Coronary ‘microevagination’ in intact fibrous cap acute coronary syndromes: another piece of the puzzle

This editorial refers to ‘Coronary microevaginations characterize culprit plaques and their inflammatory microenvironment in a subtype of acute coronary syndrome with intact fibrous cap: results from the prospective translational OPTICO-ACS study’, by C. Seppelt et al., https://doi.org/10.1093/ehjci/jead154. Pathology studies have been fundamental in understanding the mechanisms of acute coronary syndromes (ACS), highlighting the role of intracoronary thrombus as the ultimate step of serial events leading to plaque instability.1–3 Pathologists introduced the concept of plaque vulnerability and paved the way for new therapies to prevent and treat coronary artery disease.3 Intracoronary imaging modalities corroborated such concepts in in vivo settings and are being utilized [particularly, optical coherence tomography (OCT)] to identify vulnerable lesions that may benefit from aggressive medical therapies or interventional solutions.4 Despite providing a suboptimal image resolution definition for identifying cells, OCT can be applied in vivo and repeated at different time points. These aspects represent a substantial advantage vs. pathology and have generated high expectations from the scientific community, including the possibility to identify new mechanisms of ACS. With this spirit, Seppelt et al.5 performed a post hoc analysis in 557 patients from the translational OPTICO-ACS study programme, focusing on the clinical role of outward bulges of coronary plaques, defined as coronary microevaginations (CME) at the culprit lesion site. CMEs were more frequently observed in lesions with intact fibrous cap (IFC) ACS as compared with ACS due to plaque rupture (55.0 vs. 12.7%, P < 0.001). CMEs were particularly prevalent in IFC ACS, independent of a coronary bifurcation as compared with IFC ACS association with a coronary bifurcation (65.4 vs. 43.7%, respectively, P = 0.030). Authors should be congratulated for their effort to broaden our understanding of the pathophysiology of IFC ACS which encompasses about 30% of all cases. There are however some issues to be addressed. A key point for understanding the descriptive findings reported by Seppelt et al. is the definition of the lesion ‘microevagination’.5 The term evagination was first introduced in 2014 by Radu et al. to describe a peculiar vessel remodelling following the implantation of first-generation drug-eluting stents.6 In that study, the authors defined ‘evaginations’ as outward bulges in the luminal contour between the struts of drug-eluted stented coronary arteries; major evaginations (MEs) extended ≥3 mm along the vessel length, with a depth ≥10% of the stent diameter, and were frequently observed in sirolimus-eluting stents (26%) but were nearly absent in everolimus-eluting (3%) and zotarolimus (ZES)-eluting (2%, P = 0.003) stents. The macroevagination corresponds to inter-strut protrusions of the arterial wall, a sort of stent-forced remodelling of the stented coronary segment.6 The visualization of the finding, and why Seppelt et al. have borrowed the term ‘evagination’ from the stent-related complication setting to native coronary artery lesions, can be facilitated by comparing two key figures, one from the original study by Radu et al.6 (Figure 1, left panel) and the present study5 (Figure 1, right panel). In the left column, the figure shows panels A and B of Figure 2 from the study by Radu et al.6 In the right column, the figure shows panels A and B of Figure S1 from the study by Seppelt et al.5 The red bordered area in panel B, right column, looks similar to the area (with double-headed arrow) of panel A in the left column. The understanding of the mechanism of evaginations observed in the stent setting can be intuitive;6 vice versa, the understanding of the microevagination mechanism described by the authors in non-stented coronary arteries is more difficult.5 It could represent the healed intima of a prior ruptured plaque with extrusion of the pultaceous core and repair/re-endothelization of the borders of the crater; it could be an area of focal inflammation of the coronary artery that caused severe segmental remodelling of the coronary wall. Autopsy studies in patients who died due to first-generation drug-eluting stents thrombosis showed an ‘aneurysmal’ dilation of the stented arterial segments that was accompanied by a severe localized hypersensitivity reaction consisting predominantly of T lymphocytes, eosinophils, and giant cells.7 In these unfortunate events, inflammation due to a possible allergic reaction to the stent polymer may have led to a destruction of the medial wall, causing vessel ectasia. The authors speculate that there may be a possible similarity between vessel wall ‘aneurysm’ after first-generation drug-eluting stent deployment and the evaginations identified in the present work. In fact, they found an association between local vessel inflammation (clustering of monocytes), CMEs, and local thrombosis. Is this