure 6 in reference 10.

The point of Figure 4 is to show that since the first evidence for lipid accumulation in diseased arteries occurs so deep in the tunica intima, it cannot have arisen from the LDL-cholesterol carried in the lumen of the arteries. There has to be another source for this lipid accumulation.

doi: 10.1161/ATVBAHA.106.134080. Epub 2007 Feb 15.. 2007 May;27(5):1159-65.Arterioscler Thromb Vasc Biol

Early human atherosclerosis: accumulation of lipid and proteoglycans in intimal thickenings followed by macrophage infiltration

Yutaka Nakashima 1, Hiroshi Fujii, Shinji Sumiyoshi, Thomas N Wight, Katsuo Sueishi

Affiliations expand

• PMID: 17303781

• DOI: 10.1161/ATVBAHA.106.134080

Abstract

Objective: The present study was designed to clarify the morphological features of early human atherosclerosis and to determine whether specific extracellular matrix proteoglycans play a role in early atherogenesis.

Methods and results: Step and serial sections were obtained from right coronary arteries with no or early atherosclerosis. Atherosclerosis was classified into 4 grades according to the amount of lipid deposition. Coronary arteries with Grade 0 showed diffuse intimal thickening (DIT) with no lipid deposits. The extracellular matrix proteoglycans, biglycan and decorin, were localized in the outer layer of DIT. Most cases of Grade 1 and Grade 2 exhibited fatty streaks with extracellular lipids colocalizing with biglycan and decorin in the outer layer of the intima. As lipid grades increased, macrophages increased in number and were present in the deeper layers. Most cases of Grade 3 exhibited pathologic intimal thickening (PIT) with extracellular lipids underneath a layer of foam cell macrophages.

Conclusions: In early human coronary atherosclerosis, fatty streaks develop via extracellular deposition of lipids associated with specific types of proteoglycans in the outer layer of preexisting DIT. As the amount of the lipid increases in fatty streaks, macrophages infiltrate toward the deposited lipid to form PIT with foam cells.