Mechanisms of acute coronary syndromes related to atherosclerosis

INTRODUCTION — Acute coronary syndromes (ACS) represent a clinical spectrum of acute coronary artery disease that includes unstable angina, acute myocardial infarction (MI), and sudden coronary death. In most cases, the underlying mechanism is obstruction of coronary artery blood flow by a thrombus that develops as a result of fissure or erosion of an underlying atherosclerotic plaque. Less common causes are MI with nonobstructive coronary arteries, coronary artery dissection, coronary artery spasm, and coronary microvascular dysfunction.

This topic focuses on the mechanisms of ACS related to destabilization of atherosclerotic plaques. Related topics include:

●(See "Acute coronary syndrome: Terminology and classification".)

●(See "Diagnosis of acute myocardial infarction".)

●(See "Pathophysiology and etiology of sudden cardiac arrest".)

●(See "Myocardial infarction or ischemia with no obstructive coronary atherosclerosis".)

●(See "Spontaneous coronary artery dissection".)

●(See "Vasospastic angina".)

●(See "Microvascular angina: Angina pectoris with normal coronary arteries".)

FORMATION AND PROGRESSION OF ATHEROSCLEROTIC PLAQUES — Atherosclerotic plaques are present in most patients with ACS. Atherogenesis is a dynamic process. Progressive stages have been described (figure 1A-B) [1,2].

Adaptive intimal xanthoma (fatty streak) and intimal thickening — Intimal xanthoma (fatty streaks) and intimal thickening are considered the earliest manifestations of atherosclerotic disease.

"Xanthoma" is a general pathological term that describes focal accumulations of lipid-laden macrophages within the intima. In humans, xanthomata are known to regress, since the distribution of lesions in the third decade of life and beyond is very different from where these fatty streaks are seen in children [3,4]. Early fatty streaks (intimal xanthoma), which are predominantly observed also at branch points, correspond to the accumulation of macrophages within the intima.

Intimal thickening, a nonatherogenic process involving smooth muscle cells, occurs in children at similar locations as advanced plaques in adults. Histologically, intimal thickening consists mainly of smooth muscle cells in a proteoglycan-collagen matrix with little or no infiltrating inflammatory cells. Thirty percent of newborns show some intimal thickening, especially at branch points but by six months, almost all have intimal thickening. Our understanding of the pathophysiological mechanisms of their development is still very limited.

The stage beyond intimal xanthoma/intimal thickening is the more advanced plaque called "pathologic intimal thickening" and is characterized by extracellular lipid pools containing proteoglycans without necrosis [1,5]. The lipid pools consist of areas rich in hyaluronan and proteoglycans with absence of smooth muscle cells and inflammatory cells; however, the lipid pools are rich in extracellular lipid deposits. The lipid pools tend to develop in the deeper intimal layers near the arterial media. When present, macrophage and T lymphocytic infiltrates are near the luminal surface and restricted from the area of accumulated lipids.

Early calcification is frequently observed within the areas of lipid pools and likely results from the death of smooth muscle cells [6].

Inflammation and plaque progression — Atherosclerosis has been defined as a chronic inflammatory disease, with monocyte infiltration being one of the early steps [7]. The presence of intimal lipoproteins and their derived or modified products causes an increase in the expression of adhesion molecules on the endothelial surface. Adhesion of inflammatory cells involves the expression of selectins, which facilitate the firm attachment of monocytes to endothelial integrins and transmigration by way of the endothelial junctional proteins [8]. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation", section on 'Selectins'.)

Oxidation of low density lipoprotein (LDL) particles may participate in the initiation and progression of atherosclerosis and is promoted by macrophages, endothelial cells, and smooth muscle cells [9,10]. LDL oxidation can occur as a result of lipoxygenases, hypochlorous acid produced by myeloperoxidase, nitric oxide produced by inducible nitric oxide synthase, superoxide anion produced by NADPH oxidase, and from heme-derived iron [11,12]. Such reactive oxygen species derive from macrophages, endothelial cells, and smooth muscle cells. Oxidized LDL promotes chemoattraction, for example, by inducing the secretion of macrophage-chemotactic protein-1 (MCP-1) by endothelial cells [12,13]. Moreover, macrophages express several scavenger receptors, which can bind a broad spectrum of ligands, including modified lipoproteins, native lipoproteins, and anionic phospholipids, many of which facilitate the massive accumulation of intracellular cholesterol esters and free cholesterol [11].

