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Impact of Diastolic Vessel Restriction on Quality of Life in Symptomatic Myocardial Bridging Patients Treated With Surgical Unroofing: Preoperative Assessments With Intravascular Ultrasound and Coronary Computed Tomography Angiography

Originally publishedhttps://doi.org/10.1161/CIRCINTERVENTIONS.121.011062Circulation: Cardiovascular Interventions. 2021;14

    Abstract

    Background:

    Despite optimal medical therapy, a myocardial bridge (MB) can cause life-limiting symptoms in a subset of patients. While surgical unroofing has been shown to improve MB-derived refractory angina, diagnostic indices of clinical symptoms and predictors of improvement following surgery are yet to be elucidated.

    Methods:

    To identify determinants of preoperative symptoms and their improvement following the surgery, preoperative intravascular ultrasound (IVUS) and coronary computed tomography angiography were evaluated in 111 patients with symptomatic MB who underwent surgical unroofing. The primary outcome was the Seattle Angina Questionnaire summary score (the average of physical limitation, angina frequency, and quality of life scores). In addition to standard anatomic variables of an MB, degrees of extrinsic vessel restriction at end-diastole and end-systole were evaluated by IVUS using the ratio of measured vessel area and interpolated reference at the maximum compression site. The diastolic restriction was also evaluated by coronary computed tomography angiography as the maximum lumen area stenosis within the MB segment.

    Results:

    Even during diastole, IVUS revealed vessel restriction in 87% of the patients. Among the variables evaluated, vessel restriction was the strongest parameter correlating with the preoperative Seattle Angina Questionnaire summary score, particularly when assessed in diastole (P<0.0001 in IVUS, P=0.006 in coronary computed tomography angiography). The diastolic restriction by IVUS also showed a weak, but significant correlation with improvement in Seattle Angina Questionnaire summary score 6 months after surgery (P=0.004).

    Conclusions:

    Restricted arterial relaxation in diastole, rather than the degree of systolic compression or extent of an MB, seems to be the primary determinant of clinical symptoms and improvement in quality of life following surgical unroofing.

    What Is Known

    • Although common in the general population, a myocardial bridge is a potential cause of ischemic symptoms and adverse cardiac events.

    • In patients with refractory angina due to a hemodynamically significant myocardial bridge, surgical unroofing results in a significant improvement in angina and quality of life.

    What the Study Adds

    • In patients with a myocardial bridge and refractory angina, the resting vessel area can be restricted by a myocardial bridge even during diastole.

    • Diastolic vessel restriction, as assessed by intravascular ultrasound, correlates with preoperative physical activity limitations and benefit of subsequent surgical unroofing.

    • Coronary computed tomography angiography may be used as a noninvasive alternative to intravascular ultrasound in assessing diastolic vessel restriction.

    A myocardial bridge (MB) is an anatomic variant in which a portion of a coronary artery, most often the left anterior descending artery (LAD), is covered by a myocardial band.1–3 Although an MB was historically considered a benign, subsequent studies have demonstrated that an MB can lead to significant clinical symptoms, myocardial infarction, ventricular arrhythmias, or sudden death.4–9 While medical management is the first and principal strategy for treatment of a symptomatic MB,10 invasive interventions are indicated for patients with refractory angina despite optimal medical threrapy.11 In particular, mounting evidence suggests that surgical unroofing, or supra-arterial myotomy of an MB, results in improved clinical outcomes, relieving angina and improving quality of life (QOL).12–14

    For patients with refractory angina and an MB, an invasive evaluation with intravascular ultrasound (IVUS) and physiological testing can provide essential information for treatment planning and guidance of surgical procedures, if indicated.9,13,15,16 IVUS, in particular, can directly visualize the vessel wall and perivascular structures at a high resolution and in real time, enabling a precise and dynamic assessment of an MB and the tunneled coronary artery.17 Standard anatomic characteristics, such as the location, length, and thickness of an MB are indispensable information for the guidance of surgical intervention, and the degree of systolic arterial compression (a dynamic property) of an MB has been shown to correlate with progression of the coronary atherosclerosis typically observed in the segment proximal to the MB.18 Still, in clinical practice, there are MB patients with significant symptoms despite a relatively limited MB extent, thickness, and/or degree of systolic arterial compression.9 One also sees dramatic MBs on coronary angiography in patients who have no symptoms at all. We hypothesized that other properties of an MB, particularly diastolic variables such as the degree to which the vessel cannot fully dilate during coronary filling because of the MB, may more directly determine the clinical symptoms compared with the conventional anatomic variables, including systolic compression. Hence, the primary objective of this study was to evaluate unique IVUS parameters, specifically the degree of extrinsic vessel restriction at end-diastole and end-systole, which might be more associated with preoperative clinical symptoms and symptomatic improvement following surgical unroofing in patients with a symptomatic MB. A secondary objective was to examine whether these MB properties assessed by IVUS could be estimated noninvasively using standard coronary computed tomography angiography (CCTA), as it is more widely available and readily performed in clinical practice.

