Current Status of Intra-Vascular Imaging during Coronary Interventions

Most important interventional application of IVUS is plaque assessment, vessel sizing and stent implantation guidance. Image guided PCI is associated with decreased incidence of stent thrombosis and MACE rate as evident in recently published meta-analysis of IVUS guided PCI studies. Many imaging studies have shown very clearly under-expansion, edge-dissection, tis-sue-prolapse, mal apposition, and geographical miss are associated with adverse events following DES implantation, and IVI guides in optimization of stent implantation by identifying and rectifying these predictors of DES outcomes.


Introduction
Conventional angiography is poor in assessing vessel wall, mainly characterization of plaque, plaque burden, circumferential and longitudinal distribution of the plaque, and features associated with suboptimal stent deployment. ICI provides cross sectional high resolution images of vessel wall high lighting morphology & extent of plaque distribution, and helps in optimization of PCI by illustrating predictors of DES outcomes, namely under-expansion, mal apposition, and medial edge dissection after DES implantation [1].
OCT imaging has an axial spatial resolution of 10 to 20 µm, penetration depth of 1 to 2.5 mm, and lateral resolution of 20 µm. Whereas, range of IVUS axial spatial resolution is about 100 to 200 µm, maximum penetration depth-10 mm, and lateral resolution-200 µm. OCT is able to reveal more detail than IVUS due to its higher resolution but with limited depth assessment. A major drawback of

IVUS and OCT Assessment of Normal Segments and Various Plaques
Normal vessel: Three layered appearance of normal vessel, with the muscular World Journal of Cardiovascular Diseases media being revealed as a low single layer compromised between internal and external elastic lamina. Adventitia-The 3 rd and outer layer consists of the adventitia and peri-adventitial tissues. External elastic membrane is the outer layer of the vessel wall in IVUS measurement because the border of adventitia and peri-adventitial tissue is not distinct (Figure 2(a)). Intimal leading edge can be easily identified because the intima was thickened enough to be resolved as a separate layer and has sufficiently different acoustic impedance from lumen in normal segments. In normal vessels and at the sites of thin plaques, with thicknesses not exceeding 1.2 mm, the coronary artery wall appears as a three-layer structure in OCT images. Intima: signal-rich layer nearest the lumen; media: signal-poor layer in middle of vessel wall (thickness ranges from 125 to 350 micro meter-mean 200 micro meter), adventitia: signal-rich outer layer of vessel walls ( Figure 2(b)) [9] [10] A plaque was defined as a region with a loss of the three-layered structure (ie, intima, media, and adventitia) of the vessel wall ( Figure 3).
Soft plaque-Mainly lipid deposit, echo lucent in nature, not as bright as adventitia (hypoechoic). Plaques may be eccentric or concentric based on distribution of atheroma ( Figure 4). CLIMA study involving more than 1000 patients identified certain features suggestive of high risk plaques on OCT-intimal cap thickness of <75 µm findings, stenosis severity long lipid rich plaque, and macrophages as predictors of the future adverse hard clinical events, death and target lesion related myocardial infections [11].
EROSION trial showed that majority of patients (92.5%) with ACS caused by plaque erosion who were managed with aspirin and Ticagrelor without stenting remained free of major adverse cardiac events for less than 1 year and conservative medical management may be an alternative option in these patients [12].   Fibrotic plaque-Collagen rich fibrous tissue produces dense and bright echoes without acoustic shadowing which is as bright or bright as the adventitia (hyperechoic). Fibrotic tissue partially reflects ultrasound but does not cause signal dropout ( Figure 5).
Calcific plaque-As seen as a signal-poor or heterogeneous region with sharply delineated leading, trailing, and/or lateral borders. High echo brighter (Bright white) than adventitia obstructs the penetration of ultrasound (acoustic shadowing-Signal dropout behind) and reflects ultrasound rays, hence only the leading edge is detected and thickness cannot be determined [13]. IVUS is useful to assess calcium 1) Location-Superficial Calcium vs Deep Calcium, 2) The Arc of Calcium (in degree), 3) The Length of the Calcified Deposit ( Figure 6). Calcific plaque can be classified as 1) Single arc of calcium (90 degrees), 2) Two arcs calcium (180 degrees), 3) Three arcs (270 degrees), and 4) Circumferential (360 degrees) based on circumferential extent of calcium plaque ( Figure 7, Table 2). Calcium is described qualitatively according to its location: lesion versus reference and superficial (leading edge of acoustic shadowing within the shallowest 50% of the plaque and media thickness) versus deep (leading edge of acoustic World Journal of Cardiovascular Diseases shadowing within the deepest 50% of the plaque and media thickness). The sensitivity was 86.7%, the specificity was 93.3%, and the predictive accuracy was 92.3% for detecting calcium as a signal-poor or heterogeneous region with sharply delineated leading, trailing, and/or lateral borders [13].    Mixed plaque-Associates with soft and dense plaque, produces bright echoes with or without acoustic shadowing. Concentric plaques are distributed circumferentially in the vessel; concentric plaques tend to occur in areas of negative remodeling ( Figure 8) [14].
IVI should be used to assess plaque size, plaque length, plaque type, and helps in choosing stent size to cover entire diseased segment, and any need for plaque modification strategy prior to stenting to avoid under expansion, mal apposition, and edge related problems like medial edge dissection and geographical miss.

