Thrombosis plays a central role in the pathophysiology of ACS, which is primarily triggered by damage to atherosclerotic plaques through rupture, erosion, or calcified nodules. These processes expose thrombogenic material such as tissue factor and subendothelial collagen to the bloodstream, initiating platelet activation and the coagulation cascade, ultimately leading to thrombus formation within the coronary arteries. This thrombus can partially or completely occlude the vessel lumen, impairing coronary blood flow and causing myocardial ischemia and infarction [18, 19, 20, 21]. Plaque rupture is the predominant mechanism in about 70% of ACS cases. It involves the disruption of a vulnerable plaque characterized by a thin fibrous cap and a lipid-rich necrotic core. Inflammatory mediators such as matrix metalloproteinases degrade the fibrous cap collagen, weakening the plaque’s structural integrity and causing rupture. This exposes highly thrombogenic material that triggers platelet aggregation and thrombus formation [18]. In some cases, plaque rupture occurs at sites of calcified nodules, which can also contribute to thrombosis [22]. Superficial endothelial erosion accounts for approximately 30% of ACS cases and is more common in women and diabetics with hypertriglyceridemia. It involves damage to the endothelial layer without deep plaque rupture, possibly mediated by matrix metalloproteinases disrupting endothelial cell attachment. This leads to thrombus formation on an intact fibrous cap, often resulting in non-occlusive thrombi that may heal and contribute to progressive atherosclerosis [23]. Coronary artery spasm can also contribute to thrombosis by inducing endothelial injury and promoting thrombin generation, further enhancing the prothrombotic state [23]. Elevated levels of tissue factor, primarily expressed by macrophages within plaques, initiate the extrinsic coagulation cascade and play a critical role in thrombogenicity in ACS. OCT has emerged as a pivotal tool in investigating these thrombotic mechanisms (Fig. 2). Its high-resolution imaging capabilities allow detailed visualization of intraluminal and vessel wall structures, enabling detection and differentiation of thrombus types—red thrombi (rich in red blood cells) versus white thrombi (platelet-rich)—and identification of non-occlusive thrombi that may be missed by other imaging modalities. OCT also facilitates the assessment of plaque morphology, including ruptures, erosions, calcified nodules, and SCAD, thereby improving diagnostic accuracy and guiding personalized treatment strategies in ACS [24, 25]. Furthermore, the pathogenesis of ACS involves a complex interplay of inflammatory and immune processes. Activated T cells, particularly CD4+CD28 T cells, infiltrate unstable plaques and release proinflammatory cytokines like interferon-gamma, which activate macrophages and induce apoptosis of vascular smooth muscle cells. This weakens the fibrous cap and promotes plaque instability and rupture, linking adaptive immunity to thrombotic events in ACS [19].

Plaque rupture is the most frequent finding in patients with ACS and is responsible for 65% of ACS [26]. It is associated with worse outcomes after angioplasty and more commonly presents with the ST-segment elevation myocardial infarction phenotype [27]. Plaque rupture commonly arises in the setting of OCT-defined thin-cap fibroatheromas (TCFA) and is characterized by morphological features such as intimal tearing, fibrous cap disruption, or dissection (Fig. 2). When the vessel is flushed with optically transparent crystalloids or radiocontrast agents, these structural defects may exhibit minimal or absent OCT signal, often appearing as intraplaque cavities. The distinction between plaque rupture and erosion has important therapeutic implications and may inform treatment strategies, including the potential to defer stent implantation in cases of plaque erosion associated with non-critical stenosis. Due to its higher spatial resolution, OCT is superior in detecting plaque rupture that IVUS [28]. Also, research based on OCT imaging has shown that the plaque rupture phenotype ACS is associated with worse outcomes that intact fibroatheroma [29]. Toutouzas et al. [30] demonstrated that in patients with ACS, culprit ruptured plaques are not evenly distributed throughout the coronary vasculature but are more frequently localized to the proximal segments of the coronary arteries.

