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CT for Evaluation of Myocardial Cell Therapy inHeart FailureA Comparison With CMR Imaging

Karl H. Schuleri, MD,* Marco Centola, MD,*† Seong Hoon Choi, MD, PHD,*‡Kristine S. Evers, BS,* Fady Dawoud, PHD,* Richard T. George, MD,*João A. C. Lima, MD,* Albert C. Lardo, PHD*§

Baltimore, Maryland; Milan, Italy; and Uslan, South Korea

O B J E C T I V E S The aim of this study was to use multidetector computed tomography (MDCT) to

assess therapeutic effects of myocardial regenerative cell therapies.

B A C K G R O U N D Cell transplantation is being widely investigated as a potential therapy in heart failure.

Noninvasive imaging techniques are frequently used to investigate therapeutic effects of cell therapies in the

preclinical and clinical settings. Previous studies have shown that cardiac MDCT can accurately quantify

myocardial scar tissue and determine left ventricular (LV) volumes and ejection fraction (LVEF).

M E T H O D S Twenty-two minipigs were randomized to intramyocardial injection of phosphate-

buffered saline (placebo, n � 9) or 200 million mesenchymal stem cells (MSC, n � 13) 12 weeks after

myocardial infarction (MI). Cardiac magnetic resonance and MDCT acquisitions were performed before

randomization (12 weeks after MI induction) and at the study endpoint 24 weeks after MI induction.

None of the animals received medication to control the intrinsic heart rate during first-pass acquisitions

for assessment of LV volumes and LVEF. Delayed-enhancement MDCT imaging was performed 10 min

after contrast delivery. Two blinded observers analyzed MDCT acquisitions.

R E S U L T S MDCT demonstrated that MSC therapy resulted in a reduction of infarct size from 14.3 � 1.2% to

10.3 � 1.5% of LV mass (p � 0.005), whereas infarct size increased in nontreated animals (from 13.8 � 1.3% to

16.5 � 1.5%; p � 0.02) (placebo vs. MSC; p � 0.003). Both observers had excellent agreement for infarct size (r �

0.96; p� 0.001). LVEF increased from32.6� 2.2% to 36.9� 2.7% inMSC-treated animals (p� 0.03) anddecreased

in placebo animals (from 33.3 � 1.4% to 29.1 � 1.5%; p � 0.01; at week 24: placebo vs. MSC; p � 0.02). Infarct

size, end-diastolic LV volume, and LVEF assessed by MDCT compared favorably with those assessed by cardiac

magnetic resonance acquisitions (r � 0.70, r � 0.82, and r � 0.902, respectively; p � 0.001).

C O N C L U S I O N S This study demonstrated that cardiac MDCT can be used to evaluate infarct size,

LV volumes, and LVEF after intramyocardial-delivered MSC therapy. These findings support the use of

cardiac MDCT in preclinical and clinical studies for novel myocardial therapies. (J Am Coll Cardiol Img

2011;4:1284–93) © 2011 by the American College of Cardiology Foundation

From the *Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, Maryland; †Division ofCardiology, College of Medicine, Fondazione IRCCS, Azienda Ospedaliera San Paolo, Polo Universitario, Milan, Italy;‡Department of Radiology, Uslan University Hospital, University of Ulsan College of Medicine, Uslan, South Korea; and the§Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland. All authors have reported that theyhave no relationships relevant to the contents of this paper to disclose.

Manuscript received July 8, 2011; revised manuscript received August 29, 2011, accepted September 2, 2011.

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ardiac imaging techniques play a criticalrole in the evaluation of novel therapiesproviding reliable surrogate endpoints inthe ongoing effort to explore new ap-

roaches to treat heart diseases. Myocardial trans-lantation of different cell types and preparationsas been widely investigated as a potential therapyor myocardial infarction (MI) and heart failureHF) in recent years (1). Cardiac magnetic reso-ance (CMR) is one of the preferred imaging tools,

n addition to the frequently used echocardiographynd nuclear techniques, to provide reliable assess-ent of left ventricular ejection fraction (LVEF)

nd infarct size, which are generally accepted sur-ogate endpoints (2,3). Previous animal studiessing CMR showed that mesenchymal stem cellsMSC) reduced infarct size and improved leftentricular (LV) function in acute and chronic MI4–6). However, the use of CMR in the clinicaletting is limited in patients with metallic implantsnd pacemakers and is relatively complex and timeonsuming.

