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THE PRESENT AND FUTURE

REVIEW TOPIC OF THE WEEK

Left Anterior Descending ArteryMyocardial BridgingA Clinical Approach

Giuseppe Tarantini, MD, PHD,a Federico Migliore, MD, PHD,a Filippo Cademartiri, MD, PHD,b,c

Chiara Fraccaro, MD, PHD,a Sabino Iliceto, MDa

ABSTRACT

Fro

Era

Un

a c

ha

Ma

A myocardial bridge (MB) is the term for the muscle overlying the intramyocardial segment of the epicardial coronary

artery (referred to as a tunneled artery). Although MBs can be found in any epicardial artery, most of them involve the

left anterior descending artery. These congenital coronary anomalies have long been recognized anatomically, and are

traditionally considered a benign condition; however, the association between myocardial ischemia and MBs has

increased their clinical relevance. This review summarizes the prevalence, pathophysiology, and diagnostic findings,

including morphological, functional assessment, and treatment of patients with MB involving the left anterior

descending artery, suggesting a pragmatic clinical approach to this entity. (J Am Coll Cardiol 2016;68:2887–99)

© 2016 by the American College of Cardiology Foundation.

T he coronary arteries may dip into themyocardium for varying lengths, and thenreappear on the heart surface. The muscle

overlying the intramyocardial segment of theepicardial coronary artery is termed a myocardialbridge (MB), and the artery running within themyocardium is referred to as a tunneled artery.Although MBs can be found in any epicardial artery,most (70% to 98%) involve the left anteriordescending artery (LAD) (1). These congenital coro-nary anomalies have long been recognized anatom-ically, and were traditionally considered a benigncondition (2); however, the association betweenmyocardial ischemia and MBs has heightened theirclinical relevance (3). This review summarizes theprevalence, pathophysiology, diagnostic findings,and treatment of patients with MB involving theLAD, suggesting a pragmatic clinical approach tothis entity.

m the aDepartment of Cardiac, Thoracic and Vascular Sciences, University

smus Medical Center University, Rotterdam, the Netherlands; and the c

iversitè de Montréal, Montreal, Quebec, Canada. Prof. Tarantini received l

onsultant for Boston Scientific. Prof. Cademartiri is a consultant for SIEME

ve reported that they have no relationships relevant to the contents of th

nuscript received May 29, 2016; revised manuscript received August 28,

EPIDEMIOLOGY

The true prevalence of MB is not fully known andvaries widely according to the methods used to detectsuch an anatomic variant. Accordingly, an accuratespecific prevalence of LAD-MB is difficult to derive.Numerous necropsy series have been performed, withreported MB rates of 5% to 86% (4,5). On average,MBs are present in one-fourth of adults. Pathologicalseries including thin MBs, or even myocardial strandswith little hemodynamic consequences, reportedhigher rates of MBs compared with coronary angiog-raphy, which typically detects systolic compression(milking effect). Accordingly, the angiographicdetection rate of MBs varies from 0.5% to 12% (6) inresting conditions to 40% with provocative testsor intracoronary injection of nitroglycerin. Severalfactors have been postulated to account for the re-ported mismatch between the rates of tunneled

of Padua, Padova, Italy; bDepartment of Radiology,

Department of Radiology, Montréal Heart Institute,

ecture fees from St. Jude and Volcano. Dr. Migliore is

NS, Guerbet, and SOMAHLUTION. All other authors

is paper to disclose.

2016, accepted September 27, 2016.

ABBR EV I A T I ON S

AND ACRONYMS

CCT = cardiac computed

tomography

CFR = coronary flow reserve

FFR = fractional flow reserve

iFR = instantaneous wave-free

ratio

IVUS = intravascular

ultrasound

LAD = left anterior descending

artery

LV = left ventricle

MB = myocardial bridging

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arteries observed at necropsy comparedwith observations from angiography. Theseinclude the thickness and the length of theMB, the reciprocal orientation of the coro-nary artery and myocardial fibers, the pres-ence of loose connective or adipose tissuearound the bridged segment, the presence ofan aortic outflow tract obstruction (in whichthe systolic tension that develops in the MBovercomes the intracoronary artery pres-sure), the intrinsic tone of the coronaryartery wall, the presence of a proximal coro-nary fixed obstruction (which causes adecrease in distal intracoronary pressure),the state of myocardial contractility and

heart rate at the time of angiography, and observerexperience (7). The use of intravascular ultrasound(IVUS), which is more sensitive for detection of minorcompression, increases MB prevalence to 23%(8). More recently, the introduction of cardiaccomputed tomography (CCT), with its multiplane and3-dimensional capabilities, has significantly im-proved the detection rate of MB (in vivo), even whenthe milking effect and/or changes in vessel course atconventional angiography are absent or mild. Hence,the CCT-based prevalence of MBs rises to 5% to 76%,depending on the intrinsic heterogeneity of the studypopulation, scanner types, and MB pattern (superfi-cial vs. deep encasement) (6,7).

