Magnetic Resonance Imaging Quantification of LeftVentricular Dysfunction Following CoronaryMicroembolization

Marcus Carlsson,1 Alastair J Martin,1 Philip C Ursell,2 David Saloner,1 andMaythem Saeed1

Microembolization is common after coronary interventions, andtherefore this MRI study aimed to quantify the effect of coro-nary microembolization on left ventricular (LV) function. The leftanterior descending artery (LAD) was selectively catheterized inan XMR suite (Philips Medical Systems, Best, The Netherlands)in eight pigs to deliver MR contrast media to measure the LADterritory using first-pass perfusion and for intracoronary deliv-ery of the embolic agent. Cine, tagged, and delayed contrast-enhanced MRI (DCE-MRI) was performed to assess LV vol-umes, ejection fraction, radial and circumferential strain, andviability at baseline, 1 h, and 1 week after microembolization.Histopathology and histochemical staining were used to char-acterize and measure the extent of microinfarction. The LADterritory was 35% � 2% LV mass. Patchy microinfarction onDCE-MRI at 1 week was 22.0% � 3.6% LAD territory (7.5% LVmass). Microembolization caused persistent decline in ejectionfraction (baseline � 49% � 1%, 1 h � 29% � 1%, P � 0.02 and1 week � 36% � 1%, P � 0.03) and increased end-diastolic(79.6 � 3.9 ml, 85.5 � 4.5 ml, P � 0.03 and 92.4 � 6.2 ml, P �0.06, respectively) and end-systolic (40.8 � 2.1 ml, 60.2 � 3.4 ml,P � 0.02 and 59.3 � 4.8 ml, P � 0.03, respectively) volumes. Themicroembolized territory was manifested as dysfunctional re-gions for 1 week on cine and tagged MRI. Histopathology re-vealed occlusive microemboli surrounded by necrotic tissueundergoing repair. Microinfarction was visualized after coro-nary microembolization and caused LV dysfunction dispropor-tionate to the size of myocardial damage. It also changed LVgeometry and decreased radial and circumferential strain overthe course of 1 week. Magn Reson Med 61:595–602, 2009.© 2008 Wiley-Liss, Inc.

Key words: MR imaging; LV function; microinfarction; coronaryinterventions; MR contrast media; myocardial viability

Microembolization from coronary plaques is common inpatients with acute coronary syndrome following percuta-neous coronary intervention and coronary artery bypasssurgery (1–3). Microembolization has been indirectlylinked to left ventricular (LV) dysfunction after coronaryinterventions using biomarkers and functional methods(1–7). Invasive studies in animal models have shown LV

dysfunction after delivery of microspheres into coronaryarteries, but these studies did not illustrate microinfarc-tion using tomographic imaging (8,9). The observed de-crease in LV function was disproportionate to the extent ofmicroinfarction and has been attributed to the rapid in-flammatory response in the myocardium mediated by tu-mor necrosis factor (TNF)-� (10). Pharmacologic studieshave shown the benefit of glucocorticoid (methylpred-nisolone) (9) and TNF-� blocker (10) in preventing LVdysfunction resulting from coronary microembolization.

Investigators have speculated that microembolization isone of the causes of mismatch between blood flow in theepicardial coronary arteries and LV function in patients(10). A noninvasive method for visualization of microin-farction would provide a direct clinical explanation formismatch between adequate coronary blood flow and de-creased LV function. Magnetic resonance imaging (MRI)has the ability to quantify myocardial perfusion (11), re-gional and global LV function (using cine and tagged im-aging) (12,13), and myocardial viability using delayed con-trast enhancement (DCE) (14). Recently, investigators havedemonstrated discrete microinfarction on MRI after coro-nary intervention (2,5,6,15). To our knowledge, however,no study has used serial MRI to noninvasively quantify theacute (1 h) and subacute (1 week) effects of coronary mi-croembolization on regional function (radial and circum-ferential strain), global LV function, and viability. There-fore, this experimental study was designed to simulate theclinical scenario of microemboli scattering downstreamfrom coronary plaques. The specific aim of this MRI studywas to noninvasively determine whether there is a linkbetween microembolization and LV dysfunction.

