A myocardial bridge (MB) is a condition where a segment of an epicardial coronary artery passes through the myocardial muscle. While traditionally regarded as benign, MBs have been associated with various cardiovascular conditions. Therefore, assessing their hemodynamic impact is crucial for informed treatment decisions. Intracoronary functional assessments, such as fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR), have proven useful, especially under inotropic stimulation. However, their invasive nature limits their widespread clinical application. The Quantitative Flow Ratio (QFR) has emerged as a minimally invasive alternative for functional evaluation of MBs, though data on its use are still limited. This study aims to compare the diagnostic efficacy of FFR, iFR, and QFR for evaluating MBs both at rest and under stress conditions. Patients with confirmed MB on the LAD and typical angina (or abnormal noninvasive tests indicating myocardial ischemia) were included. According to a prespecified protocol, all patients underwent functional intracoronary evaluation with FFR and iFR at rest and after dobutamine and atropine intravenous infusion. QFR was also calculated for all cases both at rest and during dobutamine infusion. FFR values ≤0.80, iFR values ≤0.89 and QFR values ≤0.84 were considered indicative of significant myocardial ischemia. A total of 21 patients were included. Median FFR remained unchanged from rest (0.85) to stress (0.85), with only 1 patient showing a positive stress-FFR. In contrast, median iFR significantly decreased from 0.91 to 0.79 (p <0.001), with stress-iFR ≤0.89 in 18 patients. Resting QFR did not indicate significant hemodynamic impact of the MB (median 0.90), but under inotropic stimulation, ischemia was detected in 18 patients (median 0.79, p <0.001). QFR and iFR were concordant during stress in 19 patients, showing a significant positive correlation (Spearman’s ρ = 0.702, p = 0.037) and comparable sensitivity (0.86). QFR, computed during inotropic infusion, shows high sensitivity for detecting MB-related ischemia, comparable to stress-iFR and superior to stress-FFR. The correlation between stress-induced iFR and QFR suggests QFR as a reliable, minimally invasive alternative for functional lesion-specific evaluation in MB patients. Larger studies are necessary to confirm these preliminary findings and standardize QFR use in dynamic coronary stenosis assessments.
Graphical Abstract
Central Illustration. Diagnostic work-up example.
A myocardial bridge (MB) is a segment of an epicardial coronary artery that courses deeply within the myocardial muscle. Most commonly involving the left anterior descending (LAD) artery, this congenital anomaly was traditionally regarded as benign. Nevertheless, MBs have been linked to several pathological conditions, including silent ischemia, stable angina, acute coronary syndromes, Takotsubo cardiomyopathy, and life-threatening arrhythmias. ,,,,, Moreover, it is not uncommon to encounter patients presenting with either angina or noninvasive evidence of myocardial ischemia, with a MB as the sole relevant finding on coronary angiography. Thus, accurate assessment of the hemodynamic significance of MBs is crucial for guiding therapeutic interventions. For this purpose, intracoronary functional evaluation using both fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) indices has been tested, either at rest or during inotropic stimulation. In our previous experience, we demonstrated that using a lesion-specific diastolic index such as iFR, particularly during inotropic infusion, tends to produce results that more accurately reflect patients’ symptoms compared to FFR. However, both tests are subject to limitations and concerns due to their invasive nature, requiring the insertion of a specific wire into the coronary vessel for detailed pressure analysis. Recently, several minimally invasive tests have been developed, allowing for a functional lesion-specific evaluation, without the need for guidewire insertion. Among these, Quantitative Flow Ratio (QFR) has emerged as a novel vasodilator-free method to evaluate stenosis significance from biplane angiography using computational modeling of 3-dimensional (3D) quantitative coronary angiography (QCA) and TIMI (Thrombolysis in Myocardial Infarction) frame counts. , While QFR has been broadly validated for evaluating fixed coronary stenoses, , only one previous study has examined its use in evaluating the functional significance of a MB during rest cardiac catheterization. The aim of our study is to determine if QFR is a valuable tool for unmasking MB related myocardial ischemia and its agreement with wirebased indices, both at rest and during inotropic agent infusion.
