Although physiologic evaluation (e.g., fractional flow reserve) of intermediate lesions is well established in other coronary arteries, the left main coronary artery (LMCA) exhibits diagnostic challenges, hindering development of physiology-based decision-making algorithms. The aim of this study is to evaluate the relationship between angiographic stenosis severity (diameter stenosis, DS%), lesion location and morphologic characteristics and gold-standard pressure indices in patients with intermediate LMCA stenosis. We analyzed 34 patients with angiographically intermediate (25%–65%) LMCA stenosis who underwent intravascular ultrasound (IVUS) imaging and pressure wire assessment. Plaque burden, minimal lumen area (MLA), lesion location, and calcification were documented, and their relationships with FFR and iFR were evaluated. The iFR ( r =-0.507 p < 0.001) and FFR ( r =-0.383 p = 0.002) were only moderately correlated with DS%. FFR ( r = 0.835, p < 0.001) and iFR ( r = 0.769, p < 0.001) were significantly correlated with MLA. Presence of calcification partially blunted the correlation between structural and functional parameters. The receiver operating characteristic (ROC) curve showed the highest area under the curve (AUC) for FFR in detecting an MLA<6 mm², with a negative predictive value (NPV) of 80% and a positive predictive value (PPV) of 100%. All lesions with an MLA<6mm 2 ( n = 16) had an FFR <0.80 whereas iFR >0.89 deferred 37% of these lesions. In conclusion, angiographic percent stenosis is an unreliable indicator of hemodynamic significance in intermediate LMCA disease; given that iFR has a high false-negative rate for lesions with MLA <6 mm² despite correlating with MLA, FFR may therefore be a more suitable index for evaluating intermediate LMCA stenoses, and further studies should refine cutoffs for nonhyperemic indices and investigate their clinical implications.
Clinical Perspective
• What is already known on this topic
Optimal evaluation strategy for angiographically intermediate lesions of left main coronary artery (LMCA) is controversial. Various pressure-wire or imaging modalities are successfully employed in the non-LMCA disease, but routine implementation into LMCA disease workflows is yet to be accomplished. Current international guidelines recommend using fractional flow reserve (FFR) as the reference standard for the physiological assessment of ambiguous coronary lesions and suggest intravascular ultrasound (IVUS) to guide revascularization decisions when feasible.
• What this study adds
In this real-world all-comer patient group with intermediate LMCA disease from a tertiary care university hospital, evaluation with FFR agreed reasonably with IVUS-based minimal lumen area, without falsely deferring any cases with the conventional cutoff value of 0.80. In contrast, an iFR-based strategy resulted in higher false-positive cases, although it was superior to resting Pd/Pa. Our data show that iFR values >0.89 deferred 37% of lesions with MLA <6 mm 2, emphasizing that resting indices alone may miss truly flow-limiting LMCA stenoses, especially in the presence of calcification.
• How this study might affect research, practice or policy
Among pressure-based indices, FFR may provide sounder insights into severity of the angiographically intermediate LMCA disease, superior to non-hyperemic pressure ratios. Refinement of FFR based strategies for the LMCA disease may aid overcoming the underutilization or inaccessibility of advanced imaging modalities such as IVUS in real world setting. Clinicians may consider preferential use of FFR when physiological assessment is used to defer or proceed with revascularization of intermediate LMCA stenoses, and reserve non-hyperemic indices for cases where hyperemia is contraindicated or when the lesion is not heavily calcified.
The left main coronary artery (LMCA) supplies more than half of the left ventricular myocardium. While severe LMCA stenosis can induce extensive ischemia with significant clinical consequences, LMCA lesions concurrently present distinct diagnostic and therapeutic challenges. The LMCA’s short length and lack of a normal reference segment complicate angiographic assessment of stenosis severity. Visual estimation of LMCA narrowing is prone to interobserver variability, which can lead to misclassification. Overestimating an LMCA stenosis can result in unnecessary revascularization, whereas underestimating a truly significant lesion leaves a very high-risk condition untreated. Thus, managing an angiographically intermediate LMCA stenosis requires a reliable assessment of its flow-limiting potential. Due to the poor association between angiographic severity of coronary stenoses and their hemodynamic impact, invasive pressure-derived indices such as fractional flow reserve (FFR), and instantaneous wave-free ratio (iFR) are used to predict whether a coronary stenosis observed angiographically is associated with flow-limitation resulting in ischemia. ,,,, However, their utilization in LMCA lesions are not yet well established. Intravascular imaging methods, mostly intravascular ultrasound (IVUS), can help in making treatment decisions by revealing the structural characteristics of coronary lesions, such as the presence and extent of calcification, the minimal lumen area (MLA), diameter, and length of the lesion, as well as the cross-sectional area relative to the adventitial boundaries and plaque burden. Moreover, plaque composition may influence the relationship between pressure-derived indices and true anatomic severity especially in LMCA disease, but real-world data on this phenomenon are scarce. Therefore, we aimed to evaluate the relationship between angiographic stenosis severity (diameter stenosis), lesion location, morphologic characteristics and gold-standard pressure indices in patients with intermediate LMCA stenosis, and to explore how plaque calcification influences these correlations.