    Methods

    The data that support the findings of this study are available from the corresponding author upon reasonable request.

    Study Population and Protocols

    We retrospectively reviewed the clinical databases at Stanford Health Care for symptomatic MB patients who underwent surgical unroofing. Each patient had persistent (>3 months) typical or atypical angina, had completed a stress echocardiogram and/or CCTA to rule out obstructive coronary artery disease and identify an MB, and had undergone invasive angiography, IVUS, and physiological testing because of refractory angina despite maximally tolerated medical therapy.9,16 Patients found to have a hemodynamically significant MB by dobutamine stress diastolic fractional flow reserve (dFFR) were deemed candidates for surgical unroofing. Between August 2011 and February 2020, a total of 144 consecutive patients underwent surgical unroofing. After initial review of the IVUS, coronary angiography, and clinical data, 33 patients were excluded: 7 patients with a history of coronary artery bypass graft surgery or percutaneous coronary intervention in the LAD, 13 patients in which the distal end of the MB was not identified by IVUS because of device deliverability, and 13 patients without detailed symptomatic assessment by self-administered questionnaire at baseline. The present analysis included the remaining 111 patients. This study was approved by the institutional review board at Stanford University, and written informed consent was obtained from all patients.

    Intravascular Ultrasound

    IVUS image acquisition was performed with an automated pullback at 0.5 mm/s using a 40-MHz mechanical IVUS system (Atlantis SR Pro2 or OptiCross, Boston Scientific Corp, Marlborough, MA), placed as far distally as safely possible in the LAD. Resting IVUS was also performed within the MB to obtain the maximal arterial compression at a single location. Qualitative and quantitative assessments were performed using commercially available, validated IVUS analysis software (echoPlaque 4, Indec Systems Inc, Santa Clara, CA) at an independent core laboratory (Cardiovascular Core Analysis Laboratory, Stanford University) by investigators blinded to the clinical symptoms.

    On IVUS, an MB was identified as an echolucent half-moon sign (halo) lying on top of the artery.19Figure 1A demonstrates the IVUS assessment protocol as a diagram. As per standard preoperative IVUS assessment of an MB, we measured total MB length, halo thickness, the degree of arterial compression, the minimum lumen area within the MB region, the maximum plaque burden proximal to the MB, and the number of septal and diagonal branches originating within the tunneled arterial segment. The total MB length was measured from the first proximal appearance of the halo (MB entrance) to its distal end (MB exit). The halo thickness was measured at the thickest part above the artery during diastole. The arterial compression was calculated as (diastolic vessel area–systolic vessel area)/diastolic vessel area×100. Maximum plaque burden in a segment proximal to the MB was calculated as (vessel area−lumen area)/vessel area×100 at the location of the largest plaque burden. MB muscle index was defined as the total MB length×halo thickness (mm).20 In addition to these conventional IVUS variables, vessel restriction by the MB was assessed as a novel parameter. The degree of extrinsic vessel restriction was calculated using the ratio of the measured vessel area at the maximum compression site and the interpolated reference vessel area. The detailed calculation method of vessel restriction is shown in Figure I in the Data Supplement. The vessel area at the maximum compression site was measured at end-diastole and end-systole to calculate the percentage of diastolic and systolic vessel restriction, respectively, and the interpolated reference vessel area was obtained using the reference vessel areas located at 5 mm proximal and 5 mm distal to the MB region at end-diastole (Figure I in the Data Supplement). When there was a significant branch at the proximal or distal reference section, which caused a significant change in vessel dimension and interfered with the linear vessel size, we measured the reference vessel area at the immediate distal or proximal section of the bifurcation for the proximal or distal reference, respectively. This systematic assessment was then summarized as an “IVUS map” for guidance during the subsequent surgical unroofing procedure (Figure 1B). When >1 MB was present, the segments were combined for per-patient analyses in the present study.

    Figure 1.

    Figure 1. Intravascular ultrasound (IVUS) assessment of myocardial bridging (MB). Total MB length, halo thickness, minimum lumen area (MLA), the degree of arterial compression within the MB region, maximum plaque burden proximal to the MB, and the number of septal and diagonal branches originating within the tunneled arterial segment were measured. In addition to these conventional IVUS variables, the degree of extrinsic vessel restriction was calculated using the ratio of the measured vessel area and interpolated reference vessel area at the maximum compression site (Max CS). The vessel area at the Max CS was measured at end-diastole and peak-systole to calculate the percentage of diastolic and systolic vessel restriction, respectively, and the interpolated reference vessel area was obtained using the proximal and distal reference areas measured at end-diastole (A). The systematic assessments were summarized as an “IVUS map” for the guidance of surgical unroofing procedure (B). D indicates diagonal branch; LAD, left anterior descending artery; LCX, left circumflex artery; S, septal branch; and VA, vessel area.