Macrophages and endothelial cells also express Toll-like receptors (TLRs) on their cell surface, and contain various adaptor molecules (in particular MyD88) that participate in downstream signaling [14]. TLRs activate the proinflammatory transcription factor nuclear factor kappa-B, resulting in the production of cytokines that augment local inflammation and smooth muscle cell proliferation [15,16]. In vitro studies have shown that basal expression of TLR-4 by macrophages is upregulated by oxidized LDL [17], and that uptake of oxidized lipids into macrophages is facilitated by a CD36/TLR4/TLR6 heterotrimer that initiates TLR4 signaling [18]. These data provide a potential pathophysiological link between lipid accumulation, inflammatory cytokines, and atherosclerosis.

Fibroatheroma — Fibroatheroma, also referred to as the fibrous cap atheroma, is considered to represent the first advanced form of atherosclerotic lesion [1,19]. This lesion is characterized by the presence of necrotic core that is generated by infiltration of macrophages into lipid pools and is encapsulated by surrounding fibrous tissue (fibrous cap). The necrotic core is caused by the death of lipid-laden macrophages, also referred to as foam cells and plasma-derived lipids [20,21]. Foam cells contain cholesterol esters and free cholesterol. As plaques progress, the free cholesterol content of the plaque lesion increases, as does the free-to-esterified cholesterol ratio [22,23]. A high ratio of free cholesterol to phospholipid in cellular membrane has been shown to be toxic to cells, and therefore free-cholesterol-induced cytotoxicity may contribute to foam cell necrosis, which should be distinguished from apoptosis, which is a naturally occurring, programmed cell death leading to expansion of the necrotic core (figure 2) [24].

While the accumulation of lipid-laden foamy macrophages has an important impact on atherosclerotic lesion growth, these macrophages may die mainly through mechanisms involving apoptosis. (See "Apoptosis and autoimmune disease", section on 'Introduction'.)

Although macrophage death occurs throughout all stages of atherosclerosis, apoptotic macrophages are more frequently observed in advanced atherosclerotic lesions [25]. Extensive in vivo investigations suggest that the efficiency of phagocytic clearance of apoptotic cells (frequently referred to as programmed cell removal or efferocytosis) may be supportive in early lesions with minimal effect on lesion cellularity, whereas for late lesions, macrophages may exhibit a defective phagocytic clearance, where remnants of dead cells can lead to activation of proinflammatory responses and subsequent necrotic core expansion and lesion progression (figure 2) [26,27]. It is likely that both cellular cytotoxicity induced by free cholesterol (discussed above) and defective removal of apoptotic cells contribute to necrotic core enlargement.

Intraplaque hemorrhage is another important contributing factor to the enlargement of necrotic core. Although apoptotic macrophages may be a source of free cholesterol in the development and expansion of the necrotic core, it is unlikely that the total free cholesterol in plaques derives from foam cells alone, since a large part of the cholesterol in foam cells is esterified. Some of the cholesterol crystals in lesions are derived from red cells, as they are frequently observed at sites of hemorrhage [28]. Also, the cholesterol content of erythrocyte membrane is the richest in free cholesterol of all cells in the body. Hemorrhage into the necrotic core is a common event, and therefore it is likely that the free cholesterol in the necrotic cores also comes from red cell membranes (figure 2 and picture 1).

The source of hemorrhage is probably from leaky vasa vasorum that infiltrate the plaque mostly from the adventitia in response to a hypoxic environment created by increased lesion burden and inflammatory macrophages. The vasa vasorum within plaques typically lack an intact basement membrane, are poorly stabilized by surrounding pericytes, and exhibit poor endothelial junctions, which is likely responsible for their acquired lack of integrity [29].

In areas of plaque hemorrhage, red blood cell lysis leads to the release of free hemoglobin. Uptake of hemoglobin:haptoglobin complexes via the scavenger receptor CD163 expressed on macrophages allows for the differentiation of these cells into a unique non-foam cell phenotype characterized by lack of lipid retention and lowered expression of inflammatory cytokines such as TNF alpha. These cells play an important role in detoxification of hemoglobin-derived iron and therefore have been suggested to be atheroprotective [30,31]. However, evidence indicates that these cells play a pathogenic role in atherosclerosis by promoting plaque angiogenesis, vascular permeability, and inflammatory cell recruitment via release of vascular endothelial growth factor A [32].

