OCT Plaque Rupture


OCT in Plaque Rupture

It is now widely accepted that the majority of plaques that result in acute coronary syndromes (ACS) are small, thin walled, and lipid laden58-71. These plaques are generally below the detection limit of current imaging technologies, which is consistent with the fact that intracoronary interventions on angiographic detected plaques generally do not result in a reduction in mortality . When these plaques rupture, they release thrombogenic factors into the blood, which leads to a cascading sequence of events leading to clot formation and vessel occlusion. A more detailed description of these TCFA will be presented below, but while most ACS are caused by TCFA, the majority of the TCFAs do not result in ACS, which is a major issue for intracoronary imaging.58-60 Plaque rupture itself does not necessarily cause symptoms and depending on the amount of thrombotic response may be clinically silent.61  It has been noted that in one study of patients dying of noncardiovascular disease, up to 8% had ruptured plaques that were asymptomatic.  Several investigators have noted the presence of more than one ruptured plaque in patients experiencing a cardiovascular event.62-67  Therefore, improved risk stratification is necessary as intracoronary intervention on all TCFA is not practical or even wise.  Since the original OCT studies of plaque, OCT has demonstrated itself to be a powerful tool for identifying small thinned walled lipid filled plaque (TCFA) which has been confirmed with subsequent studies.  The question which existed at the beginning of the decade, which still exists today, is how can OCT subclassify thin walled lipid filled plaque to identify those which lead to ACS. Most OCT studies looking at plaque to date have focused on generating images of TCFA, not identifying those that lead to plaque rupture or ACS. For example, if we look at the most recent OCT publication in JACC, the conclusions are “The 3-vessel OCT imaging showed that culprit lesion TCFAs, secondary remote TCFAs, and multiple TCFAs were more common in AMI patients than in SAP patients.”100 Again, this does not directly address the clinically relevant question and does not represent a significant advance from data acquired a decade earlier through other modalities.  Likely this will require adjuvant OCT techniques, such as PS-OCT, phase sensitive OCT, elastography, image processing (such as wavelet analysis and the STICKS technique), absorption spectroscopy, and Doppler, which have, as stated, been underutilized to date.  This does not include the application of even more far forward work such as using the quantum properties of second order correlations to assess tissue composition or the use or the use of OCT tissue probes.11, 17-21, 33-35, 82-84, 90

The American Heart Association classification of plaque uses broad criteria and has recently been further subclassified based on the likelihood of rupture by Virmani et.al.68  In this subclassification, the plaque most relevant to ACS is the thin cap fibroatheroma (TCFA).  The TCFA are characterized by a thin fibrous cap (<65 µm thickness), infiltrated by macrophages and lymphocytes (at some points in its development), and few supportive smooth muscle fibers and collagen.  The cap overlays a generally hemorrhagic, necrotic lipid core with substantial penetration of angiogenic blood vessels (neovasculaization) into the intimal from the adventitia (but not within the lipid core).  Presumably, the plaque is structurally weak making it vulnerable to mechanical pressure such as shear stress, lipid expansion, or angiogenic vessel rupture.  Factors making the plaque structurally weaker include a thin intimal cap with collagen and smooth muscle depletion, the size/composition of the atheromatous hemorrhagic core, collagen type, and angiogenesis into the intima.  These factors and other can potentially be assessed by OCT.  Unfortunately, again, almost no work has been done examining these plaque properties that may allow TFCA to be subcategorized into those most likely to lead to ACS.  Of note, while evidence strongly suggests inflammation plays a critical role in plaque development, it probably is not a good marker of vulnerability as structurally weak plaque may have long since been inflamed.  This is discussed in more detail in the supplemental information/appendix.

The major TFCA marker examined to date is intimal cap thickness.  In addition, limited studies have suggested diffuse intimal borders indicate a lipid core and that OCT can (and that it is clinically relevant) measure inflammatory cell concentration.  Questions with these latter two are discussed below.  These represent almost the full scope of in vivo markers used to date.

Intimal cap thickness represents the most studied marker to date.  At autopsy, as stated, 95% of ruptured plaques have a fibrous cap thickness near the rupture site of <65 μm.69 However, due to an axial resolution of 100-150 μm (lateral 300 µm), even IVUS (as well as any other current imaging technology), is unable to measure fibrous cap thickness.7, 8, 70, 71  Figure 8 demonstrates an OCT image of a ruptured thin intimal cap.

OCT is the only modality with the resolution required for direct quantitative assessment of cap thickness. In our initial study of thin walled plaques 15 years ago, we demonstrated an ability to identify in vitro plaque intimal cap thickness below 40 µm with histological comparison.3  This is consistent with all our papers through the 90’s confirming OCTs resolution in vitro and in vivo, and supporting papers directly performing comparisons with IVUS.  These intimal cap measurements were confirmed a decade later by another group Kume et al using 35 ex vivo lipid-rich human coronary plaques demonstrating a high correlation (r=0.90, p<0.001).72  The ability to demonstrate intimal cap thickness is clearly the best demonstrated strength for OCT identifying TCFA. 

