Myocardial ischemia is an important risk factor for adverse clinical outcomes.^1-3 Clinical outcomes and functional status can be improved with revascularization of a coronary stenosis that induces ischemia.^3-5 However, revascularization of a coronary stenosis that does not include ischemia does not appear to be beneficial. For these patients, medical therapy is likely equally as effective as revascularization.^6,7 Fractional flow reserve (FFR), defined as the ratio of coronary pressure beyond a stenosis to the central aortic pressure during maximal hyperemia, is a measure of ischemia and is a validated tool for determining the physiologic significance of a stenosis. FFR-guided revascularization improves clinical and economic outcomes.^8-10 However, as with any diagnostic test, the utility of the test is dependent not only on the quality of the testing method, but also on the clinical context to which it is applied. Common factors that can confound the interpretation of FFR are listed in Table 1.¹¹ Beyond these common confounders, there are certain clinical circumstances in which FFR measurements can be misinterpreted. These include, but are not limited to, left main (LM) coronary artery stenosis with downstream disease, complex bifurcation lesions, especially after stenting, and saphenous vein graft (SVG) lesions. In this article, we review the data surrounding the application of FFR to these complex anatomic subsets.

Complex Left Main Coronary Artery Disease

The presence of LM coronary artery stenosis has serious clinical implications, and decisions regarding revascularization of intermediate LM disease based solely on angiography are unreliable.^12,13 As is the case for non-LM lesions, FFR provides an accurate assessment of the functional significance of an LM stenosis involving the ostium, mid segment, or distal LM bifurcation.^11-18 For disease confined to the LM segment, measuring FFR across an LM stenosis (FFR_LM) without additional lesions in the left anterior descending (LAD) or left circumflex (LCx) arteries (downstream disease) is similar to FFR of any other vessel. After appropriate zeroing and matching pressure to the aortic pressure, the FFR sensor is advanced beyond the stenosis and positioned into either the LAD or LCx artery, hyperemia is induced and FFR is measured. Most cardiac catheterization laboratories use intravenous adenosine infusions to induce hyperemia; however, intracoronary adenosine and intracoronary sodium nitroprusside, in the absence of contraindications, are acceptable alternatives.¹⁹ As with other vessels, an FFR ≤0.8 is indicative of a functionally significant stenosis. In the more complicated scenario of distal LM disease involving the bifurcation of the LM to LAD and LCx, FFR should be measured in both branches. Revascularization should be considered if FFR_LM is ≤0.8 in either branch vessel.

Interpreting FFR_LM in the more complex setting of downstream disease requires explanation in understanding the true FFR_LM. In order to appropriately interpret the findings of FFR_LM in this scenario, one must understand the physiology of FFR as it pertains to (1) lesions in series, and (2) reduced LM blood flow and myocardial bed size as a function of the degree of the downstream obstruction.¹¹ In the presence of downstream disease, the pressure drop across each lesion blunts the hyperemia of the other; thus, simple pressure ratios are no longer an accurate reflection of the functional significance of each individual lesion.^15,16 Clinically, this scenario is treated in a stepwise fashion: (1) the FFR wire is again appropriately zeroed and advanced across both lesions into the distal downstream vessel; (2) hyperemia is induced; and (3) the summed FFR (LM + 1 LAD = 5 FFR_epicardial) is measured to determine the need for treatment. If FFR_epicardial is ≤ 0.8, a pressure pullback is performed to determine which lesion to treat first. The lesion with the larger pressure step-up on pullback (ΔP, not FFR) is treated first (Figures 1 and 2). Subsequently, the untreated lesion is again interrogated with FFR, with FFR ≤0.8 representing functionally significant lesions that warrant revascularization. Kim and colleagues¹⁶ demonstrated the safety and efficacy of this pullback method in their case series of 131 patients with multiple intermediate stenoses of the same coronary artery.

