Current Applications and New Perspectives in Optical Coherence Tomography (OCT) Coronary Atherosclerotic Plaque Assessment: From PCI Optimization to Pharmacological Treatment Guidance

Abstract

Since its ability to precisely characterized atherosclerotic plaque phenotypes, to tailor stent implantation, as well as to guide both complex percutaneous coronary interventions (PCI) and invasive diagnostic work-ups (e.g., spontaneous coronary dissections or myocardial infarction with non-obstructive arteries), the adoption of optical coherence tomography (OCT) was raised in the past decades in order to provide complementary information to the traditional angiography and to overcome its limitations. However, the impact of OCT on daily clinical practice is currently modest, firstly because of the lack of both standardized algorithms of PCI guidance and data from prospective clinical trials. Therefore, the aim of our narrative review is to provide a comprehensive overview of the basic OCT interpretation, to summarize the evidence supporting the OCT guidance procedures and applications, to discuss its current limitations, and to highlight the knowledge gaps that need to be filled with more robust evidence.

1. Introduction

In the past two decades, the recognition of several phenotypes of atherosclerotic coronary plaques with non-univocal treatment strategy, as well as the deeper knowledge of the multiple procedural complications occurring during both the elective and urgent percutaneous coronary interventions (PCI), potentially affecting long-term clinical outcomes, is urgently required to overcome the well-known limitations of angiographic imaging. Within this growing field, multiple techniques of intra-coronary imaging, particularly optical coherence tomography (OCT), have been progressively developed in order to introduce a helpful tool, able to provide specific insights into the plaque composition or distribution and to guide more tailored coronary interventions. Nevertheless, current guidelines assigned OCT a more marginal role when compared to other techniques, particularly intravascular ultrasonography (IVUS). Hence, both OCT and IVUS are equally supported for PCI optimization (class IIA, level B) and in-stent restenosis identification (class IIA, level C). In contrast, only IVUS collected enough evidence to achieve a class IIA-level B recommendation for a severity assessment of unprotected left main disease [1,2]. In addition, the prolonged procedural times, higher costs, and a more complex image interpretation may have limited the OCT adoption in the daily clinical practice [3]. Therefore, our review aims to offer an exhaustive state-of-the-art summary of the cardiovascular applications of OCT, moving from the physical/methodological principles, and then focusing on the evidence supporting OCT-guided interventions, specifically discussing the current limitations and future perspectives.

2. Basics of Coronary Optical Coherence Tomography (OCT)

2.1. Physical Principles

First introduced in 1991 [4], optical coherence tomography (OCT) is a revolutionary imaging modality used for the first time in the field of ophthalmology to capture high-resolution, cross-sectional tomographic information of biological tissue, such as the retina and choroid at the micron level. By now, its application in this setting has been consolidated, being commonly used for the evaluation of neovascular age-related macular degeneration (AMD), central serous chorioretinopathy (CSCR), retinal vascular disorders, and other vitreoretinal disorders [5]. Moreover, the technique improved its application in various technological and medical settings, including the cardiovascular field, validated in both animal [6] and human autoptic models [7]. Briefly, OCT measures the delay of light scattered from different depths within the biological tissue using low coherence interferometry in order to reconstruct the axial reflectivity profile of the sample. This imaging method has progressively emerged as a reference technique for assessing coronary atherosclerotic plaque composition because of its higher image resolution, compared with the existing standards, such as intravascular ultrasonography (IVUS), as shown in

Table 1. Technical differences and diagnostic accuracy of OCT compared with IVUS.

	IVUS	OCT
Source of image	Ultrasound	Infrared light
Penetration depth	4–8 mm	2 mm
Axial resolution	150 μm	15 μm
Acquisition speed	0.5 mm/s	25 mm/s
Blood clearance	Not required	Contrast 10–15 mL
Necrotic core	+	++
TCFA	-	+++
Thrombus	+	+++
Stent apposition	++	+++
Dissection	++	+++
Calcium	+++	++
Ostial lesion	++	+

OCT = Optical Coherence Tomography; IVUS = intravascular ultrasonography; TCFA = Thin Cap Fibro-Atheroma; +/++/+++ = diagnostic accuracy of the technique.

, summarizing the key differences between the two techniques [8]. More specifically, OCT provides cross-sectional views of the subsurface microstructure of the biological tissue. Its images are usually obtained with a 10–20 µm tissue axial resolution, a lateral resolution of 20–90 µm and a maximal scan diameter of 6.8 mm [9]. However, some research systems might even achieve a resolution of <5 µm [10]. In contrast, the penetration depth of OCT imaging remains limited by the optical tissue properties (between 0.5 and 1.5 mm) [9].