The defining histopathological feature of plaque erosion is the absence of endothelial lining over the affected plaque and the prevalence in ACS is about 25% to 30% [26]. Although OCT offers excellent spatial resolution, it lacks the capacity to directly visualize endothelial integrity. As a result, the diagnosis of plaque erosion using OCT is primarily made by excluding the presence of fibrous cap rupture [8]. Characteristic OCT findings suggestive of plaque erosion include the presence of white thrombus overlying an intact fibrous cap, an irregular luminal surface without associated thrombus or thrombus obscuring the underlying plaque in the absence of adjacent lipid-rich plaque or calcification proximal or distal to the thrombotic site. Plaque erosion is considered “definite” when a thrombus is identified overlying an intact fibrous cap. In contrast, it is deemed “probable” in the absence of both thrombus and fibrous cap rupture, provided that irregularities of the luminal surface are present. The EROSION trials tried to investigate and create a new therapeutic landscape for ACS due to plaque erosion, offering the chance of conservative treatment [11, 27]. Double antiplatelet treatment instead of stent implantations was safe when plaque erosion resulting in stenosis 70% was identified by OCT [10]. The OCT analysis as well as the angiography, were improved with less erosion and less thrombotic material at 1-year follow-up [27]. In the randomized EROSION III trial, the use of OCT in patients with ST-segment elevation myocardial infarction and early infarct-related artery patency was associated with a reduced frequency of stent implantation during primary percutaneous coronary intervention, compared to angiographic guidance alone [11].

Calcified coronary artery lesions, particularly calcified nodules (CNs), are the least common but critical contributors to ACS and are accountable for 2% to 7% of them [31]. These complex structures drive luminal narrowing through a unique pathophysiology involving chronic inflammation, osteogenic transformation, and extracellular matrix remodeling [32, 33]. Intravascular imaging, especially OCT, has become indispensable for diagnosing CNs and guiding PCI. CNs can arise from a combination of mechanical stress and biological processes. Chronic Inflammation plays an important role with macrophages and T-cells infiltrate the plaque, releasing cytokines (e.g., IL-6, TNF-$\alpha$) that promote calcification and destabilization of the fibrous cap [32]. Moreover, osteogenic transformation in terms of the phenotypic change of vascular smooth muscle cells, expressing bone-forming proteins like osteocalcin and alkaline phosphatase, leading to microcalcifications, has a crucial role on the development of CN, together with the degradation of collagen that weakens the plaque structure and increases risk of rupture [32, 34, 35]. CNs are classified as eruptive (associated with thrombus formation and acute rupture) or non-eruptive (stable, calcified protrusions), each requiring distinct management strategies [36]. OCT allows for the visualization of fibrous cap disruption, protruding calcifications, external plaques, and calcifications both proximal and distal to the plaque. TCFA (65 µm) overlying CNs are linked to plaque vulnerability [37], while OCT can also differentiate protruding calcifications as irregular, superficial calcium deposits with sharp edges, often causing lumen compromise and also differentiate eruptive vs. non-eruptive CNs [38].

MINOCA represents a syndrome of various unknown causes, characterized by symptoms typical of myocardial infarction and the presence of myocardial necrosis, without occlusion of large subepicardial coronary arteries. MINOCA is classified according to its underlying causes as either atherosclerotic or non-atherosclerotic. In MINOCA, microcirculatory dysfunction is most often caused by a non-atherosclerotic mechanism, which serves as the leading pathophysiological factor [39]. Non-Atherosclerotic Causes of MINOCA include coronary microvascular dysfunction, coronary artery spasm, spontaneous coronary artery dissection, supply–Demand mismatch (Type II MI), and thromboembolism from distant causes. OCT plays a vital role in diagnosing and managing myocardial infarction with MINOCA, a condition where patients have heart attack symptoms but no significant coronary artery stenosis on angiography. OCT’s high-resolution imaging allows detailed visualization of the coronary artery wall, uncovering subtle abnormalities that angiography alone often misses.

Studies have shown that OCT can identify various underlying causes of MINOCA, such as plaque rupture, plaque erosion, calcified nodules, thrombus formation, and spontaneous coronary artery dissection (SCAD). For example, in one prospective study, OCT detected atherosclerotic causes in about 36% of MINOCA patients, leading to changes in treatment plans including percutaneous coronary intervention or modification of antithrombotic therapy in some cases [40], while another study found that combining OCT with cardiac magnetic resonance imaging (CMR) provided a diagnosis in 100% of MINOCA patients, highlighting the complementary nature of these tools—OCT excels at detecting coronary artery pathology, while CMR identifies myocardial injury [41]. OCT helps differentiate between atherosclerotic and non-atherosclerotic mechanisms, which is crucial because treatment strategies differ. Patients with atherosclerotic lesions detected by OCT may benefit from statins and ACE inhibitors, which reduce adverse cardiac events, whereas routine dual antiplatelet therapy may not be universally effective in MINOCA. Furthermore, OCT findings have prognostic value; patients with high-risk lesions identified by OCT tend to have worse outcomes and may require closer follow-up and tailored therapy [42]. Early use of OCT can detect hyperacute features such as thrombus or plaque disruption that might be missed if imaging is delayed, ensuring timely and accurate diagnosis. This precision in identifying the culprit lesion helps guide personalized treatment strategies, improving prognosis and reducing the risk of recurrent events [43].

