The Role of Multimodality Cardiac Imaging in the Transplanted Heart

doi:10.1016/j.jcmg.2009.06.006 2009;2;1126-1140 J. Am. Coll. Cardiol. Img.

Torre-Amione, and William A. Zoghbi Jerry D. Estep, Dipan J. Shah, Sherif F. Nagueh, John J. Mahmarian, Guillermo

The Role of Multimodality Cardiac Imaging in the Transplanted Heart

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T A T E - O F - T H E - A R T P A P E R

he Role of Multimodality Cardiac Imagingn the Transplanted Heart

erry D. Estep, MD, Dipan J. Shah, MD, Sherif F. Nagueh, MD, John J. Mahmarian, MD,uillermo Torre-Amione, MD, PHD, William A. Zoghbi, MD

ouston, Texas

eart transplantation (HT) is an established life-saving treatment option for patients with end-stage heart

ailure. Despite many advances in the field, the development of acute cellular rejection (ACR) and cardiac

llograft vasculopathy (CAV) represent significant causes of 1- and 5-year morbidity and mortality, respectively.

he search for noninvasive techniques to assess cardiac allograft function and detect treatable ACR and CAV

emains a priority objective for heart transplant professionals. In this review we will: 1) highlight the clinical

ignificance of ACR and CAV in adult cardiac transplant recipients and 2) discuss how different noninvasive

maging modalities (echocardiography, cardiac computed tomography, myocardial perfusion imaging, and

ardiac magnetic resonance) have been used in the evaluation of these clinical challenges after HT. (J Am Coll

ardiol Img 2009;2:1126–40) © 2009 by the American College of Cardiology Foundation

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eart transplantation (HT) is an establishedife-saving treatment option for patients withnd-stage heart failure. Despite many advancesn the field, the development of acute cellularejection (ACR) and cardiac allograft vascu-opathy (CAV) represent significant causes of

orbidity and mortality (1). Historically, sur-eillance for ACR and CAV has been based onnvasive procedures, which carry inherent risksnd high costs. The search for noninvasiveechniques to assess allograft function andetect treatable ACR and CAV remains ariority objective for heart transplant profes-ionals. Noninvasive imaging techniques usedn this regard include transthoracic echocardi-graphy, multidetector computed tomographyMDCT), single-photon emission computedomography-myocardial perfusion imagingSPECT-MPI), and cardiac magnetic reso-ance (CMR). The ideal test for the detection

rom the Department of Cardiology, Section of Heart Failure andnstitute, Methodist DeBakey Heart and Vascular Center, Housto

anuscript received April 9, 2009; revised manuscript received June 1

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f ACR and CAV should be highly sensitivend specific, able to evaluate changes beforend after treatment, noninvasive with higheproducibility, and associated with low costnd favorable outcome. In this review, we will:) highlight the clinical significance of ACRnd CAV in adult cardiac transplant recipients;nd 2) discuss how different noninvasive imag-ng modalities have been used in the evaluationf these clinical challenges after HT.

CR

linical significance. In ACR, effector T cellsediate an inflammatory response that leads toyocardial edema and myocyte damage. Rou-

ine surveillance of ACR is currently performedith endomyocardial biopsy (EMB) and is

ssociated with good clinical results. The cur-ent management strategy depends on the his-

art Transplantation, and Cardiovascular Imagingexas.

9, 2009, accepted June 24, 2009.

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Multimodality Cardiac Imaging in the Transplanted Heart

1127

ologic type and grade of rejection and the presencer absence of hemodynamic compromise (decreasedllograft systolic function and/or hemodynamic in-tability). Using the International Society of Heartnd Lung Transplantation revised grading system,MB grade 2R (previously 3A) or higher rejection

s considered clinically significant and prompts these of high-dose corticosteroids and possibly these of lymphocyte-depleting agents in patients withemodynamic compromise.Although EMB is considered the gold standard

or the diagnosis of ACR, its value may be limitedy sampling error, interobserver variability, andide variability in the frequency and duration of itsse as surveillance among transplant centers. Severaloninvasive imaging techniques (clinically acceptednd investigational) have been performed to detectCR at different stages in the disease process (Fig. 1).ith current advances in immunosuppression, theajority of patients who develop ACR have no

ignificant changes in left ventricular (LV) ejectionraction regardless of the imaging modality used2–4). However, monitoring cardiac allograft sys-olic function is important in suspected or provenCR because more aggressive immunosuppression

an lead to improvement in LV function in patientsith depressed function.chocardiography and ACR. CONVENTIONAL ECHO-

ARDIOGRAPHY. Although wall thickness and LVass measured by M-mode and 2-dimensional

chocardiography have been shown to increase dur-ng ACR episodes (5), ACR-induced myocardialdema may manifest by subtle changes in relativeall thickness, accounting in part for the conflicting

esults on the usefulness of these echocardiographyarameters to detect ACR (6–8). Investigatorsave also noted that the presence of a pericardialffusion in cardiac transplant recipients is associatedith a higher incidence of ACR (9). Pericardial

ffusion, however, occurs frequently in the post-perative period, hence its low sensitivity (�49%)nd specificity (�74%) to detect ACR (10).

