Angiographic evidence of arterial stenosis is usually not detected until the cross-sectional area of plaque approaches 40–50% of the total vascular cross-sectional area as Glagov et al. reported in a histopathological autopsy study with 136 left main coronary arteries from the human heart [5]. The outer wall of the artery, encompassed by the external elastic membrane (EEM) , dilates to accommodate the growing plaque. This compensatory enlargement process seems to be limited, and as the plaque area exceeds 40–50% of the EEM area, the plaque begins to encroach on the lumen. At this point, an angiogram might reveal minimal luminal narrowing [6].

Similar to a flashlight projection of a tube in three-dimensional space, an angiogram is a two-dimensional X-ray shadow of the arterial lumen along the vessel length (Fig. 26.3). So, the eccentric lumen produces conflicting degrees of angiographic diameter stenosis from different viewing angles and introduces uncertainty related to lumen size and its relationship to coronary blood flow [7]. Arterial narrowing might be incorrectly assessed owing to angulation or tortuosity, artery overlap, a short “napkin-ring stenosis ,” contrast streaming or separation as it enters an ectatic area, or X-ray beam angulation that is not perpendicular to the stenosis. Moreover, a long, moderate narrowing can be as or more hemodynamically significant than a short, focal severe narrowing (Fig. 26.4). Additional artifacts including vessel foreshortening, branch overlap, ostial origins, and calcifications further contribute to the uncertainty of the angiographic interpretation.

The degree of stenosis is judged by comparison with a “normal” reference segment that is theoretically free of disease, while the reference segment often has significant disease as demonstrated by IVUS or histopathology [8]. Furthermore, significant intra- and interobserver variability exists in the assessment of coronary narrowing [9].

As regards FFR, features such as lesion length, entrance angle, exit angle, plaque rupture, blood viscosity, and absolute flow relative to the perfusion territory are important in determining translesional hemodynamic responses to hyperemia (Fig. 26.5) [10–13]. These might explain the discrepancy between the epicardial visual luminal narrowing and FFR-based physiologic significance of the lesion in many cases (Figs. 26.6 and 26.7).

To overcome the limitations of angiography, FFR technique is a useful modality to assess the functional significance of an intermediate or ambiguous coronary lesion. For example, in the FAME study, only 35% of intermediate coronary stenoses (between 50% and 70% diameter stenosis on angiography) had an FFR ≤ 0.8 [14]. Therefore, in angiographically intermediate lesions, it is important to determine the potential flow impediment before attempting a revascularization. A meta-analysis of 66 studies revealed that FFR-based strategy improved the prognosis of coronary artery disease (CAD) patients by decreasing 20% cardiovascular events and 10% better angina relief and avoiding unnecessary revascularizations in nearly 50% of cases [15].

Several studies have demonstrated that percutaneous coronary intervention (PCI) can be safely deferred in patients with an intermediate lesion and an FFR ≥ 0.75 (or ≥0.80) [16–21]. Cardiac event rates were extremely low in this cohort of patients and even lower than that predicted if a PCI had been performed in bare metal stent era owing to the avoidance of restenosis in the deferred treatment group [16, 22]. In comparison with noninvasive techniques such as exercise electrography , stress echocardiography , and myocardial perfusion scintigraphy , FFR is more accurate in predicting the hemodynamic significance of a lesion [19]. FFR application remains the most standard indication in intermediate stenosis with unclear hemodynamic significance [9]. Thus, FFR is considered as the gold standard for the evaluation of intermediate grade stenosis.

In patients with intermediate coronary lesion, even in multivessel disease, FFR has been proven to be an effective strategy with superior clinical outcomes compared to angiographically guided PCI [17, 20, 22–26].