SCAD is characterized by the entry of blood into the layers of the coronary artery wall, leading to the formation of a false lumen that compresses the true lumen. This compression impairs coronary blood flow and precipitates ACS. The pathophysiology involves either an intimal tear allowing blood from the lumen to enter the vessel wall (“inside-out” hypothesis) or bleeding from the vasa vasorum causing an intramural hematoma without intimal rupture (“outside-in” hypothesis) [44]. Both mechanisms result in the separation of arterial wall layers and the formation of an intramural hematoma that compresses the true lumen, causing myocardial ischemia. SCAD is notably one of the most common causes of ACS in young individuals, especially young women, frequently occurring in peripartum periods and associated with conditions such as fibromuscular dysplasia. Unlike atherosclerotic disease, SCAD typically occurs without lipid-filled plaques or significant vessel wall inflammation. OCT plays a crucial role in diagnosing SCAD, particularly when angiographic findings are inconclusive. OCT enables detailed visualization of key features such as intramural hematomas, intimal tears, intima-medial flaps, and older scarred dissections. It can detect the presence or absence of fenestrations between true and false lumens, which influences the pressure dynamics within the vessel wall and guides clinical management. This imaging precision helps determine the appropriate treatment strategy, including the decision to pursue PCI or conservative management [45].

Despite advancements in PCI devices, pharmacological treatments, and procedural techniques, the occurrence of SF remains a significant concern [46]. SF can manifest either as stable angina or myocardial infarction (MI), and it may involve in-stent restenosis (ISR) or stent thrombosis (ST). Research utilizing OCT has demonstrated its capability to detect various causes of SF, such as uncovered stent struts, malapposition, and excessive tissue growth (Figs. 1,3). Through detailed imaging analysis, the composition of tissue within the stent can be classified into lipid-rich, fibrotic, or calcified types. Additionally, imaging techniques can reveal issues like stent underexpansion and the presence of thrombus. OCT’s high-resolution imaging allows detailed assessment of stent apposition, expansion, and vessel wall morphology, enabling identification of key mechanisms contributing to SF, such as uncovered stent struts, malapposition, underexpansion, and thrombus formation. Importantly, OCT provides precise characterization of neointimal tissue composition, differentiating lipid-rich, fibrotic, or calcified tissue, which aids in understanding restenosis mechanisms and tailoring treatment strategies. The presence of neoatherosclerosis or multiple stent layers on OCT has been associated with increased risk of recurrent SF, highlighting the need for optimized intervention. Quantitative OCT parameters, particularly minimal stent area (MSA) and stent expansion relative to reference vessel size, have been strongly linked to clinical outcomes. The ILUMIEN IV trial, a large prospective study, demonstrated that smaller MSA and proximal edge dissections independently predict target lesion failure, cardiac death, and stent thrombosis at two years post-PCI [47]. Similarly, the CLI-OPCI II registry confirmed that suboptimal stent implantation—defined by OCT criteria including MSA 4.5 mm², edge dissections, and residual reference segment disease—is common and significantly associated with major adverse cardiac events (MACE) [48, 49]. OCT’s ability to detect thrombus and subtle edge dissections also informs intraprocedural decision-making, guiding additional interventions such as balloon post-dilation or further stenting to optimize stent deployment and reduce adverse events [4, 46]. These findings underscore the critical role of OCT-guided PCI in improving procedural outcomes and long-term prognosis in patients undergoing stent implantation.

Fig. 3.

OCT images post-PCI. (a) OCT image showing a well-expanded and well-apposed stent. (b) OCT image showing malapposition of the stent. (c) OCT image showing significant malapposition of the stent. (d) OCT image showing a segment of stent underexpansion. White arrows: malapposed segment in figures b,c and underexpanded segment in image d. OCT, Optical Coherence Tomography; PCI, Percutaneous Coronary Intervention.