In late fibroatheromas, discrete collections of cellular debris, increased free cholesterol, and near complete depletion of extracellular matrix are observed. The fibrous cap atheroma may develop into a lesion with a significant luminal stenosis after episodes of hemorrhage with or without calcification and surface disruption. Within the area of the necrotic core, calcification is observed as punctate (>15 micrometers) areas from macrophage cell death. Such microcalcifications coalesce to form larger masses that may involve both the necrotic core and the surrounding collagen-rich extracellular matrix to form speckles and fragments of calcification [33].

Coronary arterial remodeling — An increase in lesion size compromises luminal blood flow only when 40 percent or greater cross-sectional luminal narrowing is observed. The absence of luminal loss independent of lesion burden in early plaques has been linked to compensatory enlargement of the vessel, ie, positive coronary arterial remodeling, often called the "Glagov phenomenon" [34,35].

Postmortem and intravascular ultrasound studies have revealed that positive remodeling of the coronary arterial wall associates with a higher lipid content and macrophage infiltration, as well as unstable plaque features such as acute rupture, intraplaque hemorrhage, and thin-cap fibroatheromas [36,37] (see 'Thin-cap fibroatheroma' below). Conversely, lesions of erosion or chronic total occlusion exhibit negative remodeling [36].

Thin-cap fibroatheroma — A thin-cap fibroatheroma has been defined as a lesion that is a precursor to plaque rupture, and has a necrotic core and a cap that is thin and is ruptured with an overlying luminal thrombus. Ruptured caps were measured in autopsy cases and were 23±19 microns in thickness at the site of rupture, and therefore from these measurements a thin-cap fibroatheroma was determined not only to have a necrotic core, but the cap had to be <65 microns because the 95% confidence interval was determined to be 64 microns. Therefore, in order to better characterize thin-cap fibroatheroma, a precursor lesion of rupture cap, thickness had to be <65 microns.

The fibroatheroma seems likely to be the precursor lesion to the thin-cap fibroatheroma, although definitive in vivo data suggesting this have not been shown (see 'Fibroatheroma' above). It is possible that thin-cap fibroatheromas are formed de novo.

It is possible that in some patients, the fibrous cap becomes thin due to the predominance of matrix metalloproteinases action, released from activated macrophages, which are located underneath the collagen-rich fibrous cap. In contrast, in other patients, the thickness of the fibrous cap can increase due to the predominance of collagen synthesis. Thus, the evolution of coronary artery lesions is rather dynamic [38]. The thin-cap fibroatheroma, also referred to as a "vulnerable plaque," is identified by a large necrotic core (representing approximately 25 percent of plaque area) separated from the lumen by a thin fibrous cap, less than 65 micrometers in thickness. The fibrous cap is heavily infiltrated by macrophages and to a lesser extent T-lymphocytes (picture 2) [39]. Typically, the fibrous cap exhibits a paucity or absence of smooth muscle cells. Because it resembles plaques that have ruptured in its morphological appearance (minus the cap discontinuity), this well-characterized lesion is considered a prelude to plaque rupture [1,40]. It must be acknowledged that cause-and-effect data are missing from this paradigm because we have not been able to detect vulnerable plaque in humans in vivo that eventually rupture consistently and because animal models of plaque rupture are, for the most part, lacking.

Despite morphologic similarities to lesions that have ruptured plaque, thin-cap fibroatheromas exhibit a trend toward smaller necrotic cores, fewer cap macrophages, and less calcification as compared with rupture [41]. Cross-sectional luminal narrowing in thin-cap fibroatheromas is typically less as compared with underlying stenosis in acute ruptures [41]. The vast majority of thin-cap fibroatheromas (over 80 percent) in sudden coronary death victims have <75 percent cross-sectional luminal-narrowing (or <50 percent diameter stenosis) [42].

