Association of Coronary Stenosis and Plaque Morphology With Fractional Flow Reserve and Outcomes

Importance  Obstructive coronary lesions with reduced luminal dimensions may result in abnormal regional myocardial blood flow as assessed by stress-induced myocardial perfusion imaging or a significant fall in distal perfusion pressure with hyperemia-induced vasodilatation (fractional flow reserve [FFR] ≤0.80). An abnormal FFR has been demonstrated to identify high-risk lesions benefitting from percutaneous coronary intervention while safely allowing revascularization to be deferred in low-risk lesions, resulting in a decrease in the number of revascularization procedures as well as substantially reduced death and myocardial infarction. While FFR identifies hemodynamically significant lesions likely to produce ischemia-related symptoms, it remains less clear as to why it might predict the risk of acute coronary syndromes, which are usually due to plaque rupture and coronary thrombosis.

Observations  Although the atherosclerotic plaques with large necrotic cores (independent of the degree of luminal stenosis) are known to be associated with vulnerability to rupture and acute coronary syndromes, emerging evidence also suggests that they may induce greater rates of ischemia and reduced FFR compared with non–lipid-rich plaques also independent of the degree of luminal narrowing. It is proposed that the presence of large necrotic cores within the neointima may be associated with the inability of the vessel to dilate and may predispose to ischemia and abnormal FFR.

Conclusions and Relevance  Having a normal FFR requires unimpaired vasoregulatory ability and significant luminal stenosis. Therefore, FFR should identify lesions that are unlikely to possess large necrotic core, rendering them safe for treatment with medical therapy alone. Further studies are warranted to determine whether revascularization decisions in patients with stable coronary artery disease could be improved by assessment of both plaque composition and ischemia.

The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) trial^1,2 demonstrated that in patients with stable ischemic heart disease, an FFR-guided strategy to identify hemodynamically significant lesions requiring percutaneous coronary intervention (PCI) can safely defer revascularization in lower-risk lesions and reduce the number of procedures and rates of future urgent revascularization due to unstable angina or myocardial infarction (MI) compared with lesion selection by angiography alone. The FAME 2 trial^3,4 extended these findings and demonstrated that deferring PCI in lesions with an abnormal FFR results in high rates of progressive ischemic symptoms, unstable angina, and MI, which require revascularization within 1 to 2 years. These outcomes could be prevented by PCI.^1-4 Although FFR identifies hemodynamically significant lesions likely to produce ischemia-related symptoms, less clear is why FFR might predict the subsequent risk for ACS resulting from plaque rupture and coronary thrombosis, which is usually caused by lipid-rich plaques with distinct histological features.^5-13 These observations prompted us to explore whether plaque features of vulnerability and their physiologic properties are associated, causing a relevant pressure gradient across the lesion detectable by FFR.

Ischemia is best defined as an inadequate supply of oxygen relative to myocardial demand. The most widely used tests to assess ischemia are myocardial perfusion imaging (MPI) (noninvasive) and FFR (invasive). Myocardial perfusion imaging and FFR use the abnormal blood flow in the affected vessels as a surrogate marker for ischemia. In turn, this abnormal blood flow is related to relative or complete inability of the vessel to dilate on stress. Quiz Ref IDAlthough the detection of ischemia is likely to be indicative of a severe epicardial coronary artery stenosis,¹⁴ this association is not perfect.^2,15,16 Some severely stenotic lesions may not result in detectable ischemia (stenosis without ischemia [SWOI]), whereas other lesions with only a mild to moderate degree of angiographic stenosis may induce ischemia (ischemia without significant stenosis [IWOS]).¹⁷ In the FAME study,^1,18 more than one-third of lesions with an angiographic 50% to 70% angiographic diameter stenosis demonstrated an FFR of 0.80 or less whereas one-fifth of lesions with a 71% to 90% angiographic diameter stenosis demonstrated an FFR greater than 0.80 (SWOI) (Figure 1A). In a separate prospective study of 1000 patients with 1129 coronary lesions,¹⁵ more than one-half of lesions with greater than 50% angiographic diameter stenosis had an FFR greater than 0.80, whereas 1 in 7 lesions with less than 50% angiographic diameter stenosis had an FFR of 0.80 or less (IWOS) (Figure 1B). Among lesions with 50% to 70% luminal stenosis, approximately half had an FFR of 0.80 or less, whereas the other half had a normal FFR and no lesion-specific ischemia. These observations emphasize the importance of identifying factors beyond luminal stenosis that might contribute to inducible ischemia.

