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DITORIAL VIEWPOINT

agnetic Resonance Imagingnd Troponin Elevationollowing Percutaneousoronary Intervention

ew Insights Into Myocyte Necrosisnd Scar Formation*

aul Schoenhagen, MD,† Harvey D. White, DSC‡

leveland, Ohio; and Auckland, New Zealand

erum biomarker evidence of myocyte necrosis is frequentlyound after percutaneous coronary intervention (PCI). About0% of patients develop elevated levels of creatine kinase-yocardial band (CK-MB) (1,2) and up to 48% of patients

evelop elevated troponin levels following PCI (2–9). Severalechanisms related to procedural complications such as side

ranch occlusion, dissection, and disruption of collateral flowave been proposed for these elevations. The concept of plaquembolization at the time of balloon inflation or stent deploy-ent leading to myocardial necrosis and scar formation has

een supported by observations with magnetic resonancemaging (MRI) and late gadolinium enhancement (LGE)scar” imaging after PCI (10). These data show an associationetween post-PCI elevations of troponin I with MRI-etectable scar formation.

See page 950

Following stenting, LGE may occur at the site of stenteployment and distally in the treated coronary artery (11).ntravascular ultrasound has shown a correlation betweenhanges in plaque volume before and after PCI and the massf distal hyperenhancement, but not with hyperenhance-ent at the site of stenting. Thus providing indirect

vidence that plaque embolization has occurred.

Editorials published in JACC: Cardiovascular Interventions reflect the views of theuthors and do not necessarily represent the views of JACC: Cardiovascular Interven-ions or the American College of Cardiology.

From the †Imaging Institute and Heart and Vascular Institute, Cardiovascularmaging, Cleveland Clinic, Cleveland, Ohio; and the ‡Green Lane Cardiovascularervice, Auckland City Hospital, Auckland, New Zealand. Dr. Schoenhagen reportshat he has no relationships to disclose. Dr. White has received research grants fromanofi-Aventis, Eli Lilly, The Medicines Company, National Institutes of Health,fizer, Roche, Johnson and Johnson, Schering-Plough, Merck Sharpe and Dohme,

estraZeneca, GlaxoSmithKline, Daiichi Sankyo Pharma Development, and Bristol-yers Squibb. He has also received a consultancy fee from Regado Biosciences.

Furthermore, post-PCI elevation of troponin I levels haveeen shown to be related to abnormal tissue perfusion (12)ndependent of the presence of thrombus, epicardial flow, orharacteristics of the coronary artery stenosis undergoingCI. Elevated biomarker levels are also associated withigher atheromatous plaque burden (13).The universal definition of myocardial infarction (MI)

esignates biomarker increase (with troponin preferred)rom a normal baseline to a level 3 times the 99th percentiles PCI-related MI (Type 4a) (14). The importance of thessociation between elevated biomarker levels after PCI andrognosis continues to be debated. Several studies havehown that the elevation of troponin levels after PCI istrongly associated with the composite of death and MI2,5). However, the associations have usually been with earlyutcomes (hospital or 90 days) and not with later follow-up4). A further important consideration is the level of thelevation with 1 study (6) showing that only troponin levels5 times the upper limit of normal were prognostically

mportant. In some studies (7), prognosis did not seem to benfluenced if baseline pre-PCI levels were not elevated (15).

recent meta-analysis (9) of 15 studies showed thatatients with normal baseline and any elevation of post-PCIroponin levels had increased risk of major adverse cardiacvents (death, MI, repeat PCI, and coronary artery bypassraft [CABG]) when compared with those patients withoutroponin elevation at an average follow-up of 17.7 months.or patients fulfilling the universal definition of type 4a MI

14), there was a further increased risk: odds ratio: 2.5 (95%onfidence interval 1.26 to 4.00). Patients with elevation ofroponin �3 times the upper limit of normal did not have

worse prognosis during follow-up. In general, serumiomarkers do not allow the characterization of localizationnd distribution of the underlying pathological process.

This limitation can be overcome by correlation withmaging modalities, as exemplified by the study of Locca etl. (16) in the current issue of JACC: Cardiovascular Inter-entions, which compared elevation of troponin I levelseasured by (Beckman Access 2 [Beckman Coulter, Brea,alifornia]) analyzer, which is clinically useful but not

uideline compliant (17) to MRI and LGE after PCI in 45atients. New LGE occurred in 33.3% of patients. The scarsere mostly small including �1.5% of left ventricular mass

n 14 of 15 patients and had no effect on ejection fraction.he site of the infarction was distal in 53% and proximal in7% of patients. Interestingly, post–stent dilation, probablyy causing more plaque embolization, was the only factorssociated with LGE. Elevation of biomarkers beyond 3imes the upper limit of normal occurred with CK-MB in1% of patients and with troponin I in 47% of patients.orrelation of LGE with elevation of biomarkers wasoderate, occurring in 40% of patients with elevation of

reatine kinase-myocardial band and 43% of patients with

levation of troponin I.

