Microvascular Obstruction Is Caused by Atherothrombosis in ACS Patients Undergoing PCI

The diagnosis of acute coronary syndrome (ACS) is primarily based on the mode of clinical presentation and is a term used for any conditions suggesting the acute induction of myocardial ischemia. The precise molecular and cellular triggers that lead to ACS remain poorly understood; however, histopathological studies have illustrated several mechanisms that may explain the sudden onset of symptoms in ACS patients. The most common substrate underlying ACS is thought to be rupture of a vulnerable plaque which contains a necrotic core covered by a fibrous cap. The word “thin cap fibroatheroma (TCFA)” is used to describe vulnerable plaque because histomorphometric analysis of ruptured plaques revealed fibrous cap thickness to be <65 μm in 95% of the lesions ¹. Once the disruption of the fibrous cap occurs, the lesion is no longer classified as a TCFA. In morphological measurement, plaque ruptures have the largest necrotic core 3.8±5.5 mm² followed by TCFAs 1.7±1.1 mm² with 75% of the lesions involving >120 degree of circumferential arc whereas thick cap fibroatheromas have the smallest necrotic core (1.2±2.2 mm²) ^{2, 3}. The highest positive remodeling index is seen in plaque ruptures, followed by plaque hemorrhage, TCFA, healed plaque rupture, and fibroatheroma ⁴. Also, plaque rupture and TCFA are located predominantly in the proximal portions of the coronary tree ⁵. Following the rupture of plaque, the exposure of necrotic core material to blood flow leads to thrombotic luminal obstruction with or without distal embolization of platelet rich thrombus or less commonly atherosclerotic debris.

The main causes of coronary thrombosis include plaque erosion as well as rupture, with erosion accounting for 25-35% and rupture for 65 to 75% of patients presenting with ACS in pathology series ^6-8. Erosions are found more frequently in younger individuals and especially in women < 50 years of age ⁹. There are clear morphologic differences between ruptured and eroded lesions with plaque erosion lesions being rich in proteoglycans such as versican and hyaluronan. On the other hand ruptures have a thin ruptured cap made up of type I collagen and an underlying large necrotic core ¹⁰. The incidence of intramyocardial microemboli is significantly higher in erosion (71%) as compared to rupture (42%) without prior intervention having been performed ¹¹. (Figure 1)

Figure 1. A sudden death case with acute thrombosis by plaque erosion.

Thirty-seven year old female with history of hypertension, and diabetes mellitus, complained of chest pain of one week duration. Subject had a witnessed arrest and could not be resuscitated. Postmortem angiogram showed focal severe stenosis limited to the proximal LAD (Left column). Histology identified presence of plaque erosion with non-occlusive thrombus (Thr) overlying a plaque which showed 75% cross-sectional area narrowing and an early necrotic core (Fibroatheroma with a thick fibrous cap) (Mid column, Movat pentachrome). Histologic examination of the myocardium revealed intramural platelet rich thromboemboli (red arrows) and acute myocardial infarction with acute inflammatory infiltrate (black arrowheads) (Right column, H&E)

Abbreviations: LAD, left anterior descending coronary artery; LCx, left circumferential coronary artery; LM, left main coronary artery; NC, necrotic core; RCA, right coronary artery

The concept of microvascular obstruction (MVO) of the myocardium was first described by Kloner et al., who documented a link between angiographic no-reflow phenomenon and severely damaged intramural microvessels with endothelial cell swelling, protrusions and decreased pinocytic vesicles in a canine epicardial coronary artery occlusion and reperfusion model ¹². Other studies have reported details of histologic changes of MVO with production of reactive oxygen species that lead to disruption of endothelial cells, fibrin and platelet deposition, neutrophil activation and red cell extravasation following reperfusion. ^13-16. In addition, the reperfusion-related response may be exaggerated from distal embolization of atherosclerotic debris or thromboemboli ¹⁷ especially following invasive coronary interventions.