As coronary atherosclerosis is often a diffuse process, one can assume that many LAD lesions corrupt FFR interrogation of LM lesions. However, that does not appear to be the case. Yong and colleagues¹⁷ used an experimental animal model to demonstrate that only severe, proximal LAD lesions influence FFR_LM. Using pressure sensor wires and balloon tip catheters they created an LM obstruction and downstream stenoses of variable severity in different locations. They demonstrated that FFR_LM with no LAD stenosis (FFR_true) and FFR_LM with an LAD stenosis (FFR_apparent) correlated directly with increasing severity of the LAD stenosis. For the entire cohort, the mean difference between FFR_true and FFR_apparent was 0.035 and was only > 0.05 when the FFR_epicardial was < 0.5. They also demonstrated that proximal LAD stenoses had a greater effect on FFR_apparent when compared with mid-LAD stenoses. Additionally, there were no cases in which FFR_true was < 0.75 and FFR_apparent was > 0.8, concluding that only severe proximal LAD stenoses influenced FFR _true in this model.¹⁷ Fearon and colleagues¹⁸ expanded upon these findings by translating a similar model to patients. They interrogated 91 lesions in 25 patients (71 LAD lesions, 20 LCx lesions) after percutaneous coronary intervention (PCI) of the downstream lesion. An intermediate stenosis of the LM was created using a balloon catheter. FFR was then measured in the LAD and LCx before and after re-creation of a downstream stenosis, also with a balloon catheter, within the stent that had just been deployed. They then compared FFR_true,, measured prior to re-creation of the downstream stenosis, to FFR_apparent, after the downstream stenosis had been re-created and found that FFR_true was significantly lower than FFR_apparent (0.81 ± 6 0.08 vs 0.83 ± 6 0.08; P < .001), and that the difference correlated to the severity of the disease. The authors concluded that, because of the small absolute difference in values, downstream disease does affect FFR_true, but does not have a clinically significant impact on FFR_LM if the wire is positioned in the nondiseased branch. Several sentinel works that examined the role of FFR in LM disease are summarized in Table 2.^{13,14,17,18,20-23} In conclusion, FFR_LM > 0.8 portends an excellent prognosis with medical therapy alone, whereas patients with FFR_LM ≤0.8 will likely benefit from revascularization. Furthermore, the presence of downstream disease rarely has a clinically significant effect on FFR_LM, except when the stenosis is proximal and severe.^17,18

Bifurcation Disease

Because of the limitations of two-dimensional imaging with angiography, bifurcation disease is one of the most challenging anatomic subsets in the field of PCI. Currently, provisional PCI for side branch lesions is the most common approach to bifurcation lesions, perhaps related to prior clinical trials that failed to show benefit with empiric side branch stenting as compared with balloon angioplasty or medical therapy. Visual-functional mismatch is common in bifurcation disease, and angiographic assessment tends to overestimate the severity of side branch lesions (Figure 3).^24-28 Therefore, functional assessment of side branch stenosis with FFR after main branch PCI can reduce unnecessary complex interventions and associated complications. Koo and colleagues²⁵ demonstrated the feasibility of FFR interrogation of jailed side branch lesions, and found that no stenosis < 75% had an FFR < 0.75. They also demonstrated no difference in cardiac event rates of patients treated with FFR-guided PCI of jailed side branches as compared with a similar subset of patients treated without FFR-guided PCI.²⁶ In the FFR cohort of the Nordic Bifurcation study, Kumsars and colleagues²⁹ demonstrated that kissing balloon inflation (KBI) significantly increased the FFR of the jailed side branch. However, at 8-month follow-up, this difference was no longer evident. FFR interrogation of a side branch vessel after PCI can be technically challenging and may be complicated by plaque shifting, failure to pass the wire through stent struts, ostial side branch dissection, and late positive or negative remodeling of the side branch stenosis. Furthermore, the side branches can often be small caliber vessels that supply a limited myocardial bed. Therefore, consideration should be given to the vessel caliber, angiographic severity, myocardial bed size, and operator experience prior to attempting FFR of a side branch lesion after PCI (Figure 3).

The Double Kissing Crush Versus Provisional Stenting Technique for Treatment of Coronary Bifurcation Lesions VI (DKCRUSH-VI) trial was the first randomized controlled trial to compare FFR-guided side branch intervention versus angiography-guided side branch intervention in 320 patients with true bifurcation lesions (Medina classification 1,1,1 or 0,1,1).³⁰ To standardize the approach, the FFR-guided group underwent FFR of the side branch after main branch stent deployment. If FFR ≤0.8, balloon angioplasty to the side branch was performed with KBI. If FFR after KBI remained ≤0.8, a stent was deployed in the side branch with final KBI. In contrast, the angiography group underwent KBI if the thrombolysis in myocardial infarction flow was < 3, there was more than a Type A dissection, or an ostial stenosis > 70% after the main branch stent was present. If any of these parameters persisted after KBI, a side branch stent was pursued. The authors found that 1-year target vessel revascularization and stent thrombosis rates were similar between both groups, with identical 1-year major adverse cardiac event (MACE) rates of 18.1% (hazard ratio [HR] 0.91, 95% confidence interval [CI], 0.48-1.88; P = 5 1.00).³⁰

As with all lesions, FFR of a side branch stenosis is influenced by the degree of stenosis, lesion length, lesion morphology, vessel size, upstream and downstream stenoses, and the size of the myocardial bed supplied by the side branch. Furthermore, FFR of the side branch is vulnerable to the influence of the main-branch stenosis. Therefore, when approaching bifurcation lesions where both branches have angiographic stenoses > 70%, FFR and pressure pull back should be performed under maximal hyperemia for both branches. If FFR of both branches is ≤0.8, a two-stent approach is likely indicated. However, angiographic severity, myocardial bed size, and the presence of upstream and downstream disease should all be considered prior to pursuing FFR interrogation of a side branch vessel. When applied appropriately, FFR provides an objective measurement of the severity of bifurcation lesions, and can help to guide the approach to intervention.