Usefulness of IVI in Identifying Remodelling
Remodelling refers to changes in vascular dimensions during the progression of atherosclerosis. It can be either positive (when the vascular area increases as plaque develops) or negative (when the vascular area decreases as plaque develops). 1 Intravascular ultrasound (IVUS) assesses arterial remodelling by comparing the lesion external elastic membrane (EEM) with the reference segments to generate a remodelling index (RI) [15].
Positive remodelling-Diameter of vessel at lesion site/ diameter of vessel at proximal reference >1.05 ( Figure 9).
Negative remodelling-Diameter of vessel at lesion site/ diameter of vessel at proximal reference <0.95 ( Figure 9).

Remodelling Index
The remodeling index is calculated as the EEM cross sectional area at the MLA divided by the average of the proximal and distal reference EEM CSA ( Figure 9).

Basic IVUS measurements
Choosing reference segments-choose most normal looking area (site with largest lumen with minimal plaque burden, an average having 35% to 50% plaque burden on IVUS) within 5 mm from the lesion site (maximum stenosis), and no intervening major side branches ( Figure 10).
Stent sizing ( Table 3): Selection of stent diameter should be based on mean EEM or luminal diameter of distal landing zone, and length of the stent to cover entire diseased segment extending from proximal landing zone to distal landing zone, and choose landing zones with a normal segment or reasonably healthy zone with a plaque burden of <50% ( Figure 11).     Post stenting IVUS guidance should be used, to make sure the stent is fully expanded with good apposition, and the stent covered entire plaque length.
Otherwise the recurrence of ISR or late stent thrombosis will be very high.
Stent expansion-Stent expansion describes the minimum stent cross-sectional area either as an absolute measure (absolute expansion), or compared with the predefined reference area, which can be the proximal, distal, largest, or average reference area (relative expansion). Stent expansion is calculated as MSA divided World Journal of Cardiovascular Diseases by the average reference lumen area multiplied by 100. The reference lumen area is determined from the most normal-looking slice with the reference segment, which is defined as a slice having the largest lumen area, because the external elastic membrane is not always visible by OCT compared to IVUS. Aim for achieving good expansion of stent preferably more than 90% of reference mean luminal area. If stent expansion area is <70% compared to distal or proximal reference area, it is considered as under expansion, which is associated with ST and ISR. Under expansion should be corrected with high pressure inflation of appropriate sized NC balloon. If it persists despite NC balloon dilatation, it needs OPN NC balloon or IVL or both to address deep calcium behind stent struts to get adequate expansion of stent. In some cases of severe ISR due to under-expansion with underlying severe calcification plaque modification with Rota might be considered ( Figure 12).
Mal apposition-Stent mal-apposition (or ISA) is defined as separation of the stent struts from the vessel lumen wall in a region not overlying a side branch. Stent mal-apposition and under-expansion can co-exist or occur independently.
Stent mal apposition is considered as significant when Stent adjacent vessel lumen distance is >0.3 mm with longitudinal extension > 3 mm, and it is associated with stent thrombosis and difficulty in crossing with guide wires due to ab-luminal placement of wires. Major mal apposition should be corrected with appropriately sized NC balloon, and minor mal appositions can be treated conservatively.