2.2. Image Acquisition

OCT measures the echo time delay of either back-reflected or back-scattered lights from different depths within the biological tissue using low-coherence interferometry to reconstruct the axial reflectivity profile of the sample [11]. With miniature side-looking fibre optic probes deployed through a narrow, flexible catheter, the intravascular OCT investigates the wall of the coronary arteries, performing a helical scanning pattern on the luminal surface of the vessel. Since blood strongly scatters the light and attenuates OCT signals, saline flushing is required for blood dilution during the OCT imaging [12]. However, the amount of injected saline volume and its potential ischemic complications restricted the imaging time and, thus, the amount of data acquired. Fortunately, in the last years, powerful advances in OCT technology, such as Fourier Domain (FD)/Spectral Domain OCT (SD-OCT) or swept-source OCT (SS-OCT), also called optical frequency domain imaging (OFDI) [13], enabled increased imaging speeds, thus bearing to overcome this previous limitation.

In particular, in FD/SD-OCT, the speed is determined by the readout time of the camera in a spectrometer, allowing the acquisition of 100,000 axial lines per second and generating up to 200 frames per second [14]. Differently, SS-OCT finds its strength in the wavelength-tuning speed of swept sources. Recently, different swept source technologies using wavelengths > 1 μm have emerged to improve the imaging speed in the OCT systems. The spectral resolution in SS-OCT can be much higher than that in SD-OCT due to the adoption of a narrow line width swept source, thus allowing the SS-OCT to be the technology of choice [15].

Currently, the most employed systems are the OPTIS™, which combines angiographic and OCT visualization (co-registration), and the Lunawave^® system, which provides 3D image reconstructions. Furthermore, OCT/IVUS hybrid catheter systems are now adopted for research purposes, with the potential to take advantage of both the OCT and IVUS features in a single catheter [16].

2.3. Basic Interpretation

Normal coronary artery. According to histology [17], a healthy/normal coronary artery shows a three-layered “bright-dark-bright” tissue structure at the OCT: the intimal layer appears as a bright, thin band surrounded by the medial layer, which, in contrast, appears as a relatively thick, low signal-intensity area, whereas adventitia is commonly described as the external, bright, envelope of the artery wall [18].

Fibrous, fibrocalcific and lipid plaque. As atherosclerosis progresses, the atherosclerotic plaque can be classified as fibrous, calcific, and lipid-rich [7], according to its composition. The fibrous plaques exhibit homogeneous, signal-rich (highly backscattering) regions (Figure 1A). The lipid-rich plaques demonstrate signal-poor regions (lipid pools) within the vessel wall with poorly defined borders and overlying signal-rich bands (corresponding to fibrous caps) (Figure 1B). The lipid pool is measured as the lipid arc (maximal degree of lipid pool) or as the number of involved quadrants on the cross-sectional OCT image [19]. The fibrocalcific plaques exhibit signal-poor regions with sharply delineated upper and/or lower borders (Figure 1C). Therefore, the OCT features strictly reflect the plaque composition according to the interference phenomenon: when two light beams overlap and their fields are in phase, constructive interference occurs, resulting in a more intense light; if the two fields are not in phase, destructive interference occurs, resulting in a less intense signal. Consequently, constructive interference occurs in fibrous plaques (rich in fibroblasts), thus bearing highly backscattered regions. In contrast, lipid plaques (full of foam cells) act as signal-poor regions because of destructive interference. Moreover, the optical properties of the atherosclerotic plaques depend on the different reflectivity of specific chemical components and the wavelength used for imaging. In this regard, lipid-rich plaques absorb light, thus revealing as dark (signal-poor) regions, whereas the fibrous plaques appear as bright (signal-rich) regions consistently with their higher reflectivity [11,14,17].

Fibroatheroma (FA). A fibroatheroma is characterized by a signal-rich band (fibrous tissue) overlying a signal-poor region (necrotic core). The fibrous cap thickness measured with OCT identifies both the thick-cap FA (ThCFA) and thin-cap FA (TCFA) [7].

Vulnerable plaque. TCFA, activated macrophages near the fibrous cap, a large lipid pool, and neoangiogenesis are histological features of the plaque instability detected by OCT [20] (Figure 1B). A plaque with a thin fibrous cap (commonly named TCFA) is defined by a fibrous cap thickness of <65 μm. The infiltration of macrophages within the fibrous cap appears as signal-rich, distinct, or confluent punctate regions exceeding the intensity of the background speckle noise [21]. Neoangiogenesis can be recognized as small black holes (microchannels), potentially associated with plaque growth and destabilization [22].

Three main categories of vulnerable plaques have been described as potential pathophysiologic substrates for acute coronary syndromes (ACS): plaque rupture, plaque erosion, and calcified nodule, responsible for ACS in 2/3, 1/3, and 1/20 of the cases, respectively [23].