The fibrous cap thickness of <65 micrometers is a widely accepted definition of thin-fibrous cap. However, given that tissue fixation and processing result in an approximately 25 to 40 percent shrinkage in arterial wall area in human coronary arteries with moderate to severe atherosclerosis [43], it may not be an appropriate cut-off value for the evaluation of rupture-prone plaques in vivo. In fact, optical coherence tomography studies evaluating patients with plaque ruptures have demonstrated that the disrupted fibrous cap thickness <70 micrometers was observed only in 67 percent [44], and median (interquartile range) value of cap thickness was 54 (50 to 60) micrometers, with 95 percent of the thinnest cap thickness measuring less than 80 micrometers [45]. (See "Intravascular ultrasound, optical coherence tomography, and angioscopy of coronary circulation" and "Intravascular ultrasound, optical coherence tomography, and angioscopy of coronary circulation", section on 'Optical coherence tomography'.)

PLAQUE RUPTURE — Most ACS result from the loss of integrity of the protective covering over an atherosclerotic plaque. This occurs with plaque rupture when the fibrous cap overlying the plaque gets disrupted or with erosion when the endothelial lining of the plaque is disturbed. This disruption of the protective covering allows blood to come in contact with the highly thrombogenic contents of the necrotic core (including tissue factor) [1,46].

At the rupture site, the luminal thrombus is often platelet-rich, thereby giving rise to a grossly white appearance (white thrombus), while at the proximal and distal ends near the sites of propagation of the thrombosis, it appears red (red thrombus), as it is composed of layers of fibrin and red blood cells. Over time, thrombus healing is characterized by an infiltration of smooth muscle cells, accumulated extracellular matrix proteins (ie, proteoglycans and collagen), neovascularization, inflammation, and luminal surface reendothelialization. A breach in the fibrous cap allows circulating cellular and noncellular elements of blood to come in direct contact with the highly thrombogenic components of the necrotic core and is thought to be directly responsible for the actual development of the thrombus. Historically, the necrotic core was thought to be the main source of the tissue factor; however, it is now believed that circulating monocytes, instead of macrophages alone, supply tissue factors that trigger and propagate acute thrombi overlying unstable coronary atherosclerosis [47].

Although the precise mechanism(s) of plaque rupture is poorly understood, it is widely accepted that disruption occurs at the site of a fibrous cap that is heavily infiltrated by macrophages and T-lymphocytes where the underlying necrotic core is typically large [1,7] and is associated with systemic activation of adaptive immunity [48]. While necrotic core expansion and positive remodeling may be associated with plaque progression and lesion vulnerability, the actual degradation of fibrous cap is thought to occur through the breakdown of extracellular matrix proteins by secreted matrix metalloproteinases (MMPs) [49] (see 'Fibroatheroma' above and 'Coronary arterial remodeling' above). This, together with other critical factors such as apoptosis and local rheological forces including vasospasm, has been implicated in the development of plaque rupture.

Vascular smooth muscle cells synthesize essential extracellular matrix proteins such as collagen and elastin from amino acids. Fibrillar collagens, especially type I collagen, provide most of the tensile strength to the fibrous cap. The process of collagen synthesis may be inhibited by interferon gamma secreted by activated T-cells (figure 3) [50]. Moreover, T-cell activation leads to the expression of CD40 ligands (CD40L/CD154), which bind to CD40 receptors on the macrophages, B-lymphocytes, and other cells including endothelial and smooth muscle cells [7,51-53]. The expression of CD40L on T-cells promotes tissue proteolysis through the release of MMPs.

The loss of fibrillar collagen by activated MMPs is thought to be responsible for fibrous cap thinning and therefore may play a pivotal role in the development of plaque rupture (figure 3). The initial proteolytic nick in the collagen chain is provided by collagenases MMPs-1, -8, and -13, while the gelatinases MMP-2 and -9 support further breakdown of collagen fragments [7,54-57]. On the other hand, the artery also possesses endogenous antagonists to MMPs, the tissue inhibitors of metalloproteinases [8]. Atheromatous plaques exhibit cleavage of type I collagen at the sites that are rich in macrophages expressing both MMP-1 and -13 [57]. Other proteinases capable of degrading extracellular matrix include the cathepsin family (cathepsins S and K) and the inhibitor cystatin C [58]. Unlike collagen breakdown by MMPs, elastolytic activity has been implicated more with matrix remodeling and migration and proliferation of cells [55]. While elastolysis may be more important in aneurysm formation, collagenolysis may be a major determinant of plaque rupture [59].