Over the last decade, multidetector computedomography (MDCT) has emerged as a novelomographic cardiac imaging modality. Improve-ent in spatial and temporal resolution has allowed

he implementation of myocardial applications,hich are necessary to evaluate regenerative thera-ies. Although these MDCT applications are stillnvestigative, current MDCT technology is able torovide reliable and reproducible assessment ofardiac function (7,8), myocardial viability withelayed contrast enhancement (DCE) (9–11), andyocardial blood flow (MBF) (12–14). However,hether MDCT can be used for follow-up studies

nd is able to show therapeutic effects of regenera-ive cell therapies has not been investigated. Ac-ordingly, the purpose of this study was to 1) use

DCT LV function and myocardial viability asurrogate endpoints in a randomized animal studyo evaluate outcomes of intramyocardial-deliveredell therapy and 2) evaluate the robustness andomparability of MDCT in relation to CMR.

M E T H O D S

Animal model. All animal studies were approved byhe Johns Hopkins University Institutional Animalare and Use Committee and complied with the

Guide for the Care and Use of Laboratory Animals”National Institutes of Health publication 80-23, revised985). Thirty-three female Göttingen minipigs were
urchased from Marshall BioResources (North Rose, m
ew York). MIs were induced by occlusion of theid-left anterior descending artery with an inflated

oronary angioplasty balloon as previously described15). Five animals did not survive the infarct pro-edure. Two animals died during the earlyollow-up in the first 4 days after MI induction, and

animals died between weeks 8 and 12 post-MI.herefore, a total of 22 animals were used in the

tudy.Cell harvest and isolation. The 13 animals random-zed to cell therapy received bone marrow–derivedorcine MSC. MSC were obtained, isolated, andxpanded as previously described (6). In brief, MSCere harvested when they reached 80% to 90%

onfluence. Cells were placed in cryo bags at aoncentration of 10 to 15 million MSC/ml andhen frozen in a control-rate freezer to

180°C until the day of implantation.rypan blue staining was performed to

ttest viability of thawed MSC lots beforenjection. Only MSC lots containing 85%r more of viable cells were used in thetudy.Cell transplantation procedures. Twelveweeks after MI, animals were randomizedto receive either intramyocardial injectionsof porcine MSC or phosphate-bufferedsaline to serve as a treatment (n � 13) orplacebo (n � 9) group, respectively. Myo-cardial injections were performed as pre-viously described (5,6).Cardiac MDCT. MDCT images were ac-uired at 2 time points, before randomiza-ion at week 12 post-MI and 12 weeksfter the intramyocardial injection proce-ure at week 24.

IMAGE ACQUISITION. Each animal wascanned with electrocardiographic (ECG) monitor-ng using a 0.5 mm � 64-slice MDCT scannerAquilion 64, Toshiba Medical Systems Corpora-ion, Otawara, Japan). Data acquisition for LVunction parameters and LV volumes were initiatedanually at a threshold value of 180 Hounsfield

nits in the descending aorta. A 60-ml bolus ofodixanol (Visipaque 320 mg iodine/ml, Amersham

ealth, Buckinghamshire, United Kingdom) wasnjected intravenously at rate of 5.0 ml/s,pacifiying the LV chamber during first pass. Andditional 90 ml of iodixanol was given intrave-ously after first-pass acquisitions, and DCE

mages were acquired 10 min after initial contrastelivery; 150 ml of iodixanol (0.91 � 0.04 � 103

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human equivalent dose of contrast currently usedfor MDCT angiography.

During MDCT acquisition, respiration was sus-pended and imaging was performed using a retro-spective ECG-gated MDCT protocol without dosemodulation. Imaging parameters: gantry rotationtime � 400 ms; detector collimation � 0.5 mm �64 (isotropic voxels � 0.5 � 0.5 � 0.5 mm3 � 13inepairs/cm); helical pitch � variable depending oneart rate (range 6.4 to 6.8); tube voltage � 120 kV;nd tube current � 400 mA. Animals with heartates �100 beats/min during first-pass acquisitioneceived intravenous metoprolol (2 to 5 mg) and /ormiodarone (50 to 150 mg) to achieve lower heartate for DCE acquisitions.