PECTRAL DOPPLER IMAGING. Early investigationsemonstrated altered LV diastolic twist mechanics

n the absence of systolic dysfunction to suggest thatiastolic dysfunction precedes systolic abnormalities

n patients with ACR (11). Multiple studies havelso evaluated LV Doppler inflow indexes to detectCR, including early diastolic (E) peak velocity,

ate diastolic (A) peak velocity, E/A ratio, E-waveressure half time (PHT), and isovolumic relax-tion time (IVRT) (12,13). Standard transmitral
oppler-derived indexes in cardiac transplant re- e
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ipients have had limitations in predicting ACR;hese limitations relate to the influence of severalarameters on these indexes including donor age,eart rate (which may be variable in the setting ofardiac denervation), loading conditions, and theissociation between the electrical activity of 2 atriaespecially important with the biatrial anastomosisechnique when evaluating older studies). Mena etl. (12) performed a systematic review of the pub-ished literature between 1967 and 2005 and re-orted that the majority of studies that examinedhe change in the mitral E and A peak velocitiesver time did not predict ACR and the correlationetween ACR and PHT and IVRT was not con-istent (sensitivity and specificity range for PHT3% to 87% and 76% to 98%; IVRT 28%o 85% and 80% to 98%, respectively)12). The discordance in the literature maye in part related to significant interpa-ient and intrapatient variability and theependence of these indexes on multipleactors in addition to ACR (8). In addi-ion to transmitral Doppler indexes, sev-ral studies have examined changes inulmonary vein flow indexes (8,10,14),V diastolic flow propagation (8,15), and

he myocardial performance index (16,17)o detect ACR—with conflicting results.

ISSUE DOPPLER IMAGING (TDI). Moreecently, the use of TDI to detect ACR haseen investigated, with improved results.nvestigators from Berlin, Germany, usingulsed wave–TDI obtained from the basalosterior wall, have demonstrated that aeduction in peak systolic radial velocitySm) and peak early diastolic velocity (Emalso known as Ea]) is helpful in detectingardiac rejection (sensitivity and specificityor Sm reduction �10%, �87% and �94%; sensitivitynd specificity for Em reduction �10%, 90% and6%, respectively) (3,18). These investigators havelso reported on the value of serial TDI screeningased on the high negative and positive predictivealues of changes in diastolic parameters (i.e., �10%m reduction) for ACR to guide the effective use ofMBs (19). In contrast, with the mitral valve annulussed as the site for analysis, some studies have foundignificant decreases in systolic velocities with ACR8,20), whereas other investigators have not (15).iscordant results have also been seen by color Dopp-

er or conventional TDI (12,20). These discrepanciesith regard to the clinical usefulness of these param-

A B B

A N D

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R E V I A T I O N S

A C R O N YM S

acute cellular rejection

cardiac allograft

lopathy

cardiac magnetic

ance

dobutamine stress

ardiography

endomyocardial biopsy

heart transplantation

� intravascular ultrasound

left ventricular

� major adverse cardiac

s

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uted tomography

-MPI � single-photon

ion computed

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ome studies using pulsed wave versus color TDI andsing tissue Doppler Ea from different myocardialalls or mitral valve annulus locations (3,14,15,20).inally, the E/Ea ratio—a validated parameter forstimation of LV filling pressure in the transplantedeart (21) (Fig. 2)—has been evaluated by 2 differentroups to detect ACR, with conflicting results10,14). The clinical usefulness of this TDI-derivedndex to detect ACR remains unclear given thataradoxical septal motion is noted often in cardiacransplant recipients and in the current era of immu-osuppression, patients with ACR are often asymp-omatic with normal ventricular filling pressure.

ROMISING ECHOCARDIOGRAPHIC TECHNIQUES.

ovel echocardiographic techniques have been re-ently developed and have been applied to thevaluation of ACR. These include strain and strainate imaging (22) (Fig. 3), 2-dimensional derivedntegrated backscatter (6), automated border detec-ion with acoustic quantification to measure LVeak filling rate (23), and color Doppler imaging toeasure late isovolumic relaxation myocardial ve-

ocity gradients and early diastolic timing intervalifferences (14) (Table 1). These quantitative echo-ardiographic techniques of regional and globalyocardial function show promise to identify sub-

linical LV dysfunction in a small number of cardiacransplant recipients and need further validation inarger studies.MR and ACR. Although many transplant centersse echocardiography to detect cardiac allograft

CMR*

*

*Echocardiography

Immune-Mediated Cardiac Allograft Injury

Myocardial Mononuclear Cell Infiltration

Myocardial Necrosisand Edema

Cardiac Allograft Diastolic Dysfunction

Figure 1. Different Noninvasive Imaging Techniques PerformedCellular Rejection

ACR � acute cellular rejection; CMR � cardiac magnetic resonanceand Lung Transplantation.

ystolic dysfunction in the setting of cardiac rejec- p

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ion, CMR enables imaging throughout the cardiacycle and provides excellent spatial resolution toccurately measure diastolic and systolic volumesnd hence left and right ventricular ejection frac-ions (24) (Fig. 4). CMR may also be useful in theetection of ACR by its ability to quantitatehanges in myocardial mass (25) or more specifi-ally to detect myocardial edema. The latter isccomplished by measurement of myocardial T2alues, which are elevated in the setting of increasedyocardial water content. Marie et al. (26) demon-

trated in 68 cardiac transplant recipients that aigher than normal T2 value (�56 ms) was suffi-iently accurate (sensitivity 89%; specificity 70%) toetect ACR defined by EMB (grade �2R). Anbnormal T2 value was also a strong predictor ofubsequent biopsy-defined ACR, suggesting earlyetection of ACR. Although promising, this inves-igation involved a select cohort of patients withuspected rejection on the basis of clinical or echo-ardiographic data; therefore, the true sensitivitynd specificity of this method to detect ACR innselected cohorts is currently unknown and needsurther evaluation.

