Impact of plaque characteristics on the degree of functional stenosis

Coronary atherosclerosis assessment by CCTA: detailed plaque features and atherosclerotic burden scores

Coronary CT angiography (CCTA) is now widely recognized as a useful tool to noninvasively rule out significant coronary stenosis, and is increasingly used as a gatekeeper for invasive coronary angiography, which is becoming more and more reserved for patients at high probability of coronary artery disease in need of a revascularization procedure (1). Although still not in the clinical arena, one of the most appealing features of CCTA is the ability to look be-yond the luminal stenosis and provide a detailed evaluation of the coronary wall depicting several features like plaque composition (calcified, noncalcified or mixed), plaque burden, remodeling index and degree of attenuation measured in Hounsfield units (HU), and several of these features have been associated with the future development of events (2-8) (Figure 1). In fact, the potential prognostic value of these detailed plaque features provided by CCTA has opened a new field of research in coronary artery disease, which in the last 2–3 decades has been struggling in the search of the vulnerable plaque (10,11). In addition, when looking for the same disease using a different imaging modality, is seems wise to follow the steps of previous research and therefore the excitement in this field has to be balanced by the difficulties that other imaging modalities, some of which of very high spatial resolution, have faced in the search of these vulnerable plaques. Some landmark studies that used invasive intracoronary imaging have prospectively linked several plaque features to the development of future coronary events, although with a modest positive predictive value (12-14). Studies with CCTA have also demonstrated the prognostic value of some of these detailed plaque features like positive remodeling, the presence of low attenuation plaques and the presence of a napkin ring sign. Since several coronary plaques are frequently found in the coronary tree even in low to intermediate CAD probability patients undergoing CCTA to rule out coronary stenosis (15,16), and since detailed plaque evaluation is time consuming, requires very good image quality and can be associated with low interobserver variability, another possible approach is to provide the total coronary atherosclerotic burden as a score, and some have been developed and validated as prognostic tools (17-19), providing imagers and researcher with additional tools and a change of focus from just the vulnerable plaque to the vulnerable coronary tree (20).

Figure 1 Atherosclerotic plaque features and functional impact. On the left panels [(A) volume-rendering technique; (B,C) multiplanar reconstructions] CCTA depicting a mixed plaque in the mid-segment of the left anterior descending artery with intermediate stenosis (50–70%) and several features that have been associated with the presence of ischemia and/or future events: spotty calcification (A&B), positive remodelling (B,C) and low attenuation plaque (C). On the right side panels the corresponding invasive angiography image (D) and the result of the FFR, which was in the grey zone –0.77 (E). The final clinical judgment was to proceed to revascularization and the patient was submitted to PCI. Adapted with permission from de Araújo Gonçalves et al. (9).

The search of functional information with CT angiography

Recently, CTA has been increasingly looked as a possible provider of functional information, moving from the traditional view of a purely anatomical exam. The rational for this is two-sided: on one hand, current clinical decision making on the need for myocardial revascularization is based on the presence of ischemia, since it has been extensively documented that there is no expected benefit of intervention for coronary stenosis that are not functionally significant (21,22). On the other hand, although several diagnostic tools are already available, some of them have limited diagnostic performance (like exercise ECG), several patient related potential limitations (like stress Echocardiography and cardiac magnetic resonance imaging), depend on a significant amount of radiation exposure (like single photon emission computed tomography) and have availability issues apart from some selected centers (like cardiac MRI) (23). In what concerns CCTA, the impressive reductions in radiation exposure of last generation scanners (24-26), coupled with their increasingly availability makes CTA a very attractive 2 in 1 modality to evaluate both the presence and the impact of CAD. Therefore, cardiac CT is becoming more and more a modality that is able not only to rule out CAD with a very high accuracy but also to provide functional information, moving beyond the usual classification of obstructive vs. nonobstructive to a more functional-based interpretation of signipara-doxicallyficant vs. nonsignificant CAD, a feature that is more in line with current clinical decision algorithm (9).

In line with this rational, the following research lines have been explored like myocardial perfusion imaging, fractional flow reserve computed from CTA (FFR_CT), transluminal attenuation gradients and corrected coronary opacification indexes, which have been recently reviewed elsewhere (9), and some of them are revisited in the same issue of this journal.

One additional line of research aimed at extracting functional significance out of CTA datasets, the more recent and least explored of these, is the link between certain atherosclerotic plaque characteristics and the functional impact of coronary lesions, which will be developed further in the following chapter.

