In patients with left main (LM) coronary artery stenosis which produce myocardial ischemia, revascularization therapy confers a survival benefit over medical therapy alone, both for symptomatic and asymptomatic [7–9]. Therefore, it is very crucial to exactly evaluate functional significance in intermediate left main lesion compared to intermediate non-LM lesion. Coronary angiography has limited accuracy in assessing actual stenosis severity, and there is great interobserver variability in lesions of the left main coronary artery [10, 11]. Hamilos et al. compared FFR values and the angiographic stenosis by two reviewer’s visual estimations in 213 equivocal left main coronary artery stenosis. In 55 (26%), the two reviewers disagreed whether the stenosis of LMCA was significant, insignificant, or unsure. In 158 (74%) whom the two reviewers agreed, 48 (23%) were misclassified on the basis of visual estimate of the angiogram; 23 patients had an estimated DS > 50% while the FFR was >0.80, and 25 patients had an estimated DS < 50% while the FFR was <0.80. In those, the sensitivity, specificity, and diagnostic accuracy of the visual estimate of DS > 50% to predict an FFR < 0.80 were 46%, 79%, and 69%, respectively. There was either disagreement or misclassification in 49% of all lesions. Therefore, in patients with equivocal stenosis of the left main coronary artery, angiography alone does not allow appropriate individual decision-making about the need for revascularization and often underestimates the functional significance of the stenosis (Fig. 27.3). The prevalence of visual-functional “mismatch” which means FFR > 0.80 even with luminal stenosis >50% in coronary angiogram is lower than non-LM lesion (35% vs. 57%, LM vs. non-LM). Also, the prevalence of visual-functional “reverse mismatch” which means FFR < 0.80 even with luminal stenosis <50% in coronary angiogram is higher than non-LM lesion (40% vs. 16%, LM vs. non-LM) (Fig. 27.4) [12]. Kang et al. reported the cutoff value of IVUS minimal lumen area (MLA) to predict FFR < 0.8 was 4.5 mm², and the diagnostic accuracy was good (77% sensitivity, 82% specificity, 84% positive predictive value, 75% negative predictive value, area under the curve: 0.83) in 112 patients with isolated, ostial, or mid-shaft LM intermediate lesion (Fig. 27.5) [13]. The current guideline defined that IVUS are also reasonable for the prediction of myocardial ischemia in intermediate left main disease (Class IIA, Level of Evidence B) [14]. It has been unknown which cutoff value (0.75 vs. 0.8) of FFR is optimal to decide to revascularize intermediate LM lesion. Considering the great concern about the safety of deferred LM stenosis, the use of higher cutoff value for LM FFR with high sensitivity is preferred. The deferral of revascularization in FFR-negative LM stenosis has been reported to be safe [10, 15]. Up to date, there was no prospective study to compare clinical outcomes between angiogram and FFR-guided PCI in this subset. Two thirds of patients with significant LM lesion had multiple stenotic lesions beyond LMCA. Therefore, we should consider the influence of downstream LAD or LCX disease on LM FFR in these cases. Recently, Fearon et al. created an intermediate LMCA stenosis using a deflated balloon catheter after PCI of the LAD, LCX, or both to validate the effect of downstream disease on LM FFR. They measured true FFR of the LMCA via non-diseased downstream vessel, while creating of downstream stenosis by inflating an angioplasty balloon within the newly placed stent (Fig. 27.6) [16]. They demonstrate that the presence of significant downstream disease in LAD or LCX increases the true FFR value of LM lesion itself in their study. However, the difference between LM FFR_true and FFR_app was small. (0.81 ± 0.08 vs. 0.83 ± 0.08) [11]. This difference correlated with the severity of the downstream disease.