Methods
Study population. Data from a population included in a previous prospective investigation carried out at our center between 2013 and 2018 were used. In brief, the study involved 20 patients diagnosed with typical angina and/or abnormal noninvasive tests suggestive of myocardial ischemia, where the presence of a MB on the left anterior descending (LAD) artery was confirmed by angiography and/or cardiac computed tomography (CCT). Patients with concomitant significant coronary stenoses (i.e., >50% diameter stenosis as determined by quantitative coronary angiography) or hypertrophic cardiomyopathy were excluded. All enrolled patients underwent invasive coronary angiography at our center. Invasive functional tests, including fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR), were performed in all cases, both at rest and during inotropic stimulation with dobutamine. For the current analysis, we expanded the study cohort to include patients with similar clinical characteristics who were prospectively referred to our center between 2018 and June 2024, and for whom invasive coronary angiography, along with at least one invasive functional test, was available. Quantitative flow ratio (QFR) was retrospectively calculated for all the included cases, both at rest and during simulated stress (Central Illustration). Patients with suboptimal angiographic image quality and those for whom reliable QFR evaluation (either at rest or during stress) was not feasible were excluded from the analysis. The study protocol adheres to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the local Ethical Committee.
Angiographic assessment and invasive functional evaluation. The catheterization procedure was done according to standard techniques, from a radial or femoral arterial access. All patients received 5000 IU of unfractionated heparin and 200 μg of intracoronary nitrates before insertion of the guidewire. Basal angiography was obtained in different angiographic views to better visualize and characterize the presence of MB. To unmask ischemia related to the MB, all patients underwent invasive functional evaluation with a prespecified protocol for FFR and/or iFR measurement, both at rest and during inotropic stimulation. A 6F-guiding catheter without side holes, connected to an ACIST pressure transducer (ACIST Medical System, Eden Prairie, MN) was used. Continuous digital acquisition and storage of the ECG and aortic pressure were performed using a computerized polygraph controlled by dedicated software (Mac-Laboratory, General Electric Medical Systems, Milwaukee, WI) in a personal computer. After calibration, the iFR and FFR measurements were calculated online using a 0.014-inch micromanometer-tipped guidewire (Verrata PLUS Pressure Guidewire, Volcano Corporation, Rancho Cordova, CA), and the Volcano s5i integrated Precision guided therapy system (Philips Volcano, San Diego, CA). The guidewire was advanced under fluoroscopy in the LAD as distal as possible to the MB, at a point where vessel diameter was at least 2 mm. FFR was defined as the mean distal pressure (Pd)/mean aortic pressure (Pa) across MB during maximal hyperemia, achieved by administration of intravenous 140 μg kg−1 min−1 or 200 μg intracoronary adenosine. Pd/Pa was automatically calculated by current computational software as the ratio found in the pressure recording (a cutoff point of ≤0.80 was used to detect hemodynamic relevance). iFR was calculated using a ratio of Pd/Pa across MB under nonhyperemic conditions, during the diastolic wave–free period (a period in the cardiac cycle when intrabeat microvascular resistance is inherently constant, and the flow is at its highest compared with the whole cycle). iFR was considered positive for measurements ≤0.89. Both measurements were performed in basal conditions and after inotropic stimulation by intravenous dobutamine. The infusion was started at 10 μg kg−1 min−1 and increased by 5 μg kg−1 min−1 every 5 minutes up to 20 μg kg−1 min−1 or until the patient developed symptoms or clear evidence of ischemia. An intravenous infusion of 1 mg atropine was administered when the patient did not experience symptoms/ischemia with 20 μgkg−1 min−1 dobutamine infusion. Coronary angiography and a new set of pressure measurements (FFR after repeating adenosine bolus, iFR, iFR pullback) were performed after each inotropic titration dose. An intravenous bolus of β-blocker (metoprolol 5 mg) was administered at the end of the procedure to antagonize the positive inotropic and chronotropic effect of dobutamine. Guidewire drift was finally rechecked at the end of the procedure.
QFR evaluation. Quantitative Flow Ratio analysis was retrospectively computed using the Medis QFR software from Medis Medical Imaging. Following the manufacturer’s instructions for use (IFU), QFR value was derived using 2 angiographic views, separated by at least 25 degrees. Typically, a cranial or right-cranial view and a latero-lateral view, or a caudal view, were employed. Diastolic still frames of the coronary vessel were used for 3D QCA calculation, both at rest and during inotropic infusion. Flow velocity for the TIMI frame count was manually inputted under both hemodynamic conditions. According to the QFR IFU, a threshold of 0.84 was deemed significant in our study.
Statistical Analysis. Continuous variables are expressed as mean ± SD or median (interquartile range [IQR]) and were compared using Student t-test or Mann-Whitney U test, as appropriate. Categorical variables are presented as counts (%) and were compared using chi-square or Fisher’s exact test as appropriate. Correlation between QFR values and FFR/iFR was determined with Spearman test. All P values were 2-tailed, with statistical significance set at <0.05. Analyses were performed using R version 4.1.2 (R foundation).