    Coronary Computed Tomography Angiography

    Among the 111 enrolled patients, CCTA was available for the current analysis in 89 patients; 16 patients had incompatible source data for independent reevaluation on a Stanford workstation and in 6 patients the MB exit could not be precisely determined because of motion artifact. CCTA imaging methods can be found in the Data Supplement. The vessel encasement by the MB was graded based on the previously published classification criteria: partial encasement, defined as the vessel within the interventricular groove and in direct contact with the left ventricular myocardium (Grade 1) and full encasement, defined as the vessel surrounded by the myocardium without (Grade 2) or with (Grade 3) measurable overlying muscle (Figure 2A).21

    Figure 2.

    Figure 2. Coronary computed tomography angiography assessment of myocardial bridging (MB). A, Representative images of graded MB Grade 1: left anterior descending artery (LAD) within the interventricular groove and in direct contact with the myocardium (partial encasement). Grade 2: full encasement of the LAD, but without measurable overlying muscle. Grade 3: full encasement of the LAD with measurable overlying muscle. B, The MB length was measured along the vessel axis from the proximal entrance to its distal exit, determined by the direct contact of the LAD with the left ventricular myocardium and/or the myocardial tissue overlying the LAD. In addition, diastolic vessel restriction was evaluated as area stenosis, calculated using double-oblique short-axis views and the most representative long-axis view of the coronary artery within the MB. Maximum area stenosis was obtained using the reference lumen area interpolated from proximal and distal segments located 10 mm from the MB region.

    The MB location was evaluated as the distance measured from the LAD ostium to the bridge’s entry. The MB length was measured along the vessel axis from the proximal entrance to its distal exit, as determined by the direct contact of the LAD with left ventricular myocardium and/or the myocardial tissue overlying the LAD. In addition, diastolic vessel restriction was evaluated as the area stenosis calculated using double-oblique short-axis views and the most representative long-axis view of the coronary artery within the MB. Maximum area stenosis was obtained using the reference lumen area interpolated from segments located at 5 mm proximal and 5 mm distal to the MB region, consistent with the definition used by IVUS (Figure 2B).

    Seattle Angina Questionnaire

    All patients underwent angina symptom evaluation with the Seattle Angina Questionnaire (SAQ) before surgical intervention. Optional SAQ reevaluation 6 months after the surgery was conducted in 86 patients (78%). The details of the SAQ are shown in the Data Supplement. In the present study, a delta SAQ summary score at 6 months (the score at 6 months after surgery minus the score at baseline) was also calculated as the end point of symptomatic improvement following surgical unroofing.10,12,13

    Statistical Analysis

    Categorical variables are presented as frequencies and percentages and continuous variables as medians with interquartile ranges (IQRs) or mean±SD. Continuous values were compared using the paired Student t test. Correlation between continuous variables was investigated with linear regression analysis. To explore the potential predictors of baseline limitation of daily life, univariate analysis with Spearman correlation was conducted on a patient basis where the baseline SAQ summary was included as the dependent variables, and patient clinical characteristics and MB assessments at baseline were included as the independent variables. Similarly, to explore the potential predictors of symptomatic improvement following surgical unroofing, univariate analysis with Spearman correlation was conducted, and Bonferroni correction was used to adjust P value of significance for multiple comparisons between preoperative SAQ summary score and diastolic vessel restriction (a P value of <0.05 was considered statistically significant). The agreements of anatomic MB assessment between IVUS and CCTA were expressed in Bland-Altman plots. The Bland-Altman plot depicted the differences of each pair of measurements versus their mean values with reference lines for the mean difference of all paired measurements. The limits of agreement were defined as mean±1.96 SD of absolute difference. A value of P<0.05 was considered statistically significant. All analyses were performed using JMP Pro 15 software (SAS Institute, Cary, NC).

    Results

    Patient Characteristics

    The patient’s characteristics are presented in Table 1. The median age was 46 years, and 58% of patients were women. The presence of coronary risk factors was less frequent than those commonly reported in atherosclerotic coronary artery disease studies. All the patients had a preserved left ventricular ejection fraction at baseline and were on several cardiac medications.