MATERIALS AND METHODS

Experimental Protocol

The study conformed to the Guide for the Care and Use ofLaboratory Animals (NIH Publication No. 85–23, revised1996) and approval was obtained from the institutionalcommittee on animal research. Eight female farm pigs(34 � 1 kg) were premedicated with acepromazine(1.1 mg/kg IM) followed 1/2 h later by ketamine (22–33 mg/kg IM) after a minimum of an 8-h fast. Anesthesiawas induced and maintained by isoflurane/oxygen (2–5%/2–3 L/min).

After establishing femoral artery access, the selectivecatheterization of the left anterior descending coronaryartery (LAD) was performed under X-ray contrast angiog-raphy using a 50/50 solution of saline and iohexol (Om-nipaque® 300 mgI/ml; GE Healthcare). A 3F catheter was

1Department of Radiology and Biomedical Imaging, University of California,San Francisco, San Francisco, California, USA.2Department of Pathology, University of California, San Francisco, San Fran-cisco, California, USA.Grant sponsor: National Institutes of Health; Grant number: RO1HL07295.*Correspondence to: Maythem Saeed, DVM, PhD, Department ofRadiology and Biomedical Imaging, HSW207B, 513 Parnassus Ave., Univer-sity of California–San Francisco, San Francisco, CA 94134. E-mail:maythem.saeed@radiology.ucsf.eduReceived 19 June 2008; revised 20 August 2008; accepted 1 October 2008.DOI 10.1002/mrm.21869Published online 18 December 2008 in Wiley InterScience (www.interscience.wiley.com).

Magnetic Resonance in Medicine 61:595–602 (2009)

© 2008 Wiley-Liss, Inc. 595

placed distal to the first diagonal of the LAD and theanimal was moved on a floatable tabletop to the MR sys-tem. One animal died during coronary catheterization dueto ventricular fibrillation. The LAD perfusion territory wasdetermined (see below for details) and the embolic agent(N � 7200 microsphere count, 100–300 �m, 0.25 ml solu-tion diluted with 0.75 ml saline; Embosphere®; BiosphereMedical, Rockland, MA, USA) were delivered (slowly over30 s) selectively into the coronary catheter in order toembolize the myocardium distal to the first diagonal of theLAD. The size of the embolic agent was chosen to be in themiddle range of the size of emboli retrieved after coronaryintervention (47–2503 �m) (16) and the number of embolicagent was based on previous animal studies (8,17). Theembolic agent used is biocompatible, hydrophilic, andnonresorbable; it is produced from an acrylic polymer andimpregnated with porcine gelatin, unlike polyvinyl alco-holic particles (18).

Imaging Modalities

The studies were performed in a hybrid XMR suite (Phil-ips Medical Systems, Best, The Netherlands) consisting ofan X-ray angiography system (Integris V5000, used forcoronary catheterization) and an MRI system (Intera I/T)(19). The MR system was used for visualization of the LADperfusion territory, delivery of the embolic agent, assess-ment of regional myocardial perfusion, visualization ofmicroinfarction, and assessment of regional and global LVfunction. The study protocol is shown in Fig. 1. MRI wasperformed before (baseline), 1 h (acute), and 1 week (sub-acute) after the selective delivery of the embolic agent.Another pig died 4 h after the delivery of the embolicagent. At baseline, MR first-pass perfusion imaging wasperformed during intracoronary injection of 6–10 ml of10% Gd-DOTA (Dotarem®; Guerbet, France) to determinethe LAD territory. At 1 h and 1 week after microemboliza-tion, first-pass perfusion imaging was performed to deter-mine the extent of the hypoperfused region using an intra-venous injection of 0.1 mmol/kg MR contrast media (Gd-DOTA delivered by a power injector at 3 ml/s followed by10–15 ml saline).

DCE-MRI was obtained in short- and long-axis imagesencompassing the heart (18–20 slices) 6 � 4 min afterinjection of additional 0.05 mmol/kg Gd-DOTA, to locateand quantify the extent of microinfarction.