Some cases of IWOS may be explained by the inability of angiography to discriminate the true lesion severity with accuracy owing to diffuse disease or other artifacts.¹⁹ Microvascular disease can result in inducible ischemia as detected by an abnormal MPI finding or abnormal coronary flow reserve in the absence of a severe epicardial coronary artery stenosis, which explains some cases of IWOS. Quiz Ref IDUnlike coronary flow reserve, however, FFR is derived from the epicardial pressure gradient on vasodilator-induced maximal coronary flow and excludes microcirculatory resistance. Therefore, FFR is largely independent of changes in the basal flow and status of the microcirculation or systemic hemodynamics,²⁰ and microvascular disease cannot explain FFR-positive IWOS. On the other hand, some cases of MPI-verified SWOI may be explained by short lesion length, redundancy of the arterial supply through collateral vessel formation, and a limited myocardial territory supplied by the diseased artery. Quiz Ref IDAs regards FFR, features such as lesion length, entrance angle, exit angle, size of the reference vessel, and absolute flow relative to the territory supplied are important in determining focal hemodynamic responses to hyperemia and might explain the discrepancy between the epicardial luminal narrowing and FFR-based physiologic significance of the lesion in many cases.^21,22 Regardless of the causes, angiography is recognized as a suboptimal method to assess the ischemic potential of an epicardial coronary stenosis.

Although the factors discussed above explain IWOS and SWOI in some cases, they do not explain the discrepancy in many others. Quiz Ref IDRecent reports have linked the presence of lipid-rich plaques to the presence of FFR-verified ischemia demonstrated to be independent of the degree of luminal narrowing.^23,24 In a concomitant study of radiofrequency intravascular ultrasonography (IVUS) and FFR²⁵ performed in coronary arteries with 50% to 70% angiographic diameter stenosis, only the lipid-rich plaque type correlated with a reduced FFR; the FFR was concomitantly lower in increasingly larger necrotic cores. These results were confirmed in a larger study of 407 coronary lesions in 252 patients who underwent coronary computed tomographic angiography (CTA), computed tomography–based FFR assessment, and invasive angiography and FFR assessment.²³ The presence of a large plaque volume, large low-attenuation plaque volume, and higher positive remodeling index were found to be strongly predictive of reduced FFR regardless of the degree of stenosis on multivariable analysis. Low-attenuation plaques (considered a CTA surrogate for necrotic core) with a positive remodeling index (termed 2-feature–positive plaque [2FPP]) have been reported to be associated with major adverse coronary events.^5,26 In another recent study of 484 coronary vessels,²⁴ comparison of coronary CTA-defined plaque characteristics and luminal stenosis and FFR assessed from CTA with invasive angiography and invasive FFR revealed that large low-attenuation plaques (volume >30 mm³ on CTA) constituted the strongest lesion characteristic predictive of invasive FFR. Large low-attenuation plaques yielded diagnostic improvement for detecting lesion-specific ischemia by invasive FFR beyond degree of stenosis and other lesion characteristics, including lesion length.²⁴ In studies performing CTA and MPI concurrently,^23,27 the presence of 2FPP was associated with greater than 5% total myocardial ischemia burden, and conversely the presence of significant ischemia had a high positive predictive value for detecting 2FPP. The extent of luminal stenosis was not different between plaques that caused significant ischemia and those that did not; both demonstrated mean luminal stenosis of 75%.²⁷ Therefore, large lipid-rich, positively remodeled plaque (ie, 2FPP), and not only the stenosis severity, demonstrates a strong likelihood of inflicting myocardial ischemia.