IMAGE RECONSTRUCTION AND ANALYSIS. All rawata were reconstructed at contiguous 0.5-mm slicehickness by an adaptive multisegment reconstruc-ion algorithm (16). First-pass acquisitions wereeconstructed in 10% steps from 0% to 90%hroughout the entire R-R interval using a standardernel (FC43); images were reformatted at 4-mmlice thickness in short axis and evaluated in QMassT 7.1 (Medis Medical Imaging Systems, Leiden,

he Netherlands). Endocardial and epicardial bor-ers of the LV were defined in all 10 contiguouslices, and each end-diastolic and end-systolic frameas determined to calculate LVEF, left ventricular

nd-diastolic volume (LVEDV), left ventricularnd-systolic volume (LVESV), LV stroke volume,nd LV remodeling parameters. The temporal res-lution based on gantry rotation of all MDCTcquisitions was 211.5 � 5.4 ms.

DCE-MDCT data (for myocardial scar assess-ent) were reconstructed at 80% of the R to R=

nterval using the FC43 kernel and multisegmenteconstruction. ECG editing to account for ar-hythmias was performed when necessary. Multi-lanar reformation at 4-mm slice thickness in thehort axis of the heart was implemented, and

DCT images were analyzed using a customesearch software package (Cine Tool, GE Medicalystems, Waukesha, Wisconsin). Infarct mass/olumes in DCE-MDCT images were defined by 3D of the signal intensity above the viable myocar-ium for the core infarct and 2 SD for the peri-

nfarct zone as described (16). Infarct size wasefined as infarct mass as a percentage of LV mass.oth datasets, the cine MDCT acquisitions, andCE-MDCT images, were analyzed by 2 blinded

bservers.

CMR imaging. CMR was performed at the sameime points as MDCT imaging in random order on1.5-T MR scanner (CV/i, GE Medical Systems).

IMAGE ACQUISITION. LVEF function and LV vol-mes were assessed using a steady-state free preces-ion pulse sequence (17). Six to 8 contiguoushort-axis slices were prescribed to cover the entireV, from base to apex. Image parameters were as

ollows: repetition time/echo time � 4.2 ms/1.9 ms;ip angle � 45°; 256 � 160 matrix; 8-mm slicehickness/no gap; 125 kHz; 28-cm field of view,nd 1 number of signals averages. After an intrave-ous injection of gadolinium–diethylene triamineentaacetic acid (0.2 mmol/kg body weight, Magn-vist, Berlex, Wayne, New Jersey), DCE-CMRmages were acquired 15 min later using an ECG-ated, breath-hold, interleaved, inversion recovery,nd fast gradient echo pulse sequence. DCE-CMRmages were acquired in the same location as thehort-axis cine images. Imaging parameters wereepetition time/echo time/inversion time � 7.3s/3.3 ms/180 to 240 ms; flip angle � 25°; 256 �

96 matrix; 8-mm slice thickness/no gap; 31.2 kHz;8-cm field of view, and 2 number of signalverages. Inversion recovery time was adjusted aseeded to null the normal myocardium (16).

IMAGE ANALYSIS. Cine MR images were analyzedwith QMass MR 7.1 (Medis Medical ImagingSystems). To evaluate LVEF, LV volumes andmyocardial mass endocardial and epicardial borderswere defined each in the end-diastolic and end-systolic frame in 25 to 30 contiguous slices, and LVparameters and volumes were calculated. The tem-poral resolution of the cine MR images was 21.6 �0.9 ms. DCE-CMR images were analyzed on thesame custom research software package (Cine Tool,GE Medical Systems) as DCE-MDCT images.Infarct size, determined by infarct mass as a per-centage of LV mass and infarct volume in DCE-CMR images, was defined with the same thresholdmethod described for DCE-MDCT analysis.Statistical analysis. All data are presented as mean �SEM unless otherwise stated. For infarct size andinfarct volume comparison, Pearson correlation andlinear regression analysis were used to compareMDCT and CMR. Results were confirmed byBland-Altman analysis and agreement expressed asmean � SD difference between methods at 95%confidence intervals. The MDCT and CMR datawere evaluated with a paired Student t test. All
analyses were performed in MedCalc (MedCalc

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Software, Mariakerke, Belgium). A value of p �0.05 was considered significant.

R E S U L T S

Baseline conditions. Twenty-two animals were usedn this study 12 weeks after MI induction (91.9 � 2.6ays and 87.9 � 2.0 days after MI induction forlacebo and MSC groups, respectively; p � 0.19).fter randomization, animals in both groups were of

imilar age (16.8 � 0.7 months and 15.5 � 1.1onths for placebo and MSC, respectively; p � 0.35)

nd body weight (39.3 � 1.6 kg and 35.7 � 1.9 kg forlacebo and MSC, respectively; p � 0.11).