Atherosclerotic plaque characteristics and functional information: beyond stenosis severity

The concept that there is a modest correlation between the degree of anatomical stenosis and functional significance is not new and has been pointed out in several studies using ICA and the gold standard invasive FFR (21,27) and also with CCTA and noninvasive FFR (FFR_CT) (28,29). Also important is the fact that these mismatches can also be observed on their counterparts, meaning that not only some of the apparently significant lesions (>50% and even >70% stenosis) are not causing ischemia (27), but also that nonobstructive (<50% stenosis) lesions can paradoxically be associated with ischemia, both on invasive (ICA/FFR) (30) and noninvasive (CCTA/FFR_CT) (31) coronary evaluation. In a study including 1,000 patients evaluated by invasive coronary angiography and FFR, 16% of those with nonobstructive (<50% stenosis) were reversed mismatches, having a significant (<0.80) FFR (30). Although the limitations in quantifying stenosis severity using ICA have to be acknowledged, this study reinforces the concept that nonobstructive lesions can be associated with ischemia. Interestingly in this study was the fact that these reverse mismatches were more often found in the left main and independently associated with a left anterior descending artery location and the presence of a larger plaque burden and plaque rupture, features that link atherosclerotic plaque features to functional significance of coronary lesions. Recently this relation was also depicted using CCTA. In a study that included 252 stable patients undergoing both CCTA and ICA with FFR, Park et al. were able to document an association between certain CCTA atherosclerotic plaque characteristics (APCs) and the presence of ischemia by invasive FFR (31). In their study, lesion length, positive remodelling (index ≥1.1), and the presence of low attenuation plaque (<30 HU) were independent predictors of ischemia by invasive FFR. Besides the expected finding that a significant percentage of CCTA obstructive (≥50% stenosis) lesions were not functionally significant by FFR, the most but striking result was the fact that even among nonobstructive CAD lesions, 17% were associatathero-scleroticed with ischemia, a result that was in line with the previously discussed studies that documented the visual functional mismatches between FFR and invasive coronary angiography. In another small study, including 58 patients with intermediate stenosis on CCTA undergoing ICA with FFR, the extent of coronary atherosclerotic burden quantified as aggregate plaque volume (APV), has been found to be incremental to several luminal narrowing measurements (diameter stenosis, minimum luminal diameter, area stenosis and minimum lumen area) to predict functional significance (FFR <0.80) (32). Taken together these studies underline the fact that some nonobstructive lesions but with high CTA risk features can be associated with the presence of ischemia. The reason for this might be related to the fact that these lesions with high plaque burden can be associated with endothelial dysfunction, since it has been demonstrated in small studies using virtual histology (IVUS-VH) that plaques with larger necrotic core are more prevalent in patients with endothelial dysfunction (33). The pathophysiological mechanism linking plaque features and ischemia deserves further evaluation but in any case the prognostic impact of coronary plaque burden is not a new concept. In a large study including 4,137 patients pooled from 6 IVUS studies, Nicholls et al. were able to demonstrate that percent atheroma volume (PAV) was an independent predictor of events (34). Also interesting in that study was the fact that not only PAV but also disease burden progression was associated with outcomes, a result that is in line with the recent study of Motoyama et al. relating coronary events to plaque progression documented on patients undergoing serial scans (6). Similar observations have been made using oresultptical coherence tomography and simultaneous functional assessment of the lesions. Yonetsu et al. showed a direct association of a larger lipidic arc and lipid length with microcirculatory disturbances (35). Usui et al. reported that physiological severe stenosis were twice as prevalent in thin cap fibroatheroma lesions. These reports suggest that these high risk lesions may affect the microcirculation downstream (36). Taqueti et al. recently presented data comparing CAD lesions in women and men assessed by angiography and coronary flow reserve (CFR) in which women had lower plaque burden. The adjusted cardiovascular events were higher in the women’s group, two times higher when compared to men’s, despite the lower CFR values in women’s group (37).

Recently a new terminology was proposed regarding those mismatches between anatomy and function: The NIPSS (no ischemia in the presence of significant stenosis) and the PINSS (presence of ischemia with no significant steno-sis), recognizing this interesting subset of patients in which certain plaque features might be responsible for the apparent contradiction between anatomy and physiology (38). In fact, lesions in this last subgroup can be considered “false negative” of CCTA and might explain the worse than expected prognosis of patients that don’t have obstructive lesions but have high disease burden, as it has been recently demonstrated with the use of CCTA coronary atherosclerotic burden scores (17-19) that take in consideration all lesions independent of stenosis severity. As the knowledge of coronary disease pathophysiology advances, the traditional anatomic-based dichotomic concept of obstructive vs. nonobstructive is becoming more and more outdated and becoming replaced by a concept of high vs. low risk plaque features/burden, more in line with the recent evidence provided by both invasive and noninvasive atherosclerosis imaging. Further, the field of functional assessment will be revisited in light of the recent reports. In the FUTURE trial (American Heart Association 2016), Rioufol et al., showed an increase in mortality from any cause in FFR guided management group of patients when compared to the optimal medical treatment alone, interrupting prematurely the study (39).