Saphenous Vein Grafts

The average SVG patency is estimated to be 7 to 10 years. Atherosclerotic plaque and neointimal hyperplasia are the main causes of graft degeneration. PCI of SVG lesions depends on a number of factors because the SVG contribution to myocardial perfusion is only one of three potential sources. Myocardial flow may occur through residual native flow, collateral flow, and SVG flow. In addition, stenting of the SVG is associated with reduced long-term patency and increased periprocedural complications.³¹

When bypass graft angiography reveals SVG disease, it is often difficult to determine the functional significance of the disease. The functional assessment of an SVG must take into account (1) competing flow (and pressure) from the native and conduit vessels; (2) the presence of collaterals; and (3) the potential microvascular disease due to ischemic fibrosis, scarring, prior myocardial infarction, or chronic low-flow ischemia (Figure 4). In spite of these challenges, FFR can be useful in deciding whether to treat SVG lesions. A recent study by Di Serafino and colleagues³² examined FFR-guided PCI in coronary artery bypass grafts. They studied 223 patients with stable or unstable angina and an intermediate stenosis of a bypass graft; 65 of these patients underwent FFR-guided PCI of their bypass graft, whereas 158 patients had angiographically guided PCI of their bypass graft. Despite similar baseline characteristics, a multivariate analysis demonstrated that the primary endpoint of MACE occurred in 28% of the FFR-guided PCI group versus 51% of the angiography-guided PCI group (HR 0.33, 95% CI, 0.11-0.96; P = .043). Furthermore, procedure costs were reduced in the FFR-guided PCI group, perhaps related to lower rates of PCI (35% in the FFR-guided group vs 57% in the angiography-guided group; P < .01).³² This and other relevant studies of FFR in SVG lesions is summarized in Table 3.^32-35

The theory of FFR for an SVG (FFR_SVG) is the same as for other lesions. To measure FFR_SVG, the pressure sensor is zeroed and subsequently positioned distal to the anastomosis of the graft into the native vessel. Hyperemia is then induced and FFR is measured. If the native vessel is occluded, the FFR_SVG reflects only the functional significance of the SVG lesion.³¹ Based on limited data, an FFR_SVG ≤ 0.75 can be used as the cutoff for a functionally significant stenosis.³⁵ However, if the native vessel still provides antegrade flow, the SVG and native vessel lesions act as lesions in series, and a pressure pullback during maximal hyperemia should be performed on each lesion. Here again, the lesion with the greatest pressure differential (ΔP, not FFR) should be treated first. Subsequently, the untreated lesion can again be interrogated with FFR, with consideration for revascularization if the FFR remains ≤0.8. With appropriate understanding and application of the physiology, FFR-guided PCI of SVG lesions is safe and effective, and may reduce the need for unnecessary interventions of these complex lesions.

Limitations and Alternatives

The utility of FFR in any given situation is dependent on the operator’s technical skill as well as his or her understanding of the physiology, application, and limitations of FFR. Although multiple studies have examined the role of FFR in various clinical situations, many of these studies are small and have limited outcome data. Furthermore, variability in technique and equipment complicate the interpretation of these FFR studies. However, several large, randomized controlled trials have demonstrated convincing benefits to using an FFR-guided revascularization strategy.^7-10 Other adjunctive diagnostic modalities such as intravascular ultrasound and optical coherence tomography may also be effective in guiding the approach to LM and bifurcation disease.^20,36-38 Furthermore, noninvasive imaging modalities that apply computational fluid dynamics, such as FFR derived from coronary computed tomography angiography (FFRCT), may provide functional information about presumed stenoses prior to the patient’s arrival in the catheterization laboratory.³⁹ An integrated approach that considers patient factors, operator experience, and equipment availability should be applied to each case in which adjunctive diagnostic testing is required.

Conclusions

Recent studies have proven that functional evaluation of coronary stenoses can be applied to complex anatomic substrates including LM disease, bifurcation disease, and SVGs, with similar results. Future developments, including instantaneous flow reserve and FFRCT, may provide alternatives to FFR that obviate the need for hyperemia. Other invasive techniques such as catheter-based FFR systems allow operators to use a coronary guidewire of their choice, and to perform pullback measurements without sacrificing wire position. Based on the long-term favorable outcome studies of FFR-guided revascularization, the application of FFR will continue to grow.⁴⁰ FFR is a critical tool in deciding whether to revascularize coronary artery disease in stable patients and may extend to revascularization of nonculprit lesions in acute coronary syndromes. With due consideration of the physiologic principles, FFR can be applied in almost any anatomic substrate. FFR can facilitate timely, clinically, and economically sound decision making to direct revascularization options to optimize patient outcomes. 

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