PATHOPHYSIOLOGY

Myocardial perfusion occurs primarily in diastolebecause systolic contraction transiently impedescoronary blood flow, especially to the sub-endocardium (9). Thus, MB replicates the normalmicrovascular physiology of high diastolic and lowsystolic flow, although at the level of the epicardialcoronary artery. Given that in normal conditions, only15% of coronary blood flow occurs during systole, andthat the effect of MBs is a systolic event at angiog-raphy, the clinical relevance of MBs has been ques-tioned. However, other than the usually benignnature of MBs, what do we know about them that isimportant to clinical pathophysiology? Are all LAD-MBs the same? What additional factors unmask andaggravate an MB? When does a previously asymp-tomatic patient with a congenital MB becomesymptomatic? What diagnostic tests may guide man-agement of MBs? As shown in panel A of the CentralIllustration, LAD-MBs may significantly differanatomically with respect to depth (superficial: >1 to2 mm vs. deep: >2 mm) and length of encasement(10). The latter seems to influence the dynamic

compression not only of the entrapped LAD segment,but also of the septal branches arising from or nearthe involved LAD segment (11,12). Other importantanatomic properties of LAD-MB to consider are theconcomitant number of arteries or tunneled seg-ments, and the degree of systolic diameter reductionor kinking.

Clinical and pathophysiological factors that mayunmask or exacerbate MB are the age of the patient,heart rate, left ventricle (LV) hypertrophy, and thepresence of coronary atherosclerosis (9). In this re-gard, the increase of LV diastolic dysfunction associ-ated with aging, LV hypertrophy, and coronaryatherosclerosis may worsen not only the supply-demand mismatch imposed by the bridge (9), butalso reduce microvascular reserve by compression ofthe microvasculature. Similarly, tachycardia associ-ated with increased sympathetic drive due to exerciseor emotional distress reduces flow and myocardialperfusion by shortening diastolic perfusion time, andalso increases epicardial coronary vasoconstriction aswell as contraction of the MB over the tunneledepicardial LAD (13,14) (Figure 1A). Indeed, a prolon-gation of the MB contraction due to delayed ventric-ular relaxation may impair the early hyperemicdiastolic flow beyond that which results simply fromtachycardia, reducing the diastolic perfusion time (15)(Figure 1B). Additionally, this may also cause a local-ized phasic coronary spasm that persists into diastole,because the relaxation time of the arterial vascularsmooth muscle is delayed compared with the dura-tion of diastole, especially with tachycardia, whichcontributes to further worsening the coronary perfu-sion (11). The resulting impairment of diastolic flowhas 2 secondary pathophysiological consequencesrelated to heart rate and severity and duration ofepicardial arterial compression. These consequencesare the subendocardial/transmural ischemia and theseptal ischemia caused by an “intramural steal” or“branch steal” mechanism (11,16). The latter is causedby the depressurization of septal branches within theMB, resulting in an intrabridge decrease in perfusionpressure due to a Venturi effect, or simply due to aclassic fluid dynamic entrance and viscous pressureloss in the narrowed section, causing the “branchsteal” (12,16) (Central Illustration). In this regard, mildto moderate MB compression more frequently resultsin local (septal) ischemia (due to branch steal), ratherthan distal ischemia, as shown by the presence ofnormal coronary flow or fractional flow reserve (FFR)downstream of the epicardial coronary (16). More-over, the reversal of systolic flow seen on Dopplertracings, in which retrograde flow collides withantegrade flow, causes high systolic wall shear stress

CENTRAL ILLUSTRATION LAD Coronary Artery Myocardial Bridging: Anatomic Properties and Clinical andPathophysiological Factors of MB of the LAD

Tarantini, G. et al. J Am Coll Cardiol. 2016;68(25):2887–99.

(A) Morphological variations in tunneling (length and depth of tunneled segment). (B) Pathophysiological factors that may unmask or exacerbate myocardial bridging

(MB). (C) Pathophysiological mechanisms that play a potential role in the genesis of the clinical factors related to MB, including “intramural steal” or “branch steal”

mechanism, coronary spasm, coronary artery disease, and coronary dissection. LAD ¼ left anterior descending artery.

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upstream from the bridge entrance and seems to playan important role in formation and spatial distribu-tion of coronary plaques that are usually present 20 to30 mm proximal to the entrance of MBs, wheredisturbed near-wall blood flow patterns are present(17,18). These altered biomechanical forces at thelevel of the MB may also underlie other potentialcomplications, such as plaque vulnerability/throm-bosis (17), increase in vasospasticity (19), and intimalinjury that may further develop into coronarydissection (20).