Edge dissection-Significant medial edge dissections are with linear rim of tissue with a width > 0.2 mm and a clear separation from the vessel wall or underlying plaque that was adjacent (<5 mm) to a stent edge. MED with longitudinal extension > 2 mm, lateral extension > 60˚ and involvement of deeper layers (medial or adventitia) are considered large dissections which require additional stenting to cover the dissection ( Figure 13).  Tissue prolapse-Tissue prolapsing (TP) between stent struts extending inside a circular arc connecting adjacent struts or intraluminal mass > 0.5 mm in thickness with no direct continuity with the surface of the vessel wall or highly backscattered luminal protrusion in continuity with the vessel wall and resulting in signal free shadowing. Small tissue protrusion, small tissue prolapse does not require any treatment, and major tissue prolapse are resistant to treatment. TP should be distinguished from thrombus, and large irregular tissue prolapse associate with increased MACE rate ( Figure 14).
Reference luminal narrowing-Lumen area < 4.5 mm 2 in the presence of significant plaque adjacent to stent endings.
In stent minimal luminal cross sectional area (MLA)-In stent MLA < 4.5 mm 2 and 70% of the average reference lumen area is considered significant which requires further expansion with upsized balloon. Gatto et al. observed stent MLA < 4.5 mm 2 and narrowing of references were the more common features of suboptimal stent deployment identified with OCT. Angio-co registration of OCT system which reflects the location of the OCT camera on the coronary angiogram is useful to choose stent length, landing zones and minimize geographic miss [16].
As per the recommendations of an expert consensus document of the European Association of Percutaneous Cardiovascular Interventions (2018), identify following predictors of DES outcome and rectify them to provide better acute and long term outcomes following DES implantation ( Figure 15) [17].
The most relevant targets to be achieved following stent implantation in non-LM lesions are shown. These include optimal stent expansion (absolute as well as relative to reference lumen diameter); avoidance of landing zone in plaque burden > 50% or lipid rich tissue; avoidance of large mal apposition regions, irregular tissue protrusion, and dissections.
IVI is more useful to evaluate patients with stent failure; it provides various causes of stent failure to decide appropriate treatment. Stent restenosis may be due to neo-intimal growth, neo-atherosclerosis, under-expansion, and disease progression in the stent borders. The OCT is superior to IVUS and should be the imaging modality of choice to assess stent failure (ST and ISR) because it is much more precise to determine underlying pathology.
Stent Thrombus The presence of a thrombus that originates in the stent or in the segment 5mm proximal or distal to the stent. OCT identifies stent thrombus as intraluminal lesion with irregular edges, oscillation at periphery, low density, differentiates white thrombus from red thrombus and while assessing consideration of underlying clinical situation is more important (Figure 16).
OCT assessment of stent failure mechanisms is essential to determine best therapeutic strategy-Stent edge restenosis should be treated with additional stent, Neo atherosclerosis or neointimal hyperplasia can be managed with additional stent or DEB, under-expansion or mal apposition require post-dilatation with NC balloons, and plaque modification is required in patients with neo-atherosclerosis with severe calcification or calcific plaque is responsible for under expansion.   OCT has a limited a penetration depth, it is very difficult to identify plaque burden especially in lipid rich plaque. In contrast, calcified plaque can be visualized well with OCT, whereas IVUS is not capable of penetrating calcified plaques. Therefore, IVUS should be preferred for assessing the plaque burden and vessel size in patients presenting with lipid rich plaques, whereas OCT should be preferred for calcified plaques. OCT has much higher resolution compared with IVUS and should therefore be considered for lumen assessment and stent related morphology, such as thrombosis, restenosis, edge dissection, expansion and mal apposition.