    Table 1. Patient Clinical Characteristics

    N=111
    Age, y46 (35–57)
    Male sex, n (%)47 (42.3)
    Body mass index, kg/m225.4 (23.3–28.7)
    Race/ethnicity, n (%)
     American Indian/Alaska5 (4.5)
     Asian/East Indian4 (3.6)
     Black participants1 (1.0)
     Hispanic15 (13.5)
     White participants82 (73.9)
     Other (include NA)4 (3.6)
    Ejection fraction, %61.0 (59.4–65.0)
    Hypertension, n (%)38 (34.2)
    Dyslipidemia, n (%)46 (41.4)
    Diabetes, n (%)5 (4.5)
    Family history of CAD, n (%)55 (49.6)
    Current smoking, n (%)3 (2.7)
    Current medications, n (%)
     Aspirin51 (45.9)
     Beta blocker42 (37.8)
     CCB37 (33.3)
     ACE inhibitor/ARB12 (10.8)
     Statins46 (41.4)
     Nitrates23 (29.7)
     Diuretic11 (9.9)

    Values are number (%) or median (interquatile range). ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CAD, coronary artery disease; CCB, calcium channel blocker; and NA, not applicable.

    Anatomic and Hemodynamic Assessments of Myocardial Bridging

    The results of baseline anatomic and hemodynamic MB assessments are summarized in Table 2. The median maximum plaque burden upstream from an MB was 31.3% (IQR, 19.0–46.0), demonstrating that these patients had a very low atherosclerotic burden and were quite distinct from a conventional population with atherosclerotic coronary disease. Even at end-diastole, IVUS revealed a restricted vessel area (diastolic vessel restriction >0%) at the maximum compression site in 97 out of 111 patients (87%). The degree of diastolic vessel restriction determined by IVUS correlated with the diastolic area stenosis assessed by CCTA (P<0.0001, R2=0.28, Figure 3).

    Table 2. Baseline Anatomic and Hemodynamic Characteristics and Perioperative SAQ Summary Scores

    IVUS variables (N=111)
     Number of MBs, n (%)
      190 (81.2)
      219 (17.1)
      32 (1.8)
     MB total length, mm29.9 (21.5–41.4)
     Maximum halo thickness, mm0.57 (0.43–0.83)
     MB muscle index18.6 (11.7–29.3)
     Distance between LAD ostium and MB, mm36.7 (29.1–43.6)
     Diastolic vessel area at max CS, mm26.06 (4.46–7.24)
     Systolic vessel area at max CS, mm23.59 (2.94–4.50)
     Arterial compression rate, %38.0 (29.3–44.7)
     Diastolic vessel restriction, %16.5 (6.4–27.3)
     Systolic vessel restriction, %47.9 (38.0–58.9)
     Minimum lumen area within MB, mm23.07 (2.29–3.82)
     Septal perforators within MB, n3 (2–4)
     Diagonal branches within MB, n1 (0–1)
     Proximal maximum plaque burden, %31.3 (19.0–46.0)
     Distance of maximum plaque burden from the proximal entrance of the MB, mm21.2 (13.2–29.7)
    CCTA variables (N=89)
     MB total length, mm26.0 (20.0–35.8)
     Coverage of the MB, n (%)
      Grade 1 (partial coverage)34 (38.2)
      Grade 2 (unroofed)30 (33.7)
      Grade 3 (full coverage)25 (28.1)
     Distance between LAD ostium and MB, mm40.0 (27.1–49.6)
     Interpolated area stenosis within MB, %19.9 (7.9–30.0)
    Hemodynamic measurements (N=103)
     Pd/Pa at rest0.95 (0.92–1.00)
     Stress dFFR0.64 (0.54–0.71)
    SAQ
     Preoperative SAQ summary score (N=111)44 (33–55)
     Postoperative SAQ summary score (N=86)85 (75–94)

    Values are number (%) or median (interquatile range). CCTA indicates coronary computed tomography angiography; dFFR, diastolic fractional flow reserve; IVUS, intravascular ultrasound; LAD, left anterior descending artery; Max CS, maximum compression site; MB, myocardial bridging; Pd/Pa, coronary pressure divided by aortic pressure; and SAQ, Seattle Angina Questionnaire.

    Figure 3.

    Figure 3. Diastolic vessel restriction by intravascular ultrasound (IVUS) vs area stenosis by coronary computed tomography angiography (CCTA).

    In comparison with IVUS, CCTA slightly underestimated the total MB length (29.0±14.3 versus 31.4±13.8 mm, P=0.003) with a difference of −2.4±8.7 mm, presumably due to the difference in image resolution to determine the entrance and exit of the MB segment. Accordingly, the measured distance from the LAD ostium to the MB entrance was slightly overestimated by CCTA (39.1±14.7 versus 37.3±11.5 mm, P=0.04) with a difference of 2.0±16.4 mm. However, Bland-Altman analyses for these measurements showed reasonable agreements between IVUS and CCTA (Figure II in the Data Supplement). Both variables also showed significant correlations between the 2 modalities (total MB length: P<0.0001, R2=0.61; distance from the LAD ostium to the MB entrance: P<0.0001, R2=0.55, Figure III in the Data Supplement). Halo thickness measured by IVUS was 0.44±0.05, 0.66±0.05, and 1.02±0.05 mm in CCTA Grade 1, 2, and 3 groups, respectively (P<0.0001).