Defining plaque composition is a complicated and important topic in cardiovascular OCT.  Unfortunately, other than one study in 2002, this area has been largely unexamined after our initial studies (in the 90’s) until several other works appeared in 2006.  And all these studies are limited as adjuvant techniques were not examined in vivo (such as PS-OCT for collagen), so only a small component of OCTs full diagnostic capacity has been studied.  This raises a concern about in vivo studies interpreting plaque composition and whether more basic studies should have preceded in vivo plaque imaging.  Yabushita, et al. in 2002 measured the sensitivity and specificity of OCT in vitro ranging from 71% to 98% for fibrous plaques, 95% to 97% for fibrocalcific plaques, and 90% to 94% for lipid-rich plaques among two OCT observers with good inter-observer variability (kappa = 0.83-0.84).73  Similar results were obtained by a second group in 2006.74 Two additional smaller studies were performed the same year that examined plaque composition at approximately the same time as the second study.91-92  Results varied in these studies, with one showing a 45% sensitivity and 83% specificity for identifying lipid filled plaques.  This latter study had difficulty in distinguishing lipid and calcified plaque.  Examples of different coronary artery states seen by OCT in vivo are shown in figure 9.74

In all five publications, lipid versus fibrous plaques were distinguished, at least in part, by a diffuse cap boundary in the former.  However, in a recent paper22 we questioned, based on our work and data presented in these papers, whether the diffuseness at the cap boundary was due to high scattering in the intima (rather than whether the underlying tissue is lipid or fibrous tissue), possibly from calcium or lipid crystals. This is discussed in the supplemental section/appendix and figure 10.  Future studies are required to establish the mechanism as to why some plaques have diffuse cap/core interfaces and if this can be used to identify those TCFA that progress to ACS.

Inflammatory cells have been suggested as a useful marker for OCT.  Inflammatory cells, particularly macrophages, play a critical role in the development and progression of atherosclerosis.75, 76 Their release of metalloproteases (in addition to other factors) appears to be a central mechanism in the breakdown of the collagen matrix.  In addition, release of thrombogenic factors from the local inflammation increases the likelihood of clot formation.  However, while inflammatory cells play a pivotal role in the development of TCFA, their contribution to ACS is less clear.  First, in patients with ACS, inflammation appears to be extensive through the arterial circulation, including both culprit and nonculprit regions, and may have subsided by the time of the rupture.34, 77 This concept of atherosclerosis as a systemic inflammatory state is exemplified by elevations of markers such as the WBC counts or C-reactive protein.35 Second, studies that have demonstrated high concentrations of macrophages in ruptured TCFA are measured after ACS develops.  Therefore, it is unclear whether increased concentrations of the macrophages contribute to plaque rupture or migrate into the region (and the whole vascular system) after the rupture.  A side observation of our PS-OCT study was the number of TCFAs seen which had cap thickness less than 100 µm yet no significant active inflammation17.  Third, since in 50% of patients with MI the precipitating factors are acute, such as exercise and stress, it is difficult to envision inflammatory cells as the primary rupture trigger (although critical to progression of TFCA).78 Finally, there are questions about OCTs ability to actually measure inflammatory cells in vivo, which is discussed in the supplemental information.22

3.5 Potential Approaches to TCFA Risk Stratification.

The critical question in the field of plaque vulnerability is what TFCAs will progress to ACS as at least for intracoronary interventions, treating all TCFA does not at this time seem optimal.  So the objective with OCT is going beyond just recognizing TFCA but to identifying risk stratifying features.  Intimal cap thickness is clearly an important marker and is the only one examined extensively to date.

Going back to why TCFA most likely progress to ACS provides an idea of where OCT research might be directed (ignoring the relative coagulation state of the blood).  Rupture occurs in structurally weak plaque from prior inflammation that subsequently undergo a mechanical stress.68, 69, 78  The most likely mechanical stresses are shear stress across the plaque, lipid expansion, and rupture of immature angiogenic vessels in the plaque (although the latter seems to be more prevalent in the carotid rather than the coronary).7,8 

Therefore potential properties currently not examined extensively in vivo are intima cap collagen type I, intima cap smooth muscle content, size of the lipid core relative to the plaque size, tensile strength, lipid composition, and the amount of neovascularization in the plaque (their presence is generally minimal in the lipid core itself).  For collagen and smooth muscle concentration, PS-OCT has shown promising results in the coronary in vitro and has been used with great success in vivo in other organ systems.17, 80, 86, 87  OCT elastography, either by monitoring speckle modulation or the RF signal, has been used to assess mechanical properties (tensile strength) on in vitro arteries and has been validated with agar-gelatin phantoms (see supplemental information).79, 81 OCT Doppler has been used in other organ systems to assess the presence of microvessels, but not in coronary plaque.  These therefore represent three promising areas for OCT research.  With respect to assessing lipid composition in plaque, this is a theoretical possibility with absorption OCT spectroscopy, phase sensitive OCT, dispersion analysis, tissue probes, or our recent work using the quantum effects of second order correlations (as well as other techniques discussed), but these are areas where extensive basic work is needed.11, 17-21, 33-35, 82-84, 90  In terms of estimating the lipid core to plaque dimensions, there is no evidence OCT, in its current form, is capable of achieving this for the vast majority of plaques due to penetration limits.  It has been suggested that OCT could be combined with IVUS for this purpose, but the concept of dual intravascular imaging modalities is premature if necessary at all.  In addition, the specificity for IVUS detection of lipid cores has a limited specificity so that the combination may not be as advantageous as some would suggest.  It should also be noted OCT probes and contrast agents do exist and could provide further plaque characterization, but they have essentially not been used in the coronary and are therefore reviewed elsewhere.82, 84