Plaque rupture is characterized by fibrous cap discontinuity/disruption and cavity formation, communicating with the lumen, often with superimposed thrombus [24]. A red thrombus (composed of red blood cells) is depicted as a high-backscattering protrusion with signal-free shadowing in the OCT images. In contrast, a rich, low-backscattering signal depicts a white thrombus (a platelet-rich one).

The plaque erosion is commonly defined by the presence of a thrombus with concomitant irregular lumen surface and no evidence of the fibrous cap rupture in multiple adjacent frames on OCT.

The protruding calcified nodules are described as a superficial convex-shaped structure with high-backscattering density [25]. Interestingly, the calcified nodules may be covered by a very thin fibrous cap or sometimes uncovered, and thus exposed.

3. OCT Guidance to Optimize Percutaneous Coronary Intervention (PCI): Current Evidence and Knowledge Gaps

3.1. Lesion Assessment

Before the stent implantation, OCT allows an extensive lesion assessment in terms of plaque composition (fibrous, calcific, or lipidic plaque) and distribution (plaque length and size of native vessel), thus providing useful information concerning the PCI strategy of the lesion preparation (e.g., the adoption of plaque modification techniques for concentric/eccentric calcifications, such as debulking or lithotripsy-based devices), as well as enabling a more tailored stent selection according to the real size of the native vessel and the length of the target plaque (Figure 2) [26,27].

3.2. Stent Implantation

Following the stent implantation (Figure 2), OCT may also detect correctable abnormalities, potentially associated with adverse procedural outcomes, such as stent under-expansion (SU), stent malapposition (SM), tissue protrusion (TM), or stent edge dissection (SED), as shown in Figure 3A [27,28].

Stent Under-expansion (SU). Stent expansion is adequate if the treated segment is expanded to a size comparable to the normal artery. More specifically, it is described by the minimum stent cross-sectional area (MSA), expressed either as an absolute measure (absolute expansion), or compared with the average reference lumen area (relative expansion) [29]. An inadequate SU is a well-established major predictor of stent failure [30]. Therefore, post-PCI MSA represents the most consistent and strongest parameter to predict restenosis and stent thrombosis in non-left main (LM) lesions, with an absolute cut-off value of 5.0 mm² for the drug-eluting stents (DES) and 5.6 mm² for the bare metal stents (BMS), according to a large OCT registry by Soeda et al. [31]. Consistent with these previous data, in the DOCTORS trial [32], the optimal MSA cut-off to predict the non-ischemic post-PCI fractional flow reserve (FFR) was >5.44 mm², whereas data from the CLI-OPCI registry showed that an MSA value < 4.5 mm² is associated with an increased risk of major adverse cardiac events (MACE) [33].

Regarding LM disease, the reported IVUS MSA cut-offs are >7 mm² for distal LM and >8 mm² for ostial/proximal LM [29]. In contrast, no standardized OCT-based MSA cut-offs are currently available since technical limitations in this specific anatomical setting, such as suboptimal visualization due to the large coronary size and poor blood washing, particularly within the ostial and/or proximal tract [9,34]. However, concerning the minimal lumen area (MLA), early data suggests that an MLA > 5.4 mm² assessed by OCT is a safe cut-off for distal LM-PCI deferral [35,36].

Regarding the relative stent expansion, no standardized criteria are currently available. Although the European consensus statement on the clinical use of intracoronary imaging suggested a post-PCI MSA cut off for >80% of the average reference area [29], a recent contribution by Romagnoli et al. reported that the relative SU is not associated with an increased risk of stent failure, unless when combined with an absolute MSA < 4.5 mm² [37].

Stent Malapposition (SM). In contrast to SU (MSA smaller than the average lumen reference area), SM refers to a partial/incomplete stent apposition due to the lack of contact of stent struts with the intima [38]. SM and SU may both co-exist or occur independently [29]. SM may occur either in the post-procedural period (acute SM) or it may develop later (late SM). The prevalence of acute SM is higher when assessed by OCT than IVUS (up to 50% of stents implanted), and its causes are both technical (stent under-sizing or under-expansion) and anatomical features (eccentric calcified plaque, bifurcation points) [39]. Although currently debated, several large studies reported no relationship between acute SM and adverse cardiac events [40,41,42]. In fact, since neointimal tissue proliferates over time, most malapposed struts usually disappear or decrease, as shown by the follow-up OCT, especially with mild SM [43]. Therefore, the European consensus paper recommends that acute malapposition of <400 μm with longitudinal extension < 1 mm should not be corrected because of the future spontaneous neointimal integration [29].