Methods
Study population
Thirty-four patients, who underwent elective coronary angiography due to anginal complaints in the Department of Cardiology of Istanbul University Faculty of Medicine between 2017 and 2021 and had intermediate (25-65%) stenoses in LMCA were included in this study.
Catheterization laboratory protocol
Catheterization of LMCA was performed using standard techniques. A guide catheter was selectively positioned in the left main coronary ostium. A bolus of 7,000–10,000 units of heparin was administered intravenously (IV) or intracoronarily (IC). Activated clotting time (ACT) was monitored every 30 to 60 minutes and maintained between 250 and 350 seconds with additional IV heparin doses as needed. Subsequently, 100–200 mcg of intracoronary nitroglycerin was administered. Doppler measurements were made via a 0.014-inch pressure wire (ComboWire XT, Philips Volcano Corporation, San Diego, CA, USA), advanced through the guide catheter and placed in the left coronary artery ostium. Intracoronary and aortic pressure curves were recorded simultaneously from the catheter and the wire located distally to the lesion. Measurements were repeated under basal conditions and during maximum achievable hyperemia provided by appropriate, incremental doses of intracoronary adenosine. Distal/proximal pressure ratio at rest (Pd/Pa), fractional flow reserve (FFR), instantaneous wave-free ratio (iFR) values were calculated with the pressure data obtained. Then, the IVUS catheter (Eagle Eye Digital IVUS catheter, Philips Volcano Corporation, San Diego, CA, USA) was advanced to the distal part of the lesion over a 0.014” guide wire and the resulting IVUS images were recorded. Plaque burden and minimal lumen area values were calculated from IVUS images. In addition, lesion characteristics and the presence of calcification were also recorded.
Study parameters and definitions for cutoffs
A significant MLA was defined as a value below 6 mm 2. FFR and iFR values below or equal to 0.80 and 0.89 were labelled abnormal, respectively. The presence of calcification was qualitatively described as either present or absent by evaluating varying shades of gray scale reflections. Plaque burden was manually calculated as the atheroma cross-sectional area divided by the external elastic membrane cross-sectional area.
Statistical analysis
Continuous variables were expressed as mean ± standard deviation. The distribution of the data was evaluated with the Shapiro-Wilk test. The mean values of independent groups were compared with Student’s t-test for normally distributed variables and Mann-Whitney U test for non-normally distributed variables. Correlations between the variables were evaluated using the Pearson and Spearman correlation coefficients, according to normality. The Bonferroni correction was applied to control the family-wise error rate and reduce the likelihood of Type I errors arising from multiple comparisons. Dichotomous categorization success was evaluated by area under the curve (AUC) through receiver operating characteristic (ROC) curves. A p value < 0.05 was considered statistically significant. All analyses were carried out on a computer using IBM SPSS Statistics, Version 28.0.1.1 (IBM Corp., Armonk, New York, United States) and JAMOVI, Version 2.3 (The Jamovi Project, Sydney, Australia) programs. The limited sample size of this pilot study means the results should be considered exploratory and hypothesis-generating.
Ethical statement
Prior to enrollment, informed consent was obtained from all patients. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional ethics committee of Istanbul University (Approval No. E-29624016-050.99-1793057).
Results
Study population
Table 1 provides the characteristics of study population as well as evaluated lesions.
Table 1
Characteristics of patients and lesions
| Patient characteristics | |
|---|---|
| Age | 62.4 ± 12.0 |
| Gender, Male | 28/34 (82%) |
| Diabetes mellitus | 12/34 (35%) |
| Hypertension | 16/34 (47%) |
| Dyslipidemia | 9/34 (26%) |
| Lesion characteristics | |
| Angiographic characteristics | |
| Ostial or trunk lesion | 20/34 (59%) |
| Bifurcation lesion | 14/34 (41%) |
| Angiographic stenosis severity (%) | 53.29 ± 14.24 |
| Physiological characteristics | |
| FFR | 0.78 ± 0.08 |
| iFR | 0.89 ± 0.06 |
| Discordant FFR-iFR | 11/34 (32%) |
| Concordant FFR-iFR | 23/34 (68%) |
| Pa rest (mean, mmHg) | 99.12 ± 6.69 |
| Pd rest (mean, mmHg) | 86.00 ± 5.85 |
| Pa hyperemia (mean,mmHg) | 93.35 ± 6.91 |
| Pd hyperemia (mean, mmHg) | 72.88 ± 10.04 |
| Ultrasonographic characteristics | |
| Plaque burden (%) | 55.18 ± 15.36 |
| MLA (mm²) | 7.13 ± 2.17 |
| Calcified lesion | 13/34 (38%) |
Values are mean ± SD or n/N (%).
FFR = fractional flow reserve; iFR = instantaneous wave-free ratio; Pa = aortic pressure; Pd = distal pressure; MLA = minimum lumen area.