OCT has become a vital tool for identifying neoatherosclerosis, which is increasingly recognized as an important cause of very late SF. Thanks to its exceptional resolution, OCT can clearly visualize features such as lipid-rich plaques, thin fibrous caps, macrophage accumulation, and calcifications within the neointima that develop inside stents over time. These detailed images help distinguish neoatherosclerosis from other forms of in-stent restenosis or thrombosis, which can be challenging with angiography or IVUS alone. OCT also reveals subtle signs like healed plaque ruptures and layered neointimal tissue, shedding light on the ongoing processes of plaque destabilization and healing that contribute to late stent complications. This level of insight is crucial for accurately diagnosing the cause of SF and guiding clinical decisions [37]. Beyond diagnosis, OCT plays a key role in guiding treatment strategies for neoatherosclerosis. By providing a precise assessment of lesion morphology and extent, OCT helps interventional cardiologists tailor their approach, whether that involves balloon angioplasty, drug-coated balloon therapy, or placing additional stents. It also allows for careful evaluation of stent expansion and apposition, addressing mechanical factors that may promote disease progression. Furthermore, OCT can detect thrombus and subtle dissections around the lesion, enabling timely interventions to reduce the risk of recurrent events. Detailed tissue characterization also supports decisions about medical therapy, such as intensifying antiplatelet or lipid-lowering treatments based on plaque vulnerability. Overall, OCT-guided management has been shown to improve procedural outcomes and may help prevent very late SF related to neoatherosclerosis [50, 51, 52].

Predicting which atherosclerotic plaques will trigger clinical instability and become the culprit lesions in ACS has long been a significant challenge in cardiovascular medicine. A vulnerable or unstable plaque may often involve the formation of thrombus within the plaque or vessel lumen; however, they do not always result in angina or complete vessel obstruction [53]. As a result, these lesions can remain asymptomatic for extended periods until one of these cycles culminates in a clinical event, frequently presenting as myocardial infarction or sudden death [54]. In retrospective analyses, interventional cardiologists and cardiovascular pathologists commonly designate the lesion causing coronary occlusion and subsequent death as the ‘culprit plaque’, independent of its underlying histopathologic characteristics. For prospective clinical assessment, however, an analogous terminology is required to characterize plaques that may precipitate future adverse events [55]. Coronary vulnerable plaques are typically marked by a thin fibrous cap covering a large lipid-rich necrotic core, which makes them susceptible to rupture and subsequent thrombotic events. These plaques often exhibit active inflammation, characterized by macrophage infiltration, and demonstrate expansive or positive remodeling of the vessel wall, where the artery enlarges outward to accommodate plaque growth without significantly narrowing the lumen. Additional features include spotty calcifications, neovascularization within the plaque (vasa vasorum proliferation), and intraplaque hemorrhage, all of which contribute to plaque instability. The combination of these structural and biological factors creates a high mechanical stress environment on the fibrous cap, increasing the likelihood of rupture and ACS such as myocardial infarction [56, 57, 58]. Unlike stable plaques, which tend to have thick fibrous caps and smaller lipid cores, causing gradual luminal narrowing and stable symptoms, vulnerable plaques often maintain a relatively preserved lumen until rupture occurs.

OCT is uniquely suited to detect coronary vulnerable plaques due to its high-resolution imaging capability, which allows detailed visualization of plaque microstructures in vivo. OCT identifies key features of vulnerable plaques, including TCFAs characterized by a fibrous cap thickness less than 65 micrometers overlaying a large lipid-rich necrotic core. It can also detect macrophage accumulation near the fibrous cap, which indicates active inflammation, plaque fissures as well as intraplaque microvessels, cholesterol crystals, and areas of intraplaque hemorrhage. These features are strongly associated with plaque instability and a higher risk of rupture, leading to ACS [59]. OCT’s ability to precisely measure fibrous cap thickness and differentiate tissue types with high sensitivity and specificity makes it a powerful tool for identifying plaques at high risk of causing clinical events

Beyond structural assessment, OCT can characterize plaque composition and detect thrombus, calcified nodules, and healed plaque ruptures, providing insights into the dynamic processes of plaque progression and healing. Studies have shown that non-culprit plaques identified by OCT as both lipid-rich and thin-capped are significantly associated with future ACS events, highlighting OCT’s prognostic value [60, 61]. Furthermore, advances in automated image analysis, including AI-based algorithms, are enhancing OCT’s diagnostic accuracy and helping clinicians identify patients with vulnerable plaques who may benefit from intensified medical therapy or closer monitoring [62, 63]. Histological analysis suggest that macrophage infiltration diversity and calcification characteristics may reveal plaque vulnerability. Severe sheet calcification is a marker of stable plaque, whereas fragmentation or microcalcification are markers of unstable plaques. OCT catheters combined with IVUS and infrared spectroscopy may provide ways to translate more histological patterns to intravascular images [64].