IVI Assessment of Bifurcation during the Procedure
Intravascular ultrasound imaging during the procedure allows for precise: 1) direct control of wire re-crossing through the jailed SB, 2) assessment and optimi- OCT assessment of guide wire re-crossing point, link connection and jailing struts on the SB ostium using 3D OCT image provides some more insights during bifurcation PCI. If suboptimal guide wire re-crossing and SB ostial dilatation or stent mal apposition or deformation is found, and an additional optimization World Journal of Cardiovascular Diseases

Importance of IVUS Guided Optimization of LM-PCI
LM has more elastic component that may lead to stent under expansion and recoiling, more often associated with calcific plaques with higher probability of vessel tapering. LM bifurcation disease is mostly diffuse and angiography may be inaccurate in assessing the disease severity of ostia of both branches. Whereas, World Journal of Cardiovascular Diseases IVI provides more accurate information by providing cross sectional images about plaque morphology, disease extent, severity, and size of the LMCA, LCX, and LAD vessels. Presence or absence of significant disease in the ostium of the LCX is an important factor in selecting a stent strategy (single Vs two stents). If unable to pass imaging catheter due to severe calcification or fibrosis of LM lesion needs pre dilatation with small sized balloon or plaque modification, and usage of guide extension catheter for placement of IVUS/OCT catheter. Angio assessment of Post LM PCI with two-stent technique is unreliable in detecting under-expansion and mal apposition, and IVI is the best method to show under-expansion and mal apposition which are associated with significant MACE rate and correction of these by IVI improves acute and long term outcomes [18]. Angiographic ISR is more frequent in lesions with under-expansion than without (24.1% vs 5.4%). In the 2 stent group, the lesions with complete expansion of all sites showed a restenosis of only 6%, similar to that in the single stent group  Figure 19). A smaller IVUS-MSA within any one of these segments was responsible for a higher rate of angiographic ISR and clinical major adverse cardiovascular events (MACE). Edge restenosis was predicted by residual plaque burden of >51.6% to 54.5% in the DES stented segment [19].
OCT has some theoretical advantages over IVUS, including: 1) an improved detail and resolution of superficial intra vascular structure prior to intervention, 2) a complete analysis of stent apposition and expansion and final MLA assessment, and 3) the ability to discover tissue prolapse, thrombus or edge dissection after stent implantation. OCT guidance for LM PCI was feasible, safe and was successful in 86% of patients in LEMON study [20].

Usefulness of IVI to Anticipate Side Branch Compromise
Side branch (SB) ostial stenosis can be aggravated after crossover stent deployment in the MV, the main mechanism for the SB compromise was carina shift, pre-procedural PB and luminal expansion after stenting of the distal MV were associated with the carina shift7 which is enhanced by stretching of the distal MV and a shift in the flow divider outward towards the SB ostium [21]. Presence of negative remodelling in the distal MV, particularly calcified plaque in the MV opposite to the SB orifice was a predictor of SB residual stenosis after FKB. World Journal of Cardiovascular Diseases In provisional stenting prior to FKB it would be preferable to cross through the distal strut which ensures better scaffolding of SB ostium with stent struts, guide wire through proximal strut prior to FKB is associated with mal apposition and improper scaffolding of SB ostium. In two stent technique OCT guides about the position of guide wire proximal vs distal strut to minimize mal apposition and better expansion with adequate scaffolding of SB ostium with stent struts.