Infarct size and scar volume. One placebo- and 2MSC-treated animals were excluded from analysisdue to poor imaging quality caused by motionartifacts at week 24. Infarct size, defined as infarctmass as percentage of LV mass, was reduced in allMSC-treated animals at week 24, whereas infarctsize increased in all animals in the placebo group(Fig. 1). We observed a mean expansion of 29.1 �5.7% in infarct scar volume in the placebo group(p � 0.001). MSC therapy had limited effect onotal scar volume (p � 0.1) (Figs. 1, 2C, and 2D).

At week 24, infarct size and infarct volume werereduced in MSC-treated animals compared withthose in the placebo group (p � 0.003 and p �0.01, respectively), (Table 1, Figs. 2A to 2D).Global LV function and LV volumes. Cardiac MDCT

emonstrated that the decrease in infarct size re-ulted in 14.0 � 6.7% improvement in LVEF innimals randomized to MSC therapy, whereasVEF decreased by 12.3 � 3.1% in the placeboroup (Table 1, Figs. 2E and 2F). Of note, 2nimals that received MSC therapy did not showmproved LVEF (Fig. 2F). All MDCT data forlobal LV function and LV volumes are summa-ized in Table 1.Interobserver variability. Interobserver correlationor infarct size, total infarct volume, LVEF, andVEDV were excellent (r � 0.96, r � 0.98, r �.93, and r � 0.93, respectively) in MDCT acqui-itions. The complete data are presented in Table 2.MDCT comparison with CMR. MDCT and CMRwere performed on the same day in random orderwithin 2 h following the first imaging study. Threeanimals had to be excluded from the analysis becauseCMR image data were not obtained on the dayof the MDCT imaging. In 32 CMR studies, availablethe same day as MDCT acquisitions, we found fairagreement for infarct size, infarct volume, LVEF, and
LVEDV (Fig. 3, Table 3). In addition, LVESV
showed a good correlation with both imaging modal-ities (r � 0.81; p � 0.001). Bland-Altman analysisrevealed a slight overestimation by 1.4 ml (95%confidence intervals: 16.3 to �13.6) with MDCT.Table 4 shows a direct comparison of all MDCT andMRI values at the 2 time points.

Finally, we showed that MDCT and CMRdemonstrate similar effectiveness of MSC therapyfrom week 12 to week 24 (Fig. 4). Infarct sizedecreased by mean values of 4.7 � 1.1 ml and 6.2 �2.0 ml when evaluated with DCE-MDCT andDCE-CMR in MSC-treated animals, respectively(p � 0.43). The changes in LVEF with MSCtreatment were also apparent with both imagingmodalities, with comparable mean values (4.5 � 1.0ml and 5.6 � 1.3 ml, MDCT vs. MRI, respectively;p � 0.4). The changes between the placebo- andMSC-treated animals were also detected with bothimaging modalities. Although the detected differencesbetween MDCT and MRI were not significant for allinfarct and functional parameters, the changes over timecorrelated with the assessment (Fig. 4).

D I S C U S S I O N

This is the first study to use cardiac MDCT for the

Figure 1. Infarct Assessment With DCE-MDCT

Example of delayed contrast enhancement multidetector computedtomography (DCE-MDCT) images for a placebo-treated (A and B) anmesenchymal stem cell (MSC)–treated (C and D) animal at 24 weekDCE images were reconstructed in the short axis at 4-mm slice thicness. (B and D) show the slices of the placebo-treated (A) and MSCtreated (C) animals, respectively, with a computer-generated maskdepicting the infarct area in red.

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infarct size, LV volumes, and LV function. Ourresults suggest that MDCT imaging reliably as-sessed LVEDV, LVEF, infarct size, and infarctvolumes with DCE acquisitions; MDCT imaging

Impact of MSC Therapy Assessed by MDCT

animals (n � 8) showed an increase in infarct size (A) andme (C) at week 24, whereas intramyocardial delivery of MSCfarct size (B) and stabilized infarct volume (D) in all treated ani-11). (E and F) Left ventricular ejection fraction (LVEF) wasat week 24 in placebo animals, whereas it increased in mostd animals; however, the treatment failed to improve LVEF inMI � myocardial infarction; other abbreviations as in Figure 1.

