According to the latest WHO reports, in 2019 ischaemic heart disease (IHD) has strengthened its position as a leading cause of deaths since 2000, accounting for 16% of the world’s total deaths. The rise was especially marked in low-, lower-middle, and upper-middle-income countries. Interestingly, although in high-income countries the number of deaths due to IHD declined, it still remained the main cause of death [1].

Since the early development of coronary artery angiography, it became evident that not all atherosclerotic lesion localizations are equally dangerous. Due to its anatomical features, patients with an obstruction of the left main coronary artery (LMCA) may be at exceptionally high risk. Depending on coronary artery dominance, LMCA supplies blood to 75–100% of the myocardium [2]. Knowing that, there is no wonder that LMCA in the past was known as ‘the artery of sudden death’ [3]. During the early coronarography era, clinicians reported even a 10% risk of death due to LMCA catheterization, and suggested special caution when performing angiography in patients with suspected left main coronary artery disease (LMCAD) [4]. Research available at the time reported over 50% five-year mortality among the patients who received only pharmacological treatment [5]. In the meta-analysis performed by Yusuf et al. 10-year mortality in the group of patients with LMCAD exceeded even the mortality rate of patients with the involvement of three vessels [5].

The poor prognosis of patients with LMCAD gradually improved with the development of revascularization techniques. In the 1970s, coronary artery bypass grafting (CABG) was implemented in the treatment of coronary artery disease (CAD) [6]. Surgical efficacy was proven in observational studies and early randomized clinical trials (RCT), which resulted in wide acknowledgement of this treatment as a method of choice in LMCAD [7]. The following years brought another breakthrough in the treatment of CAD. In 1978, Andreas Gruntzig published a description of five patients not suitable for CABG, including two with LMCAD, successfully treated with a novel method—percutaneous transluminal coronary angioplasty (PTCA) [8]. As he reported few severe acute complications, the initial results were promising. Yet, there was still no data on its long-term complications and safety. Further research revealed that application of PTCA in LMCA was highly unfavorable, and bore a high risk of death and restenosis [9]. It led to the grounding of the CABG position as the first choice for LMCAD treatment for almost twenty years [10].

However, the development of bare-metal stents (BMS) and, finally, drug-eluting stents (DES) led to the necessity of reconsideration percutaneous coronary interventions (PCI) as the method of LMCAD treatment, at least in some subgroups [11]. In the early 2000s, multiple studies provided evidence on the effectiveness and safety of PCI in LMCA, which was eventually reflected in 2009 as the new class IIb recommendation in ACC/AHA guidelines, starting a new chapter in coronary artery revascularization ^[12][13][14][12,13,14]. Recent years brought several highly acclaimed multicentre RCTs and large-register analyses comparing the use of CABG and PCI in LMCAD ^{[15][16][17][18][19]}[15,16,17,18,19]. Nevertheless, despite the fine quality of the aforementioned research, the long-term outcomes and prognoses of percutaneous treatment of this special disease are inconsistent.

Significant LMCA stenosis is detected in 4–6% of patients referred for coronary angiography, occasionally also in asymptomatic individuals [4]. Knowing the unfavorable prognosis of untreated LMCAD, precise evaluation of atherosclerotic plaque is essential in further management. Due to overlapping of side branches, lesion eccentricity, vessel foreshortening, and angulation, conventional coronary angiography has its limitations, especially in intermediate (40–70%) LMCA narrowing. Moreover, the significance of stenosis assessed angiographically is observer-dependent, and the reproducibility of results is low even between experienced clinicians ^[20][21][76,77]. To avoid misclassification of the disease, recent years brought the development of various adjunctive tools that are helpful in the decision-making process.

Intravascular ultrasound (IVUS) is the best-established method of intravascular imaging in LMCAD evaluation. It may provide valuable information on the plaque extent, cross-sectional characteristics of the lesion, and minimal lumen area (MLA) in LMCA and its branches (i.e., left anterior descending artery (LAD), left circumflex artery (LCx)). As it became evident that plaque burden at the MLA is an independent predictor of events, researchers strived to set an optimal threshold for determining the significance of LMCA stenosis ^[22][23][78,79]. Firstly, based on the analysis of 55 patients and a fractional flow reserve (FFR) of 0.75, Jasti et al. proposed a cut-off value of 5.9 mm^2 [24][80]. Later, the prospective multicentre LITRO study validated an MLA of 6.0 mm² as a safe value for LMCA revascularization deferral ^[25][81]. In a two-year follow-up period, between patients with MLA < 6.0 mm² who underwent revascularization and deferred patients with MLA ≥ 6.0 mm², there were no significant differences in survival and MACCE rates. Since then, the MLA of 6.0 mm² became a widely acknowledged cut-off value for deferring revascularization of the LMCA. Nonetheless, both of the aforementioned studies were conducted in Western populations. Park et al. in their analysis of 112 Asian individuals proposed IVUS derived MLA of 4.5 mm² as a cut-off value for an FFR of ≤0.8 ^[26][82]. A plausible explanation of these discrepancies may include ethnic differences in coronary artery dimensions. The mean MLA of patients included in the Asian study was 4.8 mm², while Jasti et al. reported a mean MLA of 7.65 mm² in their study group. Ethnic differences in LMCA anatomy were also supported by a comparative study of 99 Asian and 99 United States white patients (MLA 5.2 ± 1.8 vs. 6.2 ± 14 mm², respectively) ^[27][83].

