Neovascularization of coronary tunica intima (DIT) is the cause of coronary atherosclerosis.

¹602 Samuel Drive, Madison, WI, 53717, USA

Corresponding author:

Vladimir M Subbotin: moc.liamg@nitobbus.m.rimidalv

Background

An accepted hypothesis states that coronary atherosclerosis (CA) is initiated by endothelial dysfunction due to inflammation and high levels of LDL-C, followed by deposition of lipids and macrophages from the luminal blood into the arterial intima, resulting in plaque formation. The success of statins in preventing CA promised much for extended protection and effective therapeutics. However, stalled progress in pharmaceutical treatment gives a good reason to review logical properties of the hypothesis underlining our efforts, and to reconsider whether our perception of CA is consistent with facts about the normal and diseased coronary artery.

Analysis

To begin with, it must be noted that the normal coronary intima is not a single-layer endothelium covering a thin acellular compartment, as claimed in most publications, but always appears as a multi-layer cellular compartment, or diffuse intimal thickening (DIT), in which cells are arranged in many layers. If low density lipoprotein cholesterol (LDL-C) invades the DIT from the coronary lumen, the initial depositions ought to be most proximal to blood, i.e. in the inner DIT. The facts show that the opposite is true, and lipids are initially deposited in the outer DIT. This contradiction is resolved by observing that the normal DIT is always avascular, receiving nutrients by diffusion from the lumen, whereas in CA the outer DIT is always neovascularized from adventitial vasa vasorum. The proteoglycan biglycan, confined to the outer DIT in both normal and diseased coronary arteries, has high binding capacity for LDL-C.

However, the normal DIT is avascular and biglycan-LDL-C interactions are prevented by diffusion distance and LDL-C size (20 nm), whereas in CA, biglycan in the outer DIT can extract lipoproteins by direct contact with the blood. These facts lead to the single simplest explanation of all observations: (1) lipid deposition is initially localized in the outer DIT; (2) CA often develops at high blood LDL-C levels; (3) apparent CA can develop at lowered blood LDL-C levels. This mechanism is not unique to the coronary artery: for instance, the normally avascular cornea accumulates lipoproteins after neovascularization, resulting in lipid keratopathy.

Hypothesis

Neovascularization of the normally avascular coronary DIT by permeable vasculature from the adventitial vasa vasorum is the cause of LDL deposition and CA. DIT enlargement, seen in early CA and aging, causes hypoxia of the outer DIT and induces neovascularization. According to this alternative proposal, coronary atherosclerosis is not related to inflammation and can occur in individuals with normal circulating levels of LDL, consistent with research findings.

Background

Atherosclerosis, the predominant cause of coronary artery disease, remains enigmatic. Despite best efforts, available therapies protect only 30-40% of individuals at risk, and no therapeutic cure is anticipated for those who currently suffer from the disease. Delayed progress concerning pharmaceutical treatment implies that atherosclerosis drug development is in jeopardy, raising concerns among experts [1].

Logical properties and factual consistency concerning a currently endorsed hypothesis relating to coronary atherosclerosis: common perception of coronary artery morphology

A currently endorsed hypothesis is based on the following assumptions: (1) atherosclerosis is a systemic disease, initiated by endothelial dysfunction due to (2) inflammation and (3) high levels of LDL, (4) leading to lipid and macrophage deposition in the tunica intima from blood of the coronary lumen, and plaque formation (modified response-to-injury hypothesis) [2,3]. This perception is presented in mainstream scientific publications and in educational materials, whether printed or electronic. This hypothesis is typically accompanied by familiar schematics depicting the pathogenesis of coronary atherosclerosis and transition from a normal cardiac artery to a diseased state, e.g. Figure 1

Analysis of main assumptions of the currently endorsed hypothesis

Assumption: atherosclerosis is a systemic disease

Factual contradiction

Atherosclerosis never affects the entire arterial bed; it is exclusive to large muscular arteries, particularly coronary, and to a lesser extent to elastic arteries. Therefore, this systemic notion should be rejected on logical grounds; atherosclerosis is NOT a systemic disease.

Assumption: atherosclerosis is an inflammatory disease

Varieties of microorganisms are present in advanced atherosclerotic lesions, for example in specimens removed during atherectomy [7]. Fabricant et al. induced visible atherosclerotic changes in chicken coronary arteries resembling that in humans, by infecting them with herpesvirus [8-10] and suggested the viral role in pathogenesis, a view shared by many scientists (for review see [11,12]). Mycoplasma pneumonia or Chlamydia pneumoniae infections alone [13] or together with influenza virus [14] have been proposed as contributory factors in the pathogenesis of atherosclerosis, and particularly by participation in obstruction of vasa vasorum[11]. However, these cases probably do not indicate the initiation of atherosclerosis, but are more likely to represent secondary infection of degenerating/necrotic tissue. It should be emphasized that neither non-steroidal nor antibacterial anti-inflammatory treatments alter the risk of coronary atherosclerosis [15-18]. Despite the aforementioned studies [7-11,13,14], therefore, it can reasonably be claimed that no infectious cause of atherosclerosis has been demonstrated [19,20].