s, LV Function, and LV Volumes by MDCT

Group Week 12 Week 24 p Value

ass Placebo 13.8 � 1.3 16.3 � 1.6 0.005

MSC 14.3 � 1.2 9.9 � 1.3* 0.001

l Placebo 4.7 � 0.6 6.2 � 0.7 0.001

MSC 4.4 � 0.4 3.6 � 0.5† 0.1

Placebo 33.6 � 1.1 37.5 � 1.6 0.02

MSC 30.6 � 1.3 37.4 � 2.1‡ 0.0003

Placebo 33.3 � 1.4 29.1 � 1.5 0.01

MSC 32.6 � 2.2 36.9 � 2.7§ 0.03

Placebo 19.7 � 1.6 19.4 � 0.8 0.81

MSC 15.1 � 0.7 20.6 � 1.6‡ 0.004

Placebo 60.1 � 5.7 67.6 � 4.1 0.16

MSC 48.1 � 3.1 56.3 � 4.3‡ 0.01

Placebo 40.4 � 4.5 48.3 � 3.7 0.07

MSC 33.0 � 2.9 36.4 � 4.1� 0.15

SC (n � 11) versus placebo (n � 8). *p � 0.003. †p � 0.01. ‡p � nonsignificant.

� left ventricular end-diastolic; LVEDV � left ventricular end-diastolic volume;end-systolic volume; MDCT � multidetector computed tomography; MSC �

was able to assess the effect of intramyocardial-delivered cell therapy compared with placebo.These findings confirmed previous studies that usedCMR to evaluate the therapeutic potential ofintramyocardial-delivered MSC in animals withHF with chronic infarct scars (6,18). This studyintroduces MDCT imaging as an alternative car-diac imaging technique to determine efficacy ofnovel myocardial therapeutics.Myocardial infarct scar assessment by MDCT. MDCThas the capability to distinguish between viable andnonviable myocardium with DCE for the detectionof acute and chronic infarct scars, and its use hasrecently been reported in animal experiments andhuman studies; however, it is still considered aninvestigative technique (9–11,16,19). After intrave-nous delivery, iodine-based contrast agents accu-mulate in myocardial tissue damaged by MI. Thediscrimination between viable and nonviable myo-cardium results from increased attenuation valuescaused by the accumulation of iodine molecules inthe infarct area detected by MDCT. This is incontrast to enhancement mechanisms by CMR thatrely on alteration of the contrast media via interac-tions with water molecules (9). The infarct sizesdetected by DCE-MDCT in this study were sig-nificantly smaller than matching CMR values; theseresults are in accordance with previously publisheddata for acute and chronic MI (16,20). Thus,DCE-MDCT– and DCE-CMR–derived valuesfor infarct size and infarct volume should not beused interchangeably at the current status ofMDCT technology.

The extent of contrast enhancement detected byCMR has been shown to predict the response tomedical treatment in patients with HF (21). Re-duction of infarct size has been noted with DCE-CMR following myocardial cell therapy in animalstudies and patients (4–6,22,23). Thus, quantifica-tion of infarct size and infarct volume by DCE-MDCT could be a valuable surrogate endpoint,allowing the prediction of response to therapy.DCE-MDCT currently offers the highest spatialresolution for transmural characterization of infarctscars, and this can be particularly helpful in guidingintramyocardial delivery of cell-based therapies.An akinetic segment might be deemed nonviableby nuclear techniques using limited spatial reso-lution but shows some viability in DCE-MDCT,which increases the likelihood that this segmentwill eventually recover with therapeutic interven-

Figure 2.

All placeboinfarct volureduced inmals (n �

decreasedMSC-treate

Table 1. Infarct Value

Parameter

Infarct size, % of LV m

Total infarct volume, m

LVED mass, g

LV ejection fraction, %

Stroke volume, ml

LVEDV, ml

LVESV, ml

Values are mean � SEM. M§p � 0.02. �p � 0.047.LV � left ventricular; LVEDLVESV � left ventricular

tion (24).

tion


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Evaluation of cardiac function and volumes by MDCT.Evaluation of cardiac function with MDCT isaccomplished with intravenous injection of iodine-based contrast agents for opacification of the bloodpool to delineate the borders of the ventricle andapplication of retrospective ECG-gated protocolsto record the complete cardiac cycle during the R-Rinterval. Various investigators have reported a con-sistent overestimation of LVESV and an underes-timation of LVEF by MDCT with 4-slice and early16-slice technology compared with CMR; however,with the introduction of 64-slice MDCT technol-ogy and improvement in temporal resolution, theseintermethod differences in global LV function vari-ables are no longer reproduced. Temporal resolu-tion, based on gantry rotation, has been reported tobe less than 165 ms with single-source systems and

