ORIGINAL ARTICLE

Screening for Cardiac Magnetic Resonance Scar Featuresby 12-Lead ECG, in Patients with Preserved EjectionFraction

Nathan Mewton, M.D., Ph.D.,∗,† David G. Strauss, M.D., Ph.D.,‡Patricia Rizzi, M.D.,∗ Richard L. Verrier, Ph.D.,§ Chia Ying Liu, Ph.D.,∗Larisa G. Tereshchenko, M.D., Ph.D.,∗ Bruce Nearing, Ph.D.,§Gustavo J. Volpe, M.D.,∗ Francis E. Marchlinski, M.D.,¶ John Moxley, M.S.,∗Tony Killian, M.S.,¶ Katherine C. Wu, M.D.,∗ Peter Spooner, Ph.D.,∗and Joao A.C. Lima, M.D.∗From the ∗Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD;†Cardiovascular Hospital Louis Pradel, Clinical Investigation Center, Inserm 1407, Lyon, France; ‡Office of Scienceand Engineering Laboratories, Center for Devices and Radiological Health, U.S. Food and Drug Administration,Silver Spring, MD; §Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; and ¶Divisionof Cardiology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA

Background: Increased QRS score and wide spatial QRS-T angle are independent predictors ofcardiovascular mortality in the general population. Our main objective was to assess whether a QRSscore �5 and/or QRS-T angle �105° enable screening of patients for myocardial scar features.

Methods: Seventy-seven patients age �70 years with QRS score �5 AND/OR spatial QRS-Tangle �105° as well as left ventricular ejection fraction (LVEF) >35% were enrolled in thestudy. All participants underwent complete clinical examination, signal averaged ECG (SAECG),30-minute ambulatory electrocardiogram recording for T-wave alternans (TWA), and late gadoliniumenhancement cardiac magnetic resonance (LGE-CMR). Relationship between QRS score, QRS-Tangle with scar presence and pattern, as well as gray zone, core, and total scar size by LGE-CMRwere assessed.

Results: Myocardial scar was present in 41 (53%) patients, of whom 19 (46%) exhibited a typicalischemic pattern. QRS score but not QRS-T angle was related to total scar size and gray zone size(R2 = 0.12, P = 0.002; R2 = 0.17; P � 0.0001, respectively). Patients with QRS scores �6 hadsignificantly greater myocardial scar and gray zone size, increased QRS duration and QRS-T angle,a higher prevalence of late potentials presence, increased LV end-diastolic volume and decreasedLVEF. There was a significant independent and positive association between TWA value and totalscar (P = 0.001) and gray zone size (P = 0.01).

Address for correspondence: Joao A.C. Lima, M.D., Johns Hopkins Hospital, Cardiology Division, 600 N. Wolfe St/Blalock 524,Baltimore, MD 21287. Phone: 410–614-1284/Fax: 410-614-8222; E-mail: jlima@jhmi.edu

Funding Sources: NIH Cardiac Translational Research Implementation Program (CTRIP) P20 to Johns Hopkins Hospital, JoaoLima, M.D., Principal Investigator. Nathan Mewton was supported by a Postdoctoral Research Grant from the French Federation ofCardiology and also received support from the Leducq Foundation Alliance Against Sudden Cardiac Death Network Award to JohnsHopkins University.

Disclaimer: The mention of commercial products, their sources, or their use in connection with material reported herein is not to beconstrued as either an actual or implied endorsement of such products by the U.S. Department of Health and Human Services.

Disclosures: Drs. Nearing and Verrier receive royalty income from Georgetown University and Beth Israel Deaconess Medical Centerfor intellectual property licensed to GE Healthcare and to Medtronic.

C© 2015 Wiley Periodicals, Inc.DOI:10.1111/anec.12279

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Conclusion: Patients with preserved LVEF and myocardial scar by CMR also haveelectrocardiographic features that could be involved in ventricular arrhythmogenesis.

Ann Noninvasive Electrocardiol 2015;00(0):1–11

magnetic resonance imaging; death, sudden; screening; myocardial scar; T-wave alternans

BACKGROUND

Sudden cardiac death (SCD) remains an importantpublic health concern, especially for individualswith relatively preserved left ventricular ejectionfraction (LVEF), a large population in which mostSCD cases occur.1 Recently, experts in SCD pre-diction and prevention have emphasized the needfor simple and inexpensive tools and screeningstrategies to identify patients whose risk for SCD iselevated.2 The 12-lead electrocardiogram (ECG) is aroutine, relatively inexpensive first-line diagnostictool for assessing myocardial pathological statusand has been used for SCD screening in largepopulations both of asymptomatic individuals andof patients with cardiac disease.3 Findings on theefficiency of such a strategy are controversial,4 andthere is currently no guideline regarding analysis of12-lead ECGs for this purpose.

