Figure 1. A cineangiograph frame displaying complex LM and LAD coronary artery disease.

Fractional flow reserve (FFR), the ratio of translesional pressures across a stenosis, measured when microvascular resistance is fixed and minimal, has a strong association with ischemia. When used for guiding percutaneous coronary intervention compared to angiography alone, FFR produces better clinical and economic outcomes.1,2 However, like any diagnostic test, the technique and limitations of its applications should be understood for best results. FFR may be associated with predictable false-positive and false-negative results (Table 1). Because the decisions regarding revascularization of the left main (LM) coronary stenosis are critical, accuracy of FFR is especially important (Figure 1). This brief review will assist in understanding when LM FFR requires more information for optimal use.

Numerous studies support the use of FFR to assess LM coronary stenoses.3-9 In the largest of these studies, Hamilos et al demonstrated the long-term outcomes of FFR-guided decisions in 213 patients with an angiographically equivocal narrowing of the LM coronary artery.9 The 5-year survival and event-free survival rates were similar, 89.8% and 74.2%, respectively, in the nonsurgical medically treated group (FFR ≥ 0.80) and 85.4% and 82.8%, respectively, in the surgical group (FFR < 0.80) (P = .48 and P = .50, respectively). Of note, these patients had both simple (isolated LM stenoses) and complex (LM with other multivessel) coronary artery disease. There were no significant differences in outcomes when separated by degree of disease. The reliability of FFR for simple lesions is rarely an issue, but an understanding of FFR for complex LM stenoses with additional lesions in the left anterior descending (LAD) and/or circumflex artery (Cx) branches requires the operator to have a more in-depth appreciation of the physiology as applied in this important anatomic subset.

A simple, isolated LM stenosis is easily assessed by FFR in the routine fashion. One caveat to increase reliability is that ostial FFR assessment requires that the guide catheter be removed from the ostium while infusing intravenous adenosine to avoid the artifact of guide catheter pressure damping. A distal LM stenosis involving the bifurcation of the LAD and Cx can be assessed with two FFR measurements, one in the LAD and another with the pressure wire in the Cx. However, interpreting the LM FFR in the presence of significant downstream branch lesions, such as an LAD stenosis, is more complicated because the LM and LAD lesions act like serial lesions, and the true flow across the LM is potentially reduced by a severe downstream stenosis, artifactually elevating the LM FFR when measured in the unobstructed vessel.

For an accurate FFR, maximal hyperemia must be achieved across the LM stenosis. Flow through the LM artery is the sum of both the LAD and left Cx (LCx) branch flow, the magnitude of flow being proportional to the size of each artery’s viable myocardial bed. When LM FFR is measured in the unobstructed Cx artery, the reliability of this measurement will depend on whether the LAD stenosis is severe enough to impair flow. The lower LM flow would produce an erroneously elevated FFR because true maximal hyperemia would not be achieved.

In practice, the LM FFR in the setting of LM and LAD disease is assessed by placing the pressure wire sensor distal to the LAD lesion, administering adenosine hyperemia (either intravenously or intracoronary), and calculating the FFR across both lesions, which is called FFRepicardial. If FFRepicardial is > 0.80, neither lesion is physiologically significant and no further intervention is needed. However, if the FFRepicardial is ≤0.80, the operator can measure FFR in the Cx. An apparent LM FFR (FFRapp) in the Cx, of > 0.80 would seem to indicate that the LAD, but not the LM, is hemodynamically significant. However, this is not always correct. A disadvantage of this assumption is that after the LAD lesion is stented, LM flow increases and the FFRapp may now become significant, mandating further revascularization. If unprotected LM stenting is not planned, performing percutaneous coronary intervention of a downstream LAD lesion, which would lead to a significant LM FFR, may not be the best option.