mechanism plausible? If such a mechanism is indeed operational, the authors should have shown the thinning of vessel wall media and the resulting segmentary enlargement leading to the plaque CME. Unfortunately, OCT lacks the tissue penetration requisite to study the behaviour of vessel walls in response to an inflammatory stimulus. A combined assessment with intravascular ultrasound that studies the deep plaque components and vessel wall could be instrumental for this purpose in future studies. Although the authors did not clarify the mechanism of occurrence of the CMEs, the fact remains that most OCT readers must have run into this feature; its high prevalence in the present study is rather surprising, being CME detected in about 55% of cases with intact plaque fibrous cap thrombosis. There is however no comparison in the literature as to our knowledge this is the first study reporting on this OCT feature. Should authors have attempted to quantify the amount of vessel evagination, to establish a cut-off value, they might have ended up with a smaller number of plaques exhibiting plaque bulging. Furthermore, the use of measurements would have offered a more accurate method to approach the issue. New studies are now needed to confirm this segmentary focal remodelling in culprit lesions with an IFC. Whatever the mechanism leading to CME, the authors are speculating that thrombus formation is promoted by reduced shear stress; flow-dependent pathophysiologic mechanisms of ACS at non-side branch locations can be hypothesized. However, according to past studies, old healed plaque ulcerations, which represent an anatomical condition similar to CME and potentially lead to altered shear stress, did not seem features related to a higher risk of cardiovascular events.8 The authors highlight the role of CME in inducing flow alterations; in fact, an altered blood flow may work as the link connecting the presence of CME to the occurrence of ACS. This aspect however has never been proved, and intravascular studies on local shear stress in the presence of CME are needed to corroborate this hypothesis.9 The identification of IFC plaques at risk of cardiovascular events is an important topic, being IFC thrombosis responsible for about 30% of ACS.2,10 CME seems to have a role in this regard, showing the highest predictive value [area under the curve (AUC) = 0.777] for IFC ACS culprit lesions independent of a coronary bifurcation as compared with other OCT-derived criteria of plaque vulnerability, including circumferential extension of lipid pools, fibrous cap thickness, presence of macrophages, and minimal lumen area. Is CME a vulnerability feature that promotes plaque instability or is it a marker of more aggressive and perhaps more staged atherosclerosis? What is the relation between the vessel CMEs and the thrombus (if any) at the culprit cross-sections? Unfortunately, the authors are not providing a description of the longitudinal architecture of the coronary plaques that would have been instrumental to address these questions. Overall, the study provides further insights into the role of coronary inflammation in the process of plaque instability.11,12 In fact, the authors found at culprit IFC lesions an enrichment of monocytes in both culprit blood analysis (P = 0.048) and aspirated thrombi. Furthermore, the study confirmed at this site the accumulation of CD4+ T cells. Interestingly, local enrichment of monocytes observed in IFC ACS culprit lesions independent of a coronary bifurcation has been already shown in past studies on culprit ACS IFC plaques. According to Ferrante et al.,13 higher myeloperoxidase levels, a marker of neutrophil activation, were found in eroded culprit plaques as compared with ulcerated plaques. The question of whether OCT is ready as a high-resolution imaging modality to identify highly inflamed spots that may lead to IFC ACS is a key issue. Unfortunately, the predictive value for IFC culprit lesions for presence–absence of OCT-detected macrophages was only 0.481. This OCT feature is therefore rather common and may be not specific enough to quantify inflammation, encouraging the adoption of quantitative approaches to fine-tune its prognostic role. Seppelt et al. have shown that outward bulges of ACS coronary plaques, defined as CME at the culprit lesion site, are more frequently observed in IFC ACS lesions showing local inflammation and mainly located away from coronary bifurcations.5 CME may work therefore as a vulnerability feature although prospective studies are needed to confirm this preliminary finding. This contribution can be considered as a further piece in the complex puzzle of ACS with IFCs in culprit lesions. CLI Foundation is a private entity. INERSTRAT-CAD is a research project supported by the Italian Government (Fondazione Regionale per la Ricerca Biomedica, FRRB). RCR-2022-23682288 is a research project supported by the Italian Government. No data availability statement is included as the present commentary is not comprehensive of data underlying the research results.