With the administration of a paramagnetic con-rast medium, gadolinium, CMR studies have alsoeen used to detect inflammatory changes in theyocardium. Almenar et al. (2), using gadolinium-

iethylene triamine pentaacetic acid-enhancedMR in 40 cardiac transplant recipients, showed an

ncrease in relative myocardial contrast uptake in

Clinically Accepted

Investigational**

Cardiac AllograftSystolic Dysfunction

ISHLT Biopsy Grading (2004)Grade 0R No ACRGrade 1R Mild, Low-gradeGrade 2R Moderate, IntermediateGrade 3R Severe, High-grade

*

**

*

EchocardiographyScintigraphy CMR and Cardiac CT

arious Stages of Cardiac Involvement to Detect Acute

� computed tomography; ISHLT � International Society of Heart

at V

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hose without necrosis. Although their series re-uired extensive image analysis to compute changesn signal intensity in various tissues (heart andectoralis muscle) before and after administrationf contrast, our experience has shown that the usef traditional delayed enhancement CMR may alsoemonstrate areas of hyperenhancement in theetting of ACR. These areas appear to diminishfter treatment of the ACR episode (Fig. 5). Ineneral, CMR studies have been limited by smallample size with few confirmatory validations. Inddition, gadolinium use in patients with acute orhronic severe renal insufficiency (estimated glo-erular filtration rate �30 ml/min) carries a sig-

ificant risk for development of nephrogenic sys-emic fibrosis. Because of these drawbacks and theack of widespread availability, the role of CMR invaluation of ACR is still evolving.

AV

linical significance. Cardiac allograft vasculopathy,revalent in approximately 54% of survivors 10ears after HT, is characterized by diffuse intimalyperplasia that is likely the result of cumulativendothelial injuries (1,27). The early diagnosis ofAV is challenging because typical clinical symp-

oms of ischemia are lacking, given cardiac dener-ation and the fact that coronary angiography cannderestimate the severity of disease. Early recog-ition is important because rapid CAV progression,s defined by intravascular ultrasound (IVUS), haseen shown to be a powerful predictor of all-causeortality and myocardial infarction (27). Although

VUS is considered the most sensitive tool to detectAV, coronary angiography is still the standard inany transplant centers.Treatment of CAV focuses on the use of prolif-

ration signal inhibitors to decrease progression,tatin therapy for long-term survival benefit, anti-latelet therapy, and percutaneous revasculariza-ion, although the benefit may be limited because ofhe diffuse nature of the disease (27). Given therawbacks of the invasive nature and high cost ofoth IVUS and coronary angiography, a noninva-ive imaging modality is needed to identify patientst risk for CAV. Several imaging modalities (clin-cally accepted and investigational) have been usedor the detection of CAV at various stages in theisease process (Fig. 6).chocardiography and CAV. REST CONVENTIONAL

CHOCARDIOGRAPHY AND TDI. Resting wall mo-
ion abnormalities as detected by 2-dimensional
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Figure 2. Noninvasive Detection of Elevated Left Ventricular Filling Pressure inCardiac Transplant Recipients Using Doppler Echocardiography

(A) Pulsed Doppler recording of the mitral flow velocity and the corresponding annular velocitiesby tissue Doppler at the time of first right-sided cardiac catheterization. (B) Pulsed Doppler ofmitral inflow and the corresponding tissue Doppler velocities at the time of the repeat right-sided cardiac catheterization (4 weeks later). Mean measured pulmonary capillary wedge pres-sure (PCWP) decreased from 24 to 11 mm Hg. The E/Ea ratio decreased from 15 to 5, predictinga decrease in estimated wedge pressure from 24 to 9 mm Hg (PCWP � 2.6 � 1.46 [E/Ea]). E �

peak mitral inflow velocity; Ea � peak mitral annular velocity; MV � mitral valve.



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chocardiography derived from 12 different studiesre in general associated with low sensitivities�47%; range 12% to 80%) but high specificity forhe presence of CAV (�84%; range 69% to 100%),upporting the notion that this finding shouldrompt further testing to exclude CAV (13). A fewtudies have examined resting TDI to detect CAV18,28). After excluding ACR, Hummel et al. (18)eported that pulse wave TDI-derived radial peakystolic velocity (Sm value �10 cm/s) was associ-ted with a 97% likelihood for CAV, whereas Smalues �11 cm/s excluded accelerated CAV with0% probability. This group of investigators also

al Strain Derived From the Speckle-Tracking Technique

(38%), peak 47%, obtained from the parasternal short axis viewst-heart transplantation (biopsy grade 2R performed on the samein the global radial strain (58%), peak 68%, 2 weeks later afternosuppression (biopsy grade 1R). ACR � acute cellular rejection;sure.

emonstrated that serial TDI can potentially spare t


atients unnecessary routine invasive examinations28). These are promising results that need furtheralidation but may point to advanced CAV, affect-ng myocardial properties at rest.

TRESS ECHOCARDIOGRAPHY. Stress echocardiog-aphy using exercise, dipyridamole, and dobutamineas been evaluated to detect CAV (Table 2). Thelunted heart rate response to exercise because ofardiac denervation limits the sensitivity (range 15%o 33%) of exercise testing to detect CAV (29–31).n contrast, the use of pharmacologic stress testingdipyridamole and dobutamine) to detect CAV haseen shown to be more sensitive (�85%; range 50%o 100%) (32–43). The variable specificity (range1% to 95%) of dobutamine stress echocardiogra-hy (DSE) is likely a reflection of the differences inefining the presence and severity of CAV byoronary angiography. When compared withVUS—a more sensitive gold standard—the speci-city of DSE for CAV is higher (83% to 88%)42,43). In comparison, Eroglu et al. (40) demon-trated that quantitative DSE using strain ratemaging detects CAV accurately regardless of thengiographic significance and that a post-systolictrain index �34% at peak stress was the bestarameter.

