hemodynamic and intravascular ultrasound assessment of myocardial bridging: fractional flow reserve...

Hemodynamic Rounds

Hemodynamic and Intravascular UltrasoundAssessment of Myocardial Bridging: Fractional FlowReserve Paradox with Dobutamine Versus Adenosine

Abdul Hakeem, MD, Mehmet Cilingiroglu, MD, FSCAI, and Massoud A. Leesar,* MD, FSCAI

Compared to coronary angiography, both intravascular ultrasound (IVUS) and CT-angiogra-phy provide important information with respect to the morphological aspects of myocar-dial bridging (MB). However, these modalities are limited in defining the hemodynamic andclinical significance of MB. Intracoronary Doppler studies demonstrate a peculiar abnor-mal Doppler flow profile associated with MB. Fractional flow reserve (FFR) after adenosineinfusion has been used to assess the hemodynamic significance of MB, but FFR afteradenosine induced hyperemia underestimates the significance of MB. On the other hand,high-dose dobutamine by increasing the contractility of the bridging segment unmasks is-chemia induced byMB. This review outlines the role of flow velocity measurement by intra-coronary Doppler, FFR, and IVUS for assessment of patients with MB. In addition, we com-pared FFR measurements after adenosine versus dobutamine infusions for the hemody-namic assessment of MB in two patients. VC 2009 Wiley-Liss, Inc.

Key words: CFLO—coronary flow; HEMO—hemodynamics; IVUS—intravascularultrasound; BRDG—bridge; myocardial

INTRODUCTION

Myocardial bridging (MB) refers to an ‘‘intramyocar-dial’’ course of an epicardial coronary artery leading toanatomic encasement of varying length of the artery by amuscular bridge [1–4]. This entrapment can lead to oblit-eration of the lumen and hence compromise coronaryblood flow leading to ischemia [2–4]. The prevalence ofMB varies, ranging from 15 to 85% in autopsy series [2–5] to angiographic prevalence of 0.5 to 2.5% [2,6–9]. Withthe wide-spread use of coronary CT angiography, prelimi-nary reports have shown the prevalence of MB to be 26 to30% [10,11]. Data from the Mayo Clinic (9) has shownthat the angiographic prevalence was 1.57% (226 out of14416 coronary angiograms); the left anterior descending(LAD) coronary artery was the most commonly involvedcoronary artery (93%), followed by the right coronary ar-tery (5%) and then the left circumflex artery (2%).

MB is usually an incidental finding noted on routineangiography; however, it has been associated withmyocardial ischemia, infarction, arrhythmias, and evensudden cardiac death [2,3,9,12]. Data from MayoClinic have shown that MB is associated with a 36%increased risk of non-fatal myocardial infarction duringa mean follow-up of 1 year [9]. Mechanisms leading to

ischemia include systolic compression, failure of dia-stolic relaxation, and vasospasm [2–4,8,9]. MB mayalso increase the tendency for occurrence of atheroscle-rosis, especially in the proximal segment which is sub-ject to shear stress, including oscillatory flow and flowreversal leading to endothelial dysfunction. However,the coronary segment within the MB itself is generallyspared from atherosclerosis [2,4,9,12].

The characteristic angiographic appearance of MBincludes systolic narrowing or ‘‘milking effect’’ of theartery with persistent diastolic reduction in vesseldiameter [1–3,8]. However, coronary angiography

Division of Cardiology, University of Cincinnati School of Med-icine, Cincinnati, Ohio 45267

Conflict of interest: Nothing to report.

*Correspondence to: Massoud A. Leesar, MD, FSCAI, Division of

Cardiology, University of Cincinnati, Cincinnati, OH 45267.

E-mail: [email protected]

Received 1 April 2009; Revision accepted 24 July 2009

DOI 10.1002/ccd.22237

Published online 14 September 2009 in Wiley InterScience (www.

interscience.wiley.com).

VC 2009 Wiley-Liss, Inc.

Catheterization and Cardiovascular Interventions 75:229–236 (2010)

alone is limited in determining the physiological signif-icance of MB. Over the past decade, significant devel-opments in physiological assessment by fractional flowreserve (FFR), intracoronary flow velocity measure-ment by Doppler wire, and intravascular ultrasound(IVUS) have enhanced our understanding of the patho-physiology and clinical correlates of MB [13–18].

