Thin-cap fibroatheroma (TCFA), traditionally designated as vulnerable plaque, is recognized by its morphologic characteristics that resembles ruptured plaque, and the main difference is the absence of a luminal thrombus and an intact thin fibrous cap [2]. TCFAs generally contain a relatively large necrotic core, although smaller than seen in ruptured plaques; an overlying thin fibrous caps with varying degrees of macrophages and lymphocytic infiltration and few to absent SMCs (Fig. 16.2). The fibrous cap thickness as an indicator of plaque vulnerability is defined to be ≤65 μm since the thinnest portion of the remnant ruptured cap was 23 ± 19 μm, with 95 % of the TCFA caps measuring ≤65 μm [3]. Although there are similarities, TCFAs differ from ruptured plaques on the basis of trends toward a smaller necrotic core, fewer macrophages within the fibrous cap and less calcification (Table 16.1) [5].

It is generally a prevailing thought that rupture of fibrous caps occurs at their weakest point, often near shoulder regions. However, this is not always the case in our experience as we have observed an equivalent number of ruptures occurring at the mid portion of the fibrous cap. These differences were even greater when death occurred during exertion or at rest; the former ruptured in the mid fibrous cap and the latter in the shoulder region [8]. Therefore, it is reasonable to speculate that different processes may be involved as catalysts for the rupture event. It has been shown that macrophages in the fibrous cap release matrix metalloproteinase (MMP) [9] which further weaken the cap, along with high shear stress [10], macrophage cell death [11], and microcalcification and iron accumulation within the fibrous cap [12], all contribute to the eventual disruption of the cap.

Once the fibrous cap ruptures and the necrotic core contents are exposed to the flowing blood in the lumen, coagulation cascade is activated in response to the exposure of lipids and tissue factors (TF) which are present in the core. The luminal thrombus is rich in platelet (white thrombus) near the actual rupture site, while at sites proximal and distal to the rupture, there is propagation of the thrombus which is rich in erythrocytes that alternate with regions of fibrin and platelets (red thrombus). A study of aspirated thrombi from acute myocardial infarction patients examined by scanning electron microscopy (SEM), confirmed a decrease in platelet content and an increase of fibrin and red cell content in accordance with ischemic time duration [13].

We have quantified several morphologic parameters in various human coronary plaque types, including culprit lesions (Table 16.2). The number of cholesterol clefts in the necrotic core, vasa vasorum, and macrophages are significantly greater in ruptured plaques than erosions or stable plaque with >75 % cross-sectional luminal narrowing. There was a greater accumulation of hemosiderin in ruptures as compared to TCFAs.

The extent of luminal narrowing varies with underlying plaque morphology. TCFAs and fibroatheromas have the least luminal narrowing while lesions with acute plaque rupture, hemorrhage, or healed plaque rupture sites show the most stenosis [6]. The vast majority of TCFAs (approximately 80 %) have <75 % cross sectional area luminal narrowing (equivalent to <50 % diameter stenosis) (Fig. 16.3a). Forty-six percent of healed plaque rupture and 43 % of acute rupture show the severe luminal narrowing (i.e., >75 % cross-sectional area narrowing); in contrast, only 26 % of TCFAs show severe luminal narrowing.

The mean necrotic core size in lesions from sudden coronary death victims is independent of luminal narrowing and is greatest in plaque ruptures, followed by TCFAs, erosion and fibroatheromas (Table 16.2). In a detailed morphometric analysis of ruptured plaques, 80 % of necrotic cores were larger than 1.0 mm² and comprised >10 % of plaque area in approximately 90 % of the lesions. In 65 % of plaque ruptures, the necrotic core occupied >25 % of plaque area; in contrast, 75 % of TCFA had necrotic cores >10 % of plaque area. The mean cross-sectional luminal narrowing in TCFAs was 71 %, with necrotic core representing 10–25 % of the lesion. On the other hand, the length of the necrotic core in ruptures and TCFAs was similar, varying from 2 to 22.5 mm, with a mean of 8 and 9 mm, respectively [15]. In terms of the circumferential involvement of the necrotic core, 75 % of TCFAs show >120° of the intima involved by a necrotic core [6].

When we analyze the number of TCFAs by plaque morphology, the highest incidence is observed in plaque rupture followed by healed rupture and stable plaques; the incidence being the least in erosion [7]. In patients presenting with acute myocardial infarction, the incidence of TCFAs is highest in males with a mean of 3 per heart, with half as many in women (Fig. 16.3b) [14]. In patients dying suddenly, although the incidence of TCFAs was greater in men than in women, the difference was not statistically significant. In those dying from incidental death or plaque erosion, the incidence of TCFAs was lower as compared to those dying from acute myocardial infarction or sudden coronary death, without any differences observed between the two sexes.