    With coronary hemodynamic assessment, Pd/Pa at rest was near 1.0 (Table 2). At peak dobutamine stress, median dFFR was 0.64, and 105 patients (95%) had a dFFR≤0.76 distal to the MB. Six MB patients with a dFFR >0.76 underwent surgical unroofing due to significant angina accompanied by severe limitation of daily life (median SAQ summary score at baseline=33, range: 19–44).

    Correlations Between MB Properties and Angina Symptoms at Baseline

    The relationships between the baseline variables and the SAQ summary score before surgery are shown in Table 3, Figure IV in the Data Supplement. While the standard IVUS anatomic properties of an MB were not associated, the vessel area at the maximum compression site and the percentage of vessel restriction (both in systole and diastole) had statistically significant correlations with the baseline SAQ summary score. In particular, the strongest association was found with diastolic vessel restriction (P<0.0001 [95% CI, −0.617 to −0.283]). The area stenosis by CCTA was also associated with the baseline SAQ summary score (P=0.006 [95% CI, −0.514 to −0.087]), whereas no significant correlation was observed between dobutamine stress dFFR and the SAQ summary score (P=0.53).

    Table 3. Univariate Linear Regression Analysis for Baseline Seattle Angina Questionnaire Summary Score

    r95% CIP value
    Patient characteristics
     Age, y0.113−0.074 to 0.2780.25
     Male, yes0.099−0.002 to 0.0100.24
     Body mass index, kg/m2−0.155−0.105 to 0.0140.13
     Ejection fraction, %−0.0001−0.054 to 0.0541.00
    IVUS variables
     MB total length, mm0.168−0.045 to 0.2850.15
     Max halo thickness, mm0.059−0.003 to 0.0060.60
     MB muscle index0.148−0.073 to 0.3560.19
     Distance between LAD ostium and MB, mm0.009−0.241 to 0.2640.93
     Diastolic vessel area at max CS, mm20.2810.014 to 0.0680.003
     Systolic vessel area at max CS, mm20.2160.004 to 0.0410.019
     Arterial compression, %0.119−0.076 to 0.1910.39
     Diastolic vessel restriction, %−0.470−0.617 to −0.283<0.0001
     Systolic vessel restriction, %−0.271−0.430 to −0.0900.003
     Minimum lumen area within MB, mm20.014−0.012 to 0.0180.68
     Septal perforators within MB, n0.021−0.019 to 0.0240.80
     Proximal maximum plaque burden, %0.106−0.122 to 0.2730.45
    CCTA variables
     MB total length, mm0.157−0.030 to 0.4520.09
     Coverage grade0.30
     Distance between LAD ostium and MB, mm0.100−0.338 to 0.0940.27
     Area stenosis, %−0.291−0.514 to −0.0870.006
    Stress dFFR−0.066−32.417 to 16.8380.53

    CCTA indicates coronary computed tomography angiography; dFFR, diastolic fractional flow reserve; IVUS, intravascular ultrasound; LAD, left anterior descending artery; Max CS, maximum compression site; and MB, myocardial bridging.

    Surgical Unroofing to Improve Angina Symptoms

    The median SAQ summary score was 44 (IQR, 33–55) at baseline (N=111) and 85 (IQR, 75–94) (N=86) 6 months after surgical unroofing. Paired analyses showed statistically significant improvements in all 5 SAQ categories (Table 2, Table in the Data Supplement). There were no significant periprocedural complications nor have there been any major adverse events in the 111 patients, except for the first patient who underwent a repeat surgical unroofing because of ongoing angina due to incomplete unroofing at the initial procedure.

    The median delta SAQ summary score from baseline to 6 months was 36 (range, −21 to 76). Specifically, the SAQ summary score improved after the surgery (ie, delta score >0) in 84 out of 86 patients (98%); 63 patients (73%) had >1 grade of improvement in the SAQ summary score (ie, delta score >25). Table 4 shows the results of univariate and multivariate analyses looking for determinants of the delta SAQ summary score. The univariate analysis identified diastolic vessel restriction determined by IVUS and the preoperative SAQ summary score as significant variables to the delta SAQ summary score. The correlation between diastolic vessel restriction and the delta SAQ summary score is shown in Figure V in the Data Supplement. The area stenosis by CCTA also showed a similar trend, although it did not reach statistical significance (P=0.07 [95% CI, −0.020 to 0.607]). The other parameters, including standard anatomic and hemodynamic variables, did not significantly correlate with the delta SAQ summary score. With multivariate analysis, the preoperative SAQ summary score was confirmed as an independent determinant of delta SAQ summary score (P=0.02 [95% CI, −0.931 to −0.078]), while vessel restriction continued to show a trend toward statistical significance (P=0.06 [95% CI, −0.014 to 0.586]).