Despite this, the severity and effects of MBs seemto be more appropriately defined by (patho)physi-ology than by anatomy. Thus, the rare MBs causingischemia must incur complex pathophysiological dy-namics related to intrinsic and extrinsic factors,which include time-varying interactions among aorticpressure, arterial and myocardial compression, dia-stolic flow, transmural perfusion gradients, heart rateor diastolic perfusion time, and sympathetically-driven myocardial contraction and coronary vaso-constriction, all of which interact with diffuse and

FIGURE 1 Schematic of Interaction Among Tachycardia, Coronary Artery Flow, and Transmural Distribution

Tachycardia − No MBTachycardia − Severe MBRest Flow

Coro

nary

Flo

w (c

c/m

in)

Systole Diastole Time (sec)

Subepicardial flowSubendocardial flow & Peak flow delayed 20 secAverage transmural flow

10 − 20 sec

150

BA

100

50

0

Coro

nary

Blo

od F

low

(% M

axim

um M

ean

Coro

nary

Flo

w)

20 40 60 80 100 120 140 160 180 200Seconds After Release of 90-sec LAD Occlusion

90-sec occlusion

(A) Schematic of coronary artery flow. Coronary artery flow at rest (dotted blue line) and during stress hyperemia and tachycardia in the absence of a significant

myocardial bridging (MB) (solid blue line). The stress hyperemic response may be severely blunted (solid orange line) by severeMB compression of the epicardial artery

and dynamic severe stenosis that limits coronaryflow reservewith lowdistal fractionalflow reserve. (B)Differential perfusion of the subepicardium and subendocardium in

a normal nonstenosis experimental model. The rate of increase in coronary bloodflow in early diastole is fastest in the epicardium and slowest in the subendocardium. The

time delay in subendocardial hyperemia after subepicardial hyperemia is significant (range 10 to 20 s), and at the time that the initially high subepicardial hyperemia

peaks, subendocardial hyperemia has reached only about 50% of its peak. Many factors may impede this rapid early diastolic hyperemia including (rarely) MBs. As the

diastolic perfusion time shortens because of tachycardia, there is not enough time between serial systoles for the impeded and slowly increasing diastolic coronary blood

flow to adequately supply the subendocardium. Adapted with permission from Gould and Johnson (14). LAD ¼ left anterior descending artery.

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focal atherosclerotic disease that is beyond anatomicdescription.

CLINICAL PRESENTATION

An MB of the LAD is usually an incidental finding onangiography or autopsy. Nevertheless, patients withMB may present with stable (exercise-induced)symptomatic or silent myocardial ischemia, as well aswith acute coronary syndrome due to complicationspotentially related to the presence of an MB, such ascoronary spasm, thrombosis, and coronary dissection(20) (Central Illustration). Other reported clinical pre-sentations are syndrome X, myocardial stunning ortransient ventricular dysfunction, Takotsubo syn-drome/cardiomyopathy, and life-threatening ven-tricular arrhythmias and sudden death (4,21–24).Given the low prevalence of these clinical findings,the correlation with data from diagnostic testing toidentify whether this broad spectrum of clinicalischemic symptoms are related directly to MB, orindirectly to concomitant vasospasm, atherosclerosis,or none of the preceding, is extremely challenging.

MORPHOLOGICAL ASSESSMENT

The original definition and classification of MB hasbeen developed with invasive coronary angiography(2). However, because of the lack of a true gold

standard for diagnosing MB, a number of diagnosticmodalities have been used to assess its anatomic/morphological and functional significance (Table 1).

At coronary angiography, the MB typically appearsas a systolic narrowing, or “milking” of the vessel,with a “step-down” and “step-up” demarcating theaffected area, and complete or partial decompressionin diastole (Figures 2A and 2B) (25). The reduction indiastolic coronary arterial diameter ranges from 24%to 58%, compared with the 71% to 99% systolicreduction (26). Systolic narrowing at the bridge can beaccentuated by intracoronary injection of nitroglyc-erin, which vasodilates adjacent nonbridged coronarysegments (27). Adjunctive intravascular imagingmight be useful to improve the detection rate, and tobetter characterize the length, thickness, and locationof the MB. The IVUS hallmark of the presence of atunneled segment of LAD is a variable degree ofcompression that persists into diastole, with thetypical finding of the “half-moon phenomenon,” anecholucent area present only between the bridgedcoronary segment and epicardial tissue throughoutthe cardiac cycle (28). The etiology of this phenome-non is not well understood, presumably representingthe intramyocardial course of the LAD, but it couldalso result from the fiber optic probe bending at theMB site. Regardless, this finding remains highlyspecific because it can be detected only in the MB

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segment with systolic compression, and not in adja-cent reference segments without compression (28).IVUS also remains an important diagnostic tool tocharacterize the presence, severity, and distributionof subangiographic atherosclerosis, coronary dissec-tion, or other complications that might be associatedwith MB, with their inherent treatment implications(e.g., appropriate stent selection and placement)(8,29). Few data exist on optical coherencetomography, although this technique may theoreti-cally improve the characterization of the vesselwall, providing more information on pathologicalchanges (30).