Apoptosis may also play a critical role in the development of plaque rupture [60] (see "Apoptosis and autoimmune disease", section on 'Molecular mechanisms of apoptosis'). Macrophage and smooth muscle cell apoptosis have been observed in both progression and regression of the atherosclerotic plaque [61]. Plaque rupture sites typically show fewer or an absence of smooth muscle cells, which are the principal cells required for the synthesis of extracellular matrix proteins and maintenance of the fibrous cap. In vitro studies have shown that various mediators secreted by macrophages and T-lymphocytes, including interferon-gamma, Fas ligand, tumor necrosis factor-a, interleukin-1, and reactive oxygen species, can promote smooth muscle cell apoptosis [62], which may account for the decrease in smooth muscle cells seen in thin cap fibroatheroma and ruptured plaques [63].

Although macrophage apoptosis is frequently observed at the sites of plaque rupture, it remains unknown whether apoptosis alone is capable of triggering the primary event [64]. In vitro studies have identified potent mediators, such as oxidized low density lipoprotein, as capable of inducing macrophage apoptosis [60]. INF gamma has been shown to induce apoptotic cell death of THP-1 macrophages [61], while it also leads to further synthesis of macrophage chemoattractant protein-1, which may promote additional inflammatory responses.

Morphologically, a plaque that has ruptured shows an intraluminal thrombus overlying a thin disrupted fibrous cap, which is infiltrated by macrophages and T-lymphocytes [65]. The thrombus is in contact with an underlying necrotic core (picture 3). The fibrous cap consists mainly of type I collagen with varying degrees of macrophages and lymphocytes, whereas the smooth muscle cell component within the cap is absent or sparse. In lesions that have ruptured, the mean thickness of the fibrous cap is 23±19 micrometers, with 95 percent of the cap measuring less than 65 micrometers [39]. Although it has been widely accepted that fibrous cap rupture occurs at its weakest point, often near shoulder regions, autopsy studies using serially cut sections demonstrate an equal number of ruptures occurring at the midportion of the fibrous cap [46]. In some patients, plaque rupture might be related to abrupt cholesterol crystallization within a rupture-prone plaque, but further work is needed to confirm that this actually occurs in vivo [66].

Plaque fissure is observed in <10 percent of lesions and is typically associated with pan-coronary inflammatory activation and systemic evidence of innate and adaptive immunity activation [67,68]. Of note, autopsy studies of sudden coronary death victims have shown that approximately 40 percent of plaque ruptures occur at lesion sites with less than 50 percent diameter stenosis [69].

Biomechanical and imaging studies have examined the role of hemodynamic shear stress in the destabilization of vulnerable plaques [70-72]. Regions of high circumferential "hoop" stress and disturbed flow may contribute to plaque rupture. Higher shear stress (normal to the circumferential stress, parallel to the intimal surface) protects the artery wall from lesion formation and complication. Shear stress influences processes that govern fibrous cap morphology and composition [73], where increased peak circumferential stress is greater in thinner fibrous caps [70]. Regions with high circumferential stress typically exhibit high strain [72] and, when applied to the weakened fibrous cap, may precipitate rupture, particularly in the presence of microcalcifications [74,75].

Vulnerable plaques and future rupture — Extensive efforts have been devoted to identify these rupture-prone "vulnerable plaques" [1,76-78]. Advances in imaging technologies allow us to evaluate several morphologic features of coronary plaques in relation to the development of ACS in vivo, whereas the strategies to detect and treat vulnerable plaques for the prevention of plaque rupture need further refinements.

Computed tomography (CT) angiography is emerging as a promising approach for the noninvasive assessment of coronary artery stenosis and plaque characteristics [79-83].

One clinical study has reported a potential usefulness of CT angiography to identify vulnerable plaques that have not yet ruptured in patients who have not experienced an acute coronary event [84]. Among a total of 1059 patients who underwent CT angiography, two important CT characteristics, positive remodeling and low-attenuation plaque, were identified in 45 patients, and in another 27 patients only one feature was present. Of the 45 patients with these two characteristics, 10 (22.2 percent) developed ACS over a mean follow-up of 27 months, whereas one patient (3.7 percent) with a single feature developed ACS. In contrast, of the 820 patients who were negative for both features, only four (0.5 percent) developed ACS. This study suggests that coronary lesions showing both positive remodeling and low-attenuation plaques on CT angiography are at a higher risk of future acute coronary events. However, the very low positive predictive value of vulnerable plaque for subsequent ACS in this study and in other similar studies [85] makes this approach of limited clinical value also because of radiation exposure, use of contrast media, and cost.