Not only is IVUS a useful tool for LMCAD assessment, but also it may provide important information on stent adequate expansion and apposition. Early insights from the MAIN-COMPARE registry provided evidence on a better prognosis of patients with LMCAD who underwent PCI under the guidance of IVUS in comparison to only conventional angiography ^[28][84]. The reduction in three-year incidence of mortality was especially marked in the group of patients who received DES (4.7% vs. 16.0%, log-rank p = 0.048) and no difference was observed in the group treated with BMS (8.6% vs. 10.8%, log-rank p = 0.35). Further registry studies supported these findings ^[29][30][31][85,86,87]. The meta-analysis of ten studies performed by Ye et al. revealed that IVUS-guided PCI of LMCA impressively reduced the risks of all-cause death by 40% compared with angiography-guided PCI ^[32][88]. The benefit of IVUS-guidance may especially include stent optimization. It was proved in an early analysis of RCTs by Doi et al. that post-intervention minimum stent area (MSA) measured by IVUS was an important factor that could predict in-stent restenosis (ISR) after nine-months of follow-up, and the authors suggested an MSA threshold of 5.7 mm² for paclitaxel-eluting stents ^[33][89]. In the EXCEL trial IVUS-substudy there was a strong association between the group of patients with small final MSA (4.4–8.7 mm²) and the occurrence of adverse events during long-term follow-up, compared with patients with the largest MSA (11.0–17.8 mm²) ^[34][90]. The currently best-known proposed MSA cut-off values that predicted ISR are 5.0 mm² for LCx, 6.3 mm² for LAD, 7.2 mm² for confluence zone, and 8.2 mm² for LMCA ^[35][91]. However, nowadays some clinicians advocate for higher MSA thresholds, as in the DK-CRUSH VIII trial (>10 mm², >7 mm², >6 mm² for LMCA, LAD, and LCx, respectively) ^[36][92]. To sum up, IVUS is an important tool that can improve PCI performance, leading to fewer procedural-related complications and a better prognosis in patients with LMCAD.

Optical coherence tomography (OCT) is a newer method that can provide excellent resolution images influencing a better assessment of plaque phenotype and identification of PCI-related complications. However, due to technology that requires proper blood clearance, OCT cannot be applied to coronary artery ostia. Another drawback includes low tissue penetration which limits the utilization of this method in LMCA stenosis assessment ^[37][93]. Despite that, recent studies investigated its outcomes in PCI of LMCA in comparison with IVUS and conventional angiography, especially in bifurcation disease. In the retrospective analysis of 730 patients, OCT was found to be superior to angiography in distal LMCA stenting with no difference compared to IVUS-guidance ^[38][94]. In the LEMON trial that analyzed the feasibility, safety, and impact of OCT-guided LMCA PCI, the primary endpoint of procedural success was achieved in 86% of subjects, suggesting that OCT may be a suitable tool for PCI guidance in distal LMCA ^[39][95]. Although contemporary results are promising, further research that investigates safety, long-term outcomes in big arteries, and OCT correlation with physiological assessment is needed.

Knowing the limited accuracy of conventional coronary angiography in the evaluation of LMCAD significance, a physiological assessment may deliver crucial information on the ischemic potential of vessel narrowing, determining further management strategy. A study conducted by Hamilos et al. proved that the FFR threshold of ≥0.80 for LMCA revascularization deferral is safe and clinical outcomes in such patients were similar to those who obtained surgical treatment based on the FFR values < 0.80 ^[40][96]. The data on the safety and feasibility of FFR-based deferral was later supported by various meta-analyses, RCTs, and register studies ^{[41][42][43][44]}[97,98,99,100]. Moreover, decisions based on visually assessed 50% diameter stenosis (DS) may not accurately reflect the hemodynamic and functional significance of the vessel narrowing, especially in LMCA. Interestingly, an analysis of 152 patients revealed that the optimal cut-off value of DS for predicting FFR ≤ 0.80 was 43%, and multiple studies supported visual-functional mismatch in patients with LMCA lesions ^[40][45][46][96,101,102]. However, it is noteworthy that FFR interpretation in patients with bifurcation disease or downstream stenoses requires special caution, as it may cause under- or over-estimation of LMCA narrowing functional significance ^[47][48][49][103,104,105].

Apart from the pre-PCI assessment of LMCAD, FFR is also a useful tool in post-PCI functional optimization or jailed side branch management. According to previous studies that focused on functional significance of side branches after bifurcation crossover stenting, angiography alone tends to overestimate the functional severity of stenoses ^[50][51][106,107]. When it comes to LMCA, Lee et al. reported that only 16.9% of patients that underwent simple crossover stenting had FFR < 0.80 in jailed LCx, and no correlation between FFR values and angiographic percent DS was found ^[52][108]. Moreover, at five years, patients with higher FFR values had lower target lesion failure (TLF) rates, while no difference in such outcomes was found based solely on DS. It suggests insufficient angiographic accuracy in the evaluation of jailed LCx functional significance and, consequently, that in most cases complex procedures can be avoided by postinterventional FFR assessment.

Recently, instantaneous wave-free ratio (iFR) established the position of a valuable tool that provides outcomes non-inferior to FFR in CAD treatment ^[53][54][55][109,110,111]. However, data on its safety and long-term clinical outcomes in LMCAD assessment is currently limited. A study by Warisawa et al. indicates that iFR cutoff ≤ 0.89 for LMCA revascularization deferral is safe, and at a median follow-up of 30 months, MACCE rates were similar to patients that underwent invasive management ^[56][112]. If confirmed in further studies, iFR may become an important adenosine-free alternative to FFR in LMCAD evaluation.