ROGNOSTIC VALUE OF ECHOCARDIOGRAPHY. Thelinical usefulness of noninvasive imaging inAV relates also to the test’s prognostic value

Table 3). Several investigators have demon-trated the impact of resting wall motion abnor-alities and DSE findings on major adverse

ardiac events (MACE) after HT, includingeart failure, unstable angina, myocardial infarc-ion, revascularization, retransplantation, andardiac death (32–37,42,44 – 48). The majority oftudies were performed more than 3 years afterT, with a follow-up on average of �3 years.he negative predictive value of a normal DSEas very high (�3% risk of experiencing MACEver the ensuing year). As demonstrated by Spest al. (42), serial DSE may best prognosticateased on the finding that worsening DSE resultsere as predictive of subsequent events as serial

oronary angiography or IVUS. Based on theseverall results, annual evaluation with DSE is ancceptable alternative to invasive means for de-ection of CAV in transplant centers experiencedn stress echocardiography.

ROMISING ECHOCARDIOGRAPHIC TECHNIQUES.

ontrast-enhanced echocardiography is a recent

Figure 3. Global Radi

(A) Global radial strainin a patient 1 week poday). (B) Improvementenhancement in immu

echnique that allows quantification of coronary

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ow reserve and/or myocardial perfusion mismatcho detect significant coronary artery disease. Prelim-nary studies in cardiac transplant recipients usingtress echocardiography with contrast (49,50) showelatively high accuracy (85% to 89%) to detectAV (Table 2). Moreover, Tona et al. (51) haveemonstrated the validity of a lower coronary flowelocity pattern and flow reserve with contrastchocardiography as noninvasive markers of CAV-elated MACE. These results, however, are based

Table 1. Studies Evaluating the Accuracy of Different Echocardi

Author, Year (Ref. #)Total Patients

(Prevalence of ACR)

Angermann et al., 1997 (6) 52 (18%*) Integrate

(PW 2D-

(Septal 2

Puleo et al., 1998 (15) 121 (13%) PW-TDI

(Ea of in

Mankad et al., 1999 (20) 78 (18%) Color-co

(combindiasto

(posteriotime-g

Moidl et al., 1999 (23) 94 (20%) Automat

(peak fill

(peak fill�18%

Stengel et al., 2001 (8) 41 (39%) PW-TDI

(Aa of la

Dandel et al., 2002 (3) 190 (17%*) PW-TDI

(Sm of b

(Ea of ba

Palka et al., 2005 (14) 44 (27%) PW and

(Ea of se

(peak lat

(onset E

(onset ET

Sun et al., 2005 (10) 2-D and standard Doppler Grade �

(�2 amo

223 (37%*) Post-HT

183 (27%*) Post-HT

264 (29%*) PW-TDI

(Aa of se

Marciniak et al., 2007 (22) 31 (32%) Color TD

(mid-LVP

(mid-LVP

*Prevalence of ACR based on the percentage of biopsies with ACR defined by tclinical symptoms. ‡Peak late isovolumic relaxation myocardial velocity gradientand early diastolic septal MV annulus velocity (EMed). �Timing difference betwvelocity (EMitr).Aa � peak late diastolic velocity; ACR � acute cellular rejection; dB � decibe

transplantation; IVRT � isovolumic relaxation time; LVPW � left ventricular poswave 2-dimensional-integrated backscatter; Sm � peak radial systolic velocity;

n a small number of patients, and further valida- a

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ion studies are warranted before widespread adop-ion can be advocated.PI and CAV. MPI DIAGNOSTIC VALUE. Similar toSE, several studies have examined MPI using exer-

ise, dipyridamole, and dobutamine to detect CAVTable 2). The overall sensitivity and specificity rangef MPI to detect CAV is broad (21% to 92% and 55%o 100%, respectively) (45,46,52–56). This variabilityay be explained by differences in the timing of the

xaminations, the stressors and/or MPI agents used,

phy Techniques to Detect Acute Cellular Rejection

Methodrameter Cutoff Value)

Gold Standard(EMB Score) Sensitivity

ackscatter Grade �1B

crease �1.5 dB) 88%

increase �1.5 dB) 83%

Grade �3A

r wall �16 cm/s) 76%

TDI Grade �1B

eak MV systolic and peakelocity �135 mm/s)

93%

ll tissue Doppler diastolicient integral �0.26)

91%

order detection Grade �2

rate �4.0 EDV/s) 100%

rate �4.0 EDV/s anduction)

100%

Grade �3A

l MV annulus �8.7 cm/s) 82%

Clinically relevant†

posterior wall reduction �10%) 88%

posterior wall reduction �10%) 89%

r M-mode TDI Grade �3A

MV annulus �12 cm/s) 69%

R MVG‡ �0.1/s) 88%

e –onset Emed§ ��35 ms) 81%

–onset EMitr� �15 ms) 81%

PE, IVRT �90 ms E/A �1.7)

months 57%

months 60%

/lateral MV annulus �9.0 cm/s) 67%

Grade �1B

adial peak systolic strain �30%) 85%

adial peak systolic SR �3.0 s-1) 80%

MB score. †Clinically relevant ACR defined as EMB grade �2 plus grades 1A and 1e left ventricular posterior wall. §Timing difference between onset of mitral earlynset of early diastolic velocity at lateral tricuspid (ETric) annulus and LV early di

� peak early diastolic velocity; EDV � end diastolic volume; EMB � endomyocr wall; MV � mitral valve; NPV � negative predictive value; PE � pericardial effustrain rate; TDI � tissue Doppler imaging.

ogra

(Pa Specificity NPV

d b

IB in 89% 97%

D-IB 85% 96%

ferio 88% 96%

ded

ed plic v

71% 98%

r warad

61% 97%

ed b

ing 70% 100%

ingred

95% 100%

tera 53% 82%

asal 95% 97%

sal 97% 98%

colo

ptal 46% 80%

e IV 58% 93%

wav 84% 92%

ric 84% 92%

1B

ng

�6 54% 68%

�6 93% 86%

ptal 49% 78%

I

W r 90% 93%

W r 86% 90%

he E B when accompanied byof th diastolic velocity (E wave)een o astolic lateral MV annulus

ls; Ea ardial biopsy; HT � heartterio sion; PW 2D-IB � pulsedSR �

nd the variable criteria used to diagnosis CAV.



