Pathogenesis of Atherosclerosis in 2015 and Adventitial (Erzengin’s) Atherosclerocalcification

Research Article

J Cardiovasc Disord. 2015; 2(2): 1016.

Pathogenesis of Atherosclerosis in 2015 and Adventitial (Erzengin’s) Atherosclerocalcification

Erzengin F¹*, Bursuk E²

¹Department of Cardiology, Previous Dean, University of Istanbul, Istanbul Medical Faculty, Istanbul, Turkey

²Program of Biomedical Technologies, University of Istanbul, Vocational School of Technical Sciences, Istanbul, Turkey

*Corresponding author: Erzengin F, Department of Cardiology, Previous Dean, University of Istanbul, Istanbul Medical Faculty, Istanbul, Turkey

Received: June 18, 2015; Accepted: September 04, 2015; Published: September 08, 2015


Formation of atherosclerotic and calcified plaque begins and grows up not only beneath the endothelium (intimae), but also in the adventitial subepithelium on the coronary arteries. MSCT is a unique non-invasive method for the detection of coronary atherosclerotic plaque morphology, and for the diagnosis of silent ischemia, lumen narrowing calcification of adventitia.

Keywords: Adventitial (Erzengin’s) atherosclerotic calcification; Formation of atherosclerotic calcification plaques on the adventitia; Multi slice computed tomographic angiography


The term atherosclerosis refers to the thickened and hardened lesions, which have lipids and calcifications in the intimae and media of elastic and muscular arteries. To date, the primary cause of arterial atherosclerotic calcification has not yet been elucidated. It is generally accepted that atherosclerotic and calcified lesions first appear and develop within the innermost layer of the arteries (at the intimae). In 1995, the American Heart Association (AHA) described that the earliest lesions of atherosclerosis (fatty streaks or type III lesions) are present in the intimae of the aorta from childhood. Today, it is known that atherosclerosis begins as early as fetal life, especially in the fetuses of hypercholesterolemic mothers [1]. Formation and progression of atherosclerotic plaques and calcifications in all arterial beds of intimae have been well documented by many authors, such as V. Fuster and E. Falk [1-4], who subdivided the formation and progression of these plaques into several phases summarized below. As known, arterial calcification plays a major role in development of atherosclerosis and osteonecrosis protein is effective in the formation of this calcification [5]. Most lipids deposited in atherosclerotic lesions (atherosclerotic components) are derived from plasma Low-Density Lipoproteins (LDLs) that enter the vessel wall through injured or dysfunctional endothelium. Within the normal population, fatty streaks often appear in the aorta and coronary arteries starting from the ages of 5 to 10; these are considered as the initial/starting points of plaque development. Type I lesions consist of macrophage-derived foam cells that contain lipid droplets; Type II lesions contain macrophages and smooth muscle cells with extracellular lipid deposits; Type III lesions contain smooth muscle cells surrounded by extracellular connective tissue, fibrils, and lipid deposits; Type IV plaques consist of confluent cellular lesions with large amounts of extracellular lipid intermixed with fibrous tissue; and Type Va plaques possess an extracellular lipid core covered by a thin fibrous cap. Both phase III and IV plaques can evolve into phase V fibrotic plaques, characterized by type Vb or Vc lesions, with or without predominant calcification. Type VI lesions are occlusive thrombi overlying a superficial erosion of markedly stenotic and fibrocalcific phase V plaques [2-7]. In Phases II to V, vulnerable lipid-rich plaques are prone to disruption due to their high lipid content. Raised plaques appear later, generally by 20 years of age, and are present in areas such as the endothelium of proximal Left Anterior Descending (LAD) coronary artery, where fatty streaks are most prevalent in early life [3]. When fully opened, the total surfaces of all arteries in humans are approximately 800 square meters. Arteries produce more than 250 active substances. There are several types of plaque: Some are flat yellow dots or lines (fatty streaks), while others are raised above the surface as oval humps, which range in color from white to yellow (raised fibro lipid plaques) [1-7]. With early atherosclerotic lesions (fatty streaks or type III lesions) in the aortic root and coronary arteries, the lesion consists of lipid-laden monocyte-derived macrophage foam cells and a few T lymphocytes beneath an intact endothelium. It is generally accepted that only endothelial cells, monocyte-derived macrophages or foam cells, and a few T cells participate in the early inflammatory and immune responses that give rise to the early atherosclerotic lesions. These early atherosclerotic lesions (fatty streaks or type III lesions) represent a dynamic balance of the entry and exit of lipoproteins by endothelium injury, resulting in a predominance of lipoprotein exit and final scarring [1-7]. During the progression of the disease, the oxidative modified LDL (oxLDL), the inflammatory and immune response is accompanied by a fibro-proliferative response in which the vascular smooth muscle cells play dominant roles [1-12]. OxLDL has many proinflammatory properties, which explain the local up regulation of inducible endothelial cell adhesion molecules – even before lesion formation – in hypercholesterolemic atherosclerosis and plaque instability leading to atherothrombotic events [1-7]. OxLDL has proinflammatory and cytotoxic effects. It is recognized by the macrophage scavenger receptor, promoting intracellular lipid accumulation and foam cell formation. Such as the endothelial dysfunction or/activation (vascular cell adhesion molecule 1), monocyte adherence, injuring lipoprotein retention, oxLDL, inflammatory/immune response, macrophage scavenger foam cell formation, endothelial shear stress, turbulent flow, high blood pressure on the vessels’ walls and the role of Nitric Oxide (NO), prostacyclin, endothelin-1, acetylcholine, vascular Cell Adhesion Molecule-1 (CAM-1), Cell Adhesive Molecules (CAM or surface glycoproteins), Intercellular Adhesion Molecule-1 (ICAM-1) promote or enter though the injured or dysfunctional endothelium and subendothelial lipid accumulation and at the end lipid core formations occur. Monocytes (macrophages) adhere to the surface of endothelium (intimae) through specific molecules, such as the Monocyte Chemotactic Protein-1 (MCP-1) and Macrophage Colony-Stimulating Factor (M-CSF) [1]. Before or after their death, macrophage or foam cells can release various substances, including oxLDL and free radicals. During chronic minimal endothelial injury or dysfunction, plasma low-density proteins enter through the injured endothelium, leading to accumulation of lipids (oxLDL), while the macrophages produce atheroma masses or atheromatous component.