Cine MRI were obtained in the short-axis view coveringthe whole LV and used for assessment of LV volumes,

ejection fraction (EF), and systolic wall thickening (radialstrain). Tagged MR images were acquired in three contig-uous short-axis slices to measure circumferential strain.

MRI Parameters

Cine MRI was performed with a steady-state free preces-sion (SSFP) sequence: TR/TE/flip angle � 3.5 ms/1.75 ms/70°, slice thickness � 10 mm, no slice gap, FOV � 25 �25 cm, matrix size � 160 � 152, heart phases � 16. Cinetagged MRI was performed with a tagged turbo-field echoplanar (TF-EPI) sequence in the short-axis view: TR/TE/flip angle � 35 ms/6.1 ms/25°, slice thickness � 10 mm, noslice gap, FOV � 24 � 24 cm, matrix size � 128 � 45, heartphases � 16, EPI factor � 11, tag technique � complemen-tary spatial modulation of magnetization (CSPAMM) withvertical and horizontal tag orientation obtained in onebreath-hold, line spacing � 8 mm. A saturation-recoverygradient-echo sequence was used for MR first-pass perfu-sion: TR/TE � 4.5/2.2 ms, slice thickness � 10 mm, FOV �26 � 26 cm, matrix size � 128 � 128, � � 20°. Sixshort-axis slices spaced to encompass the perfusion terri-tory were used to determine the LAD territory with anintracoronary injection of MR contrast media (acquisitiontime � 3 RR intervals/dynamic) and four short-axis slicesto determine the embolized region with intravenous deliv-ery of MR contrast media (acquisition time � 2 RR inter-vals/dynamic). DCE-MRI was performed with an inver-sion-recovery gradient-echo (IR-GRE) sequence in theshort- and long-axis views: TR/TE/flip � 5 ms/2 ms/15°,slice thickness � 3 mm, no slice gap, FOV � 26 � 26 cm,matrix size � 256 � 162. The inversion time was chosen tonull normal myocardium.

MR Image Analysis

MR images were analyzed using Segment v1.6 (http://segment.heiberg.se) (20). The LAD territory was quantifiedas the hyperenhanced myocardium in first-pass perfusionMRI during intracoronary injection of 10% Gd by auto-matic thresholding of the region with signal intensity (SI)2.0 SD above the mean SI of remote myocardium, andexpressed as percentage of LV mass. The extent of thehypoperfused region after microembolization was deter-mined as the percentage of the LAD territory that washypoenhanced during first-pass intravenous perfusionMRI. This was performed on inverted first-pass images sothat the affected embolized myocardium became hyperen-hanced. The hypoperfused region was automatically quan-tified by thresholding within the perfusion territory. Athreshold of SI 2.0 SD above the mean SI of remote myo-cardium was used.

End-diastolic volume (EDV), end-systolic volume (ESV),and EF were calculated by delineation of the endocardiumin the cine images, and LV mass was quantified as thedifference between endocardium and epicardium. Systolicwall thickening (radial strain) was measured in eight seg-ments using three consecutive short-axis slices as previ-ously described (21). The extent of microinfarction wasdetermined on DCE-MRI using automatic delineation ofthe pixels within the embolized region with SI greater than3.0SD of remote myocardium. Circumferential strain anal-

FIG. 1. Study protocol.

596 Carlsson et al.

ysis was performed on MR tagged images using the HARPsoftware (Diagnosoft Inc., USA) (12). Peak strain was cal-culated as the mean of the most negative value in eachanimal, and the average of the three slices was presented.

Histopathology

At the conclusion of the second imaging session (at 1week), the animals were euthanized by an intravenousinjection of saturated KCl (30–40 ml). The hearts wereexcised and the LV was dissected free, weighed, and cutinto 10-mm-thick slices parallel to the plane of the atrio-ventricular groove. The LV slices were immersed for15 min in 2% triphenyltetrazolium chloride (TTC). Digitalimages of the slices were obtained, converted to black andwhite, and quantified using ImageJ 1.30v (National Insti-tutes of Health; http://rsb.info.nih.gov/ij). Microinfarctionon TTC was quantified by thresholding the pixels withSI � 3 SD of remote myocardium within the LAD territoryidentified on first-pass perfusion MRI. Tissue samples ob-tained from the embolized and remote regions were pro-cessed in a routine fashion and embedded in paraffin.Sections 5 �m thick were stained with hematoxylin andeosin and Masson trichrome. TTC and microscopic analy-sis were used to measure the extent of microinfarctedtissue and characterize the myocardial damage and theassociated healing, respectively.