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imilar to the DSE literature, the sensitivity to detectAV overall increases with the inclusion of studies thatefine CAV as coronary stenosis �50% (45,54,57). Inddition, early studies were performed using thallium,hich may encounter more attenuation artifacts than

echnetium-labeled radiopharmaceuticals and may ac-ount for the reported reduced accuracy compared withore recent studies (sensitivity �86% and specificity80%) using technetium-labeled agents (46,52–54).Compared with exercise and dipyridamole, dobut-

mine has been reported to be advantageous as atressor because of its more reliable induction ofschemia in cardiac transplant recipients (inotropicffect, less blunted heart rate response). Moreover, these of vasodilators with MPI may be limited in cardiacransplant recipients because the diffuse, microvascularAV may impair the necessary increase in coronaryow reserve to trigger the flow heterogeneity to detectignificant stenosis. Despite these observations, more

A

B

Figure 4. CMR Assessment of Left and Right Ventricular Systolic FCardiac Rejection

(A) Pre-treatment biventricular dysfunction with a large thrombus inthere was substantial improvement in biventricular function, and ththerapy. Full-motion cine images can be viewed online. LVEF � leftfraction.

ecent studies using dipyridamole MPI have demon-


trated comparable sensitivity (range 80% to 92%) andpecificity (range 86% to 92%) to dobutamine stress

PI to detect CAV (46,52–54).PI PROGNOSTIC VALUE. Similar to DSE, the po-

ential clinical usefulness of SPECT-MPI relates tots prognostic value. Although exercise testinginked with echocardiography and MPI is associ-ted with low sensitivity to detect CAV, investiga-ors have demonstrated that a normal exercise MPIt 1 year is a significant predictor of 1- and 5-yearurvival (45,48). Elhendy et al. (58) reported on 65atients who underwent symptom-limited bicyclexercise with technetium-99m tetrofosmin MPInd demonstrated a similar ability to predict cardiaceath in comparison with dobutamine. In contrasto these studies, Bacal et al. (34) reported thathallium scintigraphy with treadmill testing in amaller number of patients was not an independentredictor of long-term 4-year survival.

tion Pre- and Post-Treatment of an Episode of

e right ventricular apex (arrow). (B) Two weeks post-treatmentrombus appears to have decreased in size with anticoagulationtricular ejection fraction; RVEF � right ventricular ejection

unc

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harmacologic stress MPI also has significantrognostic value (Table 3). Two different inves-igators demonstrated that a normal dobutaminetress MPI study was associated with a 96%o 98% negative predictive value for MACE at

2 years (54,58). In comparison, the use ofipyridamole MPI to predict MACE after HT is

imited to 1 study (46) that demonstrated a lowerensitivity and negative predictive value, possiblyecause of the longer duration of follow-up6.5 � 2 years), supporting the notion that serialtress testing, whether with DSE or MPI, isequired to maintain high sensitivity for subse-uent events and for better prognostication.DCT coronary angiography and CAV. Initial studiesith CT examined the diagnostic value of coronary

alcium scoring with electron beam tomography toetect CAV, with conflicting results (59). MDCToronary angiography, however, has been shown to

ShA

1 Week Post-Transplant; EMB grade 1R

B

4 WeeksPost-Transplant;EMB grade 2R

C

6 Weeks Post-Transplant;EMB grade 1R

Figure 5. Hyperenhancement on Cardiac Magnetic Resonance Im

(A) No hyperenhancement 1 week post-transplant. (B) Areas of hyping an episode of (grade 2R) ACR. (C) Follow-up demonstrating nea(red arrows) after treatment with intravenous steroids and enhanceresolving (grade 1R) ACR. ACR � acute cellular rejection; EMB � en

etect significant coronary disease with relatively s

imagDownloaded from

igh sensitivities (70% to 100%) and specificities81% to 100%) (60–66) (Table 2). MDCT offershe advantage of evaluating the coronary lumen asell as the wall. This may be potentially useful

linically to allow detection, grading, and follow-upf CAV, given that wall thickening and intimalyperplasia are pathologic characteristics of CAV.reliminary studies have demonstrated that changes

n vessel wall can be accurately assessed usingongitudinal and cross-sectional images of the cor-nary arteries to ensure adequate visualization ofhe concentric grey area surrounding the contrast-nhanced vessel lumen (63,66) (Fig. 7). Further-ore, up to � 50% of the segments considered

hickened by MDCT may be considered normal byoronary angiography, highlighting the potentialor early CAV detection (63). There is, however, aaucity of studies correlating changes in vesselall by MDCT to IVUS to assess its true

Axis 4 Chamber -

es in a Patient With ACR

hancement in the lateral wall and basal septum (red arrows) dur-mplete resolution of the hyperenhancement in the lateral wallt of immunosuppression with corresponding EMB revealingyocardial biopsy.