The clinical implementation and widespread use ofCCT has also improved the characterization and un-derstanding of MBs (31). The advantage of CCT in theassessment of MB is related to its fully 3-dimensionalcapability, which is associated with high spatial andcontrast resolution. CCT can easily visualize the cor-onary lumen, the vessel wall, and the myocardialwall, hence allowing accurate definition of the MB’smorphological features (31). The CCT scan protocol isnot different from the conventional protocol used toassess coronary artery stenosis. Post-processingsoftware is helpful for the precise definition of thelength and depth of the MB. CCT-based reclassi-fication of the LAD’s anatomic course includes normal(within the epicardial fat), superficial intra-myocardial, and deep intramyocardial courses(Figure 3). A field in which CCT has shown evidence ofthe importance of MB is Takotsubo syndrome. Thissyndrome has been shown to be associated with asignificantly higher prevalence of MB on the LAD (21).Cardiac magnetic resonance can provide anatomiccoronary imaging, but because of limitations inspatial resolution and technical failures, it cannotprovide reliable and robust insight into the intra-myocardial depth of the LAD.

FUNCTIONAL ASSESSMENT

As in fixed stenosis, intracoronary physiology tech-niques represent a valuable alternative to coronaryangiography. However, these diagnostic tools arehampered by the complex hemodynamics, cyclicchanges in luminal dimensions, and noncircularlumen morphology of the bridged LAD. Becausethese dynamic stenoses are dependent on the degreeof extravascular compression and intramyocardialtension and are unmasked by chronotropic andinotropic stimulation, their invasive assessmentshould not be limited to resting conditions. Accord-ingly, although the traditional use of FFR, requiringonly 2 mean pressures to be obtained during maximal

(adenosine-induced) hyperemia, is accepted as thegold standard for assessment of fixed coronary le-sions, this is largely inadequate for assessment of thehemodynamic significance of an MB (32,33). More-over, MB may cause significant diastolic pressuregradients and artificially normal or negative systolicpressure gradients (systolic distal pressure is greaterthan systolic proximal pressure) as a result of systolicpressure overshooting; this is completely differentfrom fixed stenosis, in which the difference betweenmean and diastolic pressure gradient values acrossthe lesion are not significant (Figure 4) (33). Thisphenomenon may produce an artificial elevation inthe mean pressure used by traditional FFR (averagesystole and diastole), resulting in an underestimationof hemodynamic significance of the MB (Figures 2Cto 2G) (33). Diastolic FFR with the use of dobut-amine challenge is a more appropriate approach fortesting the hemodynamic significance of MB becausethe MB has less influence on diastole, whereas FFR onthe basis of mean pressures should be used withcaution (34). Escaned et al. (34) demonstrated thatcombining low-dose intracoronary adenosine (20 mg)with moderate-dose intravenous dobutamine infu-sion (20 mg/kg/min) increased the likelihood ofunmasking larger diastolic pressure gradients in pa-tients with LAD-MB and ischemia in noninvasivetests, showing that diastolic FFR identifies a signifi-cant proportion of hemodynamically relevant MBsthat conventional FFR did not identify. The investi-gators also found that the angiographic severity ofMB was modified by dobutamine. Another smallstudy of 18 patients with MB reported that the use ofdobutamine-diastolic FFR resulted in larger gradientsin 3 patients; however, the investigators failed to finda correlation with major adverse cardiac events (12).Besides these 2, there are no other studies correlatingdiastolic FFR using adenosine, dobutamine, or bothwith noninvasive parameters of ischemia, or withclinical outcomes (35). Recently, the instantaneouswave-free ratio (iFR), a pressure-only index that takesan alternative approach to the isolation of the he-modynamics of a stenosis from the microcirculation,has been introduced. It does not need the adminis-tration of vasodilators; instead, it samples intra-coronary pressure during the diastolic “wave-free”period—a period in the cardiac cycle when intrabeatmicrovascular resistance is inherently stable andminimized, and the flow is at its highest comparedwith the whole cycle (36). The iFR is a diastolic-specific index, and for this reason, it appears prom-ising in MB physiological evaluation. Also, iFR allowsanatomic mapping by means of coregistration (iFRScout). Figure 2 shows a typical clinical example that

TABLE 1 Myocardial Bridging and Imaging Modalities

ImagingModality Description Semiology Diagnostic Criteria Pros Cons X-Rays Contrast

PharmStress

Invasive

CAG Invasive technique usingselective catheterization ofcoronary arteries.