On the other hand, the clinical implications of IVUS- and OCT-detected late SM are still under debate. Three registries of patients with stent thrombosis consistently identified stent malapposition as a frequent underlying abnormality [44,45,46]. In contrast, Im et al. [47] and the multicenter CLI-OPCI LATE study [48] reported no difference in the long-term clinical outcomes between patients with and without late SM. Consequently, no recommendations on properly managing patients with incidentally detected late SM are currently available.

Tissue Protrusion (TP). The extrusion of tissue (either plaque or thrombus) outside the stent area is defined as TP. OCT-based analysis classified TP into three groups according to the prolapse degree (smooth, disrupted, and irregular protrusion) and the severity of the underlying vessel injury. Interestingly, Soeda et al. reported that irregular protrusions with moderate-to-severe vessel injury were an independent predictor of adverse clinical events at the one-year follow-up [31]. However, recent contributions focused on the procedural setting irrespective to the TP phenotype. In this regard, in patients undergoing elective PCI, the volume of TP was found to be associated with post-procedural myocardial injury, whereas no net effect on the clinical outcomes has been reported [49]. In contrast, in the CLI-OPCI ACS sub-study, a residual intrastent plaque/thrombus protrusion > 500 μm after ACS-PCI was associated with an increased risk of adverse events at the follow-up [50].

TP detected by OCT is usually smaller than those detected by IVUS and usually disappears and/or is replaced by neointima during the follow-up [51]. However, additional balloon inflations may be performed when the major prolapses occur (lumen area < 4 mm²). Moreover, the preventive adoption of thrombectomy devices (such as aspiration catheters) may be helpful, particularly during acute myocardial infarction associated with high thrombus burden [52].

Stent Edge Dissection (SED). Vessel luminal surface disruption with a visible flap within 5 mm of either proximal or distal stent edges is defined as SED [53]. Typically, it occurs as a consequence of landing the stent in unhealthy segments (lipid or fibrocalcific plaques), the adoption of oversized stents compared to the landing zone or aggressive post-dilatation within the stent edges to achieve the optimal luminal expansion. As a result of its higher resolution, OCT enables the identification of extensive SEDs, usually missed by IVUS or angiography [39]. However, the actual clinical impact of most OCT-detected SEDs is still a matter of debate. Prati et al. showed that dissections > 200 μm at the distal stent edge were associated with a higher risk of adverse events [33], although several other studies did not confirm this evidence [31,54,55]. Many authors argued that a potential explanation of these discordant results is that the majority of OCT-detected SEDs are unlikely to be clinically significant since most of them evolve into complete healing on the follow-up [51]. Indeed, the European consensus document currently recommends only considering for correction the deep (involving medial or adventitia) and long (>2 mm) SEDs with lateral extension (<60°), or those with angiographic evidence of the flow limitation and/or inadequate residual MSA (4.5 mm²) [29].

Strut Coverage Thickness (SCT). SCT may be measured as the distance between the neointima’s endoluminal surface and the stent strut’s luminal side [53]. According to the recent contribution by Jinnouchi et al. [56], histologically competent strut coverage is defined by the presence of luminal endothelial cells and ≥2 layers of smooth muscle cells with the surrounding matrix. Furthermore, the most accurate cut-off value to identify stent strut coverage validated by histology is a neointimal thickness ≥ 40 μm by OCT. Although a thicker neointimal proliferation may cause in-stent restenosis (especially with old BMS) [57], an incomplete strut coverage is associated with the occurrence of cardiovascular events, such as late stent thrombosis, especially with first-generation DES (G1-DES) [58,59]. In this regard, Won et al. reported that a cut-off value of uncovered stent struts near 5.9% is associated with a higher incidence of death, myocardial infarction, and stent thrombosis [60]. This underlines the critical prognostic role of SCT and the procedural relevance of an aggressive post-dilatation of the deployed stent, which may help improve the struts’ embedment and ease their endothelization (Figure 3b,c) [61]. However, OCT resolution is insufficient to precisely identify the endothelial cells and thus discriminate between the types of stent coverage. Therefore, recent preclinical models combining fibrin-targeted near-infrared fluoroscopy and OCT revealed that a sizeable percentage of struts deemed covered by OCT are covered by fibrin, particularly in DES, thus representing a thrombogenic nidus [62]. Consequently, in the OCT setting, caution should be applied when adopting “strut coverage” as a surrogate of re-endothelization.