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The use of MDCT does pose the technicalhallenge of reducing the heart rate enough (ideally65 beats/min) to minimize motion artifact. As a

esult of cardiac denervation, the resting heart raten cardiac transplant recipients is typically elevated,etween 80 and 110 beats/min. Pre-medicationith beta-blockers has been associated with a de-

rease and delay in heart rate reduction. Pre-edication with relatively high doses and increased

requency of beta-blockers have reduced the heartate in cardiac transplant recipients to an acceptableevel in some studies (63,67), whereas heart ratesemained high, despite similar efforts, in anothertudy (66). A high mean heart rate during MDCTcanning can impair image quality, as reported byichler et al. (62) with incomplete visualization in7% of patients (mean heart rate 87 � 9.7 beats/in) mainly owing to cardiac motion. With newer

4-slice scanner technology and multisector recon-truction algorithms, however, a heart rate of �80eats/min may permit adequate visualization.Despite this limitation, several studies report a

elatively high diagnostic image quality with 81% to6% of the coronary segments defined as either ofiagnostic or satisfactory quality (60,62,63,66). A

DE-CMR*

IVUS*

Echocardiography*(Doppler, TDI, SRI)

IVUS*Coronary

Angiography*MDCT*

ED

CoroH

CardInduc

M

Cardiac Allograft Diastolic Dysfunction

Epicardial Coronary Stenosis

FactorsReperfusion Injury, Cardiac Rejection, CMV,HTN, Dyslipidemia, Insulin Resistance, Immunosuppression Medication

Figure 6. Different Noninvasive Imaging and Invasive TechniquCardiac Allograft Vasculopathy

CE � contrast-enhanced; CMR � cardiac magnetic resonance; CMVenhancement cardiac magnetic resonance; DSE � dobutamine stresound; MDCT � multidetector computed tomography; MPI � myocDoppler imaging.

ommon reason, however, for nonevaluability of cor- a


nary segments relates to the small-vessel nature ofAV (60,66). The published reproducibility analysisf MDCT (64-slice) angiography to detect significantAV seems good with an inter-rater kappa coefficientf 0.70 with a standard error of 0.104 (95% confidencenterval: 0.496 to 0.905) (66). Potential limitations of

DCT scanning in cardiac transplant recipients re-ate to the radiation and contrast media exposuressociated with this technique, which is especiallymportant given that chronic renal failure is frequentn cardiac transplant recipients (1) and pre-existingenal disease is a well-accepted risk factor for contrast-nduced nephropathy. Preliminary studies, however,ave demonstrated that with pre- and post-test hy-ration and use of oral N-acetylcysteine in patientsith normal baseline renal function, contrast-acquired

enal dysfunction is an uncommon clinical problem60,63,66).MR and CAV. Delayed enhancement CMR may beseful indirectly for the detection of CAV, based onhe ability to identify areas of delayed hyperen-ancement that likely correspond to silent myocar-ial infarctions (68). Steen et al. (68) examined 53ardiac transplant recipients with delayed enhance-ent CMR performed within 4 weeks of coronary

MDCT*

Clinically Accepted

Investigational**thelial

nction

y Intimal plasia

Allograft Ischemia

ardialosis

Cardiac Allograft Systolic Dysfunction

Small VesselDisease

*

**

*

EchocardiographyScintigraphy CMR Cardiac CT

**

*

DSECE-Echo Stress-MPI

erformed at Various Stages of Cardiac Involvement to Detect

ytomegalovirus; CT � computed tomography; DE-CMR�delayedhocardiography; HTN � hypertension; IVUS � intravascular ultra-al perfusion imaging; SRI � strain rate imaging; TDI � tissue

ndoysfu

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1135

ancement with distinct subendocardial involve-ent as “infarct typical” and likely indicative ofyocardial infarction. The prevalence of this pat-

ern increased with worsening of CAV (present in

Table 2. Studies Evaluating the Accuracy of Different Noninvasi

Author, Year (Ref. #)Total Patients

(Prevalence of CAV)

Exer

Collings et al., 1994 (30) 51 (27%)

Mairesse et al., 1995 (31) 37 (11%)

Cohn et al., 1996 (29) 51 (51%)

Dipyrid

Ciliberto et al., 1993 (35) 80 (31%)

Ciliberto et al., 2003 (36) 68 (37%)

Dobut

Akosah et al., 1994 (33) 41 (51%)

Herregods et al., 1994 (41) 28 (50%)

Akosah et al., 1995 (69) 45 (53%)

Derumeaux et al., 1995 (37) 41 (38%)

Derumeaux et al., 1996 (38) 64 (47%)

Spes et al., 1996 (43) 46 (26%)

Akosah et al., 1998 (32) 22 (32%)

Derumeaux et al.,¶ 1998 (39) 37 (46%)

37 (70%)

Spes et al., 1999 (42) 109 (46%)

Bacal et al., 2004 (34) 39 (38%)

Eroglu et al.,# 2008 (40) 42 (19%)

Contrast-

Rodrigues et al.,** 2005 (49) 35 (29%)

Tona et al.,†† 2006 (50) 73 (47%)

Ciliberto et al., 1993 (45) 50 (30%)

Rodney et al., 1994 (55) 25 (52%)

Smart et al., 1991 (56) 73 (26%)

Ciliberto et al., 2001 (46) 78 (15%)

Carlsen et al.,� � 2000 (52) 67 (7%)

Elhendy et al., 2000 (53) 50 (60%)

Hacker et al., 2005 (54) 63 (17%)

M

Romeo et al., 2005 (63) 44 (14%)

Sigurdsson et al., 2006 (64) 54 (30%)

Gregory et al., 2006 (60) 20 (80%)

Pichler et al., 2008 (62) 60 (20%)

von Ziegler et al., 2008 (66) 26 (19%)

Vermes et al., 2006 (65) 50 (19%)

*In years � SD; if SD not reported, range of years is given. †Coronary stenosis �IV. �Modified mean Standford class III to IV. ¶Derumeaux et al. examined the aconventional and quantitative stress echocardiography (post-systolic strain inde††Tona et al. used contrast-enhanced adenosine stress echocardiography to anarrowing. §§Cross-sectional coronary obstruction �70% on autopsy. � �Carlsenby coronary segment. ##Any abnormal wall thickening by IVUS. ***IVUS intimaCAV � cardiac allograft vasculopathy; CCA � conventional coronary angiograpMPI � myocardial perfusion imaging; NR � not recorded.