2D visualization of the anatomyof the coronary arteriesthrough luminography thatallows the measurements oflumen diameter.

Milking effect Most frequently used.Anatomic/dynamic assessment.

No functional va þþ þþ �

IVUS Invasive technique usingselective catheterization ofcoronary arteries, andinsertion of the probe acrossthe region of interest.

3D visualization of the anatomyof the coronary artery thatallows accuratemeasurements of lumendiameter/area and of thevessel wall.

Half-moon Identify:� Proximal plaque� Negative arterial

remodeling� Extent of phasic arterial

compression

Not commonly uNo functional va

þþþ þþ �

IntracoronaryDoppler

Invasive technique usingselective catheterization ofcoronary arteries andinsertion of a wire across theregion of interest.

Evidence of specific alteredfunctional patterns ofhemodynamic significanceassociated with MB.

Fingertip � Functional evaluation ofcoronary lesions andmicrovascular disease

� Simulation of dynamicmyocardial obstruction

� Endothelial functiontesting/coronaryvasospasm assessment.

Longer procedur ePharmacological effects.No standard cut ith Ade

or DobOff-label use of ylcholine

þþþ þþ þþ

FFR Invasive technique usingselective catheterization ofcoronary arteries andinsertion of a wire across theregion of interest.

Determination of a reduction ofthe ratio between themaximum achievable bloodflow in a diseased coronaryartery and the theoreticalmaximum flow in a normalcoronary artery.

FFR <0.75–0.80 Functional evaluation of:� Fixed lesions (gold

standard)� Dynamic coronary

obstruction

Longer procedur eAdenosine is ma oryPharmacological effectsPd/Pa as averag systole

and diastole

þþþ þþ þþ; Ade

iFR Invasive technique usingselective catheterization ofcoronary arteries andinsertion of a wire across theregion of interest.

Ratio of proximal and distalcoronary pressures over thewave-free period in diastole.

iFR <0.86 (gray zone0.86–0.93)

Functional evaluation of:� Fixed lesions� Dynamic coronary

obstructionDiastolic specific indexAde not mandatory

Longer procedur eFurther validatio eded

þþþ þþ þ/�

Noninvasive

CCT 3D noninvasive techniqueperformed on outpatientbasis; not technicallydifferent from any othercontrast-enhanced CT.

Accurate visualization of thecourse of coronary arteriesinto the epicardial fat andwithin the myocardial wall;can define degree of radialinvolvement of coronarywall and myocardial wall.

At least 1mm of myocardiumcovering the coronary artery(i.e., deep intramyocardialcourse).

More accurate thanangiography.

Shows atherosclerosis withinthe coronary segment.

Widely tested for the detectionand definition of MBs.

Not readily availNo functional va

þ þþ �

TAG Noninvasive techniqueperformed on outpatientbasis; not technicallydifferent from any othercontrast-enhanced CT.

Linear regression coefficientbetween luminal attenuationand axial distance from thecoronary ostium.

Drop in HU per 10 mm length ofcoronary artery; variablethresholds depending ondifferent methods

The same of CCT þ additionalfunctional assessmentat rest.

Not tested on M þ þþ �

FFRct Noninvasive techniqueperformed on outpatientbasis; not technicallydifferent from any othercontrast-enhanced CT.

CT-derived computational fluiddynamics application.Resembles invasive FFRconcept. Not performedduring stress.

FFR <0.75–0.80 The same of CCT þ additionalfunctional assessment atrest.

Not tested on M þ þþ �

Continued on the next page

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TABLE 1 Continued

ImagingModality Description Semiology Diagnostic Criteria Pros Cons X-Rays Contrast

PharmStress

CTP Noninvasive techniqueperformed on outpatientbasis that provides stressperfusion information.

Reversible stress-inducedmyocardial perfusion defectin the absence ofangiographic coronary arterydisease.

Segmental subendocardialperfusion defect

Usually combined with CCT canprovide anatomic andfunctional assessment of theeffect of MB.

Not readily availableNot tested on MBs

þþþ þþþ þþ; Ade

SPECT Noninvasive techniqueperformed on outpatientbasis that provides stressperfusion information.

Reversible stress-inducedmyocardial perfusion defectin the absence ofangiographic coronary arterydisease.

Segmental perfusion defect Physiological assessment offunctional effect of MB.