The reasons for the low predictive yield of vulnerable plaque identification have been clarified by the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study, a prospective, multi-center study, in which 697 patients with ACS were enrolled. These patients underwent three-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronary intervention [86]. The three-year cumulative rate of major adverse cardiovascular events (death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization due to unstable or progressive angina) was equally attributable to recurrence at the site of culprit lesions (13 percent), as well as to nonculprit lesions (12 percent). Furthermore, among 595 thin-cap fibroatheromas in nonculprit lesions at baseline, the major adverse cardiovascular events occurred in only 26 lesions (5 percent) at a median follow-up of 3.4 years (estimated Kaplan-Meier event rate, 4.9 percent). This is probably because the vast majority of vulnerable plaques heal [38] and because imaging techniques are unable to identify plaques that will cause ACS due to erosion or coronary functional alterations. Other technologies, such as near-infrared spectroscopy, have also been used to identify lipid core plaques, as reported in the PROSPECT II (Providing Regional Observations to Study Predictors of Events in the Coronary Tree II) multicenter trial [87].

Plaque healing — Clinical studies using intravascular imaging have suggested that a majority of thin-cap fibroatheromas tend to heal over time, while a smaller fraction are responsible for ACS at follow-up [38].

Healed lesions occur at sites of prior rupture with thrombus formation, which may or may not be associated with symptoms. They are defined as a third category of atherosclerotic plaques, the other two being nonprogressive and progression-prone plaques.

Healed lesions are identified on the basis of a disrupted fibrous cap with an overlying repair reaction consisting of smooth muscle cells surrounded by proteoglycans and/or a collagen-rich matrix, with or without fibrin depending on the phase of healing [88]. The matrix within the healed fibrous cap generally begins as an early proteoglycan-rich mass along with type III/IV collagen, which eventually progresses into a type I collagen-rich lesion from organization of the thrombus (picture 4) [89]. Healed ruptures frequently exhibit multiple layers of necrotic cores interspersed by fibrous tissue (so-called buried caps), with the earliest of rupture sites located in deeper intima suggestive of previous thrombotic events, which sequentially lead to lesion progression [89].

A 2019 study using optical coherence tomography intravascular imaging found that patients with recurrent ACS have a distinct atherosclerotic phenotype compared with those with chronic stable angina, including a much lower prevalence of healed coronary plaques. These findings suggest that although atherosclerotic disease phenotype and burden are important predisposing factors for acute coronary disease, other factors, including plaque healing, may determine the natural history of a patient toward either recurrence of acute events or long-term clinical stability. Thus, plaque healing strategies might become a new therapeutic target [90,91]. It has been shown that the luminal narrowing increases as the number of ruptures increases [88,89].

PLAQUE EROSION — Plaque erosion represents the second most common lesion after plaque rupture associated with acute thrombosis in the coronary circulation. Erosions differ from rupture lesions, as there is an absence of fibrous cap disruption (image 1).

The primary cellular characteristics of plaque erosion include an abundance of smooth muscle cells within a proteoglycan-rich matrix, and absence of surface endothelium without a prominent lipid core [92]. There are generally few macrophages and T-lymphocytes close to the lumen [1]. The underlying lesion morphology also differs from rupture since it involves early lesions such as pathologic intimal thickening or fibroatheromas without an extensive necrotic core, hemorrhage, or calcification. There is no communication between necrotic core and the lumen. There is usually a smooth muscle-cell-rich region close to the lumen that separates the thrombus from the underlying necrotic core or lipid pool. An absence of endothelium, secondary to apoptotic loss of endothelial cells, allows flowing blood to come in contact with collagen that leads to thrombus formation.