    Table 4. Univariate and Multivariate Linear Regression Analysis for Improvement of SAQ Summary Score After Surgical Unroofing

    VariablesSimple regression analysisMultiple regression analysis
    r95% CIP valueβ95% CIP value
    Patient characteristics
     Age, y−0.015−0.305 to 0.2630.88
     Male, yes0.0003−4.125 to 4.1151.00
     Body mass index, kg/m20.120−0.346 to 1.2560.26
     Ejection fraction, %−0.015−0.968 to 0.8540.90
    IVUS variables
     MB total length, mm−0.111−0.464 to 0.1590.33
     Max halo thickness, mm0.053−8.284 to 13.5790.63
     MB muscle index−0.008−0.251 to 0.2330.94
     Distance between LAD ostium and MB, mm−0.059−0.449 to 0.2600.60
     Diastolic vessel area at max CS, mm2−0.201−3.299 to 0.0070.052
     Systolic vessel area at max CS, mm2−0.130−4.003 to 0.8460.20
     Arterial compression, %−0.094−0.539 to 0.2170.40
     Diastolic vessel restriction, %0.2870.107 to 0.5920.0050.232−0.014 to 0.5860.06
     Systolic vessel restriction, %0.161−0.060 to 0.4780.13
     Septal perforators within MB, n−0.053−3.056 to 1.9270.65
     Proximal maximum plaque burden, %−0.030−0.293 to 0.2230.79
    CCTA variables
     MB total length, mm−0.106−0.548 to 0.2800.52
     Coverage grade0.50
     Distance between LAD ostium and MB, mm0.030−0.238 to 0.3490.71
     Area stenosis, %0.216−0.020 to 0.6070.07
    Stress dFFR0.017−30.675 to 36.2390.87
    Preoperative SAQ summary score−0.450−0.908 to −0.4570.002−0.288−0.931 to −0.0780.02

    CCTA indicates coronary computed tomography angiography; dFFR, diastolic fractional flow reserve; IVUS, intravascular ultrasound; LAD, left anterior descending artery; Max CS, maximum compression site; MB, myocardial bridging; and SAQ, Seattle Angina Questionnaire.

    Discussion

    The present study investigated the relationship between preoperative imaging variables and severity of clinical symptoms in patients with an MB undergoing surgical unroofing for refractory angina. The main findings of this study were: (1) the resting vessel size can be restricted by an MB even during diastole, (2) vessel restriction assessed by IVUS and CCTA significantly correlates with the baseline SAQ summary score, particularly when evaluated in diastole, and (3) patients who have greater diastolic vessel restriction experience greater improvements in SAQ scores after surgical unroofing, though that is influenced by their poor quality of life at baseline. The results of this study may help clinicians predict the benefit of surgical unroofing and determine optimal management in patients with a significant MB and refractory angina despite maximally tolerated medical therapy.

    Notably, nearly 90% of the drug-refractory symptomatic MB patients evaluated in this study showed incomplete vessel dilation following systolic compression, or “diastolic vessel restriction”, the degree of which appears to be an important determinant of clinical symptoms, as well as the benefit from surgical intervention. While in clinical practice, the severity of an MB is often judged by the extent and degree of systolic vessel compression or angiographic milking, the current findings highlight the importance of diastolic variables in the comprehensive assessment of MBs. Indeed, coronary blood flow in the LAD predominantly occurs during the diastolic phase of the cardiac cycle. In the presence of a flow disturbance in systole by vessel compression, effective antegrade blood perfusion may rely almost exclusively on the diastolic coronary flow, but the flow in this phase can be diminished with delayed or restricted arterial relaxation affected by the overlying muscle band.17,19 The symptoms caused by this mechanism may be further exacerbated with shortening of diastole due to tachycardia during exercise or increased workloads in daily activities.

    The exact pathophysiology of diastolic vessel restriction by an MB is yet to be investigated. Histologically, an MB consists of muscle bands overlying in close proximity to a coronary artery, which can directly affect flexibility of the encased vascular wall and its extensibility in diastole.1–3 Considering the significant improvement of QOL achieved immediately after surgical unroofing, as shown in the present study as well as other clinical reports,12–14 the vessel restriction by an MB may be a reversible change in vessel size. On the other hand, there is also a possibility that vessel wall stress repetitively caused by an MB over the long term may lead to structural changes in the vessel wall, potentially resulting in negative arterial remodeling, which may not be corrected with this surgical procedure. Although routine follow-up with IVUS or CCTA after the surgery is challenging unless clinically indicated, longitudinal studies may elucidate this remaining question. Further investigation is also ongoing to verify the durable effect of surgical MB unroofing on long-term symptomatic improvement.