This review outlines the role of flow velocity mea-surement by intracoronary Doppler wire, FFR, andIVUS for the assessment of patients with MB. In addi-tion, we compared FFR measurements after adenosineversus dobutamine infusions for the hemodynamicassessment of MB in two patients.

Case 1

A 38 year-old-man with no significant past medicalhistory presented with exertional angina. The patient

underwent treadmill sestamibi stress test. At peak exer-cise, he had a 1 mm down-sloping ST-segment depres-sion in the inferolateral leads. The sestamibi studyrevealed small inferolateral ischemia. The patient sub-sequently underwent cardiac catheterization, whichdemonstrated normal right coronary artery and the evi-dence for MB in the LAD, (Fig. 1A and B); LVEFwas 50% with anteroapical hypokinesis. Because thearea of ischemia was not congruent with the LAD ter-ritory and to assess the impact of MB on distal myo-cardial perfusion, a 0.014 inch pressure guidewire wasadvanced to the distal LAD. IVUS evaluation at base-line revealed the evidence for MB with systolic nar-rowing of the lumen of the artery and the presence ofcharacteristic ‘‘half-moon’’ morphology (Fig. 1B andC). In addition, IVUS demonstrated that the length ofbridging segment was 30 mm.

Fig. 1. Panels 1A and 1B, demonstrate MB in the LAD during diastole and systole at base-line; Panels 1C and 1D, demonstrate IVUS images of MB during diastole and systole; panel1E, demonstrates worsening of MB during dobutamine infusion; panel 1F, demonstrates reso-lution of MB after stenting of the LAD. [Color figure can be viewed in the online issue, whichis available at www.interscience.wiley.com.]

230 Hakeem et al.

Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).

Fig. 2. Panel 2B, demonstrates FFR 5 0.82 after adenosine infusion; panel 2C, demonstratesFFR 5 0.75 after dobutamine infusion at 20 lg/kg/min; panel 2D, demonstrates FFR 5 0.71after dobutamine infusion at 40 lg/kg/min; panel 2E demonstrates FFR 5 0.92 after stenting.[Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Assessment of Myocardial Bridging 231


After administration of intravenous adenosine (140lg/kg/min) infusion, FFR was 0.82 and patient did nothave chest pain during adenosine infusion (Fig. 2B).An FFR of 0.82 was inconsistent with patient’s angina.Subsequently, the patient underwent intravenous dobut-amine infusion to evaluate the physiological signifi-cance of MB while the pressure guidewire was in thedistal LAD. After 20 lg/kg/min of dobutamine infu-sion, FFR dropped to 0.75 (Fig. 2C) and subsequentlyto 0.74 after 30 lg/kg/min of dobutamine infusion.When dobutamine infusion was increased to 40 lg/kg/min, FFR further dropped to 0.71 (Fig. 2D) and thepatient developed chest pain. Coronary angiogramdemonstrated worsening of MB (Fig. 1E).

Based on angina symptoms, FFR of 0.71 by dobut-amine challenge, and ST-segment depression duringtreadmill stress test, the patient underwent stenting of theLAD. In the bridging segment, the distal reference media

to media diameter of the LAD by IVUS was 2.5 mm andthe proximal reference media to media was 2.75� mm.A 2.5 � 16 mm TaxusTM stent ((Boston Scientific,Natick, Massachusetts) was deployed in the distal LADand subsequently a 2.75 � 20 mm TaxusTM stent wasdeployed to the proximal segment. Finally, a 3.0 � 15mm Quantum MaverickTM (Boston Scientific, Natick,MA) balloon catheter was advanced and stents were post-dilated at 16 ATM. Following stenting, the angiogramdemonstrated no evidence for MB (Fig. 1F); after stent-ing, FFR was 0.92 (Fig. 2E). At follow-up, the patient’sangina completely resolved and treadmill sestamibi stresstest at one year demonstrated no evidence for ischemia.

Case 2

A 54 year-old-man with history of hypertensionand smoking was evaluated for recurrent angina.

Fig. 3. Panels 3A and B, demonstrate MB in the LAD during diastole and systole at baseline;panel 3C and D, demonstrate IVUS images of MB during diastole and systole; panel 3E, demon-strates diffuse narrowing of the LAD after dobutamine infusion at 50 lg/kg/min; panel 3F, demon-strates resolution of diffuse narrowing of the LAD after intracoronary nitroglycerin administration.[Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

232 Hakeem et al.


Echocardiogram revealed normal left ventricular ejec-tion fraction with mild hypokinesis of anteroapical seg-ment. Based on history of recurrent angina, he under-went treadmill sestamibi study. The patient developedchest pain during peak exercise with a maximal heartrate of 150 beats per minute associated with ST-seg-ment depression in the anterior precordial leads. Sesta-mibi imaging revealed small anteroapical ischemia.