Statistical Analysis

Data are presented as mean � SEM. The Wilcoxon signed-rank test was used to determine whether variables differed

between time points and regions of the LV. A P-value ofless than 0.05 was considered statistically significant.

RESULTS

Embolized Myocardium

Regional Perfusion

The LAD territory was visualized as a differentially en-hanced region during the intracoronary administration ofMR contrast media prior to the delivery of the embolicagent (Fig. 2). The extent of the LAD territory was 35% �2% of LV mass. One hour after administration of the em-bolic agent, the hypoperfused embolized territory was vi-sualized as a hypoenhanced region on first-pass perfusionand the extent of this hypoenhanced region was 69.4% �9.6% of the LAD territory. At 1 week the hypoenhancedregion was significantly smaller compared to that 1 h aftermicroembolization (23.5% � 6.7% of LAD territory, P �0.03).

Regional Viability

The embolized region was slightly enhanced with fuzzyborders 1 h after microembolization. The extent of micro-infarction was 6.8% � 0.8% of the LAD territory. Theextent of microinfarction at 1 week was significantly largerthan at 1 h (22.0% � 3.6% of the LAD territory, P � 0.03).The size of true microinfarction on TTC staining (25.2% �5.6% of the LAD territory) was not significantly differentfrom the hyperenhanced region on DCE-MRI (P � 0.41;Fig. 3).

Regional Function

Coronary microembolization caused a significant declinein the radial strain (systolic wall thickening) of the embo-lized region as illustrated on cine MRI (Fig. 4). At 1 h, thedecrease in radial strain was also observed in remote myo-cardium. The decline in radial strain was also pronouncedat 1 week predominantly in the embolized region (Fig. 5).

Tagged MRI provided quantitative assessment of thedecline in circumferential strain caused by microemboli-zation. At 1 week there was no recovery in circumferentialstrain of the embolized region (Fig. 6). In remote myocar-dium, there was a significant change in circumferentialstrain of the apical slice, but not in basal or mid-ventric-ular slices. The sequential changes in circumferentialstrain throughout the cardiac cycle are shown in Fig. 6. At

FIG. 2. Use of the XMR suite for coronary catheterization andcharacterization of microinfarction. a: X-ray coronary angiographyduring injection of iodinated contrast media through the 3F coronarycatheter (arrow) distal to the first diagonal of the LAD. b: TheLAD-perfusion territory (white arrowheads) was revealed by injec-tion of 10% contrast media in the coronary catheter. c,d: Thehypoperfused region on first-pass perfusion within the LAD territory(black arrowheads established in b and shown for clarity) at 1 h (c)and 1 week (d) after embolization.

FIG. 3. Demonstration of patchy microinfarction at 1 h and 1 weekon DCE-MRI and TTC. Microinfarction was not clearly defined at 1 h(left) but becomes more apparent (black arrows) at 1 week onDCE-MRI (middle).

Microembolization and LV Dysfunction 597

baseline there was no difference in peak strain betweenembolized (–17% � 2%) and remote myocardium (–17 �1, P � 0.69). In the embolized territory, peak strain de-creased to –10% � 2% 1 h after delivery of the embolicagent (P � 0.02). At 1 week there was no recovery ofcircumferential strain in the embolized territory (–7% �1%, P � 0.31 vs. 1 h and P � 0.03 vs. baseline). Circum-ferential strain in remote myocardium showed a trend ofdeterioration to –15% � 1% at 1 h and –14% � 1% at 1week, however the decrease, was not significant (P � 0.37and 0.31 respectively).