Figure 3. Quantitative Assessment of MDCT and CMR Values

The relation between MDCT and cardiac magnetic resonance (CMRume was evaluated for 16 animals at both time points. (A and B) M8-mm slice thickness, respectively, with an underestimation of infarsis. (C and D) Good correlation of infarct volume with less underesrelation of both modalities with minimal underestimation of LVEF b

Table 2. Interobserver Variability for MDCT

ParametersCorrelation

Coefficient (r)95% CIfor r

Infarct size, % of LV mass 0.96 0.93–0.98

Infarct volume, ml 0.98 0.95–0.99

LVED mass, g 0.84 0.71–0.92

LV ejection fraction, % 0.93 0.87–0.96

Stroke volume, ml 0.84 0.70–0.91

ED volume, ml 0.92 0.84–0.96

ES volume, ml 0.93 0.86–0.96

CI � confidence interval; ED � end-diastolic; ES � end-systolic; other abbrevia

volume. Abbreviations as in Figures 1 and 2.

83 ms with dual-source MDCT technology (7).Our results are in accordance with studies compar-ing single-source and dual-source 64-sliceMDCT—with CMR showing small differencesbetween both modalities and narrow Bland-Altmanwindows (25–29). In our study, we observed goodcorrelation coefficients for LVEDV and LVEF, andwe were able to confirm the linear relationshipbetween both volumetric imaging techniques for LVfunction and LV remodeling parameters, making bothtomographic imaging methods interchangeable forLV function and LV volume assessment.

Evaluation of the cardiac structure, LV volumes,and LV function—specifically LVEF—is an inte-gral step in determining prognosis and therapy forpatients with HF (30). Human trials, using a varietyof cell-therapy approaches, have used improve-

infarct size, infarct volume, LVEF, and LV end-diastolic (ED) vol-T and CMR showed a fair correlation for infarct size at 4-mm andze by DCE-MDCT compared with DCE-CMR in Bland-Altman analy-tion by DCE-MDCT than that for infarct size. (E and F) Good cor-DCT. (G and H) MDCT and CMR show excellent correlation of ED

Significance Level(p Value)

Difference(Mean)

95% CI forMean

�0.0001 0.6 3.0 to �1.8

�0.0001 0.05 0.8 to �0.7

�0.0001 �0.9 3.9 to �5.7

�0.0001 �1.1 4.8 to �7.0

�0.0001 �0.1 5.2 to �5.3

�0.0001 3.1 14.9 to �8.7

�0.0001 3.2 12.7 to �6.2

s as in Table 1.

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ments in LVEF as an endpoint (3). Compared withvolumetric changes, using LVEF as an endpoint hasthe advantage of denoting a survival difference andis an accepted surrogate measure for mortality (31).The magnitude of treatment effect on LVEF seenin these trials has ranged from 5% to 9%, whereasthe change in the control groups has ranged from�2% to 4% (32).Advantages and limitations of MDCT imaging. As anovel cardiac imaging option for LV function andviability, MDCT offers some solutions for thedifficulties faced in CMR. MDCT can be safelyperformed in patients with metallic implants,such as pacemakers, defibrillators, and prostheses,who are inappropriate candidates for CMR. Al-though CMR is considered the reference stan-dard for cardiac function and myocardial viabil-ity— based on the accuracy and reproducibility ofmeasurements—the duration of CMR acquisi-tions with multiple prolonged breath-holds arerequired to obtain adequate datasets, are timeconsuming, and are impossible in patients with claus-

Table 3. Correlation and Bland-Altman Analysis of MDCT and C

ParametersCorrelation

Coefficient (r)Linear Regression

Equation

Infarct size, % LV mass

Total 0.70 y � 0.9x � 9.4

Week 12 0.37 y � 0.5x � 14.1

Week 24 0.89 y � 1.0x � 7.5

Placebo 0.44 y � 0.5x � 15.4

MSC 0.82 y � 1.1x � 6.1

Total infarct volume, ml

Total 0.81 y � 1.3x � 1.9

Week 12 0.68 y � 1.2x � 2.3

Week 24 0.87 y � 1.3x � 1.9

Placebo 0.73 y � 1.1x � 2.7

MSC 0.86 y � 1.5x � 1.2

LV ejection fraction, %

Total 0.90 y � 1.1x � 3.2

Week 12 0.87 y � 1.1x � 2.4

Week 24 0.92 y � 1.1x � 3.5

Placebo 0.88 y � 1.4x � 12.1

MSC 0.91 y � 1.0x � 3.6

ED volume, ml

Total 0.82 y � 0.7x � 19.3

Week 2 0.84 y � 0.6x � 23.6

Week 24 0.81 y � 0.8x � 12.2

Placebo 0.81 y � 0.7x � 18.5

MSC 0.81 y � 0.7x � 15.9

Total: n � 32; week 12, week 24, placebo, MSC: n � 16.CMR � cardiac magnetic resonance; other abbreviations as in Tables 1 and 2