Results
Patient characteristics. Out of the 20 patients originally included in the previous study, QFR evaluation was deemed possible in 7 cases. The remaining 13 subjects were excluded due to low-quality angiographic images (excessive vessel overlap or shortening, absence of at least 2 angiographic projections at least 25° apart), which prevented adequate QFR analysis. Fourteen patients, who underwent coronary angiography between 2018 and June 2024 and met the study inclusion criteria, were added to the study population ( Figure 1 ). Consequently, a total of 21 patients, with demonstrated myocardial ischemia/anginal symptoms and a MB on the LAD, were included in the final study cohort. Fifteen patients (71%) presented typical anginal symptoms. In 9 (43%) cases, a positive noninvasive stress test had been previously conducted. Patients’ baseline characteristics are summarized in Table 1 . The mean age was 53 ± 17 years. Five patients (24%) were female, 4 (19%) had a previous history of diabetes mellitus, 10 (48%) had hypertension, and 7 (33%) had dyslipidemia. Four (19%) reported a family history of coronary artery disease (CAD), and 8 (38%) were active or former smokers. The median left ventricular ejection fraction (LVEF) was 61% [IQR 57.0-64.0]. Seven (33%) patients were previously treated with beta-blockers. At discharge, 19 out of 21 patients were prescribed beta-blocker therapy at the maximum tolerated dose, with relief of anginal symptoms. None of the included patients underwent surgical unroofing or percutaneous intervention.
Study Flow chart.
Table 1
Baseline characteristics of the study population
| Baseline characteristics | Overall n 21 | |
|---|---|---|
| Age (years) | 53 [±17] | |
| Female | 5 (23.8) | |
| Hypertension | 10 (47.6) | |
| Dyslipidemia | 7 (33.3) | |
| Diabetes Mellitus | 4 (19.0) | |
| COPD | 2 (9.5) | |
| Coronary artery disease | 0 (0.0) | |
| Family history of coronary artery disease | 4 (19.0) | |
| Atrial Fibrillation | 2 (9.5) | |
| Smoke history | 8 (38.0) | |
| Stroke | 0 (0.0) | |
| Chronic kidney disease | 1 (4.7) | |
| PAD | 2 (9.5) | |
| LBBB | 1 (4.7) | |
| BB assumption | 7 (33.3) | |
| CCB assumption | 0 (0.0) | |
| Nitrates assumption | 1 (4.7) | |
| Aspirin assumption | 8 (38.0) | |
| P2Y 12 inhibitors assumption | 5 (23.8) | |
| Symptoms characteristics | ||
| Angor | 15 (71.4) | |
| CCS I | 7 (46.7) | |
| CCS II | 5 (33.3) | |
| CCS III | 3 (20.0) | |
| CCS IV | 0 (0.0) | |
| Dyspnoea | 6 (28.5) | |
| NYHA I | 3 (50.0) | |
| NYHA II | 2 (33.3) | |
| NYHA III | 1 (16.7) | |
| NYHA IV | 0 (0.0) | |
| Noninvasive proven ischemia | 9 (42.9) | |
| Stress myocardial scintigraphy | 4 (44.4) | |
| ECG stress test | 4 (44.4) | |
| Echocardiographic stress test | 1 (11.2) | |
| Echo/invasive characteristics | ||
| Ejection fraction (%) | 60.6 [57.0-64.0] | |
| IVS thickness (mm) | 10.3 [8.8-12.3] | |
| LV mass indexed (g/m 2) | 93.0 [77.3-105.5] | |
| Severe valvulopathy | 0 (0.0) | |
| Invasive LVEDP | 16.8 [15.0-19.5] | |
Values with () are expressed as absolute number (percentage). Values with [] are expressed as median [interquartile range] except for age which is expressed as media [± standard deviation].