nly 25% of patients with mild CAV compared fi

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ith 84% in patients with severe CAV). Theresence of “infarct-typical” hyperenhancement waslso associated with worse LV function and highernd-diastolic and -systolic volumes. Although these

maging Techniques to Detect CAV

Time Post-HT(yrs)* Gold Standard Sensitivity

Stress Echocardiography

4.2 (1–17) CCA† 29%

2.8 � 1.4 CCA‡ 0%

2.5 (1–6) CCA† (IVUS)§ 33% (15%)

ole Stress Echocardiography

2.3 � .5 CCA† 100%

2.9 � 1.9 CCA† 100%

ne Stress Echocardiography

4.8 (0.25–10) CCA† 100%

3.2 � 1.3 CCA‡ 50%

4.8 � 0.3 CCA‡ 96%

3.3 � 1.7 CCA† 100%

3.3 � 1.2 CCA† 100%

4.8 � 2.6 CCA‡ (IVUS)� 83% (79%)

.17 (0.04–0.33) CCA† 100%

3.1 � 1.7 CCA‡ 65%

4.7 � 1.8 CCA‡ 92%

3.2 � 3.1 CCA‡ and/or IVUS� 72%

7.2 � 2.6 CCA† 64%

6.0 � 4.0 CCA‡‡ 75%–88%

anced Stress Echocardiography

6.0 � 2.6 CCA† 70%

8.0 � 4.5 CCA† 82%

Exercise MPI

1.7 (1–5) CCA‡ 67%

3.1 � 1.1 CCA‡‡ 77%

Dipyridamole MPI

2.5 � 1.3 CCA† or autopsy§§ 21%

2.7 � 1.9 CCA‡‡ 92%

5.6 (2.1–12) CCA† 80%

Dobutamine MPI

6.4 � 2.8 CCA† 90%

7.4 � 3.5 CCA† 82%

Coronary Angiography

7.6 � 3.8 CCA† 83%¶¶

NR CCA† (IVUS)## 94% (92%¶¶)

5.8 � 4.4 IVUS*** 70%¶¶

8.5 � 5.2 CCA††† 88%

7.7 � 4.1 CCA† 100%

7.7 � 4.0 CCA† 87%¶¶

in at least 1 vessel. ‡Any coronary obstruction including luminal irregularities. §cy of stress echocardiography in a single group of patients at 2 different time pponse). **Rodrigues et al. used contrast-enhanced dobutamine stress echocardiogs coronary flow reserve. ‡‡Coronary stenosis �50% in at least 1 vessel and/or s. study included 4 patients with bicycle exercise testing as the stressor. ¶¶Sensitivkness �0.5 mm. †††Coronary stenosis �70%. Modified from Thorn et al. (13).T � heart transplantation; IVUS � intravascular ultrasound; MDCT � multidetecto

ve I

Specificity

cise

82%

97%

85% (85%)

am

72%

87%

ami

41%

71%

52%

77%

NR

56% (83%)

0 59%

95%

73%

88%

91%

79%–88%

Enh

96%

87%

100%

100%

88%

86%

92%

55%

87%

DCT

95%¶¶

79% (95%¶¶)

92%¶¶

97%

81%

100%¶¶

50% Standford IVUS class III toccura oints. #Eroglu et al. usedx res raphy to assess perfusion.sses ignificant diffuse luminalet al ity and specificity analysisl thichy; H r computed tomography;

ndings suggest that CMR might be useful in the



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etection of CAV, the clinical significance andathologic basis of these findings are unknown.alidation and prospective outcome-based studies

re currently underway.

onclusions

espite many advances in the field of HT, ACR,nd CAV represent significant causes of early andate morbidity and mortality, respectively. Differentmaging modalities, including echocardiography,PECT-MPI, MDCT, and CMR have been usedfter HT to monitor multiple clinically importantarameters of cardiac graft structure and function.n general, echocardiography represents the primaryoninvasive modality for monitoring cardiac func-ion in transplant recipients based on its ability toetect abnormalities of ventricular systolic function,

uating the Accuracy of Different Noninvasive Imaging Technique

#)Total Patients

(Prevalence of MACE)Time Post-HT

(yrs)*Le

2-Dimensional Echocardiogra

5) 80 (9%) 2.3 � 1.5

(48) 46 (11%) NR

109 (15%) 3.2 � 3.1 �

6) 78 (22%) 2.7 � 1.9

6) 68 (28%) 2.9 � 1.9

Dipyridamole Stress Echocard

5) 80 (9%) 2.3 � 0.5

6) 68 (28%) 2.9 � 1.9

Dobutamine Stress Echocard

) 76 (16%) 4.8 (0.25–10)

(37) 41 (5%) 3.3 � 1.7

) 64 (25%) 4.8 � 2.4

63 (56%) 4.8 � 2.6

) 22 (10%) 0.17 (0.04–0.33)

109 (15%) 3.2 � 3.1 �

39 (25%) �4.0

CE-Stress Echocardiogra

66 (17%) 9.0 � 4.0

Dipyridamole MPI

6) 78 (22%) 2.7 � 1.9

Dobutamine MPI

) 77 (13%) 7.4 � 3.5

(58) 166 (10%) 7.4 � 2.5

le, range is provided. †Tona et al. used CE echocardiography to assess accuracy o�2.6). �Hacker et al. compared visual¶ and semiquantitative# (summed stress scoesting; however, both stress modalities shared similar ability to predict cardiac d; HT � heart transplantation; MACE � major adverse cardiac event; MPI � myormality.

rovide estimation of right- and left-sided filling a


ressures with reasonable accuracy, and evaluateericardial effusions or other complications fromepeated biopsies.