An intense accumulation of extracellular matrix molecules such as hyaluronan and versican (proteoglycan) are observed at the sites of plaque erosion, whereas there is relatively little accumulation of proteoglycans and hyaluronan at plaque rupture sites [92]. Flow disturbance may favor endothelial activation with expression of TLR-2, a selective accumulation of hyaluronan, a ligand of TLR-2, and neutrophil recruitments, thus promoting de-endothelialization and neutrophil-rich thrombus formation [93,94]. Indeed, postmortem studies have shown that coronary thrombi superimposed on eroded plaques contain a much higher density of myeloperoxidase-positive cells than thrombi superimposed on ruptured plaques [95]. Systemic myeloperoxidase levels are also elevated in patients with ACS presenting with eroded plaque as compared with those presenting with rupture, suggesting that elevations in selective inflammatory biomarkers may reflect specific acute coronary events [95,96]. A 2018 study found increased expression of hyaluronidase-2, which transforms high-molecular-weight hyaluronan into proinflammatory low-molecular-weight hyaluronan in peripheral blood mononuclear cells of patients with plaque erosion assessed by optical coherence tomography. Local release of low-molecular-weight hyaluronan can directly promote fibrin polymerization, which may facilitate smooth muscle cell migration and plaque progression, as well as stimulation of TLR-2 and formation of neutrophil-platelet aggregates, promoting thrombus formation [97,98].

The risk factors for erosion are poorly understood and are different from those for rupture (see 'Clinical correlates' below). It has been speculated that coronary vasospasm might be involved in the pathophysiology of erosion [99]. Data from patients suffering from coronary artery spasm demonstrated by optical coherence tomography imaging that erosions occurred in more than one-fourth of patients with many of these containing thrombus [100].

Calcific nodules — Fibrocalcific plaques are characterized by the presence of dense, calcific nodules that disrupt the luminal surface and protrude into the lumen [1,101,102]. Calcified lesions are difficult to identify in vivo given the limited resolution of angiography but have been identified in approximately five to eight percent of patients with ACS by optical coherence tomography [103,104]. These lesions are generally more prevalent in older individuals with tortuous and heavily calcified coronary arteries and in the right coronary artery. Heavily calcified arteries often show large plates of calcified matrix with surrounding areas of fibrosis, inflammation, and neovascularization, which may be formed by fragmentation of necrotic core calcium.

CLINICAL CORRELATES — As discussed above, plaque rupture and plaque erosion are the first and second, respectively, most common immediate pathologies associated with ACS.

Intraluminal thrombosis after exposure of the blood to calcified nodules has been observed. However, its incidence in sudden coronary death victims is less than 5 percent. Imaging studies have shown a higher incidence of up to 10 percent, likely because living patients with ACS are older than sudden coronary death victims [105,106] (see 'Imaging observations' below). Irrespective of underlying pathology, the formation of intraluminal thrombus is the cause of ACS.

Other causes of ACS are presented above. (See 'Introduction' above.)

In instances when rupture (or erosion) does not lead to thrombotic occlusion of the vessel, symptoms may not be present, and plaque healing results in plaque progression and greater luminal narrowing [88,89].

Autopsy studies have shown that when intraluminal thrombi are identified in patients with sudden cardiac death and acute myocardial infarction (MI), the underlying pathology is rupture 55 to 75 percent of the time, erosion 25 to 40 percent of the time, and calcified nodules less than 5 percent of the time [1,39,69,76-78,107-109]. In vivo studies in patients presenting with ST-segment elevation MI (STEMI) using high-resolution optical coherence tomography (OCT) intravascular imaging of culprit plaques have shown a similar distribution of plaque morphologies [105].

In acute STEMI, approximately 75 percent of cases are due to plaque rupture, and the remaining 25 percent are attributed to plaque erosion [76]. This finding has been confirmed by clinical studies utilizing high-resolution OCT [77].

In non-ST-elevation ACS using OCT, plaque rupture was found in 47 percent of cases [78]. These findings have been confirmed using intravascular ultrasound [110]. (See "Intravascular ultrasound, optical coherence tomography, and angioscopy of coronary circulation", section on 'Atherosclerotic plaques'.)

Primarily based on autopsy findings from sudden coronary deaths, healed ruptures contribute to a significant increase in plaque burden and luminal narrowing. They generally occur in the absence of cardiac symptoms. First-time ruptures that precipitate sudden cardiac death are responsible for only 11 percent of acute thrombi [89]. In plaques with less than 20 percent diameter stenosis, the incidence of healed plaque rupture is 16 percent; in lesions with 21 to 50 percent stenosis, the incidence is 19 percent; and in plaques with greater than 50 percent narrowing, the incidence is 73 percent [88].