Not readily availableNo anatomic valueLow spatial resolution for

subendocardial defects

þþþ þþ þþ; Ade, Dyp,Dob

PET Noninvasive techniqueperformed on outpatientbasis that providesquantitative stress perfusioninformation.

Reversible stress-inducedmyocardial perfusion defectin the absence ofangiographic coronary arterydisease. Provides global andregional CFR quantitativevalues.

Segmental perfusion defect Physiological assessment offunctional effect of MB.

Not readily availableNo anatomic valueNot tested on MBsLow spatial resolution for

subendocardial defects

þþ þþ þþ

CMR Noninvasive techniqueperformed on outpatientbasis that provides stressperfusion information.

Reversible stress-inducedmyocardial perfusion defectin the absence ofangiographic coronary arterydisease.

Segmental subendocardialperfusion defect

Physiological assessment offunctional effect of MB.

Not readily availableNo anatomic valueNot tested on MBs

� þþ þþ; Ade

Stress TTE Noninvasive techniqueperformed on outpatientbasis that provides stresskinetic information.

Reversible stress-inducedmyocardial hypokinesia inthe absence of angiographiccoronary artery disease.

Segmental hypokinesia Physiological assessment offunctional effect of MB.

Readily available.

No anatomic value � � þþ; Dyp, Dob

TDE Noninvasive techniqueperformed on outpatientbasis that provides stressperfusion information.

Reversible stress-inducedmyocardial perfusion defectin the absence ofangiographic coronary arterydisease.

Provides regional (mostly LAD)CFR qualitative assessment.

Segmental perfusion defect Physiological assessment offunctional effect of MB.

Readily available.

No anatomic value � þþ þþ; Dyp, Dob

2D ¼ 2-dimensional; 3D ¼ 3-dimensional; Ade ¼ adenosine; CAG ¼ coronary angiography; CCT ¼ cardiac computed tomography; CFR ¼ coronary flow reserve; CMR ¼ cardiac magnetic resonance; CT ¼ computed tomography; CTP ¼ cardiac computed tomographyperfusion; Dob ¼ dobutamine; Dyp ¼ dypiridamole; FFR ¼ fractional flow reserve; FFRct ¼ computed tomography–derived fractional flow reserve; iFR ¼ instantaneous wave-free ratio; LAD ¼ left anterior descending; MB ¼ myocardial bridge; Pa ¼ proximal pressure;Pd ¼ distal pressure; PET ¼ positron emission tomography; Pharm Stress ¼ pharmacological stress; SPECT ¼ single-photon emission computed tomography; TAG ¼ transluminal attenuation gradient; TDE ¼ transthoracic Doppler echocardiography; TTE ¼ transthoracicechocardiography.

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FIGURE 2 Intracoronary Hemodynamics From a Patient With MB

BASAL DOBUTAMINE STRESS

Continued on the next column

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highlights the differences in LAD-MB functionalevaluation between FFR (mean pressure) and iFR(diastolic pressure) with anatomic mapping, both atrest and after dobutamine. However, the use of iFR inthis setting remains to be validated.

Finally, the use of Doppler-tipped guidewires formeasurements of intracoronary flow velocity andcoronary flow reserve may reveal both: 1) the retro-grade flow during systole immediately proximalto the bridged segment; and 2) the “fingertipphenomenon,” an abrupt early diastolic flow accel-eration, rapid mid-diastolic flow deceleration, and amid-to-late diastolic plateau (“spike-and-dome”pattern) (37).

When invasive tools to evaluate ischemic poten-tial of MB are not available, functional noninva-sive imaging tests may be helpful. Stressechocardiography, stress cardiac magnetic reso-nance, single-photon emission computed tomogra-phy, and positron emission tomography can detectthe functional effect of an MB of the LAD (38).Compared with the others, cardiac magnetic reso-nance has a better spatial resolution to detectsegmental and subendocardial perfusion defects.More recently, new post-processing techniques areavailable for the derivation of functional informationfrom the anatomic assessment provided by CCT.These techniques are mostly post-processing algo-rithms: transluminal attenuation gradient andcomputed tomography (CT)–derived FFR (39). Theformer corresponds to the linear regression coeffi-cient between luminal attenuation and axial dis-tance from the coronary ostium (40). The CT-derivedFFR is a computational fluid dynamics simulation ofadenosine-mediated hyperemia applied to CCT im-aging, and is on the basis of attenuation through thecoronary artery associated with morphology of the

FIGURE 2 Continued

(A and B) Diastolic and systolic angiographic appearance,

respectively, of an LAD-MB at resting conditions. (E and F) The

different angiographic appearance of the same vessel in dias-

tole and systole during dobutamine infusion (20 mg/kg/min).