The patient underwent cardiac catheterization,which demonstrated MB involving a long segmentextending from mid to distal LAD (Fig. 3A and B).IVUS of the LAD demonstrated that the lesion lengthwas 64 mm and there was evidence for MB withsystolic narrowing of the lumen of the artery with thepresence of characteristic ‘‘half-moon’’ morphology(Fig. 3B and C).

Because of small size of the ischemic defect, thepatient was continued on medical therapy, but he con-tinued to experience exertional angina despite therapywith beta-blockers. He subsequently underwent repeat

cardiac catheterization and physiological evaluation ofthe MB. A 0.014 inch pressure guidewire wasadvanced to the distal part of the LAD and FFR of theLAD was measured. After intravenous administrationof adenosine (140 lg/kg/min), FFR was 0.82 (Fig. 4B).The FFR of 0.82 was reassuring, but contradictory tothe fact, the patient had recurrent angina and ischemiaby the stress test. Based on persistence of symptomsand positive stress test, he underwent dobutamine stresstest while the pressure guidewire was in the distal partof the LAD. After dobutamine infusion at 20 and thenat 30 lg/kg/min, FFR was 0.82 (Fig. 4C and D). Whendobutamine infusion was increased to 40 and then to50 lg/kg/min, FFR further dropped to 0.72 and 0.70,respectively (Fig. 4E and F). Coronary angiogramrevealed severe diffuse narrowing of the LAD (Fig.3E), which resolved after intracoronary nitroglycerininfusion (Fig. 3F).

Because MB involved a long and diffuse segment ofthe LAD, it was deemed that stenting would be

Fig. 4. Panel 4B, demonstrates FFR 5 0.82 after adenosine infusion; panels 4C and 4D, dem-onstrate FFR 5 0.82 after dobutamine infusion at 20 and 30 lg/kg/min; panel 4E, demon-strates FFR 5 0.72 after dobutamine infusion at 40 lg/kg/min; panel 5F, demonstrates FFR 50.70 after dobutamine infusion at 50 lg/kg/min. [Color figure can be viewed in the onlineissue, which is available at www.interscience.wiley.com.]



associated with an increased risk of complicationsincluding stent fracture and restenosis. The patient wasadvised to undergo coronary artery bypass grafting orsurgical myotomy; however, he declined surgery andwas continued on medical therapy with an increaseddose of beta-blockers. At 1-year follow-up period, hisangina has persisted despite the maximum dose of beta--blockers, calcium channel blockers, and nitrates.

DISCUSSION

We demonstrated that angiographic and functional se-verity of MB could be unmasked after inotropic stimula-tion by dobutamine infusion. After adenosine infusion,FFR in both cases was 0.82, indicating that MB was nothemodynamically significant, whereas after dobutamineinfusion, FFR in both cases was <0.75. Such a paradox,‘‘FFR paradox,’’ has not been reported in patients withfixed coronary artery stenosis. In this respect, Bartuneket al. [19] demonstrated that among patients with iso-lated coronary artery stenosis, comparison of adenosinewith dobutamine up to 40 lg/kg/min resulted in a similarvalue of FFR measurements.

The mechanism that underlies ‘‘FFR paradox,’’ agreater FFR drop with dobutamine than with adenosineamong patients with MB, is likely owing to increasedcontractility of muscle fibers overlying arterial segmentin response to dobutamine [1–5,13–18] and that, in turn,decreased minimum lumen diameter and increased thelength of bridging segment, as previously reported [20].In contrast, it has been reported that among patients withfixed coronary stenosis and no evidence for MB, bothdistal coronary pressure and Pd/Pa decreased to a sameextent during intracoronary adenosine and high-dosedobutamine infusion [19]. Likewise, among patientswith fixed coronary artery stenosis, minimum lumendiameter at the stenosis did not differ at baseline andafter high-dose dobutamine infusion [19].