This association between large necrotic cores and low FFR (independent of luminal stenosis) cannot be readily explained by the currently recognized determinants of physiologic lesion severity. Fractional flow reserve is presumed to measure the net physiologic effects of a coronary stenosis by maximally dilating the distal arteriolar bed with the administration of adenosine. Although the reduced FFR in the absence of severe stenosis (IWOS) cannot be explained by adenosine-mediated arteriolar dilatation, nitroglycerin (invariably given before adenosine administration) may not induce dilatation at the site of a plaque containing a large necrotic core with extraluminal expansion and positive remodeling. Quiz Ref IDIf a lipid-rich plaque is associated with local inability of the stenotic vascular segment to dilate to the same extent as the rest of the vessel (possibly owing to a maximally stretched vessel similar to the glagovian limit²⁸), the result would be a relative pressure drop at the time of maximal hyperemia. This process could underlie some of the unexplained cases of IWOS. On the other hand, luminally stenotic plaques without large necrotic cores and without outwardly stretched vessels (eg, fibrotic or fibrocalcific plaques) may retain locally vasodilatory potential and at least partially explain SWOI.^29-31 If this explanation is valid, then the absence of ischemia may signal the presence of preserved vasodilatory capacity, which may also indicate that the plaque is unlikely to contain a large necrotic core.

Local oxidative stress and vascular inflammation have also been proposed to contribute to impaired vasodilator capacity.^30,31 The lipid-rich necrotic core, a hallmark of the vulnerable plaque, inflicts local oxidative stress³² and thus could play a contributory role.¹⁷ The relationship between plaque composition (fibrous, fibrofatty, fatty, or calcific as identified by IVUS radiofrequency spectral analysis) and the vasodilatory potential of the local epicardial coronary artery evaluated by acetylcholine challenge suggested that only the presence of a necrotic core was associated with impaired vasodilator responses.²⁹

In the last decade, the identification of the hemodynamic significance of coronary artery lesions has become increasingly important. The FAME and FAME 2 studies demonstrated that revascularization guided by FFR is superior to angiography-guided therapy and optimum medical therapy (OMT).^1,4 In the FAME trial¹ (Figure 2A), the reduction in rates of major adverse cardiac events at 1 and 2 years with FFR-guided therapy compared with angiography-guided therapy was driven by a significant decrease in the incidence of MI and the need for urgent revascularization.^1,2 Analyses of the results of the FAME study² (Figure 2A) demonstrate that the superiority of the FFR-guided therapy most likely emerges from safe deferral of FFR-negative lesions to OMT, decreasing unnecessary procedures and their consequent complications (Figure 2A). The FAME study also demonstrates that, compared with angiography-driven therapy, the FFR-guided strategy decreases the likelihood of MI by one-third (6.1% vs 9.9%) and urgent revascularization in a setting of MI by two-fifths (7.3% vs 12.7%). In the FAME 2 trial (Figure 2B), deferring PCI of stenotic lesions with an FFR of 0.80 or less resulted in higher rates of urgent revascularization (16.0% vs 4.0%) and postprocedure death or MI (8.2% vs 6.5%) compared with PCI for such lesions.^3,4 In that study,^3,4 the main difference in outcomes emerged from the need for urgent revascularization in the OMT group. As a result, it is currently believed that all FFR-positive lesions should be treated with revascularization. However, the rates of death and MI were not significantly different between the 2 groups in the FAME 2 study⁴; there was an 8.2% chance of death or MI in 2 years in the FFR-positive lesions treated with OMT alone, compared with 6.5% rate in the OMT group⁴ (Figure 2B). Therefore, we can conclude from these observations that (1) lesions with negative FFR findings can be treated safely with OMT alone and (2) although lesions with positive FFR findings are at higher risk for future events, whether all FFR-positive lesions need revascularization remains unclear.

In FAME and FAME 2, an FFR-based strategy resulted in reduced rates of MI (and the composite outcome of death or MI), especially in the postprocedural period, and in reduced rates of new-onset ACS. This result raises an important issue. Although FFR identifies hemodynamically significant lesions likely to produce ischemia-related symptoms, how does FFR also predict the likelihood of ACS and MI that usually result from plaque rupture and coronary thrombosis?

Examining the outcomes of different types of stenoses in the FAME trials allows formulation of a hypothesis regarding their possible underlying composition (Figure 3). As mentioned before, plaques with large necrotic cores should be predictive of ischemia and ACS. Conversely, despite luminal narrowing, the absence of ischemia (reflecting preserved vasodilatory capacity or SWOI) indicates plaques without large necrotic cores. This finding suggests that ischemia may be a sensitive but not specific surrogate for the presence of a positively remodeled plaque with a large necrotic core and that the lack of ischemia indicates absence of such lipid-rich plaques with a normal vasodilator response.²⁷ Therefore, in the FAME trial, an FFR value of greater than 0.80 in 104 lesions with angiographic stenosis severity of 71% to 90% might suggest the absence of large necrotic core–carrying 2FPP in that subgroup. Conversely, the 218 plaques with intermediate luminal stenosis (50%-70% by angiography) with an FFR of 0.80 or less probably indicates large-volume 2FPP or longer lesions in which the severity could not be determined accurately by angiography (Figure 3).