Low density lipoprotein cholesterol lowering, in particular with statin treatment, may modify the characteristics of the atherosclerotic plaque in a way that thickens the fibrous cap, reduces lipid accumulation, dispels inflammation, and shrinks the volume of the lipid core. These morphologic changes should lead to "stabilization" of plaques, reducing their risk of rupture. This issue is discussed separately. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease", section on 'Timing and mechanisms of benefit'.)

Imaging observations — Plaque rupture has been thought to be present when coronary angiography shows complex lesions, which consist of stenosis with irregular, rough borders, and ulceration with or without intraluminal filling defects suggestive of a thrombus [111-113]. The presence of angiographic complex lesions is associated with rapid progression of coronary stenosis [114-116]. An OCT study in patients with ACS found that the prevalence of plaque rupture was 44 percent, plaque erosion was 31 percent, and calcified nodule was 8 percent [103]. Similar findings were observed in another study [105].

A substantial proportion (40 percent) of patients with acute myocardial infarction (MI) have angiographic evidence of multiple complex lesions; this has been termed "multiple plaque instability" [117]. This situation is associated with adverse clinical outcomes. Angioscopic studies support this concept by showing the presence of multiple yellow plaques, ie, vulnerable plaques, throughout the coronary tree in patients with acute MI [118]. Furthermore, three-vessel intravascular ultrasound imaging demonstrated that culprit plaque rupture, remote plaque rupture, and multiple plaque rupture were all more frequent in patients with acute MI as compared with those with stable angina [119]. However, in morphologic autopsy studies, the incidence of multiple rupture sites in an individual is less than 5 percent [120]. Similar findings have been confirmed by OCT showing pan-coronary vulnerability in patients with a ruptured culprit plaque but not in those with a non-fissured culprit plaque.

PATHOGENETIC CLASSIFICATION OF ACUTE CORONARY SYNDROME — A pathogenetic classification of ACS has proposed segmenting coronary artery thrombosis caused by plaque rupture into cases with or without signs of concomitant inflammation [121]. This distinction may have substantial therapeutic implications as direct antiinflammatory interventions for atherosclerosis emerge, especially those of plaque rupture, which could be distinguished by optical coherence tomography. At present, this distinction has not been demonstrated clinically [122].

A third mechanism is plaque erosion that may be on the rise in an era of intense lipid lowering. Identification of patients with ACS resulting from erosion may permit a less invasive approach to management than the standard of care.

A fourth mechanism is represented by functional alterations of coronary circulation, including epicardial and microvascular spasm, which typically operate in ACS that occurs without apparent epicardial coronary artery thrombus or stenosis. Emerging management strategies may likewise apply selectively to this category of ACS. This more mechanistic approach to the categorization of ACS provides a framework for future tailoring, triage, and therapy for patients in a more personalized and precise manner (figure 4).

SUMMARY

●Most acute coronary syndromes (ACS) result from the loss of integrity of the protective covering over an atherosclerotic plaque. The loss of the protective endothelial covering allows blood to come in contact with the highly thrombogenic contents of collagen and/or necrotic core of the plaque and allows luminal thrombosis to occur. (See 'Formation and progression of atherosclerotic plaques' above.)

●Plaque rupture is the major cause of ACS thrombi. It is characterized by lesions that exhibit relatively large necrotic cores with a thin disrupted fibrous cap. Luminal blood comes in direct communication with the necrotic core, and thrombosis may result. (See 'Plaque rupture' above.)

●In a large subset of patients, ACS are caused by plaque erosion. The pathobiology of plaque erosion is different than that of plaque fissure and is characterized by accumulation of hyaluronan and neutrophils, leading to de-endothelialization and thrombus formation. (See 'Plaque erosion' above.)

●ACS in the absence of atherosclerotic plaque rupture or fissure can be caused by coronary artery dissection, coronary artery spasm, and coronary microvascular dysfunction. The prevalence of these mechanisms of coronary instability is lower than that of plaque fissure or erosion but probably underestimated. (See 'Introduction' above.)