So this classical pathway or famous well known cascade of atherosclerosis brings about the formation of the atheroma in 1995 by AHA of atherosclerotic lesions [1-3]. This pathway of formation of atherosclerosis and calcifications almost universally were accepted in the intimae (under the endothelium). In spite of the fact that, there is no any doubt of this classical pathway or rule of the cascade of formation of atherosclerotic calcifications. Atherosclerosis is a focal disease in the intimae of large and medium sized systemic arteries. It has been well documented that, focal calcification in atherosclerotic plaques is very common in humans’ arteries and nicely shown that coronary calcification in adults is almost always atherosclerosis related intimae until today [9]. We have recently shown this with the MSCT method (previously 320 slices; currently 640 slices) using within a device which has a computerized magnifying glass. On the other hand making a comparison between MSCT, coronary angiography, perioperative findings and histopathological data which detected by light and electron microscopy and environmental SEM (By using a microtome, slice samples can be taken, across the walls of samples classical histopathological routine investigation and addition to chemical analysis can be taken by means of energy dispersive X-ray mobile monitoring the surface of specimen by SEM). We strongly emphasized that, the classical cascade of the atherosclerotic and calcified plaques formation appear and develop not only beneath the intimae (sub endothelium) or media, but also in adventitial epithelium on the coronary arteries. We have surprisingly determined that the adventitial side of the calcification develops much faster and more severely than that of the intimae and medial side on the arterial vessel walls.

MSCT of coronary angiography with 64 slice technologies was first described by Leschka S, et al [8]. Currently, we have performed our studies with MSCT at the beginning 64 slice and later on 320 slice with magnifying glass, which are very important tool for the non-invasive evaluation of coronary arterial pathologies. Moreover, the MSCT is an excellent and important technique for showing the location and size of plaque formation and calcification in the arteries [8-9]. It has been well documented in the last three decades that the cascade of atherosclerotic plaque formation begins from beneath the endothelial cells of the coronary arteries [1-23]. The media calcification of the coronary arteries was also described as Mönckeberg’s Sclerosis many years ago, and while rare in coronary arteries, it is frequent in other types of arteries (particularly in the arteries of the leg and aorta) [1,2,4,9,17,18]. All calcification of arteries are directly related with atherosclerotic burden or component [4,9,17,18]. Until today it has not written yet anything about our findings of adventitial atherosclerosis and calcifications [19-21]. In a two-year randomized study in 1997 on identical twin yeanlings, we determined that there were significant parallels between umbilical obesity and epicardial lipid mass. Moreover, we demonstrated that the epicardial lipid mass is statistically significantly associated with adventitial localization over the arteries [9].

We have recently shown with MSCT-320 and 640 that the formation of atherosclerotic and calcified plaques begin not only in the intimae, but, surprisingly, also under the adventitial epithelium of the coronary arteries. The adventitial calcifications develop more rapidly than the subendothelial (the intimae) calcified plaques. On the other hand, the medial calcifications develop far more frequently on the subendothelium of the aorta and its main branches, such as the carotid, vertebral, cerebral, renal, mesenteric, ilio-femoral, and peripheral arteries. Interestingly, the formation of calcified plaque begins more frequently beneath the subepithelium of the adventitia, and quickly develops towards to the lumen of arteries, following the same classical and accepted cascade on the coronary arteries. These calcifications mostly begin in the middle of the atheromatous component. Cholesterol (particularly oxLDL) and macrophage cells easily arrive to the adventitia vasa vasorum of the coronary arteries from blood and/or by diffusion from epicardial fat accumulation around the heart appears in three different types: a) Intracellular in the heart, b) Epicardial and c) Pericardial adipose tissue around the heart. Intracellular fat is the microscopic lipid accumulation within the cytoplasm cardiac myocytes, and can result from myocardial ischemia, cell damage and/or cell death. The epicardial fat tissue is located between the outer wall of the myocardium and the visceral layer of pericardium, while the pericardial fat exists anterior to the epicardial fat layer and therefore located between visceral and parietal pericardium. Due to the close anatomic relation between myocardium and the epicardial fat, the two tissues share the same microcirculation. Through the vasa vasorums, diffusion way or potential interactions through paracrine and vasocaine mechanism between epicardial fat and adventitia of coronary arteries or myocardium are strongly suggested [24,25] (Figure 1, Figures 3-10).