Global LV Function

Microembolization was associated with a persistent de-cline in EF over the course of 1 week. The EF measured oncine MRI was 49% � 1% at baseline, 29% � 1% at 1 h (P� 0.02) and 36% � 1% at 1 week (P � 0.03 as comparedwith baseline and 1 h) (Fig. 7). The decrease in EF wasassociated with LV dilatation as shown by the increase inESV from 36 � 2 ml at baseline to 50 � 1 ml at 1 h (P �0.02) and 51 � 4 ml at 1 week (P � 0.03 compared tobaseline). Similarly, EDV increased from 79.6 � 3.9 ml atbaseline to 85.5 � 4.5 ml at 1 h (P � 0.03) and 92.4 � 6.2ml at 1 week (P � 0.06 compared to baseline). Adminis-tration of the embolic agent caused acute bradycardia(from 103 � 6 bpm to 78 � 4 bpm, P � 0.03) and the heartrate recovered at 1 week to 92 � 3 bpm (P � 0.06 vs.baseline and P � 0.03 vs. acute). Cardiac output decreasedfrom 3.9 � 0.2 L/min to 1.9 � 0.1 L/min 1 h after micro-embolization (P � 0.02) and partially recovered at 1 weekto 3.0 � 0.1 L/min (P � 0.06 vs. baseline and P � 0.03 vs.acute).

Histopathology

TTC staining demonstrated patchy microinfarction in theembolized region (Fig. 3). Microscopic examinationshowed tongues of healing microinfarction extending fromendocardium to epicardium. The patchy microinfarction

was comprised of granulation tissue including newlyformed collagen, macrophages, and fibroblasts, and scat-tered plasma cells (Fig. 8). Single and clustered embolicmicrospheres were identified in different-sized arteries,largely occluding the lumens. The vascular obstructionincluded not only the embolic agent but also associatedorganizing thrombus (fibrin and red blood cells) resultingin occlusion of vessels of greater diameter than the em-bolic agent. Remote myocardium did not show any evi-dence of the presence of microspheres or microinfarct.

DISCUSSION

The main findings of this study were that: 1) DCE-MRIdelineated patchy microinfarction at 1 week and there wasmicroscopic confirmation of the presence of the embolicagent occluding blood vessels in this region, 2) microem-bolization changed LV geometry by increasing LV vol-umes, 3) microembolization was associated with a pro-found decline in radial (systolic wall thickening) and cir-cumferential strain over the course of 1 week, 4) themagnitude of LV dysfunction was disproportionate to therelatively small extent of microinfarction, and 5) MRI hasthe potential to establish a link between microinfarctioncaused by microembolization and LV dysfunction.

There has been extensive debate regarding the detection,markers, and significance of microinfarction (2–4,7,10).Recently, the American College of Cardiology and the Eu-ropean Society of Cardiology acknowledged the detrimen-tal consequences of coronary microembolization in pa-tients in their 2007 guidelines (1). Clinical studies havefound that the elevation of creatinine kinase-MB and tro-ponin after coronary intervention reflects discrete micro-infarction (6,15). Detection of microinfarction may explainthe clinical cases in which there is dissociation betweenepicardial arterial blood flow and LV dysfunction.

Exogenous emboli were used, but the histologic findingsresemble plaque gruel or embolization of thrombus in thesetting of acute infarction and plaque rupture. Microscopicexamination revealed the formation of thrombus with fi-brin and blood cells inside the blood vessels and inflam-matory cells in the microinfarction. These findings arevirtually identical to the autopsy findings of coronary em-

FIG. 5. Radial strain (systolic wall thickening) is shown in eightsegments at baseline, 1 h, and 1 week. The area of microemboli-zation is located between segments 2 and 5 and shows dysfunction.The MR image (right) shows the location of the regions used foranalysis of wall thickening. *P � 0.05 compared to baseline.

FIG. 4. Multislice cine MR images at 1 h (left) and 1 week (right) aftermicroembolization acquired at ED and ES. Decreased function isseen in the anteroseptal wall (black arrowheads).

598 Carlsson et al.

boli from plaques in patients (34,35). Therefore, we pro-pose that this microinfarction model in swine representsischemic cardiomyopathy (23) and can be used to nonin-vasively test the effects of gene or stem cell therapy(21,28).

