In recent years, a paradigm shift in the evaluation of coronary artery lesions has been witnessed. Moving away from assessing their anatomical features on coronary angiograms, emphasis on their functional importance is now prioritised.¹ A number of randomised controlled trials has solidified the superiority of a physiology-guided strategy over an anatomy-guided approach, and the favourable outcomes from up to 5 years of follow-up for patients in whom the decision for revascularisation was based on fractional flow reserve (FFR) values.^2-4 Although the disconnect between the anatomical severity of a lesion and its functional impact has been largely ascribed to the inherent shortcomings of the coronary angiogram as a diagnostic tool, it is not entirely explained by them.

Insights on the interplay between the hemodynamic significance of coronary lesions and plaque morphology can be gained from studies that have concomitantly used imaging and FFR. Choosing FFR over other modalities that quantify ischemia has the advantage of providing information on the lesion level, thus allowing accurate correlations with the findings from imaging. Regarding the choice of the imaging modality, studies have used intravascular imaging [intravascular ultrasound (IVUS) and optical coherence tomography (OCT)] and coronary computed tomography angiography (CTA). The inherent limitations of each imaging modality, such as spatial resolution, interobserver reproducibility issues, and non-uniform definitions of plaque characteristics, should be kept in mind when interpreting study results. In addition, the disconnect between anatomy and physiology holds also true even for the more advanced intravascular imaging modalities; a meta-analysis of 2,807 lesions underlined the modest diagnostic accuracy of IVUS and OCT for the identification of hemodynamically significant lesions.⁵

CTA

CTA coupled with either invasive FFR or FFR_CT (a proxy for FFR that is derived noninvasively from the CTA dataset) has been frequently used (Table 1). Commonly assessed plaque characteristics are the percent aggregate plaque volume (%APV), presence of positive remodelling, low attenuation plaques, and plaque calcifications. Which of these features is an independent predictor of ischemia? Because these plaque characteristics frequently coexist, the answer is somewhat elusive and may explain inconsistencies among studies.

Table 1: Studies Linking Plaque Characteristics Assessed With Coronary CTA to FFR

Author (Year)Ref	Plaque Characteristics	Result
Gaur et al. (2016)6	Volume, non-calcified, low-density non-calcified, calcified, calcified	Low-density non-calcified independently associated with ischemia
Park et al. (2015)7	Positive remodelling, low attenuation plaque, spotty calcification	Positive remodelling and low attenuation plaque, but not spotty calcifications associated with ischemia
Nakazato et al. (2016)8	Positive remodelling, low attenuation plaque, spotty calcification	Positive remodelling, but not low attenuation plaque or spotty calcification associated with ischemia
Nakazato et al. (2013)9	Aggregate plaque volume	%APV improves identification, discrimination, and reclassification of ischemic lesions
Rizvi et al. (2017)10	Positive remodelling, low attenuation plaque, % plaque diffuseness	% plaque diffuseness may help improve the accuracy of coronary CTA
Baskaran et al. (2017)11	Dense calcium volume, plaque volume, non-calcified plaque volume	Dense calcium volume was not an independent predictor of ischemia
Driessen et al. (2018)12	Plaque length and volume, plaque burden, non-calcified/partial calcified/calcified plaque, low-attenuation plaque, positive remodelling, spotty calcification, napkin ring sign	Non-calcified plaque volume, low-attenuation plaque, positive remodelling and spotty calcification independently associated with ischemia (assessed by FFR)

In patients with intermediate lesions (diameter stenosis less than 70%) who underwent angiography, FFR measurement, and CTA, it was plaque burden (%APV) that had the greatest predictive value for detection of ischemia.⁹

In a substudy of the NXT (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps) trial, 484 vessels were assessed by CTA and FFR_CT.⁶ Plaque burden, as measured by plaque volume, was inversely related to FFR irrespective of the severity of stenosis. Plaques were further classified as non-calcified, low-density non-calcified, or calcified. The presence of low-density non-calcified plaques was the only independent predictor of ischemia among plaque characteristics; indeed, the presence of such a plaque with a volume of ≥30mm³ coupled with FFR_CT ≤ 0.80 increased the diagnostic yield of CTA.