TCFAs and plaque ruptures show a predilection for certain anatomic locations within the coronary tree. The majority of acute and healed ruptures and TCFAs are concentrated in the proximal and mid portion of the three major coronary arteries, and are rarely observed in the distal portion of these arteries (Fig. 16.4) [7]. By far, the most frequent location is the proximal portion of the LAD coronary artery, with sites in the proximal left circumflex and mid to proximal right coronary arteries being half as common.

It has been observed that the fibrous cap thickness is dependent on the extent of macrophage infiltrate; the thinner the fibrous cap, the greater the number of macrophages, whereas the thicker the fibrous cap, the fewer the macrophages. In serial sections of TCFAs, the necrotic core was located deep within the plaque; i.e., away from the lumen but over a relatively short distance of <1.4 mm, the lipid core approaches the lumen. Therefore, histologically the presence of suspected TCFAs may be better identified through serial sectioning [16].

Intraplaque hemorrhage in non-culprit sites of the coronary vasculature is more common in hearts with ruptures versus stable plaques without luminal thrombi. The mean ± SD number of acute hemorrhages in non-culprit lesions from patients with rupture was 2.5 ± 1.3 versus none in erosion (p = 0.0001) and 0.05 ± 0.6 in stable plaques (p = 0.04) [2]. Evidence of prior hemorrhages as analyzed by anti-glycophorin A staining (a protein specific to erythrocyte membranes) was significantly greater in TCFAs than in fibroatheromas with early or late necrotic cores or lesions with pathologic intimal thickening. The degree of glycophorin A staining correlated with both necrotic core size and the extent of macrophage infiltration suggesting that erythrocytes may directly contribute to necrotic core expansion and lesion instability [17].

Ira Tabas has reported in the mouse model that it is the apoptotic cell death of foamy macrophages, which contribute to the formation of necrotic core that contains phospholipids, cholesterol esters and free cholesterol [18]. Also, impaired phagocytic efficiency of macrophages to effectively clean up apoptotic bodies i.e., defective efferocytosis further contributes to the progression of necrotic core [17, 18]. In man, we have observed that foamy macrophages infiltration into lipid pools and apoptotic cell death of these cells leads to early necrotic core formation. However, it is not only apoptotic foamy macrophages that contribute to the accumulation of free cholesterol but other sources should also be considered that may expand the necrotic core. Studies from our laboratory have shown that hemorrhage into a plaque is a common event that is most frequently observed in cases of plaque rupture and severe coronary artery disease. The membranes of red blood cells are rich in lipid content and constitute 40 % by weight that exceeds all other cell types [19]. Excess membrane cholesterol of red blood cells can phase separate and form immiscible membrane domains consisting of free cholesterol arranged in a tail-to tail orientation favoring crystal formation [20]. The insudation of lipoproteins within the plaque matrix, dead and dying foamy macrophages, along with accumulation of erythrocytes membranes that are rich in free cholesterol all collectively influence both the biochemical composition and size of the necrotic core. The origin of intraplaque hemorrhage is also debated between those who believe that it is the influx of blood from the luminal through plaque fissuring to others who propose that it is leakage from intraplaque vasa vasorum. However, we favor of the latter since it is often the case that intraplaque erythrocyte extravasation is seen in the absence of plaque fissure and hemorrhage is associated with a high density of vasa vasorum within and close to the necrotic core (Fig. 16.5). Further, some reports demonstrated dysmorphogenesis of the vasa vasorum with absence of mural cells and presence of poor endothelial cell junctions [22]. It is possible that these immature or leaky vessels also allow diffusion of plasma molecules and diapedesis of leucocytes as well as erythrocytes [23], which may serve as the driving force of further centripetal angiogenesis from the adventitia [24].

Intraplaque hemorrhage could potentially provoke recruitment of inflammatory cells [25]. The precise signaling pathways for the cell migration are not fully understood but it is postulated that proteins in coagulated blood could contribute to inflammatory cell activation [26]. However more importantly, recent studies have elucidated the significance of oxidative stress associated with extravasated erythrocytes providing a rapid influx of hemoglobin (Hb) and continued inflammation in the intraplaque area. Free Hb can also bind and inactivate nitric oxide (NO), a potent signal molecule that plays a critical role in the relaxation of smooth muscle and reduced expression of endothelial adhesion molecules, eventually leading to cell injury [27].

A major protective mechanism against Hb toxicity is mediated by haptoglobin (Hp), an abundant serum protein whose major function is to bind excess Hb. In atherosclerotic plaques, the primary route for clearance of the Hb-Hp complex involves the CD163 receptor expressed on immunosuppressive macrophages with M2 polarized phenotype [28]. Another method for protection is provided by the presence of heme oxygenase-1 (HO-1) which has anti-oxidative, anti-inflammatory, anti-apoptotic and possibly immune-modulatory properties and is expressed in endothelial cells, macrophages and SMCs [29]. In ApoE deficient mouse models with over expression of heme oxygenase-1, decreased atherosclerotic lesions have been reported [30].