In patient 1, since there was no stenosis in the RCA norwere there wall motion abnormalities in the inferolateralsegments, we concluded that small inferolateral ischemiarepresents artifact, which was not evident at follow-upimage, suggesting that the follow-up study had a betterimage quality. The disparity between the results of adeno-sine FFR and dobutamine FFR may lie in the fact thatdobutamine by increasing the contractility of musclefibers overlaying the LAD may induce ischemia and suchan effect does not occur with adenosine. In this respect,Escaned et al. [21] have demonstrated that after dobut-amine infusion systolic minimum lumen diameterdecreased and the length of the compressed segmentincreased significantly. In addition, they have demon-strated that FFR after dobutamine infusion was signifi-cantly lower compared with adenosine infusion. In case

2, it was noted that FFR after adenosine infusion was0.82 and that further dropped to 0.70 after maximumdobutamine infusion. In addition, small anterolateral is-chemia correlated with the FFR after dobutamine infusionthan with the FFR after adenosine infusion.

Physiological Assessment of MB by FFR

FFR is most commonly utilized in the cath lab fordetermining the physiological significance of coronarystenoses [22,23]. FFR is a ratio of mean distal coronaryartery pressure (Pd) to the mean aortic pressure (Pa)measured at maximal hyperemia induced by intrave-nous adenosine infusion. In the absence of coronarystenosis, Pd should be equal to Pa, hence normal FFR(Pd/Pa) is 1.0. A FFR value <0.75 is considered abnor-mal. It has an overall diagnostic accuracy of 93% indetermining ischemia compared with stress test [22].Unlike coronary flow reserve (CFR), FFR is independ-ent of changes in heart rate and blood pressure.

Diefenbach et al. [24] were the first to demonstratethat inotropic stimulation with 30 lg intravenous orci-prenalin (a beta-agonist) unmasked angiographicallysilent MB in 25 of 62 patients (40%) who had anginaand that resulted a significant increase in the degreeand length of MB segments. It has been known thatdiastolic FFR with a cutoff value of 0.76 has a highersensitivity compared with FFR for detection of ische-mia (96% vs. 88%, respectively). In this context,Escaned et al. [21] investigated the value of dobut-amine challenge for the physiologic assessment of MBin 12 symptomatic patients with positive stress test.They compared the hemodynamic significance of MBby FFR and diastolic FFR at baseline and after dobut-amine challenge up to 20 lg/kg/min; diastolic FFRwas obtained from postprocessed, digitally acquiredelectrocardiogram and pressure signals. Although bothFFR and diastolic FFR dropped significantly afterdobutamine infusion, diastolic FFR identified hemody-namic significance of MB in five patients (diastolicFFR <0.76), whereas FFR was <0.75 in only onepatient. These data indicate that hemodynamic signifi-cance of MB can be unmasked by dobutamine infu-sion. Furthermore, development of a notable diastolicpressure gradient indicates that MB influences diastolichemodynamics and, consequently, diastolic FFR mea-sured after dobutamine infusion identifies a subset ofpatients with significant MB that may not be as evidentby conventional FFR measurements [21].

From a more practical standpoint, in a busy cardiaccatheterization laboratory, calculation of diastolic FFR ishowever very cumbersome. Moreover, Escand et al. [21]used dobutamine up to 20 lg/kg/min and a higher rate-pressure product was reached in patients with diastolic

234 Hakeem et al.


FFR �0.76 than in those with a diastolic FFR >0.76(16,413 � 1,586 vs. 11,914 � 2,879 mm Hg, respec-tively, P ¼ 0.01) indicating suboptimal inotropic responseamong patients with a diastolic FFR >0.76. On the otherhand, in the present study, dobutamine infusion up to50 lg/kg/min unmasked anatomic and hemodynamicsignificance of MB with a significant drop in FFR value.

Taken together, our cases demonstrate that, in contrastto patients with fixed coronary stenosis, FFR measure-ment after adenosine infusion underestimates the signifi-cance of stenosis in patients with MB. In contrast, FFRmeasurement after a high-dose dobutamine infusion is apromising strategy to unmask the significance of MB.

Compared to coronary angiography, both IVUS andCT-angiography provide important information withrespect to the morphological aspects of MB. However,these modalities are limited in defining the hemody-namic and clinical significance of MB [2–6]. AlthoughMB is usually an incidental finding during routineangiography, it has been associated with adverse out-comes including angina, acute coronary syndromes,and even sudden cardiac death [9]. It is, however,unknown whether evaluating the physiological signifi-cance of an incidental angiographic MB by dobutamineFFR would predict the event rates during follow-up.