In a substudy of the PACIFIC (Prospective Comparison of Cardiac PET/CT, SPECT/CT Perfusion Imaging and CT Coronary Angiography With Invasive Coronary Angiography) trial, Driessen and colleagues have recently reported the effects of plaque burden and morphology on myocardial blood flow and FFR. Following a comprehensive evaluation of quantitative and qualitative plaque characteristics in 610 arteries by coronary CTA, these were correlated to myocardial perfusion obtained by positron emission tomography (PET) and FFR. Despite the fact that all plaque features correlated to FFR, in multivariate analyses the only independent predictors of FFR were the presence of non-calcified plaque, low-attenuation plaque, positive remodelling, and spotty calcifications. Figure 1 presents an example of a lesion with adverse plaque characteristics resulting in an ischemic FFR value.¹²

 

Figure 1: Nonobstructive Lesion With Adverse Plaque Characteristics Causing Ischemia

IVUS

FIRST (Fractional Flow Reserve and Intravascular Ultrasound Relationship Study) used IVUS virtual histology to explore the relation of plaque characteristics with ischemic FFR. Ischemic FFR values had a modest correlation with plaque burden but not with any other plaque morphology, and this correlation was true for main vessels and side branches.^13,14 Similar findings, with correlation of FFR to total plaque volume but no relationship to IVUS-defined plaque composition, were reported by other study groups.^15,16 The discrepancy between an IVUS-based characterisation of the plaque and its hemodynamic significance could be translated in differential patient outcomes; this will be tested in the FLAVOUR (Comparison of Clinical Outcomes Between Imaging and Physiology-Guided Intervention Strategy in Patients With Intermediate Stenosis: Fractional Flow Reserve and IVUS for Clinical Outcomes in Patients With Intermediate Stenosis) trial.¹⁷

OCT

Despite its superior spatial resolution (tenfold greater than IVUS), OCT-derived minimum lumen area has a similarly modest ability to discern between ischemic and non-ischemic lesions, using an FFR value of 0.8 as the cut-off. A head-to-head comparison of OCT with IVUS in 47 cases yielded similar c-statistics for both modalities, with OCT performing marginally better in small vessels with a reference diameter <3 mm.¹⁸ Nonetheless, when a lower value of FFR of 0.75 was used to define ischemic lesions, the predictive ability of OCT was superior to IVUS.¹⁹

It should be noted that to date, most OCT-based studies that investigated the relationship with FFR had used just minimum lumen area as a metric and did not report data on plaque characteristics or features of vulnerability, an area in which this modality excels. Preliminary data point to the fact that the identification of thrombus or plaque ulceration can accurately predict FFR with a sensitivity and specificity that exceed 90%.²⁰ A correlation of FFR with the minimal thickness of the fibrous cap has been reported in lipid-rich plaques of diabetic patients,²¹ and this has been corroborated by a report of more prevalent thin-cap fibroatheromas with decreasing FFR values.²²

What Is the Link Between Plaque Morphology and Ischemia?

Taken together, the aforementioned findings provide clues to the pathophysiological mechanism that underpins the presence of low-density plaques and inducible ischemia.²³ Low-density plaques contain necrotic cores that are characterised by endothelial dysfunction, oxidative stress, and inflammation. The inability of low-density plaques to vasodilate was demonstrated by using IVUS with radiofrequency spectral analysis. The segmental endothelial function of plaques was assessed with acetylcholine, and it was only the presence of a necrotic core that was associated with endothelial dysfunction.²⁴

It is therefore hypothesized that local endothelial dysfunction, oxidative stress, and inflammation in plaques with necrotic cores do not allow for vasodilation during physiological or pharmacological stress, thus resulting in ischemia, as opposed to plaques without necrotic cores that maintain a vasodilatory capacity.

Importantly, the ischemic potential of plaques is not a function of the ensuing luminal stenosis but rather of large plaque burden coupled with morphological features of vulnerable plaques, such as positive remodelling and low-density necrotic cores.²⁵

Novel noninvasive metrics related to plaque morphology, such as wall shear stress calculated from three-dimensional coronary angiographies, are emerging and hold the potential of refining risk stratification for patients with coronary artery disease.²⁶