3.3. Follow-Up Stent Evaluation (Figure 2)

Neoatherosclerosis. Neoatherosclerosis (NA) or in-stent de novo atherosclerosis consists of developing a complete neo-atheroma of lipid-laden foamy macrophages with or without a necrotic core and/or calcification within the nascent intima following the stent implantation [63]. While the atherosclerotic process in the native vessels typically materializes through several years, in-stent NA usually occurs in a shorter interval after the PCI and appears to be more common after DES implantation rather than BMS implantation [64]. A limited body of evidence investigated the clinical significance of NA detected by OCT on the long-term outcomes of patients undergoing PCI. Interestingly, according to Sumino et al., patients with at least one stent affected by NA reported an increased incidence of adverse events compared with patients without NA (25% vs. 6%, p = 0.002) [65]. Similar results were obtained by Kuroda et al. in a study where patients with NA showed significantly higher rates of clinical events than those without NA (36.9% vs. 9.3%, p < 0.001) [66]. However, despite these promising results, a large-scale, randomized study still needs to be completed to elucidate whether the early detection of NA by OCT could improve long-term outcomes after coronary stenting.

In-Stent Restenosis (ISR). ISR is classified as luminal narrowing of >50% in a stented coronary segment or within 5 mm of a stent edge (Figure 4, panel A). Pure and early (<1 year from stent implantation) ISR is characterized by the proliferation and migration of vascular smooth muscle cells leading to the development of significant neointimal hyperplasia communicating with the native plaque. Conversely, late ISR (>1 year from stent deployment) is usually associated with the development of a novel fibroatheroma within the stent struts (NA) [63]. Intracoronary imaging, mainly OCT, can help to reveal ISR aetiology, allowing us to discriminate between mechanical (SU, undersizing, stent fracture, SED, nonoverlapping stents) and biological promoter mechanisms (neointimal hyperplasia, NA). Interestingly, Yamamoto et al. suggested an OCT-based classification of different ISR phenotypes: homogeneous high-intensity tissue (type I), heterogeneous tissue with signal attenuation (type II), heterogeneous speckled tissue (type III), mixed tissue containing poorly delineated region with an invisible strut (type IV), mixed tissue containing sharply delineated low-intensity region (type V), and bright protruding tissue with an irregular surface (type VI). Of note, the potential clinical significance of this classification has been further explored by the authors in a series of patients undergoing balloon angioplasty for DES-ISR. The incidence of stent fracture was significantly higher in both type I and IV. In contrast, the minimal reduction in the neointimal volume was reported in the type I lesions and maximal in the type III lesions. Finally, the duration between the stent implantation and ISR resulted significantly longer in types IV and VI [67].

Stent Thrombosis (ST). According to the current European guidelines on myocardial revascularization, in the setting of stent thrombosis, OCT should be used after vessel recanalization to guide a more effective thrombus removal and select the most effective treatment to avoid recurrences [1]. Figure 4 (panel B) shows an image of ST detected by OCT. The Bern [46], the PESTO [44], and the PRESTIGE [45] registries showed that OCT performed at the time of the acute event is feasible and able to detect the underlying cause of ST in the vast majority of the cases. According to data from these three registries [44,45,46], uncovered struts and SU were mainly associated with acute (<24 h post PCI) and subacute (1–30 days) stent thrombosis, while NA and late stent restenosis were the most frequent mechanisms of late (>30 days) and very late (>12 months) ST.

Interestingly, a high incidence of SM has been reported in patients admitted with ST, regardless of the time span. However, it is worth acknowledging that possible multiple mechanisms causing ST may coexist; thus, the clinical relevance of SM detected by OCT in the setting of ST is still unclear and specific procedural recommendations are missing. Therefore, adequately powered randomized controlled trials aiming to examine the potential long-term impact of intravascular imaging to guide revascularization due to stent failure are needed.

4. Specific Clinical Settings of OCT-Guided PCI

4.1. Complex Bifurcation Lesions

OCT guidance is currently recommended by the most recent joint consensus documents on bifurcation lesion PCI [68]. OCT allows careful evaluation of bifurcation anatomy, plaque composition, and vulnerability, thus influencing the revascularization strategy: bifurcation angle < 50%, length from the proximal branching point to the carina tip < 1.70 mm, and the presence of lipid-rich plaque contralateral to the side-branch ostium area have been found to be independent predictors for side branch complications after bifurcation stenting [69]. In addition, OCT may be used to select the correct stent size and assess the optimal stent implantation [33,39]. More recently, a new technique has been described, the so-called Bifurcation and Ostial OCT Mapping (BOOM); it empowers the identification and mapping of the side branch ostium, minimizing protrusion of stent struts into the main branch and thus ensuring the complete coverage of the side branch ostium [70]. Moreover, several studies agreed to accord OCT a unique role in the guidance and optimization of the side branch rewiring prior to the final kissing balloon inflation with the adoption of 3D reconstructed images [71,72,73].