Physiological Assessment of MB byIntracoronary Doppler Flow Studies

CFR is defined as the ratio of average peak velocityachieved at peak hyperemia to average resting flow veloc-ity obtained after intracoronary injection of adenosine. Anormal CFR value should be above 3.0 [25]. We did notperform Doppler studies, but a number of studies [26,27]demonstrated a peculiar abnormal Doppler flow profileassociated with MB characterized by abrupt early dia-stolic flow acceleration and rapid mid diastolic decelera-tion followed by mid to late diastolic plateau in thebridged segment, hence called the spike and domeappearance or fingertip phenomenon. These changes rep-resent increased blood flow generated in diastole by arapid decrease in resistance of the distal coronary vesselscausing the early spike and persistent reduction in dia-stolic diameter leading to the doming. These findings cor-related with delayed diastolic luminal gain of the coro-nary artery on simultaneous frame by frame analysis ofangiograms. Furthermore, it has been demonstrated thatintravenous beta-blocker therapy with esmolol attenuateddiameter reduction during both systole and diastole andalso significantly reduced the average diastolic peak flowvelocity within the bridge segment, which was accompa-nied by improvement of symptoms [28]. In addition tothe fingertip phenomenon described among patients withMB, Ge et al. [13] reported antegrade flow reversal dur-

ing systole recorded by Doppler flow measurements,which was accentuated by administration of nitroglycerin.Increased dilation of the proximal coronary segment tothe MB may account for the accentuation of antegradeflow reversal by nitroglycerin.

Assessment of MB by IVUS

The excellent spatial resolution of IVUS allowsdetailed real time visualization of the vessel wall. Geet al. [14,15] reported the ‘‘half-moon phenomenon’’ inpatients with an MB, presumably representing theintramyocardial course of the LAD. This finding wasthought to be highly specific because it could bedetected only in the MB segment with systolic com-pression and not in adjacent reference segments with-out compression. The precise incidence of MB byIVUS remained unknown. Tsujita et al. [16] reportedthat IVUS-detectable MBs were detectable in 23% ofpatients with atherosclerosis of the LAD. In the pres-ence of a half-moon phenomenon by IVUS, milkingcan be provoked by intracoronary provocation tests,even if the bridge is angiographically undetectable.IVUS studies have also consistently shown high inci-dence of atherosclerotic plaque in the coronary arterysegment immediately proximal to the myocardialbridge with no involvement of the MB segment itselfand relative sparing of the distal segment. Furthermore,the lumen size of the MB segment was significantlysmaller than those of proximal and distal reference seg-ments, even in diastole. The intramyocardial coursemay limit the diastolic dimensions of the lumen. TheIVUS ‘‘half-moon’’ sign appears to be more sensitivethan the ‘‘finger-tip’’ sign by Doppler because ‘‘half-moon’’ sign was present in 100% of patients with MB,whereas the ‘‘finger-tip’’ sign by intracoronary Dopplerwas present in 87% of patients.

Klues et al. [17] reported hemodynamic, angio-graphic, and IVUS features immediately and sevenweeks after successful coronary stent implantation inthree symptomatic patients with MB. Stenting of theMB abolished phasic lumen compression, diastolicflow abnormalities, and clinical symptoms. Coronaryangiography after seven weeks revealed lumen enlarge-ment without any systolic or diastolic diameter reduc-tion. Intracoronary Doppler revealed a further increasein CFR. IVUS revealed no evidence for stent fracture.After stenting, all three patients reported an improve-ment of angina and exercise tolerance.

CONCLUSIONS

MB is the most common congenital coronary anom-aly and is commonly located in the mid segment of the



LAD. MB has been considered a benign condition;however, it has been associated with myocardial ische-mia, myocardial infarction, and sudden death. Althoughthe diagnostic criteria are different, the reported inci-dence of MB varies from 0.5 to 2.5% in angiographicstudies and from 15 to 85% in autopsy series. FFRafter adenosine infusion does not underestimate the sig-nificance of stenosis when the cross-sectional area ofthe stenosis is fixed. In contrast, FFR measurementafter dobutamine infusion among patient with MBresults in different FFR than adenosine, which mayhave different clinical significance. Since dobutamineis a non-physiological stimulus, further studies areneeded to define the roles of FFR after dobutamineinfusion for the hemodynamic assessment of MB andto investigate its role for risk stratification in patientswith MB.

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