(C and G) Proximal pressure (Pa) (red tracing) and distal

pressure (Pd) (yellow tracing) measurements from the same

patient. FFR measurements are negative and nonsignificantly

different, both at baseline (FFR 0.88) (C) and during

dobutamine/adenosine intravenous infusion (FFR 0.87) (G).

In contrast, instantaneous wave-free ratio (iFR) measurement

at rest is in the “gray zone” (iFR 0.89) (D), and becomes

definitely positive during dobutamine infusion (20 mg/kg/min)

(iFR 0.83) (H). (I) Finally, iFR with anatomic coregistration

(iFR Scout) for simultaneous MBmapping. FFR¼ fractional flow

reserve; other abbreviations as in Figure 1.

FIGURE 3 CCT of a Patient With 2 Atypical Intramyocardial Courses of the LAD

and the LCX

(A and B) Volume rendering images with vessel tracking; (C and D) longitudinal curved

multiplane reconstructions. The intramyocardial course of the LAD (A and C) is quite

extensive (74 mm), and involves the middle and distal segments of the vessel. It does not

show overlying myocardial tissue; therefore, it can be addressed as superficial. The

intramyocardial course of the LCX (B and D) is also quite extensive (65 mm), and

involves the distal segment of the vessel. It shows overlying myocardial tissue;

therefore, it can be addressed as deep. CCT ¼ cardiac computed tomography; LAD ¼ left

anterior descending artery; LCX ¼ left circumflex.

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vessel lumen and other parameters (41). Bothmethods have not been tested on series of patientswith MBs. Recently, CT scanners of the latest gen-eration have also been used to perform CT stressperfusion. Hybrid scanners combining imagingtechniques have also been introduced, and might beuseful for a combined anatomic and functionaldefinition of coronary lesions and MBs. Yet, thereare no available data on the use of hybrid techniquesfor the definition and characterization of MBs.

MANAGEMENT

There is no accepted anatomic or functional clas-sification of MBs that would provide the basis forrequiring a specific treatment for a patient. More-over, the variability in clinical symptoms, resultsof noninvasive tests, and the concomitant presenceof other conditions, such as coronary artery dis-ease, hypertrophic cardiomyopathy, or valvularheart disease, may independently influence treat-ment options and outcomes of patients with MB. Aproposed management strategy for MB of the LADon the basis of the presence of clinical symptomsand/or objective signs of ischemia is shown inFigure 5.

PHARMACOLOGICAL THERAPY. Schwarz et al. (42)proposed the following classification of MB in theabsence of coronary artery disease: type A, clinicalsymptoms and no objective signs of ischemia; type B,clinical symptoms and objective signs of ischemia bynoninvasive stress test; and type C, clinical symptomsand objective altered intracoronary hemodynamics(by quantitative coronary assessment/coronary flowreserve/intracoronary Doppler). The 5-year follow-updata on the basis of this classification showed thattypes B and C responded well to b-blockers orcalcium-channel antagonists. Patients with type C MBrefractory to medical therapy were treated withstenting of the MB. On the basis of previous patho-physiological considerations, the mainstay of medicaltreatment should focus on relieving potential triggersand hemodynamic disturbances that aggravate theMB, such as hypertension/hypertrophy, increasedheart rate, reduced diastolic coronary filling period,and inappropriate contractility and compression ofthe coronary arteries. Accordingly, b-blockers areconsidered first-line therapy because of their nega-tive chronotropic and inotropic effects, and becauseof the reduction in sympathetic drive (exertion orstress-induced) (4,26,42). Calcium-channel blockersmay offer additional benefit by reducing concomitantvasospasm incremental to the aforementioned

FIGURE 4 Intracoronary Hyperemic Pressure Measurements at Baseline and During Dobutamine Challenge in MB

ECG

Adenosine ic Adenosine + Dobutamine iv

Pres

sure

(mm

Hg)

150

90

30

110

70Pa

Pd

Pa

Pd

Pa

Pd

30

Schematic of recorded ECG, Pa, and intracoronary Pd. The overshooting of Pd over Pa noted during dobutamine challenge contributes to the

characteristic negative systolic and positive protodiastolic pressure gradients. This phenomenon may produce an artificial elevation in the

mean pressure used by traditional FFR (average systole and diastole), resulting in an underestimation of hemodynamic significance of the MB.

Adapted from Escaned et al. (34). ECG ¼ electrocardiogram; ic ¼ intracoronary; iv ¼ intravenous; other abbreviations as in Figures 1 and 2.