4.2. Left Main (LM) Disease

Despite the OCT technical limitation in the analysis of the deep plaque components, large vessels, or ostial segments favoring the development of IVUS as the gold standard imaging modality for LM-PCI, many previous studies have demonstrated the feasibility and safety of OCT for the assessment of unprotected non-ostial LM disease [74,75]. In particular, the studies conducted by Cortese et al. demonstrated the superiority of OCT compared with angiography for distal LM stenting (21.2% vs. 12.7% of one-year target-lesion failure rate, p = 0.039) with no reported difference with IVUS [76,77]. More recently, the prospective multicenter LEMON study has been the first to report a predefined standardized protocol for OCT-guided mid/distal LM-PCI [78]. In conclusion, OCT has been supported as a reliable alternative to IVUS for mid-distal LM lesions but currently remains challenging at the ostium, even in highly experienced hands.

4.3. Spontaneous Coronary Artery Dissections (SCAD)

SCAD is a non-atherosclerotic disease, typically affecting young women with few conventional cardiovascular risk factors. Interestingly, despite being a rare condition in both peripartum and post-partum, SCAD is designated as the most common cause of myocardial infarction related to pregnancy [79]. It is characterized by the development of an intramural hematoma (IMH), compressing the true lumen of the vessel. When angiography is not diagnostic for SCAD, mostly when the intimal flap is absent or not clearly visible, imaging techniques such as IVUS or OCT may be used for confirmation. Although each technology has relative advantages, OCT is generally favored for SCAD imaging because of its higher spatial resolution [80]. As a general guideline summarized by the recent position papers of the SCAD Study Group, OCT should be reserved for situations where angiography is not diagnostic for SCAD or when intracoronary imaging is independently used for guidance during PCI [80,81]. Particularly, if PCI is requested, OCT is highly recommended, not only in order to confirm the correct wire position in the true lumen but, above all, to give a complete evaluation of the SCAD lesion. In this way, it may help to guide decision-making on the stent size, avoiding stent malapposition with the risk of resorption of intramural hematoma [82] and long stenting [83].

4.4. Myocardial Infarction with Non-Obstructive Coronary Artery Disease (MINOCA)

Myocardial infarction with non-obstructive coronary artery disease (MINOCA) has been described as a puzzling entity with multiple underlying mechanisms, including both epicardial and microvascular causes [84]. Therefore, the recently standardized diagnostic work-up for MINOCA suggested by the scientific statement of the American Heart Association assigned intravascular imaging a central role, particularly when plaque disruption, SCAD, or coronary thrombus/emboli are suspected [85]. In this regard, multiple studies highlighted the importance of OCT in MINOCA diagnosis, particularly contributing to elucidating the underlying cause. Indeed, one of the first OCT studies on MINOCA patients showed that plaque disruption or thrombi were visible in 39% of the population included in the study [86]. Moreover, Reynolds et al. reported that combining both OCT and CMR allowed the identification of the cause of MINOCA in 84.5% of patients [87]. Interestingly, in a contribution by Shin et al., 26% of MINOCA patients presenting with a provocative positive test showed plaque erosion at OCT analysis, suggesting that intravascular evaluation is essential also in the MINOCA patients with suspected coronary artery spasm, since the underlying mechanisms of MINOCA may also overlap with each other [88].

5. Potential Impact of OCT Assessment on Pharmacological Treatment

In addition to its multiple interventional applications aiming at PCI optimization, OCT has been recently used to assess atherosclerotic plaque modifications resulting from specific pharmacological treatments (Table 2). We, therefore, summarize the current drugs affecting plaque composition specifically evaluated with intracoronary imaging.

5.1. Statins

Since the well-known pleiotropic effects of statins significantly contributes to lowering the systemic inflammatory response [89,90], multiple studies validated their key protective role against the development of vulnerable atherosclerotic plaques [91]. In this regard, a growing body of evidence shows that OCT provides clear proof of statin-mediated plaque stabilizing effects by assessing several factors involved in plaque’s destabilization, particularly the fibrous-cap thickness (FCT). In 2009, Takarada et al. found that the statin treatment significantly increased FCT in patients with recent myocardial infarction and hyperlipidemia [92]. Similarly, Nishiguchi et al. demonstrated that the early initiation of statins (pitavastatin 4 mg from baseline vs. pitavastatin 4 mg from 3 weeks after baseline) increased the FCT considerably during the first three weeks of follow-up and further during 36 weeks of follow-up [93]. Interestingly, on top of a prompt administration of statins, high doses of these agents allow greater plaque stabilization, according to several authors. Hou et al. showed an increase in FCT and a substantial reduction of thin-cap fibroatheroma and macrophages in patients treated with high-dose statins [94]. Furthermore, the Easy-Fit STUDY highlighted that intensive statin therapy improved the plaque stabilization, explicitly focusing on other vulnerability markers such as lipid arc and macrophage reduction [95]. These results are also supported by a recent meta-analysis of nine OCT studies (6 randomized controlled trials and 3 observational studies) with a total of 341 patients (390 lesions), confirming the central role of statins in both increasing FCT and decreasing the lipid arc [96].