trophobia. Thus, CMR is limited to specialized centers, t

which is in contrast to the widely accessible cardiacMDCT. MDCT imaging is fast and offers good tem-poral and excellent spatial resolution; however, MDCTacquisitions require iodinated contrast agents and involveradiation exposure.Future perspective. To translate cardiac functionnd viability assessment with MDCT into clini-al trials, standardized low-dose protocols areeeded, especially to minimize overall radiationxposure because follow-up studies are requiredor outcome assessment. In the latest generationf MDCT scanners, ECG-gated tube currentodulations are commonly applied in retrospec-

ive acquisitions for evaluation of cardiac function7). Low-dose DCE protocols have been reported (9).

e recently described a prospectively gated protocol forigh-resolution DCE-MDCT imaging that lowered theadiation dose by an order of magnitude (33).

In addition to cardiac function and viability,DCT is able to assess MBF. Cardiac CT perfu-

ion is based on the same first-pass principle asMR (14), which has been used to evaluate cell

SignificanceLevel

(p Value)Mean Difference

(Bias) SD95% CI for

Mean

�0.0001 �7.5 4.27 0.8 to �15.9

0.16 �7.5 5.23 3.0 to �18.0

�0.0001 �7.5 3.06 �1.7 to �13.3

0.09 �7.4 4.22 1.7 to �16.5

�0.001 �7.6 4.07 0.2 to �15.4

�0.0001 �3.2 1.71 0.3 to �6.6

0.004 �3.0 1.77 0.3 to �6.4

�0.0001 �3.3 1.76 0.3 to �6.9

0.001 �3.3 1.94 0.4 to �7.0

�0.0001 �3.0 1.53 0.3 to �6.2

�0.0001 �0.9 3.81 6.6 to �8.5

�0.0001 �0.9 3.69 6.1 to �8.0

�0.0001 �0.9 4.19 7.3 to �9.1

�0.0001 0.3 3.43 7.6 to �7.0

�0.0001 �2.2 3.78 5.0 to �9.6

�0.0001 �0.02 6.63 15.9 to �16.0

�0.001 �1.2 5.90 15.7 to �18.0

�0.001 1.1 7.44 16.3 to �14.1

�0.001 �3.1 6.38 11.1 to �17.3

�0.001 3.0 7.10 18.8 to �12.7

MR

herapy (5). Semiquantitative and quantitative as-


D E C E M B E R 2 0 1 1 : 1 2 8 4 – 9 3

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sessments of MBF with MDCT have been reportedin experimental animals (9,13). Cardiac MDCT ispoised to offer a comprehensive evaluation of novelmyocardial therapeutics.

Figure 4. Comparison of MDCT and CMR Values for MI and LVE

Data of placebo- (n � 8) and MSC-treated (n � 8) animals imagedthe absolute difference of MDCT and MRI values, effectiveness of M(∆change). (A and B) Both DCE-MDCT and DCE-CMR detected signi(C) The changes over time showed a fair correlation between MDCas infarct volume was compared (p � 0.0001), showing a modest cwith MDCT and CMR. Importantly, the effectiveness of MSC therapywere not significantly different between MDCT and CMR evaluation

Table 4. Comparison of MDCT and CMR Studies (N � 32)

Parameter Groups

Pla

Week 12

Infarct size, % of LV mass MDCT 13.8 � 1.3

CMR 20.1 � 1.6

Total infarct volume, ml MDCT 4.5 � 0.5

CMR 7.1 � 0.8

LVED mass, g MDCT 35.0 � 1.4

CMR 37.3 � 2.5

LV ejection fraction, % MDCT 33.3 � 1.4

CMR 34.0 � 2.6

ED volume, ml MDCT 60.1 � 5.7

CMR 56.6 � 4.7

Week 24: MSC (n � 8) versus placebo (n � 8). *p � 0.01. †p � 0.001. ‡p � 0.Abbreviations as in Tables 1, 2, and 3.