LV Function

The current noninvasive study using cine and tagged MRIdemonstrated that decreased radial and circumferentialstrain, as well as global LV function, persisted for 1 weekafter microembolization. The decrease in regional LV func-tion was localized in the embolized region with a trendtoward decreased function in remote myocardium. Thesechanges are most likely attributable to the decrease in EF.The nonsignificant decrease in EDV at 1 week compared tobaseline (P � 0.06) may be explained by a relatively smallsample size.

Previous studies (8–10) have shown a mismatch be-tween coronary blood flow and LV function early aftermicroembolization using microspheres and ultrasoniccrystals embedded in the myocardium, respectively. Astudy in dogs (9) showed that severe LV dysfunction oc-curred within hours after injection of a small embolicagent (42 �m) followed by complete recovery of functionwithin 5–6 days. Our findings of persistent decline inregional and global function at 1 week using a larger em-bolic agent (100–300 �m) are in line with findings insheep using a 90-�m embolic agent (22). The difference inresponse to microembolization between studies may beattributed to 1) species variation, including the presence ofextensive collateralization and a faster heart rate in dogsbut not in humans or pigs (25); 2) the number and size ofthe embolic agent used (25,26); and 3) invasive vs. nonin-vasive methodologies to obtain data. These functional

FIG. 6. Circumferential strain (Ecc) throughout the cardiac cycle (x-axis shows fraction of the RR interval) in the microembolized and remotemyocardium in basal (a), mid (b), and apical (c) slices. Mean values � SEM from all animals are shown at baseline (open squares), 1 h (opendiamonds), and 1 week (filled triangles). Examples of MR tagged images are shown at ED and ES at corresponding anatomical positions.Black and white arrows denote the locations used for strain measurements of microembolized and remote myocardium, respectively. Therewas a progressive decline in circumferential strain over 1 week in the embolized region and a tendency toward decreased strain in remotemyocardium in the apical slice at 1 week.

Microembolization and LV Dysfunction 599

changes have been attributed to progressive loss of cellintegrity, possible myocyte slippage, and/or ongoing apo-ptosis (23,24). Other investigators proposed that the de-crease in function is due to inflammatory response medi-ated by TNF-� (9). It is possible that the early LV dysfunc-tion in this study is caused by the myocardial ischemiashown on first-pass perfusion and histopathology. Thehistopathology showed obstruction of microvessels by theembolic agent with surrounding thrombosis and granula-tion tissue. However, myocardial stunning or hibernationcannot be excluded in this acute and subacute study, andtherefore studies with longer follow-up are needed to ad-dress the effects of chronic microinfarction on LV functionand myocardial perfusion.

The magnitude of LV dysfunction in the present studyshould be viewed in the light of previous studies of con-tiguous infarction in swine showing a minor decrease inEF (49.6%) with 5.1% LV infarction (27), a moderate de-crease (41%) with 16.6% LV infarction (28), and a severedecrease in EF (35.1%) at 28.7% LV infarction (29) com-pared to previously reported normal EF (56% � 3%) inpigs (30). Hence, the decrease in EF to 36% at 1 week aftermicroembolization in the present study is disproportion-ate to the size of damaged myocardium.

Characterization of Embolized Myocardium on MRI

The use of the XMR suite allowed for coronary catheter-ization using X-ray fluoroscopy, delineation of the LADterritory using first-pass perfusion MRI (11), delineation ofmicroinfarction using DCE-MRI (14), and assessment of LVvolumes and function using cine (13) and tagged MRI (12)in a single session. This capability enabled us to draw theconclusion that there is a close link between microembo-

lization and LV dysfunction. The potential of MRI, PET,and SPECT for assessing contiguous myocardial infarctionhas previously been demonstrated (31), but the compre-hensive evaluation of microinfarction has not been welldescribed using noninvasive imaging modality.

The injection of the embolic agent into the LAD causedfocal microinfarction observed on DCE-MRI and TTC at 1week. MRI did not show microinfarction at 1 h, which maybe attributed to an incomplete necrotic process at thisstage. The reference method of detecting myocardial in-farction using TTC also failed to detect microinfarction 8 hafter microembolization (32). The reduction in the size ofthe hypoperfused region at 1 week compared to 1 h onfirst-pass perfusion can be explained by 1) a decrease ininterstitial pressure related to edema resorption, and 2) thediminished release of local vasoconstrictive agents intothe embolized territory. Unlike contiguous reperfused in-farction, patchy microinfarction spread over the transmu-ral extent of the LAD territory.