5.2. PCSK9 Inhibitors

Anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (PCSK9 inhibitors), a novel game-changer class of drugs in cholesterol management, have been studied in two large randomized clinical trials assessing any modification of atherosclerotic plaque phenotype, potentially leading to a consistent reduction of major cardiovascular events [97,98].

The HUYGENS study is a randomized multicenter, double-blind, placebo-controlled trial aiming to compare the effects of evolocumab (a PCSK9 inhibitor) on plaque composition by the use of OCT in patients undergoing coronary angiography for non-ST-segment elevation myocardial infarction [97]. In this study, 161 patients were randomized to either evolocumab monthly or placebo for 52 weeks. Interestingly, patients on evolocumab achieved significantly lower LDL-C levels (28.1 vs. 87.2 mg/dL; p < 0.001), as well as a greater increase in the minimum FCT (+42.7 vs. +21.5 μm; p = 0.015) and decrease in both the maximum lipid arc (−57.5 vs. −31.4; p = 0.04) and macrophage index (−3.17 vs. −1.45 mm; p = 0.04) compared with those in the placebo group [97]. Similarly, the PACMAN-AMI study is a double-blind, placebo-controlled, randomized clinical trial enrolling 300 patients undergoing PCI for acute myocardial infarction and subsequently randomized to receive either alirocumab or the placebo for 52 weeks, in addition to high-intensity statin treatment [98]. Intracoronary imaging was used to assess the changes in plaque burden and composition in non-infarct related arteries; notably, a greater increase in mean FCT and a more significant reduction in mean angular extension of macrophages were exhibited in the alirocumab group, as compared to the placebo group [98].

These data appear consistent with the hypothesis that PCSK9 inhibitors work by stabilizing atherosclerotic plaque. However, further studies are warranted to elucidate if these treatments may also significantly reduce the burden of major adverse cardiovascular events in patients with previous myocardial infarction.

5.3. Antidiabetic Drugs

There is limited evidence assessing the atherosclerotic plaque modifications driven by antidiabetic drugs with OCT. Hong et al. have shown the effect of pioglitazone, a thiazolidinedione-type antidiabetic medication, on coronary neointimal hyperplasia (NIH) assessed by OCT in patients with type 2 diabetes mellitus undergoing PCI [99]. Interestingly, patients treated with pioglitazone presented a consistent plaque regression as showed by a significant reduction in the neointimal volume, compared with patients in the control group (25.02 ± 17.78 mm³ vs. 55.10 ± 30.01 mm³, p < 0.001) [99]. On the other hand, Yamamoto et al. aimed to evaluate the potential impact of vildagliptin, a well-known dipeptidyl peptidase 4 inhibitor, on the coronary plaque stability using OCT in impaired glucose tolerance patients with coronary artery disease [100]. The authors found a significant difference in both the FCT and lipid arc in patients receiving vildagliptin (35.7 ± 50.8 μm vs. −15.1 ± 25.0 μm, p = 0.002 and −9.0° ± 25.5° vs. 15.8° ± 16.8°, p = 0.0017, respectively), thus suggesting a potential, drug-driven, benefit in the plaque stabilization [101]. Lastly, the effects of novel sodium-glucose co-transporter-2 (SGLT2) inhibitors on NIH have been studied with OCT after PCI [101]. At 12-month follow-up, the NIH resulted significantly lower in the patients on empagliflozin than in the control group (137 ± 32 vs. 168 ± 39 μm, p = 0.02), supporting the hypothesis that in patients with type 2 diabetes, empagliflozin might attenuate neointimal progression after the DES implantation compared with the standard therapy.

5.4. Colchicine

Several studies strongly highlighted the beneficial effects of colchicine and anti-inflammatory drugs in lowering cardiovascular events in patients with CAD [102,103,104,105,106]. However, their specific effects on atherosclerotic plaque composition are largely unknown, according to current evidence. Moving from the hypothesis that colchicine may directly promote a favorable plaque healing process following AMI, Montarello et al. designed the COCOMO-ACS study [107] as a multicenter, randomized, double-blind, placebo-controlled, phase-2 clinical trial evaluating the potential effects of colchicine on atherosclerotic plaque stabilization by OCT in patients with recent non-ST-elevation myocardial infarction. The study is still ongoing; however, it will establish whether colchicine may confer additional clinical benefits in patients with CAD.

Table 2. Summary of the available evidence on OCT-based plaque modification of different pharmacological treatments.