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The underlying mechanism of MRI myocardial tissuenhancement with nonspecific extracellular contrast agentsuch as gadolinium is the increased distribution volume forhese molecules within the infarct region with delayedashout in comparison to the normal myocardium (18).elayed contrast-enhanced MRI is well validated in the

dentification of chronic myocardial scar (19,20). It hasufficient spatial resolution to differentiate patterns of trans-ural or subendocardial necrosis in the distribution of

bstructed vessels (20,21), and more diffuse, patchyatterns of necrosis related to distal embolization (22). Ineveral single-center trials, the prognostic impact of

RI-detected scar has been demonstrated in differentatient populations (23–25).It is important to consider issues related to scar size with

GE imaging. The minimal detectable scar volume de-ends on the spatial resolution of the MRI sequence. In theurrent study (16), similar to most other studies, spatialesolution was 1.4 � 1.7 mm in plane with slice thickness ofmm and a 2-mm gap. Therefore, the minimal resolvable

olume from a theoretical standpoint would be about 0.02l. However, practically, a bigger volume (a few times theinimal resolvable volume) is necessary to differentiate scar

rom noise. In the current study (16), the mean scar size was.83 g (about 40 times the minimal resolvable volume),quivalent to 0.53% of the size of the normal left ventricularyocardium. This is relatively small in comparison to other

tudies after intervention (2 g) (22), PCI and CABG (5 g)26), CABG (4.4 g) (27), and reperfused acute MI (20.6 g)28). The timing between myocardial injury and LGEmaging is important, because serial MRI studies performeduring the acute phase of MI have shown that the size ofelayed gadolinium enhancement may significantly change

mmediately after reperfusion, secondary to resolution ofnterstitial edema in reversibly injured myocardium withinhe peri-infarction zone (28–31).

Previous studies describe LGE imaging for the identifi-ation, characterization and quantification of periproceduralyocardial necrosis after PCI (22,26,30) and coronary

ypass surgery (CABG) (27). In these studies, the mass ofnfarcted tissue correlated with elevation of biochemical

arkers of myocardial damage (32). In contrast, the current

Table 1. Comparison of Troponins With MRI for Detecting Myocyte Necros

Contemporary Troponin Assays

Cutoff: normal vs. pathologic Well-defined

Sensitivity/spatial resolution Very sensitive, no localization

Time pattern of rise and fall Well known but limitations, e.g., delayed responsefrom nonreperfused myocardium

Method standardization High

Relation with prognosis Controversial (2,4,5–8,15)

Fulfills universal definition of MI Few

MI � myocardial infarction; MRI � magnetic resonance imaging.

ata by Locca et al. (16) demonstrate that in many patientsith elevated troponin I, LGE imaging could not identify

vidence of scar. The investigators raise the question as tohether current cutoff levels of biomarkers are too sensitive,

eading to overdiagnosis of post-PCI MI. An alternativexplanation in the context of uncomplicated PCI would bemall and patchy myocardial necrosis related to distalmbolization of plaque (11,22,33). False negative resultsith LGE imaging would be expected in patients withultiple small areas of necrosis, if individual scar area were

maller than the spatial limitation of the MRI sequence.Animal and post-mortem studies may provide further

nsights. However, more important will be clinical trialsomparing quantitative extent of biomarker elevation andGE scar with clinically meaningful outcome. Small studies

how an independent predictive value of delayed LGEmaging in patients undergoing coronary revascularization,ither PCI or CABG, during a median follow-up of 2.9ears (26). However, long-term outcome data from well-esigned, prospective, multicenter trials are lacking. In theesign of such trials, it will be critical to consider thenability of differentiating procedure-related versus pre-xisting infarction, therefore requiring pre- and post-perative MRI acquisitions. Strict standardization of imagecquisition and analysis, including contrast dose and thresh-ld definition for identification of scar is vital (34–36). Aimitation of MRI is the contraindication in patients witheduced kidney function (glomerular filtration rate �30l/min) because of concerns about nephrogenic systemic

brosis (37). Table 1 compares troponins, including theewer higher sensitivity troponins (38), with MRI foretecting myocyte necrosis. Much of the data are evolving.Future clinical trials, correlating clinical outcome with

oth biomarkers and comprehensive MRI imaging (LGEnd T2-weighted), characterizing scar and the at-risk areaarly after infarction, respectively (31,39,40), will providemportant further insight into periprocedural necrosis.

owever, even if such data will eventually be available, it isnrealistic to propose pre-and post-procedural LGE foroutine PCI. In the context of the current debate aboutealth care costs, it appears more realistic that such data willalibrate levels of biomarker elevation to corresponding scar

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ass and distribution and help define clinical biomarkerriteria for defining post-PCI MI.

eprint requests and correspondence: Prof. Harvey D. White,reen Lane Cardiovascular Service, Auckland City Hospital,rivate Bag 92024, Victoria Street West, Auckland 1142, Newealand. E-mail: HarveyW@adhb.govt.nz.

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ey Words: coronary artery bypass graft � late gadoliniumnhancement � magnetic resonance imaging � myocardialnfarction � myocyte necrosis � percutaneous coronary

ntervention � scar � serum biomarker � troponin.