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pharmacological effects of b-blockers. Randomizedclinical trials assessing the effect of b-blockers orcalcium-channel blockers are lacking. Pure vasodila-tors, such as nitroglycerin, are not indicated becausethey can worsen symptoms due to the increasedsystolic compression of the tunneled artery, tachy-cardia, and proximal vessel dilation, which mayaggravate the flow reversal in the proximal coronarysegment to MB (27). Ivabradine, by reduction of theheart rate via specific inhibition of If ion channels,might be considered in place of or together with alower dose of b-blockers and calcium-channelblockers. Aggressive risk factor modification is rec-ommended because of the inherent risk of the MBinducing atherosclerosis; antiplatelet therapy shouldbe considered when subclinical atherosclerosis isdetected.PERCUTANEOUS OR SURGICAL TREATMENT. Othertherapeutic approaches include stents, minimallyinvasive coronary artery bypass grafting (CABG), orsurgical myotomy. Although percutaneous coronarystent implantation may ameliorate hemodynamicabnormalities and improve symptoms (37), no studieshave demonstrated normalization of myocardialperfusion when a perfusion defect was present beforestent implantation. Moreover, concerns related toperforation during stent deployment (up to 6.3%)(43), stent fracture (case reports) (44,45), in-stentrestenosis (bare-metal stents: up to 75% at 1 year;

drug-eluting stents: 25% at 1 year) (46,47), and stentthrombosis (case reports) (48,49), have limited theiruse in these settings. Available evidence on thesecomplications is summarized in Online Table 1.Although the restenosis rate with bare-metal stents ishigher than that observed with drug-eluting stents,the rate of target vessel revascularization of tunneledarteries treated with drug-eluting stents remainshigher than that observed with atherosclerotic le-sions, but not bridged lesions (43). When both arepresent, Tsujita et al. (50) have shown that stentsextending into MBs have higher rates of target lesionrevascularization compared with those ending prox-imal to the MB because the minimum cross-sectionalarea of stents extending into the MB was significantlysmaller. Thus, recognition and location of themaximal plaque burden with respect to the MB is ofthe utmost importance (50). Whether current bio-absorbable scaffolds may have a role in this settingremains to be established, considering the concernsraised about their radial strength and the negativeinteraction between vessel size and in-scaffoldthrombosis. Medical therapy appears to be the treat-ment of choice for the vast majority of patients withMB in the absence of randomized trials comparingoptimal medical treatment versus percutaneouscoronary intervention with drug-eluting stents.Accordingly, an ischemia-guided revascularizationusing drug-eluting stents may be limited to the small

FIGURE 5 Management Strategy for LAD-MB

LAD Myocardial bridging

No clinical symptoms Clinical symptomsand/or objective signs

of ischemia

- Relieve potential triggers*- Risk factors modification- Consider antiplatelet therapy if atherosclerosis is detected

Follow-up

(+)

(+) (-)

Follow-up

Improvement

Stent/Surgical option (CABGor supra-arterial myotomy)

- β-blockers/calcium channel blockers- Consider Ivabradine together with lower dose of β-blockers/calcium channel blockers- Avoid pure vasodilators- Relieve potential triggers*- Risk factors modification- Consider antiplatelet therapy if atherosclerosis is detected

Flow diagram showing proposed management strategy of MB of the LAD on the basis of the presence of clinical symptoms and/or objective

signs of ischemia. *See text. CABG ¼ coronary artery bypass grafting; other abbreviations as in Figure 1.

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percentage of severely symptomatic patients who arerefractory to maximal medical treatment and whoare not surgical candidates. Surgical options for MBare more invasive, and include either supra-arterialmyotomy (51) and/or CABG (52). Potential complica-tions of myotomy include wall perforation, particu-larly in the case of a deep subendocardial course,ventricular aneurysm formation, and post-operativebleeding (53). CABG is favored over myotomy incases of extensive (>25 mm) or deep (>5 mm) MB (therisk of myotomy can be considerable), or when thebridged coronary segment fails to decompresscompletely in diastole (myotomy is unlikely to correctthe persistent diastolic compression) (54). The

available evidence, focusing on surgical approachesto MB, is summarized in Online Table 2. Overall, theavailable data suggest that surgical therapy appearsto be safe and effective, and we recommend thistherapeutic approach in the very rare cases ofseverely symptomatic patients who are refractory tomedical therapy, or when the percutaneous approachhas failed or is considered not to be safe.

REPRINT REQUESTS AND CORRESPONDENCE: Prof.Giuseppe Tarantini, Department of Cardiac Thoracicand Vascular Sciences, University of Padua MedicalSchool, Via N. Giustiniani 2, 35121 Padova, Italy.E-mail: giuseppe.tarantini.1@unipd.it.

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KEY WORDS fractional flow reserve,instantaneous wave-free ratio, intravascularimaging, percutaneous coronary intervention

APPENDIX For supplemental tables, pleasesee the online version of this article.