Functional assessment. During invasive stress test, 16 subjects (76%) reached the target dobutamine dose of 20 μg kg−1min−1. In 5 (24%) patients, dobutamine infusion was interrupted before reaching the maximal dose due to the onset of severe angina. Two patients also required intravenous bolus administration of atropine. During inotropic stimulation, all patients experienced anginal symptoms, and 19 out of 21 (90%) exhibited dynamic ischemic changes on ECG. As reported in Table 2 , the inotropic challenge caused an increase in the median double product from a median value of 8400 to 17030 (p <0.001). The 3D computed diastolic minimal lumen diameter (MLD) at the level of MB significantly decreased during the dobutamine stimulus compared to basal values (from 2.05 mm to 0.90 mm respectively; p <0.001). Similarly, a significant increase in the percentage of diastolic stenosis at the level of MB was demonstrated (from 31% to 51%, p <0.001, Figure 2 ). Fractional flow reserve measurements before and after inotropic challenge were available for 13 of the 21 patients, while both iFR and QFR data were collected for all cases. The changes in functional test values from baseline to stress conditions for each patient are illustrated in Figure 3 and summarized in Table 2 . The median FFR at rest was 0.85 [IQR 0.82–0.90], with all measurements exceeding the cutoff value of 0.80. During dobutamine infusion, FFR tested positive in 1 case, with no significant differences in median FFR values between rest and stress conditions (median stress FFR 0.85, IQR 0.84–0.88; p = 0.54). The median iFR at rest was 0.91 [IQR 0.89–0.93], with 8 patients exhibiting a value ≤ 0.89. During dobutamine infusion, a significant decrease in iFR values was observed (median 0.79, IQR 0.73–0.85; p <0.001), with stress-iFR resulting ≤ 0.89 in all but 3 patients. In both resting and stress conditions, iFR pullback showed a step-up at the level of MB. At rest, none of the patients presented a significant QFR value (median 0.90, IQR 0.88–0.96). During inotropic infusion, significant ischemia was detected by QFR (≤0.84) in 18 out of 21 patients (median 0.79, IQR 0.74–0.83; p <0.001). Nineteen patients exhibited concordance between iFR and QFR values, both tested during inotropic infusion. Among the 2 discordant cases, one initially tested positive on stress-iFR but subsequently tested negative on stress-QFR, while the other tested positive on stress-QFR after initially testing negative on iFR. A positive significant correlation between stress-induced iFR and QFR was found (Spearman’s rank correlation coefficient 0.702; p value = 0.037). No significant correlation was found between iFR and QFR when no inotropic agent was administered, as well as between FFR and QFR. As reported in Supplementary Table 1 , low sensitivity was demonstrated for all 3 tests when conducted at rest and for stress-FFR. However, during inotropic infusion, the sensitivity values for iFR and QFR were higher and comparable (0.86 for both tests).
Table 2
Vessel characteristics and functional evaluation of each patient included in the study
| N° | Age | Diameter (mm) | MLD (mm) | Stenosis (%) | Systolic pressure (mmHg) | Diastolic pressure (mmHg) | Heart rate (bpm) | Double product | Target HR (%) | FFR | iFR | QFR | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Rest | Dob | Rest | Dob | Rest | Dob | Rest | Dob | Rest | Dob | Rest | Dob | Rest | Dob | Rest | Dob | Rest | Dob | Rest | Dob | |||