All 34 patients had angiographically intermediate LMCA disease. The mean age was 62.4 ± 12.0 years, and 28 patients (82%) were male. 12 patients (35%) had diabetes mellitus, 16 (47%) had arterial hypertension and 9 (26%) had dyslipidemia. Regarding lesion location, 20 patients (59%) had LMCA stenoses in the ostial or shaft (body) segment, while 14 (41%) had distal bifurcation involvement. Mean FFR was 0.78 ± 0.08 and mean IVUS MLA was 7.13 ± 2.17 mm 2. Mean angiographic stenosis severity was 53.3 ± 14.2 %.
Overall diagnostic agreement among FFR, iFR and MLA
Using an MLA threshold of 6 mm², IVUS identified 16 out of 34 lesions (47%) as significant. FFR ≤ 0.80 was observed in 20 lesions (59%), and iFR ≤ 0.89 in 13 lesions (38%) ( Figure 1 ). MLA showed a strong correlation with both FFR ( r = 0.835, p < 0.001) and iFR ( r = 0.769, p < 0.001) ( Figure 2 ). FFR and iFR were also highly correlated with each other ( r = 0.756, p < 0.001). Consequently, out of 34 lesions, 10 (29%) had concordantly abnormal FFR, iFR and MLA, and 12 (35%) had concordantly normal FFR, iFR and MLA corresponding to a concordance frequency of 65% in all cases. Presence of concordant normal iFR and FFR virtually ruled out MLA <6 with 100% specificity, although it was only seen in 66% (12/18) of cases. An abnormal FFR alone was able to identify all lesions with a MLA <6. While all cases with MLA <6 had abnormal FFR, 6 (38%) had false negative iFR ( Figure 1 ). Because the discordant subgroup was small, these concordance comparisons are descriptive and should be interpreted with caution.
Number of patients divided into FFR-iFR groups within the MLA <6 and MLA >6 groups.
The table displays the correlations of resting Pd/Pa, iFR, and FFR with MLA, as well as the diagnostic abilities for detecting MLA <6.
Correlations between angiographic, ultrasonographic and hemodynamic parameters
Angiographic percent diameter stenosis (DS%) demonstrated a weak inverse correlation with IVUS-derived MLA ( r =–0.332, p = 0.007) and a weak positive correlation with plaque burden ( r = 0.298, p = 0.017). Moreover, higher DS% values were associated with moderately lower iFR ( r =–0.507, p < 0.001) and FFR ( r =–0.383, p = 0.002). Plaque burden measured by IVUS was strongly inversely correlated with MLA ( r =–0.742, p < 0.001), and it also correlated inversely with iFR ( r =–0.615, p < 0.001) and FFR ( r =–0.741, p < 0.001).
Impact of calcification and lesion location on relationship between ultrasonographic and hemodynamic indices
Thirteen lesions (38%) were classified as calcified and 21 (62%) as noncalcified. Concordant versus discordant FFR-iFR cases did not differ significantly with regard to calcification prevalence or lesion location. Calcification appeared to attenuate the correlation between MLA and the pressure-derived indices (FFR and iFR), but this observation should be interpreted cautiously because of the small sample size ( Figure 3 ). Aside from calcification effect, concordant and discordant cases had comparable mean angiographic DS%, FFR, iFR and plaque burden ( Table 2 ).
Correlation graphics between FFR and iFR in relation to MLA in calcified and noncalcified plaques, respectively.
Table 2
Comparison of FFR-iFR discordant and concordant lesions
| Parameter | Discordant | Mean | Standard deviation | p |
|---|---|---|---|---|
| DS% | 0 | 53.78 | 14.79 | 0.905 |
| DS% | 1 | 53.00 | 14.18 | |
| Ostial lesion | 0 | 0.57 | 0.51 | 0.713 |
| Ostial lesion | 1 | 0.64 | 0.50 | |
| Plaque burden | 0 | 54.39 | 16.80 | 0.681 |
| Plaque burden | 1 | 56.77 | 12.59 | |
| MLA | 0 | 7.41 | 2.49 | 0.768 |
| MLA | 1 | 6.53 | 1.12 | |
| Pa | 0 | 99.96 | 6.93 | 0.297 |
| Pa | 1 | 97.36 | 6.07 | |
| Pd | 0 | 86.87 | 4.81 | 0.215 |
| Pd | 1 | 84.18 | 7.52 | |
| Pa hype | 0 | 93.91 | 6.71 | 0.503 |
| Pa hype | 1 | 92.18 | 7.52 | |
| Pd hype | 0 | 73.78 | 10.07 | 0.458 |
| Pd hype | 1 | 71.00 | 10.18 | |
| PdPa | 0 | 0.87 | 0.04 | 0.970 |
| PdPa | 1 | 0.87 | 0.07 | |
| FFR | 0 | 0.78 | 0.09 | 0.782 |
| FFR | 1 | 0.77 | 0.05 | |
| iFR | 0 | 0.88 | 0.07 | 0.506 |
| iFR | 1 | 0.91 | 0.02 |
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