    In general, the prevalence of an MB has been reported to be 0.4% to 33% by angiography,4 23% by IVUS,22 3.5% to 58% by CCTA,21 and up to 85% in autopsy series.23 Aside from the diverse study populations, the wide range of those reported rates are likely attributable to the different sensitivities of various diagnostic modalities for the detection of an MB. Specifically, contrast angiography is the least sensitive imaging, as an MB can be diagnosed only indirectly by detecting systolic squeezing or milking of the artery.3,22 This limitation also precludes precise identification of the entrance and exit of an MB segment, which is crucial not only for guidance of surgical intervention, but also for calculation of diastolic vessel restriction investigated in the present study. As of today, IVUS is considered one of the most useful clinical imaging modalities to provide detailed anatomic characteristics of an MB by directly visualizing the bridging myocardial band and its geographic relationship with the LAD and involved branches. Optical coherence tomography is also commercially available as a higher-resolution intravascular imaging technology for assessment of CAD. However, its limited signal penetration and the need of ultrafast pullback during contrast flush preclude the direct visualization of an MB beyond the artery and more importantly, the dynamic assessment of systolic compression and diastolic restriction of the artery. In contrast, despite the lower spatial resolution and inability to measure vessel dimensions throughout the cardiac cycle, CCTA may offer unique advantages as a noninvasive, widely available clinical imaging tool. As expected, in the present study, the lower spatial resolution of CCTA possibly resulted in slight underestimation of the MB length, with corresponding overestimation of the distance from the LAD ostium compared with IVUS. Overall, however, the mean differences in those measurements were clinically acceptable (−2.4 mm for MB length and +2.0 mm for the distance from the ostium to the MB entrance), and reasonable agreements between the 2 modalities were also confirmed with the Bland-Altman and correlation analyses. Although CCTA may not be sensitive enough in predicting the symptomatic improvement by surgical intervention, its ability to provide a complete 3-dimensional map of the coronary tree in relation to an MB and the significant correlation between the diastolic area stenosis by CCTA versus the baseline SAQ summary score observed in the present study may support the use of this imaging technique to triage patients for further invasive testing and possible treatment with surgical unroofing.

    Interestingly, dobutamine-stress dFFR as another diastolic variable was not associated with the baseline SAQ summary score nor diastolic vessel restriction assessed by IVUS. This might be because, per the current study design, nearly all the patients had a dFFR ≤0.76 (ie, hemodynamic significance of the MB), with only a small range of dFFR values (IQR, 0.54–0.71). Furthermore, while clinical utility of conventional hyperemic full-cardiac cycle FFR in fixed coronary stenoses has been well validated, the interpretation of inotrope-stress dFFR to assess the hemodynamic significance of an MB remains to be fully established in large population studies. Diastolic FFR, rather than mean FFR, is necessary in assessing the hemodynamic significance of an MB because an MB is a dynamic rather than a fixed stenosis, primarily affecting diastole rather than both systole and diastole. For a fixed stenosis, there is a similar drop in systolic and diastolic pressures across the stenosis, so that the mean drop in pressure can be used in determining hemodynamic significance. By contrast, the primary hemodynamic disturbance generated by an MB occurs in diastole, particularly early diastole, where there is a delay in luminal diameter recovery due to arterial compression from the MB. Furthermore, within an MB, there is an increase in the peak systolic pressure as the vessel is compressed, which may even surpass the systolic aortic pressure (systolic overshoot), and result in retrograde systolic flow. This increase in systolic pressure raises the mean FFR, resulting in an underestimation of the pressure gradient being generated in diastole, and therefore an underestimation of the hemodynamic significance by mean FFR.24 A recent clinical study with instantaneous wave-free ratio and dobutamine-induced hyperemic wave-free period pressure ratio also provided a proof of concept of using the diastolic component of pressure waves for the functional assessment of dynamic stenoses, but the use of a resting index during inotrope-stress needs further investigation.25 Of note, the degree of diastolic vessel restriction observed in the present study (IVUS: 16.5 [IQR, 6.4–27.3]; CCTA: 19.9 [IQR, 7.9–30.0]) was not necessarily severe enough to cause significant ischemia by itself, suggesting the possible existence of a complex interaction of hemodynamic disturbances occurring in systole and diastole in the development of myocardial ischemia and clinical symptoms. This raises the question of potentially varying utility of the numerous diastolic indices that each measure a different portion of the diastolic cycle, and whether a unique physiological index involving parts of both diastole and systole may be more accurate. Further research including assessment of vessel restriction during inotrope-stress is warranted to investigate integrative diagnostic indices to represent the exact pathophysiology of symptomatic MBs.