The study by Ozaki et al. ¹⁸ presented in this issue of Circulation: Cardiovascular Imaging involved 70 ACS patients, who were separated on the basis of presence of TCFA (n=32) and non-TCFA (n=38) identified by optical coherence tomography (OCT). The definition used for TCFA was a fibrous cap <70 μm and a lipid rich plaque involving >90 degree of circumferential arc, which is somewhat different from the histopathological characteristics because of inability of OCT to determine the area of the necrotic core. MVO was assessed by late gadolinium enhancement cardiovascular MRI (LGE-CMR) and was more frequently observed in patients with TCFA (38%) as compared to those without TCFA (8%) following percutaneous coronary intervention (PCI) with stenting. While it is logical that following balloon dilatation and stent placement, necrotic materials behind the fibrous cap of TCFA would be released and cause distal embolization, why only the presence of TCFA made such a big difference in the development of MVO is unclear. There were no differences in the prevalence of thrombus (TCFA 81% vs. non-TCFA 63%, p=0.12) or plaque rupture (TCFA 59% vs. non-TCFA 37%, p=0.09) in their study. How can we reconcile this result with our current understanding of differences between rupture, TCFA, and erosion? Ozaki et al. used the term TCFA for plaques that had ruptures, which to us is not an appropriate as the two are not interchangeable since the ruptured plaques have a disrupted cap rather than an intact cap. A more appropriate classification would have been the lesions with rupture, TCFA without rupture, and thick cap fibroatheroma (presumably corresponding to plaque erosion), and further stratification by thrombus burden. By using this classification schema the mechanisms of MVO would likely have been more clearly elucidated. Therefore, we remain at a loss for fully comprehening the findings of this study except that presence of necrotic core of >90 degrees and a thin fibrous cap is associated with greater MVO.

It is also interesting that aspiration of the thrombus, which results in intensive negative pressure that may change lesion morphology, was applied in 78% of TCFA group and 53% of non-TCFA group. From histologic examination of ACS patients, it has been shown that 70% of the aspirates contain atherothrombotic materials ¹⁹, thus the results of low MVO presence in TCFAs in this study may have been due to aspiration. In patients undergoing PCI, it has been reported that atheroemboli is a frequent phenomenon especially in atherosclerotic vein graft (over 90% of cases) ²⁰, and we illustrate one such case with distal embolization following stenting in native coronary artery (Figure 2). This not only holds true for aspiration devices, but also for other distal protection devices such as filter wire or other methods, and pharmacologic vasodilators such as verapamil or adenosine in the prevention of no-reflow. Further investigations are definitely needed in whom OCT has been performed to determine plaque morphology in order to understand and attenuate MVO in ACS patients.

Figure 2. An autopsy case with atheroembolization in intramyocardial arteries.

Sixty-eight year old male who underwent stent placement for the treatment of unstable angina one week prior to sudden death. Postmortem angiography (Upper left images) and OFDI (left middle) reveled non-occlusive thrombus within the stented segment of mid LAD . Histological sections of the stented coronary artery (Upper right images, Movat pentachrome) demonstrated disruption of a thin fibrous cap by stent strut (asterisks) which penetrated into the necrotic core (NC). Histologic section of the myocardium revealed intramyocardial obstruction of microvessels by atheroemboli (black arrows) (Bottom images, H&E). Note presence of spindle shaped cholesterol crystals within microvessels and necrotic core.

Abbreviations: LAD, left anterior descending coronary artery; LCx, left circumferential coronary artery; OFDI, optical frequency domain imaging; Thr, thrombus

Lastly, as demonstrated in the study, the use of multiple modalities may provide more detailed information as compared to situations where only a single modality is used. Further, in vivo clinical studies are essential to determine what we can only infer from autopsy studies. However, in this era of ample non-invasive and catheter-based new technologies, it is essential to use the right terminology and to interpret results with great caution when interventions themselves induce changes in plaque characteristics. Furthermore, we should be aware of limitations of each technology. For example, the ability of OCT to detect TCFA wanes by the presence of foamy macrophages on the luminal surface which exhibit bright signals on OCT and may mimic TCFA ²¹, therefore it may be ideal to combine OCT with IVUS. Similarly, CMR may underestimate or fail to identify the area of MVO due to slow penetration of contrast over time.