Characterization of Embolized Myocardium onHistopathology

Histopathology confirmed that the embolic agent was lo-calized in the LAD territory and did not spread to remotemyocardium. Similar findings have been previously ob-served using fluorescent embolic agents delivered selec-tively into the coronary arteries (22,33). Microsphere-in-duced myocardial microinfarction in pigs revealed diffuse,patchy scarring associated with perivascular fibrosis ongross and histologic examination. The current experimen-tal model differs from those involving contiguous large

FIG. 8. a,b: Masson’s trichrome. a: At low magnification a tongue ofhealing infarct (I) extends from the epicardial surface (out of field, atright) to the endocardium (at left) surrounded by viable myocardium(V). b: A microsphere (black arrow) occludes a small artery sur-rounded by healing infarct. A more prominent proximal vessel ispartially obstructed by organizing thrombus. c,d: Hematoxylin-eo-sin. c: At high magnification, the border between infarct is indicatedby markedly inflamed granulation tissue (G) and viable myocardium(V). d: Two microspheres (black arrow) obstruct a small artery thathas a greater diameter than either of the individual microspheresbecause organizing thrombus (fibrin and red blood cells) traps themwithin the vessel lumen (arrowheads). Scale bars: a and b: 400 �; cand d: 100 �.

FIG. 7. Left panel. Global functional parameters at baseline (whitebars), 1 h (gray bars), and 1 week (black bars). MR images in theright panels show the functional evolution over time in one animal.*P � 0.05.

600 Carlsson et al.

myocardial infarcts by producing numerous tiny infarctedzones caused by the blockage of microvessels (36). Previ-ous studies showed a correlation between infarction sizeand plasma troponin I and T in dogs with contiguousinfarction (37). The relation between these plasma biomar-kers and microinfarction was recently addressed in pa-tients (6).

Clinical Implications

Clinical manifestations that could plausibly be associatedwith microinfarction include unstable anginal episodesthat do not meet diagnostic criteria for acute myocardialinfarction and non-Q-wave infarctions. Patchy microin-farction may be subclinical in some patients, but the cu-mulative effect of repetitive microinfarction could eventu-ally result in clinically evident deterioration of cardiacperformance and alterations in LV structure. MRI has thepotential to link this deleterious effect of coronary micro-embolization to LV dysfunction after coronary interven-tion. Detection of microinfarction may explain the clinicalcases in which there is a dissociation between epicardialarterial blood flow and LV dysfunction.

Limitations

In order to obtain good temporal spatial resolution fromthe first-pass perfusion, fewer slices were acquired com-pared to DCE-MRI. This may have resulted in an under-sampling of the hypoperfused territory on first-pass perfu-sion. However, the first-pass perfusion slices were spacedto encompass the entire perfusion territory to minimizethis possibility. Higher-spatial-resolution imaging tech-niques are required to better demonstrate early microin-farction. A previous study has shown that the emboli sizesduring percutaneous coronary intervention differ widely(47–2505 �m) (16). Thus, more studies are needed to ad-dress the effects of various sizes and numbers of embolicagents on LV function. It should be noted that a syntheticembolic agent was used in this experimental study, whichdiffers from microemboli shed from atheroscleroticplaque. Endogenous microemboli contain various vasoac-tive compounds that affect the myocardium. However, theorganizing thrombi observed on histopathology surround-ing the embolic agent and the resulting microinfarctionwere similar to pathology findings in patients (34,35).

CONCLUSIONS

This is the first study to demonstrate a link between mi-croembolization and persistent LV dysfunction using MRI.Microinfarction caused LV dysfunction disproportionateto the size of myocardial damage. MRI may be useful forinvestigating the possibility of microembolization as thebasis for discrepancies between apparently adequate cor-onary blood flow and decreased function after clinicalcoronary interventions.

ACKNOWLEDGMENTS

We thank Carol Stillson for help with the experimentationand Loi Do for technical assistance.

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