With regard to the detection of ACR, when thechocardiography literature is taken as a whole,here are inconsistencies among various reportsrought about by small sample size, variability inhe reference gold standard used, and differentutoff points for the different echocardiographyarameters evaluated. Today, echocardiographicechniques lack the sensitivity and specificity toeplace EMBs to detect clinically significant ACR.romising echocardiography techniques involvingDI and strain imaging are associated with rela-

ively high negative predictive values in the detec-ion of ACR. However, further validation andutcome-based studies are required before a specificchocardiography parameter can be recommended

Detect MACE

h of Follow-Up(Months)

Detection of MACE

NPVSensitivity Specificity

WMA

9.8 � 4.5 100% 73% 100%

45 � 20 40% 98% 93%

in some cases 75% 65% 94%

78 � 24 41% 97% 85%

72 � 36 80% 68% 90%

raphy

9.8 � 4.5 100% 71% 100%

72 � 36 80% 68% 90%

aphy

10 � 2 100% 41% 100%

6.0 100% 66% 100%

24 (18–28) 100% 69% 100%

.0 (4–14) 83% NR NR

32 � 11 100% 61% 100%

in some cases 94% 57% 98%

48 60% 86% 87%

19 � 5 86%‡ 75%‡ 97%

91%§ 62%§ 97%

78 � 24 53% 82% 86%

22 (12–48) 90%¶ 72%¶ 98%

90%# 88%# 98%

30 69% 71% 95%

celeration time of diastolic flow velocity ‡(cutoff value �840 ms) and coronary3) analysis. **Elhendy et al. study (65 of the 166 patients reportedly underwent). Modified from Thorn et al. (13).ial perfusion imaging; NPV � negative predictive value; NR � not recorded;

Table 3. Studies Eval s to

Author, Year (Ref.ngt

phy

Ciliberto et al., 1993 (3

Verhoeven et al., 1996

Spes et al., 1999 (42) 60



iog



iogr

Akosah et al., 1994 (33

Derumeaux et al., 1995


Lewis et al., 1997 (47) 8


Spes et al., 1999 (42) 60

Bacal et al., 2004 (34)

phy

Tona et al.,† 2006 (51)


Hacker et al.,� 2005 (54

Elhendy et al.,** 2002

*Mean � SD; if not availab f deflow reserve §(cutoff value re �exercise not dobutamine t eathCE � contrast enhanced card

s a screening index to minimize the use of serial

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iopsies. CMR, similar to echocardiography, canccurately detect ventricular systolic dysfunction,nd newer CMR techniques may allow the detec-ion of myocardial edema and necrosis—hallmarksf ACR.In contrast, with respect to CAV, stress imaging

ith DSE and MPI and coronary angiography withDCT are powerful techniques to identify this late

omplication with high accuracy. DSE is the most-tudied technique with significant prognostic valueomparable to that of IVUS and invasive coronaryngiography. For transplant centers experienced intress echocardiography, an invasive examination toetect significant CAV can be reserved for patientsith an abnormal annual DSE. Although echocar-iography has the advantage of lower cost, the usef MPI, especially with dobutamine, is a compara-le alternative in cardiac transplant recipients givents prognostic value. MPI may be especially usefuln patients with inadequate acoustic windows de-pite the use of a contrast echocardiography agentnd in centers without adequate experience in DSE.

Newer CMR techniques may allow the detection

Figure 7. MDCT Coronary Angiography Demonstration of Cardi

(A) Total vessel occlusion of left anterior descending (LAD) is illustrocclusion by MDCT volume-rendering angiography. (C) Maximum inproximal of occlusion, an excentric noncalcified plaque is depictedchanges throughout the LAD course, causing no to minimal luminacircumflex; LM � left main coronary artery; MDCT � multidetectorvon Ziegler et al. (66) with permission.

f abnormal hyperenhancement to detect CAV H

imagDownloaded from

oninvasively; further pathologic and outcometudies, however, are needed. With the ability of

DCT coronary angiography to evaluate the cor-nary wall in addition to the lumen, MDCT hashe potential for earlier detection of CAV comparedith echocardiography, MPI, and CMR. This ear-

ier detection of CAV may enhance research in thiseld and prompt the early use of proliferation signal

nhibitors or other investigations to minimize CAVisease progression and improve outcome. Furtheralidation of MDCT, however, is needed in largertudies. Furthermore, because this technique is alsossociated with radiation and contrast exposure, theisk/benefit ratio needs to be concomitantly evalu-ted, given the need for serial examinations and theigh incidence of renal insufficiency in this patientopulation.

eprint requests and correspondence: Dr. Jerry D. Estep,ethodist DeBakey Heart and Vascular Center, Cardi-

logy, Smith Tower, 6550 Fannin Street, Suite 1901,

llograft Vasculopathy

by conventional coronary angiography. (B) Corresponding LADsity projection; grey arrows indicate site of total vessel occlusion;cross-sectional image (note diffuse hypodense vessel wallgularities in conventional coronary angiography). LCX � leftputed tomography; RCA � right coronary artery. Adapted from

ac A

atedtenin al irrecom

ouston, Texas 77030. E-mail: [email protected].


mailto:[email protected]



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doi:10.1016/j.jcmg.2009.06.006 2009;2;1126-1140 J. Am. Coll. Cardiol. Img.

Torre-Amione, and William A. Zoghbi Jerry D. Estep, Dipan J. Shah, Sherif F. Nagueh, John J. Mahmarian, Guillermo

The Role of Multimodality Cardiac Imaging in the Transplanted Heart

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The Role of Multimodality Cardiac Imaging in the Transplanted Heart