Fearon et al have brought clarity to this conundrum by identifying the degree of severity of downstream lesions, which makes the FFRapp unreliable.10 To validate this concept, a model of a complex LM and LAD stenosis was created in patients in the catheterization lab after LAD stenting. An intermediate LM stenosis was created by positioning a partially deflated balloon catheter in the normal LM and another balloon catheter in the newly stented LAD. Using two pressure wires, the effect of increasing the severity of the LAD lesion and its impact on LM FFR measured in the unobstructed Cx was demonstrated. The true LM FFR (FFRtrue), measured in the nondiseased (ie, Cx) vessel, was compared with the FFRapp, measured in the presence of an increasingly severe LAD created during LAD balloon inflation. The FFRtrue was statistically but clinically insignificantly lower than FFRapp (0.81 ± 0.08 vs 0.83 ± 0.08; P < .001), a difference that correlated with the severity of the downstream disease
(r = 0.35; P < .001). In all cases in which FFRapp was > 0.85, the FFRtrue was > 0.80. The important observation of this study was that the FFRtrue was significantly lower than FFRapp only when downstream stenoses in the LAD (or LCx) were very severe with FFRepicardial < 0.60. In these situations, an intravascular ultrasound assessment of the LM with a threshold minimal luminal area of < 6.0 mm2 is recommended.

The reliability of the LM FFR will always depend on operator technique, accurate hemodynamic signal acquisition, and adequate maximal hyperemia. The complex LM FFR can be used in nearly all cases, as FFRepicardial > 0.60 is a very common result. It should be reassuring to the practitioner that the data from in vitro, animal, and human studies of LM stenosis demonstrate that in most cases, downstream disease does not have a clinically significant impact on the assessment of FFR across an intermediate LM stenosis.9-11

1. Pijls NH, Fearon WF, Tonino PA, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. J Am Coll Cardiol. 2010;56:177-184.

2. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease [published erratum appears in N Engl J Med. 2012;367:1768]. N Engl J Med. 2012;367:991-1001.

3. Bech GJ, Droste H, Pijls NH, et al. Value of fractional flow reserve in making decisions about bypass surgery for equivocal left main coronary artery disease. Heart. 2001;86:547-552.

4. Jasti V, Ivan E, Yalamanchii, et al. Correlations between fractional flow reserve and intravascular ultrasound in patients with an ambiguous left main coronary artery stenosis. Circulation. 2004;110:2831-2836.

5. Jiménez-Navarro M, Hernández-García JM, Alonso-Briales JH, et al. Should we treat patients with moderately severe stenosis of the left main coronary artery and negative FFR results? J Invasive Cardiol. 2004;16:398-400.

6. Legutko J, Dudek D, Rzeszutko L, et al. Fractional flow reserve assessment to determine the indications for myocardial revascularisation in patients with borderline stenosis of the left main coronary artery. Kardiol Pol. 2005;63:499-506.

7. Suemaru S, Iwasaki K, Yamamato K, et al. Coronary pressure measurement to determine treatment strategy for equivocal left main coronary artery lesions. Heart Vessels. 2005;20:271-277.

8. Lindstaedt M, Yazar A, Germing A, et al. Clinical outcome in patients with intermediate or equivocal left main coronary artery disease after deferral of surgical revascularization on the basis of fractional flow reserve measurements. Am J Heart. 2006;152:156.e1-e9.

9. Hamilos M, Muller O, Cuisset T, et al. Long-term clinical outcome after fractional flow reserve-guided treatment in patients with angiographically equivocal left main coronary artery stenosis. Circulation. 2009;120:1505-1512.

10. Fearon WF, Yong AS, Lenders G, et al. The impact of downstream coronary stenosis on fractional flow reserve assessment of intermediate left main coronary artery disease: human validation. JACC Cardiovas Interv. 2015;8:398-403.

11. Yong AS, Daniels D, De Bruyne B, et al. Fractional flow reserve assessment of left main stenosis in the presence of downstream coronary stenoses. Circ Cardiovasc Interv. 2013;6:161-165.

Morton J. Kern, MD, MSCAI, FAHA, FACC
Professor of Medicine
University of California, Irvine
Irvine, California
Chief
Medical Health Care Group
Veterans Administration Long Beach Heath Care
System
Long Beach, California
mortonkern2007@gmail.com
Disclosures: Speaker for St. Jude Medical Inc., Volcano Therapeutics, Acist Medical Inc., and Opsens Inc.; consultant to Heartflow.