Intravascular coronary imaging and its relation with functional lesion assessments

The 3-dimensional and dynamic nature of the coronary vasculature cannot be fully appreciated by planar angiography. Frequently, defining the proper angiographic angulation that provides a straight, nonforeshortened view of the target coronary segment without overlapping of other vessels may be a challenge in the catheter laboratory. In addition, determination of disease severity by angiography is hampered by the diffuse nature of atherosclerosis and its most common eccentric growth in the vessel wall. Hence, lesions can appear more stenotic in one orthogonal view than in the other, making clinical decisions difficult. The so-called intermediate lesion is the more prevalent phenotype in the coronary tree. The American Heart Association/American College of Cardiology/Society for angiography and Interventions (AHA/ACC/ SCAI) guidelines define an intermediate coronary lesion as a plaque producing a 50–70% angiographic stenosis (40). These plaques represent a heterogeneous group of coronary lesions, which may or may not be hemodynamically flow limiting. Intravascular imaging, particularly IVUS, was granted a class IIb indication (level of evidence B) for the “IVUS may be reasonable for the assessment of non–left main coronary arteries with angiographically intermediate coronary stenoses” and a class IIa indication (level of evidence B) for the “IVUS is reasonable for the assessment of angiographically indeterminant left main coronary artery disease” in the American Guidelines. In the European guidelines is also a class IIa indication (level of evidence B) for the “IVUS to assess severity and optimize treatment of unprotected left main lesions”. For other intermediate lesions IVUS is not endorsed by the European Guidelines in the absence of prospective randomised evidence (41).

IVUS minimum luminal cross-sectional area (MLA) has proved to be a good morphometric surrogate of coronary physiology. IVUS MLA showed a direct correlation with coronary flow reserve determined by Doppler flow-wire (r=0.831, P<0.001) (42). FIRST trial, demonstrated, in a cohort of 350 patients with intermediate lesions and FFR ≤0.8, a MLA <3.07 mm² (64.0% sensitivity, 64.9% specificity and area under curve of 0.65) and a FFR correlation with plaque burden size (r=−0.220, P<0.001) (43). Han et al. reported similar results after assessing 881 lesions with a MLA <3.0 mm² (and MLA<2.75 mm² for Asians) (44). In 2014, a meta-analysis pooled 15 studies enrolling a total of 3,428 patients (3,775 lesions), showing a mean MLA of 2.59 mm² with 73% sensitivity, 66% of specificity and AUC =0.778 (45). The optical coherence tomography (OCT) was also used to evaluate lesions with FFR ≤0.75 and demonstrated a correlation with MLA <1.91 mm², minimum lumen diameter (MLD) <1.35 mm, plaque burden >70% (46). Thus, accessing only FFR ≤0.8 lesions, Gonzalo et al., compared OCT and IVUS measurements presenting an IVUS MLA of 2.36 mm² and 1.95 mm² for OCT, with a relative difference of 32.3±26% and absolute difference of 0.65±0.62 mm² (limits of agreement of –0.57 to 1.87 mm²) (47). The MLD value for IVUS was 1.59 mm², 1.34 mm² for OCT with a relative difference of 19.5±16%, absolute difference of 0.27±0.23 mm² (limits of agreement of –0.20 to 0.72 mm²) and area of stenosis of 61% for IVUS and 70% for OCT (46). When assessed using virtual histology (IVUS-VH) inter-mediate lesions showed a prone to have less necrotic core (14.2±8% vs. 19.2±10.2%, P=0.08) and greater plaque burden (54.6±0.7% vs. 51.7±0.7% P=0.1) (Table S1) (48). In 73 patients studied pre-intervention, an MLA of ≥ 4.0 mm² had a diagnostic accuracy of 89% in predicting a coronary flow reserve >2.0. Likewise, IVUS has been correlated with noninvasive single-photon emission computed tomography (SPECT) (49). A 4 mm² MLA by IVUS had 88% sensitivity and 90% specificity to discriminate the SPECT (+) group from the SPECT (–) group. The relatively simple cut-off of 4.0 mm² MLA can be used as a criterion in the clinical decision making process. This cut-off value has also been identified using fractional flow reserve (FFR) as the gold standard in the assessment of lesion severity (50). The association of MLA and ischaemia has been revisited more recently using an existing IVUS imaging database: 170 coronary lesions (150 patients) which were imaged with IVUS and underwent stress myocardial single-photon emission computed tomography (SPECT) were analysed. By receiver operator characteristic curve analysis, the best cut-off value of MLA was ≤2.1 mm² (38.6% positive predictive value, and a 91.3% negative predictive value versus lesions with a positive SPECT) area under the curve: 0.690, 95% CI: 0.615 to 0.759, P<0.01 (51).

Table S1 IVUS and OCT studies comparing invasive imaging with fraction flow reserve
Full table

There have been previous comparative studies showing good to excellent correlation between CCTA and IVUS geometrical parameters (52). This has led to the use of CCTA to prospectively evaluate changes in IVUS-like parameters such as MLA (53).

It is worth noting that this value does not apply to small vessels (54) or to large segments such as the left main (LM) or venous bypass grafts.

Conclusions

In this fast moving field of advanced coronary imaging, CTA has moved from just a “rule-out CAD” modality and has been explored in several different lines of research, due to its unique ability to non-invasively depict several atherosclerotic plaque features and quantify the extent of plaque burden in the coronary tree. One of the most interesting research lines is exploring the relation between these plaque features and coronary burden of disease, not only with adverse outcomes but also recently with the development of ischemia, which might help to understand the pathophysiological link between anatomy and function in ischemic heart disease and a better identification of patients at risk of future coronary events.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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