OCT Assessment of Predictors of SB Closure
The assessment of stent configuration over SB orifice and guide wire re-crossing portion with 3D OCT imaging before KBI provides important information to achieve optimal bifurcation strategy. Proper POT enlarges the distal site of jailed struts, which increase the likelihood of optimal distal wiring. Stent configuration is classified into two types-1) link free carina type, (No link connection on the carina)-Distal guide wire re-crossing is required to provide better stent opposi- LM group compared to propensity score-adjusted group that was not treated with this strategy [24].
Stent struts at ostial LCX after provisional stenting impacted the narrowing of the Ostial area at follow up OCT study and main pathological predictors for LM stent failure are mal apposition and struts crossing an ostial LCX supported the importance of the opening the stent struts jailing the SB. The 3D OCT imaging facilitates the achievement of complete removal of jailed struts and fully apposed struts in the bifurcation segment, which may lead to improvement of KBI compared to 2D OCT imaging or angio guidance.
In patients with bifurcation PCI with provisional stenting (PS) an additional two stent strategy may be necessary in 3% -47% of cases after provisional stenting. In PS, SB dissection and bail out two stent deployed occurred in 10.5% and 5.6% after KBI, respectively, even when dedicated IVUS guided KBI was performed. Imaging guidance is useful to avoid unnecessary bail out two stenting in PS which will reduces MACE rate.

IVUS Assessment of Severity of LMCA Disease
Atherosclerotic plaque of the LMCA is qualitatively different from else-where in coronary tree, with minimal necrotic core content and less thin fibro-atheroma than the proximal segment of the other coronary arteries particularly the LAD, which is more prone for ruptures [25]. Conventionally an angiographic cut off of >50% diameter stenosis (equivalent to >75% area stenosis) has been used to indicate hemodynamic significance, which is on the bases of early work in an animal model by Gould that demonstrated a reduction in hyperemic flow across lesions beyond this disease degree of stenosis [26].
Oveido et al. demonstrated that LM disease extending into the proximal LAD, LCX or both may be seen in 90%, 66.4% and 62% of patients, respectively, whereas ostial daughter vessel lesions without LMCA involvement was present in only 9.3% of LAD and 17.1% of LCX vessels, and the carina was always spared [27].
Fractional flow reserve (FFR) is the gold standard for identifying myocardial ischaemia (FFR ≤ 0.80) and to determine the functional significance of LM bifurcation [28]. To predict myocardial ischaemia in LM disease, the cut-off value for the IVUS-derived minimum lumen cross-sectional area (IVUS-MLA) has been recognised as 4.5 -6.0 mm 2 [29]. The IVUS MLA in LM seems to be population-dependent. The average IVUS MLA in the patients included in two different studies was strikingly different (7.6 mm 2 in the US study and 4.8 mm 2 in the Korean study) [30]. In a prospective multicentre LITRO study, investigators evaluated the safety of an IVUS-MLA threshold of 6 mm 2 to guide decision making on revascularization in 354 patients with LM disease.
In 179 patients with an LM segment IVUS-MLA of ≥6 mm 2 revascularization was deferred, whereas the remaining 152 patients with an IVUS-MLA < 6 mm 2 were revascularized. Importantly, the two-year event-free survival from cardiac death and MI was 97.7% in those patients who had no LM revascularization, compared with 94.5% in the revascularized group [31]. Recent ESC guidelines proposed that LM patients ( Figure 21) with an IVUS MLA of <4.5 mm 2 should be recommended for revascularization, IVUS MLA between >4.5 mm 2 and <6 mm 2 should be evaluated with FFR, if FFR positive need revascularization and negative needs to be treated conservative medical management, and if IVUS-MLA of ≥6 mm 2 revascularization of LMCA should be deferred [32].
OCT is considered as non-applicable for coronary arteries ostia and might be limited in case of large vessel but it scores over IVUS in identification of thrombus, coronary dissection and in complete stent opposition due to its better spatial resolution. It is comparable to IVUS in assessing mid and distal LMs specific features such as diameter discrepancies, tapered anatomy, plaque eccentricity and high probability of calcification that are difficult to correctly analyze by angiography alone.
OCT image acquisition may not be possible in extremely tight and unstable lesions, requiring pre-dilatations to get adequate blood free field with contrast

OCT Assessment for Crush Evaluation
In crush techniques, post crushing OCT run shows very clearly about the length of crushed segment in the MV and adequacy of crushed segment of SB stent proximal portion in MV. If crush is inadequate due to under sized balloon, upsizing of balloon is required to do repeat crushing to ensure crushing is adequate prior to implanting MB-MV stent ( Figure 22).