    Clinical Implications

    There are several causes of ischemia and normal coronary arteries, including microvascular dysfunction, coronary vasospasm, and myocardial bridging.26,27 To date, there are no established guidelines for treatment of QOL-limiting symptomatic MBs, particularly for patients with refractory angina despite maximally tolerated medical therapy. Medical management primarily consists of beta-blockers to reduce compression of the artery by the muscular band and slow the heart rate, thereby increasing the diastolic period.10,28 However, the latter effect may be diminished in the presence of diastolic vessel restriction, as observed in the majority of the current study population. Theoretically, stent placement can directly resolve both the systolic compression and diastolic restriction by the MB, but controversy exists due to potential complications, such as coronary perforation, stent strut fracture, and in-stent restenosis, derived from mechanical interaction between the permanently implanted metallic device and the MB.29,30 In addition, the myocardial band limits the extent to which the stent can expand the vessel, and based on our findings, this extent may be most limited in the most severe cases. In contrast, surgical unroofing can potentially correct these pathologies and has been attempted in patients with symptomatic MB since 1975 with excellent mid- and long-term outcomes reported.31 Single-center experience mounting at our institution in both the adult and pediatric populations has also demonstrated significant improvements in all dimensions of SAQ scores after surgical unroofing without any major complications or death.13–15 To assure complete unroofing with minimum risk of surgical complications, however, detailed preoperative evaluation, such as an IVUS map of the MB, is crucial since the epicardial adipose tissue overlying the LAD artery often precludes operators from precisely identifying a tunneled coronary segment during surgery. More importantly, it would be ideal to define patients a priori who would most benefit from invasive treatment of an MB. Although multiple factors may account for the difference in individual symptoms and treatment response, the current results suggest the clinical feasibility of invasive or even noninvasive evaluation of such factors associated with QOL impairment and possible prediction of the benefit of surgical treatment in patients with severe symptomatic MB. While the present study focused on clinical symptoms as the primary end point, further research is warranted to investigate whether this finding is also applicable to risk stratification and improvement in hard end points, such as myocardial infarction, ventricular arrhythmias, or sudden cardiac death. Ultimately, the optimal treatment option should be determined for each patient with a significant MB using versatile anatomic and hemodynamic assessments.

    Limitations

    First, while this study represents the largest series of patients with symptomatic MB who underwent surgical unroofing in the literature, it was based on a retrospective analysis with a relatively small sample size at a single center. Thus, larger clinical studies should confirm the applicability of the present results. In addition, this was a select group of patients with MB with refractory angina despite maximally tolerated medical therapy. Therefore, there was no control group to determine the role of vessel restriction in less symptomatic MB patients, potentially limiting application of the findings to the general population with an MB. Second, this was a single-vessel analysis specific to the LAD. Still, the LAD is recognized as the most common location of an MB and an important determinant in patient prognosis.3,32 In addition, among the enrolled 111 patients, there was no patient with a significant MB in a non-LAD vessel based on review of the exercise echocardiogram, CCTA, and coronary angiogram. Third, the follow-up SAQ assessment was not mandatory and therefore, was not available in all the enrolled patients, raising a possibility of selection bias. Fourth, in the present study, we could not assess the pure benefit from surgery because the SAQ summary score is a subjective measure of symptoms and has an upper limit (ie, the maximum SAQ score is 100), which influences statistical outcomes. To truly validate the effect of surgery on symptoms, a randomized controlled trial with sham surgery, albeit challenging, would be needed. Alternatively, repeat invasive testing following surgery could provide objective measures of change but is also challenging financially and ethically, particularly in patients who are reporting that they feel well. Finally, the present study evaluated the outcomes up to 6 months. Longer-term follow-up is warranted to evaluate the sustainability of effect of surgical unroofing for the treatment of symptomatic MBs.

    Conclusions

    In patients with an MB and refractory angina, diastolic vessel restriction determined by IVUS and CCTA correlates with the limitation of their activity in daily life. In addition to the conventional anatomic and hemodynamic MB assessments before unroofing surgery, this simple index may add further information to predict the degree of improvement in quality of life by surgery in certain patient subsets.

    Nonstandard Abbreviations and Acronyms

    CAD

    coronary artery disease

    CCTA

    coronary computed tomography angiography

    dFFR

    diastolic fractional flow reserve

    IQR

    interquartile range

    IVUS

    intravascular ultrasound

    LAD

    left anterior descending artery

    MB

    myocardial bridge

    SAQ

    Seattle Angina Questionnaire

    Supplemental Materials

    Expanded Methods

    Online Figures I–V

    Online Table

    References 33–39

    Disclosures Dr Tremmel has received honoraria from Abbott Vascular, Boston Scientific, Medtronic, Terumo, and Philips. Dr Nieman has reported unrestricted, institutional research support from Siemens Healthineers, HeartFlow, Inc, Bayer; consulting for Siemens Medical Solutions. The others authors report no conflicts.

    Footnotes

    The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCINTERVENTIONS.121.011062.

    For Sources of Funding and Disclosures, see page 1034.

    Correspondence to: Jennifer A. Tremmel, MD, MS, Stanford University Medical Center, 300 Pasteur Dr, Room H2103, Stanford, CA 94305-5218. Email

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