Study	Year	Study Design	Follow-Up (Months)	Study Drug	Clinical Setting	Effects on Atherosclerotic Plaque
Takarada et al. [92]	2009	Non-RCT	9	Statins	AMI	Increase in FCT
Nishiguchi et al. [93]	2018	RCT	9	Pitavastatin	AMI	Increase in FCT
Komukai et al. [95]	2014	RCT	12	Atorvastatin	Unstable Angina	- Increase in FCT - Decrease in lipid arc and macrophage accumulation
Hou et al. [94]	2016	RCT	12	Atorvastatin	CAD	- Increase in FCT - Reduction in TCFA - Reduction in macrophage accumulation
Hong et al. [99]	2015	RCT	9	Pioglitazone	CAD	Decreased neointimal hyperplasia
Yamamoto et al. [100]	2021	RCT	6	Vildagliptin	CAD	- Decreased lipid arc - Increased minimum FCT
Hashikata et al. [101]	2020	RCT	12	Empagliflozin	CAD	Decreased neointimal hyperplasia
Räber et al. [98]	2022	RCT	13	Alirocumab	AMI	- Increase in minimum FCT - Reduction in mean angular extension of macrophage
Nicholls et al. [97]	2022	RCT	13	Evolocumab	AMI	- Increase in minimum FCT - Decrease in maximum lipidic arc - Decrease in macrophage index
Montarello et al. [107]	2021	RCT	18	Colchicine	AMI	Ongoing

RCT = Randomized Clinical Trial; AMI = Acute Myocardial Infarction; FCT = Fibrous Cap Thickness; CAD = Coronary Artery Disease; TCFA = Thin Cap Fibro-Atheroma.

Table 2. Summary of the available evidence on OCT-based plaque modification of different pharmacological treatments.

Study	Year	Study Design	Follow-Up (Months)	Study Drug	Clinical Setting	Effects on Atherosclerotic Plaque
Takarada et al. [92]	2009	Non-RCT	9	Statins	AMI	Increase in FCT
Nishiguchi et al. [93]	2018	RCT	9	Pitavastatin	AMI	Increase in FCT
Komukai et al. [95]	2014	RCT	12	Atorvastatin	Unstable Angina	- Increase in FCT - Decrease in lipid arc and macrophage accumulation
Hou et al. [94]	2016	RCT	12	Atorvastatin	CAD	- Increase in FCT - Reduction in TCFA - Reduction in macrophage accumulation
Hong et al. [99]	2015	RCT	9	Pioglitazone	CAD	Decreased neointimal hyperplasia
Yamamoto et al. [100]	2021	RCT	6	Vildagliptin	CAD	- Decreased lipid arc - Increased minimum FCT
Hashikata et al. [101]	2020	RCT	12	Empagliflozin	CAD	Decreased neointimal hyperplasia
Räber et al. [98]	2022	RCT	13	Alirocumab	AMI	- Increase in minimum FCT - Reduction in mean angular extension of macrophage
Nicholls et al. [97]	2022	RCT	13	Evolocumab	AMI	- Increase in minimum FCT - Decrease in maximum lipidic arc - Decrease in macrophage index
Montarello et al. [107]	2021	RCT	18	Colchicine	AMI	Ongoing

RCT = Randomized Clinical Trial; AMI = Acute Myocardial Infarction; FCT = Fibrous Cap Thickness; CAD = Coronary Artery Disease; TCFA = Thin Cap Fibro-Atheroma.

6. Conclusions

In the last decade, OCT has emerged as a valuable tool for interventional cardiologists to precisely characterize the atherosclerotic plaque phenotype, tailor stent implantation, and guide more complex interventional procedures. Recently, multiple contributions also supported its feasibility of assessing plaque modifications during the follow-ups of patients on different pharmacological treatments. However, despite its helpfulness in several settings, OCT’s current adoption in catheterization laboratories is still modest, and its impact on clinical practice has thus far been limited. This might be mainly due to the lack of both standardized algorithms of PCI guidance and data from prospective clinical trials, along with a more complex image interpretation compared with other intracoronary imaging techniques requiring a specific learning curve. In this regard, a novel framework for automatic plaque characterization driven by artificial intelligence has been developed in order to overcome the inter-operator variability, showing excellent diagnostic accuracy [108]. In the same direction, a standardized step-by-step workflow (MLD MAX) has been tested in the LightLab study, showing improved safety and efficacy metrics compared with previous variable workflows, despite no statistically significant differences in the procedural time having been observed [109].

In conclusion, there is an urgent need for more robust evidence from ongoing randomized studies aiming to assess the real impact of OCT-guided angiography and PCI on long-term clinical outcomes. Concordantly, more efforts must be served to educate cardiologists on the potential uses and benefits of this intracoronary technique in routine clinical practice since, in this era of “tailored medicine”, the appropriate adoption of OCT might significantly translate into a substantial improvement of clinical outcomes in patients with coronary artery disease invasively or medically managed.