Because an abnormal FFR indicates a very severe stenosis or a plaque with a large lipid burden or both, treating all FFR-positive stenoses with PCI will lead to the revascularization of most plaques with features of vulnerability independent of the degree of luminal narrowing. On the other hand, treating all stenoses with a normal FFR with OMT alone appears to be safe, because such stenoses would have little, if any, large lipid-rich 2FPP (Figure 4). The study by Motoyama et al²⁶ demonstrated that 2FPP was associated with the highest (22.5% for 27 months) event rate; events were more likely to occur in those with larger volumes, bigger necrotic cores, and a greater positive remodeling index. This more severe 2FPP, which might be associated with impaired local vasodilator capacity, would likely cause ischemia or FFR positivity. In the study by Motoyama et al,²⁶ plaque without a positive remodeling index or low-attenuation plaque had a very low (<0.5% during 27 months) event rate. The long-term follow-up of these patients in a subsequent study³³ indicated that the 10-year event rates in positively remodeled stenosis with lipid-rich 2FPP is 9-fold higher than in the luminally stenotic lesions without 2FPP.³³ Similarly, among patients treated with OMT in the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study,¹³ ACS events during 3 years occurred in only 5 of 1650 plaques (0.3%) that by radiofrequency IVUS had a plaque burden of less than 70%, a lumen area of greater than 4.0 mm², and no thin-cap fibroatheroma.

We therefore propose that the benefit of FFR-guided therapy is based on the association of local vasodilator reserve and features of plaque vulnerability, that is, the extent of vascular remodeling, plaque volume, and size of the necrotic core. Fractional flow reserve is thus able to identify lesions indirectly with a low risk for plaque rupture and coronary thrombosis that may be treated effectively with OMT alone, while also identifying probably most lesions at high risk for future ACS and those producing unacceptable degrees of angina owing to extreme luminal compromise.

Normal vasodilatory capacity is a prerequisite for lack of a significant pressure drop during hyperemia. Hence, a coronary stenosis with a normal FFR has a low likelihood of having plaques with high-risk features. This finding makes FFR a reliable tool to detect sizable vulnerable plaques independent of the severity of luminal narrowing. The deferral of FFR-negative lesions to OMT is therefore safe and avoids unnecessary revascularization and stent procedures, reduces periprocedural complications, and results in fewer late stent-related events (thrombosis and restenosis) compared with a more liberal angiography-guided approach. In essence, FFR may be considered a security checkpoint that prevents most plaques with vulnerable features from going undetected (Figure 5).

The combination of ischemia testing (eg, MPI and invasive or noninvasive FFR) with plaque composition assessment (eg, CTA, radiofrequency IVUS, and optical coherence tomography) to guide revascularization decisions may further improve risk stratification and patient outcomes compared with either strategy alone. As tools to assess plaque composition become prospectively validated to predict subsequent major adverse cardiac events, which was demonstrated with radiofrequency IVUS in the PROSPECT study,¹³ future trials should be performed to compare the utility of FFR alone vs plaque composition assessment alone vs a combined approach in guiding revascularization decisions for patients with stable coronary artery disease and those with stabilized ACS.

Corresponding Author: Jagat Narula, MD, PhD, MACC, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 (narula@mountsinai.org).

Accepted for Publication: February 12, 2016.

Published Online: April 20, 2016. doi:10.1001/jamacardio.2016.0263.

Author Contributions: Drs Ahmadi and Narula had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Ahmadi, Narula.

Acquisition, analysis, or interpretation of data: Ahmadi, Stone, Serruys, Wong, Nørgaard, O’Gara, Chandrashekhar, Narula.

Drafting of the manuscript: Ahmadi, Stone, Leipsic, Narula.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ahmadi, Shaw, Narula.

Administrative, technical, or material support: Ahmadi, Narula.

Study supervision: Leipsic, Narula.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.