a good correlation for LVEF evaluation with MDCT and CMR. Abbreviati

Study limitations. This animal study was conductedwithout any medical therapy given to patients afterMI. Therefore, the chronic MIs expanded and theinfarct size increased in the placebo group, consis-

ssessment

he same day with both modalities were compared to evaluatetherapy, and correlation of the evaluated changes over timet differences of infarct size with MSC therapy (p � 0.0001).d CMR assessment. (D to F) These differences were also apparentlation of both modalities. (G and H) Values for LVEF were similars apparent with both imaging modalities, and detected changesthe studied animals (p � 0.06). (I) The ∆change analysis showed

o

p Value

MSC

Week 24 Week 12 Week

16.3 � 1.6 0.02 14.5 � 1.4 9.4 � 1

24.9 � 1.1 0.03 23.3 � 2.1 15.8 � 2

5.9 � 0.7 0.002 4.4 � 0.5 3.5 � 0

9.9 � 0.9 0.03 7.8 � 0.9 6.0 � 1

37.8 � 1.4 0.08 33.5 � 1.6 39.4 � 2

41.3 � 2.4 0.16 32.2 � 1.9 37.8 � 1

29.1 � 1.5 0.03 34.7 � 2.5 38.5 � 3

27.8 � 1.9 0.01 35.9 � 2.6 41.7 � 3

67.6 � 4.1 0.16 48.7 � 4.0 54.7 � 3

65.1 � 2.5 0.08 50.2 � 3.5 53.5 � 4

p � 0.02. �p � 0.003. ¶p � 0.04.

F A

on tSCficanT anorrewas in

ceb

p Value24

.7* 0.005

.0† 0.01

.7‡ 0.04

.1‡ 0.04

.8 0.10

.4 0.05

.2§ 0.02

.3� 0.02

.8¶ 0.44

.69¶ 0.67

03. §

ons as in Figures 1, 2, and 3.


D E C E M B E R 2 0 1 1 : 1 2 8 4 – 9 3

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tent with results from a clinical study using nonin-vasive imaging techniques conducted in the early1980s (34). With modern medical therapy, de-creases in infarct size are anticipated in chronic MI,as shown in a recent CMR study (35). To compli-cate matters, additive effects of angiotensin-converting enzyme inhibition with beta-blockade incombination with cell therapy have been described(36). Although these limitations are evident in thecurrent study, the goal of this study was to demon-strate the usefulness of MDCT to evaluate theeffect of myocardial therapies.

However, there are some limitations that mayaffect the transfer of the reported MDCT protocolsand results to human trials. First, the animalspresented had elevated heart rates, which are usuallyconsidered a relative contraindication for MDCT.Although the reported MDCT protocols provedreliable even under these unfavorable conditions,patients with elevated heart rates above 60 to 70beats/min may receive negative chronotropic med-ication to reduce the heart rate for coronary CTangiography. This will affect the value of functionalanalysis because ventricular volumes change if beta-blockers are applied; however, beta-blockers onlyhave to be given if coronary CT angiography ismandated. Second, no tube current modulation wasapplied, as is routinely done now in patient studiesto reduce radiation exposure. Increased image noiseon systolic images of ECG-gated tube current

Physiol 2008;294:H2002–11.

1

comparison with c

regional LV function assessment. Third, because ofthe passive contrast kinetics of iodine-based con-trast agents and the limited collateral circulation inpigs, DCE-MDCT imaging of chronic infarct scarsin this animal model required a relatively large doseof iodine to cause a sufficient change in the volumedistribution in the myocardial bed. In this study,we used 1.5 times a human equivalent dose,although successful viability imaging in humanshas been reported in several studies with standardcontrast volumes used for coronary CT angiog-raphy (37).

C O N C L U S I O N S

This animal study suggests that cardiac MDCT canbe reliably used to evaluate infarct size, infarctvolumes, LV volumes, and LV function afterintramyocardial-delivered MSC therapy with sen-sitivity similar to CMR and showing similarchanges at follow-up. These findings support theuse of cardiac MDCT in preclinical and clinicalstudies as a noninvasive imaging technique fordetecting therapeutic effects of novel myocardialtherapies.

Reprint requests and correspondence: Drs. Karl H. Schul-eri and Albert C. Lardo, Image Guided CardiotherapyLaboratory, Johns Hopkins School of Medicine, Divisionof Cardiology, 1042 Ross Building, Baltimore, Maryland

modulation may affect the accuracy of global and 21205. E-mail: [email protected] and [email protected].

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Key Words: CMR y delayedcontrast enhancement yGöttingen minipig y heartfailure y MDCT ymesenchymal stem cell y
myocardial infarction.

ct for evaluation of myocardial cell therapy in heart failure · a 1.5-t mr scanner (cv/i, ge...

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