References

1. Toth G, Hamilos M, Pyxaras S, et al. Evolving concepts of angiogram: fractional flow reserve discordances in 4000 coronary stenoses. Eur Heart J 2014;35:2831-8.
2. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213-24.
3. Zimmermann FM, Ferrara A, Johnson NP, et al. Deferral vs. performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year follow-up of the DEFER trial. Eur Heart J 2015;36:3182-8.
4. Xaplanteris P, Fournier S, Pijls NHJ, et al. Five-Year Outcomes with PCI Guided by Fractional Flow Reserve. N Engl J Med 2018;379:250-9.
5. D'Ascenzo F, Barbero U, Cerrato E, et al. Accuracy of intravascular ultrasound and optical coherence tomography in identifying functionally significant coronary stenosis according to vessel diameter: A meta-analysis of 2,581 patients and 2,807 lesions. Am Heart J 2015;169:663-73.
6. Gaur S, Øvrehus KA, Dey D, et al. Coronary plaque quantification and fractional flow reserve by coronary computed tomography angiography identify ischaemia-causing lesions. Eur Heart J 2016;37:1220-7.
7. Park HB, Heo R, ó Hartaigh B, et al. Atherosclerotic plaque characteristics by CT angiography identify coronary lesions that cause ischemia: a direct comparison to fractional flow reserve. JACC Cardiovasc Imaging 2015;8:1-10.
8. Nakazato R, Park HB, Gransar H, et al. Additive diagnostic value of atherosclerotic plaque characteristics to non-invasive FFR for identification of lesions causing ischaemia: results from a prospective international multicentre trial. EuroIntervention 2016;12:473-81.
9. Nakazato R, Shalev A, Doh JH, et al. Aggregate plaque volume by coronary computed tomography angiography is superior and incremental to luminal narrowing for diagnosis of ischemic lesions of intermediate stenosis severity. J Am Coll Cardiol 2013;62:460-7.
10. Rizvi A, Hartaigh BÓ, Danad I, et al. Diffuse coronary artery disease among other atherosclerotic plaque characteristics by coronary computed tomography angiography for predicting coronary vessel-specific ischemia by fractional flow reserve. Atherosclerosis 2017;258:145-151.
11. Baskaran L, Ó Hartaigh B, Schulman-Marcus J, Gransar H, Lin F, Min JK. Dense calcium and lesion-specific ischemia: A comparison of CCTA with fractional flow reserve. Atherosclerosis 2017;260:163-8.
12. Driessen RS, Stuijfzand WJ, Raijmakers PG, et al. Effect of Plaque Burden and Morphology on Myocardial Blood Flow and Fractional Flow Reserve. J Am Coll Cardiol 2018;71:499-509.
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15. Jin XJ, Tahk SJ, Yang HM, et al. The relationship between intravascular ultrasound-derived percent total atheroma volume and fractional flow reserve in the intermediate stenosis of proximal or middle left anterior descending coronary artery. Int J Cardiol 2015;185:56-61.
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17. Kang J, Koo BK, Hu X, et al. Comparison of Fractional FLow Reserve And Intravascular ultrasound-guided Intervention Strategy for Clinical OUtcomes in Patients with InteRmediate Stenosis (FLAVOUR): Rationale and design of a randomized clinical trial. Am Heart J 2018;199:7-12.
18. Gonzalo N, Escaned J, Alfonso F, et al. Morphometric assessment of coronary stenosis relevance with optical coherence tomography: a comparison with fractional flow reserve and intravascular ultrasound. J Am Coll Cardiol 2012;59:1080-9.
19. Usui E, Yonetsu T, Kanaji Y, et al. Efficacy of Optical Coherence Tomography-derived Morphometric Assessment in Predicting the Physiological Significance of Coronary Stenosis: Head-to-Head Comparison with Intravascular Ultrasound. EuroIntervention 2018;13:e2210-e2218.
20. Burzotta F, Nerla R, Hill J, et al. Correlation between frequency-domain optical coherence tomography and fractional flow reserve in angiographically-intermediate coronary lesions. Int J Cardiol 2018;253:55-60.
21. Reith S, Battermann S, Jaskolka A, et al. Relationship between optical coherence tomography derived intraluminal and intramural criteria and haemodynamic relevance as determined by fractional flow reserve in intermediate coronary stenoses of patients with type 2 diabetes. Heart 2013;99:700-7.
22. Usui E, Yonetsu T, Murai T, et al. Prevalence of Thin-Cap Fibroatheroma in Relation to the Severity of Anatomical and Physiological Stenosis. Circ J 2017;81:1816-23.
23. Ahmadi A, Stone GW, Leipsic J, et al. Association of Coronary Stenosis and Plaque Morphology With Fractional Flow Reserve and Outcomes. JAMA Cardiol 2016;1:350-7.
24. Lavi S, Bae JH, Rihal CS, et al. Segmental coronary endothelial dysfunction in patients with minimal atherosclerosis is associated with necrotic core plaques. Heart 2009;95:1525-30.
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Keywords: Angina, Stable, Acetylcholine, Calcinosis, Calcium, Constriction, Pathologic, Coronary Angiography, Coronary Artery Disease, Coronary Vessels, Diabetes Mellitus, Fibrosis, Follow-Up Studies, Hemodynamics, Inflammation, Lipids, Multivariate Analysis, Necrosis, Oxidative Stress, Perfusion Imaging, Plaque, Atherosclerotic, Positron-Emission Tomography, Prospective Studies, Reproducibility of Results, Tomography, Emission-Computed, Single-Photon, Thrombosis, Tomography, Optical Coherence, Vasodilation

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