Assumption: a high level of LDL initiates and is the main cause of atherosclerosis

High levels of LDL are an important risk factor, and lowering LDL levels is the most significant pharmaceutical tool in coronary atherosclerosis prevention. However, the statement that high levels of LDL are the main cause of coronary atherosclerosis is inconsistent with established medical concepts.

---

In addition to reporting significant findings on the precise location of lipid depositions during initiation of coronary atherosclerosis, this work univocally demonstrates that normal coronary tunica intima is not a single-layer endothelium covering a thin acellular compartment, as is commonly claimed in all mainstream scientific publications and educational materials (e.g. Figures 1 and 2), but a multi-layer cellular compartment where cells and matrix are arranged in a few dozen layers.

---

Summary

(1) A hypotheses underlining our efforts to approach coronary atherosclerosis must be consistent with undisputed facts concerning the subject. Furthermore, a hypothesis should incorporate logical evaluation, and not contradict established and proven concepts in biology and medicine without well-grounded reasons.

(2) Atherosclerosis occurs in arteries with normal DIT, while sparing the rest of arterial bed. However, while normal DIT exists in numerous arteries [120,194], some of these are never affected by atherosclerosis; coronary arteries are almost always the target. On logical grounds, an arterial disease that never affects some arteries but usually affects certain others is not systemic.

(3) Coronary atherosclerosis is not an inflammatory disease, as multiple clinical trials demonstrate no correlation between anti-inflammatory therapies and risk of disease.

(4) High LDL levels are not a fundamental cause of coronary atherosclerosis, as lowering such levels protects only 30-40% of those at risk. Furthermore, humans and animals with normal LDL levels can suffer from coronary atherosclerosis.

(5) Neovascularization of the normally avascular DIT is the obligatory condition for coronary atherosclerosis development. This neovascularization originates from adventitial vasa vasorum and vascularizes the outer part of the coronary DIT, where LDL deposition initially occurs.

(6) It is suggested that excessive cell replication in DIT is a cause of DIT enlargement. Participation of enhanced matrix deposition is also plausible. An increase in DIT dimension impairs nutrient diffusion from the coronary lumen, causing ischemia of cells in the outer part of coronary DIT.

(7) Ischemia of the outer DIT induces angiogenesis and neovascularization from adventitial vasa vasorum. The newly formed vascular bed terminates in the outer part of the coronary DIT, above the internal elastic membrane, and consists of permeable vasculature.

(8) The outer part of the coronary DIT is rich in proteoglycan biglycan, which has a high binding capacity for LDL-C. While in avascular DIT, biglycan has very limited access to LDL-C due to diffusion distance and LDL-C properties; after neovascularization of the outer DIT, proteoglycan biglycan acquires access to LDL-C particles, and extracts and retains them.

(9) Initial lipoprotein influx and deposition occurs from the neovasculature originating from adventitial vasa vasorum – and not from the arterial lumen.

(10) Although lipoprotein deposition in the outer part of the coronary DIT is the earliest pathological manifestation of coronary atherosclerosis, intimal neovascularization from adventitial vasa vasorum must precede it.

Therefore, in the coronary artery tunica intima, a previously avascular tissue compartment becomes vascularized. All other tissue compartments are developed (both phylogenetically and ontogenetically) with constant exposure to capillary bed and blood, therefore their tissue components were selected not to bind LDL. This is why atherosclerosis is mostly limited to the coronary arteries. To my knowledge the only other example – the avascular cornea – shows the same lipid deposition after neovascularization.

The author does not claim that his hypothesis offers an immediate solution. Intimal cell proliferation, producing DIT and its later expansion, is cell hyperplasia, meaning that newly arrived cells are similar to normal residual cells, making systemic targeting very difficult. While the author strongly believes that intimal neovascularization is the crucial step in the pathogenesis of coronary atherosclerosis, there are obvious concerns about angiogenesis inhibition in a heart with an already jeopardized myocardial blood supply. The author does not intend to suggest an immediate solution. The goal was to evaluate the hypothesis and the perceptions that we exercise in approaching coronary atherosclerosis logically and factually, and to offer a more coherent model. Furthermore, the intent was to underline paradoxical observations that could provide new insights into mechanisms of the disease. Atherosclerotic plaque growth and rupture are not paradoxical but anticipated events. In contrast, initial lipid deposition in outer layers of DIT with no deposition in inner layers is a paradoxical observation, and requires an explanatory model that differs from the accepted one. However, to recognize the paradox, correct perception of the coronary artery structure, where pathology occurs, must not be distorted by incorrect illustrations and verbal descriptions. When we name or depict things incorrectly, often just for nosological reasons, the incorrect perception of events may persist in spite of growing knowledge, impeding our attempts to discover the truth.