| 1 | 68 | 2.30 | 1.40 | 1.70 | 0.70 | 35 | 56 | 130 | 170 | 80 | 70 | 65 | 120 | 8450 | 20,400 | 79% | 0.82 | 0.86 | 0.93 | 0.81 | 0.88 | 0.71 |
| 2 | 63 | 2.20 | 1.90 | 1.60 | 0.90 | 60 | 90 | 120 | 110 | 80 | 70 | 69 | 135 | 8280 | 14,850 | 86% | 0.82 | 0.92 | 0.87 | 0.79 | 0.87 | 0.68 |
| 3 | 73 | 2.70 | 2.40 | 2.10 | 0.45 | 14 | 80 | 120 | 125 | 70 | 95 | 86 | 135 | 10320 | 18,620 | 92% | 0.95 | 0.95 | 0.93 | 0.92 | 0.88 | 0.74 |
| 4 | 75 | 2.30 | 2.10 | 1.60 | 1.00 | 46 | 65 | 115 | 125 | 75 | 90 | 77 | 125 | 8855 | 15,625 | 86% | 0.89 | 0.83 | 0.80 | 0.65 | 0.89 | 0.69 |
| 5 | 68 | 2.70 | 2.20 | 2.00 | 1.10 | 46 | 82 | 125 | 130 | 90 | 90 | 102 | 135 | 12750 | 17,550 | 89% | 0.90 | 0.85 | 0.86 | 0.76 | 0.91 | 0.82 |
| 6 | 68 | 2.70 | 2.18 | 2.05 | 1.00 | 19 | 49 | 135 | 130 | 80 | 80 | 76 | 129 | 10260 | 16,770 | 85% | 0.90 | 0.80 | 0.85 | 0.70 | 0.92 | 0.80 |
| 7 | 54 | 2.30 | 1.50 | 1.60 | 0.60 | 31 | 45 | 120 | 120 | 70 | 70 | 78 | 142 | 9360 | 17,040 | 86% | 0.81 | 0.84 | 0.89 | 0.67 | 0.88 | 0.76 |
| 8 | 65 | 2.10 | 1.00 | 2.50 | 0.50 | 52 | 79 | 105 | 120 | 100 | 80 | 66 | 137 | 6930 | 16,440 | 88% | 0.93 | 0.92 | 0.89 | 0.85 | 0.98 | 0.86 |
| 9 | 63 | 2.20 | 1.80 | 2.10 | 0.90 | 19 | 46 | 150 | 150 | 90 | 75 | 80 | 125 | 12000 | 18,750 | 80% | 0.84 | 0.84 | 0.91 | 0.80 | 0.98 | 0.82 |
| 10 | 62 | 2.30 | 1.70 | 1.60 | 1.00 | 42 | 51 | 160 | 150 | 89 | 80 | 55 | 130 | 8800 | 19,500 | 82% | 0.84 | 0.85 | 0.94 | 0.80 | 0.94 | 0.67 |
| 11 | 61 | 3.30 | 2.90 | 2.30 | 2.10 | 30 | 43 | 140 | 160 | 90 | 90 | 60 | 135 | 8400 | 21,600 | 85% | 0.90 | 0.88 | 0.95 | 0.90 | 0.90 | 0.89 |
| 12 | 33 | 3.70 | 3.20 | 3.00 | 1.90 | 9 | 26 | 120 | 130 | 75 | 80 | 58 | 150 | 6960 | 19,500 | 80% | 0.85 | 0.82 | 0.92 | 0.73 | 1.00 | 0.77 |
| 13 | 24 | 3.10 | 2.90 | 3.10 | 2.10 | 21 | 32 | 110 | 125 | 75 | 80 | 78 | 120 | 8580 | 15,000 | 61% | – | – | 0.93 | 0.87 | 0.99 | 0.83 |
| 14 | 18 | 3.10 | 2.60 | 2.10 | 1.40 | 24 | 38 | 100 | 100 | 55 | 60 | 53 | 100 | 5300 | 10,000 | 50% | – | – | 0.95 | 0.92 | 0.87 | 0.88 |
| 15 | 64 | 2.40 | 2.10 | 1.60 | 0.70 | 34 | 57 | 130 | 170 | 90 | 100 | 50 | 95 | 6500 | 16,150 | 61% | – | – | 0.86 | 0.69 | 0.86 | 0.61 |
| 16 | 35 | 3.00 | 2.40 | 2.40 | 0.70 | 27 | 75 | 120 | 215 | 80 | 135 | 65 | 158 | 7800 | 33,970 | 85% | – | – | 0.91 | 0.78 | 0.97 | 0.83 |
| 17 | 58 | 2.70 | 2.50 | 1.90 | 1.00 | 31 | 50 | 120 | 120 | 85 | 80 | 65 | 135 | 7600 | 17,350 | 83% | 0.81 | 0.85 | 0.88 | 0.75 | 0.89 | 0.74 |
| 18 | 55 | 2.70 | 2.30 | 2.10 | 0.80 | 30 | 56 | 125 | 125 | 85 | 75 | 67 | 135 | 7625 | 15,790 | 82% | – | – | 0.90 | 0.75 | 0.93 | 0.76 |
| 19 | 56 | 2.80 | 1.90 | 1.80 | 0.80 | 31 | 39 | 115 | 140 | 85 | 80 | 63 | 140 | 7615 | 15,840 | 85% | – | – | 0.93 | 0.85 | 0.95 | 0.83 |
| 20 | 54 | 2.50 | 2.20 | 2.20 | 1.30 | 20 | 67 | 120 | 135 | 75 | 85 | 65 | 135 | 9325 | 16,780 | 81% | – | – | 0.93 | 0.85 | 0.88 | 0.82 |
| 21 | 23 | 2.30 | 2.00 | 1.90 | 0.80 | 25 | 50 | 125 | 140 | 80 | 80 | 59 | 130 | 7950 | 17,030 | 66% | – | – | 0.91 | 0.72 | 0.86 | 0.79 |
| Median | * 53 | 2.66 | 2.18 | 2.05 | 0.90 | 31 | 51 | 120 | 130 | 80 | 80 | 66 | 135 | 8400 | 17,030 | 83 | 0.85 | 0.85 | 0.91 | 0.79 | 0.90 | 0.79 |
| IQR | * [±17] | 2.3- 2.8 | 1.9- 2.4 | 1.7- 2.2 | 0.7- 1.1 | 21-35 | 45- 67 | 120- 130 | 125- 150 | 75- 89 | 76.2- 90 | 64- 77 | 125 −137 | 7615- 9325 | 15,840– 18,750 | 79.6- 85.5 | 0.82- 0.90 | 0.84 −0.88 | 0.89- 0.93 | 0.73- 0.85 | 0.88- 0.96 | 0.74- 0.83 |
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