Usefulness of IVUS in CTO Interventions
IVUS evaluation gives longitudinal information of CTO segment for proper entry point, and cross-sectional information of intimal plaque, sub-intimal space, true lumen and false lumen, and any vessel perforation, extravasation, sub-intimal dissection while tracking guidewire across long segment complex CTO lesions ( Figure 24).

Antegrade Approach of CTO
IVUS in SB at the site of CTO is helpful for antegrade puncture of proximal blunt cap by confirming guidewire location, intimal vs sub-intima. IVUS guided re-entry from subintimal space during antegrade dissection and re-entry after parallel wire failure and when no retrograde option is possible. IVUS is also helpful after STAR with long subintimal segment, by advancing IVUS in false lumen and try to re-enter intima with stiffer wire (Figure 25) by showing an example of a procedure (Figure 26(a) & Figure 26(b)).

IVUS in Retrograde Approach of CTO
IVUS is very useful to clarify retrograde wire location and the exact point of where is possible to try to make the connection between antegrade and retrograde wires, and permits to optimize stent sizing and expansion in complex coronary reconstruction (Figure 27).

IVUS Identifies Location of Antegrade and Retrograde Wires during Retrograde PCI
It is also helpful in identifying dissection planes in distal bifurcations, eliminates the need for antegrade injections prior to stenting thereby reduces risk of propagation of iatrogenic dissection distally or retrograde in the aortic wall (ostial RCA CTO) [33] and reduces the risk of CIN by reducing the volume of contrast particularly in Diabetics, elderly, and in patients with low GFR.

Does IVI Change PCI Outcomes?
Recent meta-analysis of 26,503 patients from three randomised and 14 observational studies (including two studies dedicated to LM stenosis and three studies dedicated to bifurcation stenosis). Intravascular ultrasound-guided PCI was significantly associated with more, longer and larger stents. Regarding clinical outcomes, IVUS-guided PCI was associated with a significantly lower risk of death, MI, ST and TLR [34] (Table 4).

IVUS Guidance Saves Lives in LM PCI Compared to Angio Guided PCI
Image guided PCI associated with decreased incidence of stent thrombosis and MACE rate which is evident in recently published Meta-analysis, ADAPT-DES [6], ULTIMATE [4], and IVUS-XPL [5]

OCT New Algorithm-MLD MAX
New Algorithm is proposed by light lab study investigators to implement simple work flow chart to make it simple and convenient to use while performing OCT guided interventional procedures. Each OCT run serves a separate purpose. The pre-PCI run helps determine the PCI strategy, and the post-PCI run allows for optimization of the stent as  (Figure 28) 1a) Morphology This new algorithm helps a beginner to interpret in a simple way. According to this classification pre-OCT run useful to assess requirement of plaque modification of the vessel before stenting. The morphology of a coronary artery ( Figure 29) includes lipid plaque, fibrotic plaque, and calcium (mild, moderate and severe- Table 6) or sometimes any of the combination to decide direct stenting or plaque modification with complaint or non-complaint balloons (regular NC/OPN NC), Atherectomy (rotational/orbital) or IVL or ELCA followed by stenting (Table 7). 1b) Length: For selecting the landing zones-Visually scan for largest luminal area, Place landing zones in healthy tissue (i.e. EEL visualization). In the absence of EEL to represent healthy tissue find the largest lumen to avoid areas of TCFA or lipid pools so as to not land your stent edge in these high risk areas ( Figure  30). Length of the stent is equal to the length between proximal and distal landing zones.

Conclusion
IVI is very useful in complex PCI in identifying plaque morphology, choosing plaque modification strategy, assessing adequacy of plaque modification, selecting proper devise size (diameter and length) in order to cover diseased segment, and choosing proper landing zones. Post PCI intravascular imaging identifies predictors of DES outcomes mainly under-expansion, edge dissection, mal apposition and helps in rectifying these issues. IVI guided PCI is associated with significantly reduced stent thrombosis and MACE rate compared to angio guided PCI.

Conflicts of Interest
The author declares no conflicts of interest regarding the publication of this paper.