Two 12-lead ECG markers with proven capacityfor SCD and cardiovascular mortality risk stratifica-tion are spatial QRS-T angle �105°, which detectsabnormal repolarization, and QRS score >5, whichdetects myocardial scar.5–9

The use of late gadolinium enhancement car-diac magnetic resonance (LGE-CMR) accuratelyidentifies and quantifies myocardial scar andcharacterizes the heterogeneous tissue surroundingthe dense core of the scar (“gray-zone”).10 Thereis increasing evidence that the total scar size byLGE-CMR and gray-zone extent are strong predic-tors of cardiovascular outcomes and ventriculararrhythmogenesis in various cardiac settings.11–14

Several studies performed in patients presentingwith ventricular arrhythmias or an indicationfor implantable cardiac defibrillator (ICD) haveshown that LGE-CMR-detected fibrosis is anindependent predictor of adverse outcomes andarrhythmic events.15–17 At this point, the accumu-lated studies in humans relating myocardial fibroticscar determined by LGE-CMR to arrhythmicoutcomes provide solid support promoting thistechnique for SCD risk stratification.18 However,little is known about the relationship of LGE-CMR in patients at lower clinical arrhythmic risk

with electrocardiographic features associated withadverse cardiac events.

The principal objective of this study was tocharacterize the underlying myocardial substrateas determined by LGE-CMR of patients identifiedby screening an entire health system ECG databasefor those with QRS score �5 AND/OR QRS-T angle�105°. The secondary objective was to assess therelationship between these 12-lead ECG and LGE-CMR indices to T-wave alternans (TWA) and latepotentials (LP) by high-resolution signal averagedECG (SAECG).

METHODS

Patients

The study protocol was approved by theJohns Hopkins Hospital (JHH) Institutional ReviewBoard. All enrolled patients gave written informedconsent. (ClinicalTrial.gov number: NCT01353131)

All 12-lead ECGs acquired and stored in theJHH ECG Muse (GE Healthcare, Waukesha, WI,USA) system between October 1, 2009 and March31, 2010, from patients age 21 to 100 years wereexported into Magellan ECG Research WorkstationSoftware (GE Healthcare) and analyzed by a singleblinded observer. The spatial QRS-T angle andthe QRS score were obtained for each ECG19 andpatients were eligible for the study if the QRS-Tangle was �105° AND/OR the QRS score was �5.

ECGs were analyzed with 12SL software (GEHealthcare) in the Magellan ECG Research Work-station software (GE Healthcare). Vectorcardio-grams were reconstructed from 12-lead ECGs usinga publicly available transformation matrix.20 Thespatial QRS-T angle was calculated based on thedifference between the mean QRS- and T-axes.7

Diagnostic statement codes and Q-, R-, and S-wave durations and amplitudes were importedinto Microsoft Excel (Redmond, WA, USA). ECGconfounder (conduction) types for QRS scoringwere classified based on diagnostic statementcodes, QRS duration and QRS axis, and then QRS

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scores were calculated (see Data S1 and Figure S1for additional information).

For all eligible patients, the electronic medicalrecords were then screened by a team of trainedresearch coordinators with physician oversight todetermine patients’ clinical status. Patients werefurther excluded if: age >70 years old, LVEF �35%(LVEF determined by any cardiac ultrasound,cardiac MRI, LV angiography, and SPECT studyperformed within the last 12 months), severechronic renal insufficiency (estimated glomerularfiltration rate �30 mL/minutes), reduced lifeexpectancy (advanced cancer, renal or respiratoryfailure, severe cachexia, or severe incapacitation)and contraindication to LGE-CMR. Patients with-out any prior LVEF documentation within theirmedical records were assumed to have a normalLVEF value �50%. After clinical screening, theremaining eligible patients were contacted bymail and phone call. The patients who agreedto participate were scheduled to undergo thecomplete study screening protocol.

Study Protocol

Clinical Assessment

All patients underwent a complete physician’sreview of personal and family medical history.

ECG Acquisition and Analysis from Study Visit

12-lead ECG recordings and high-resolutionSAECGs (GE Healthcare) were acquired at rest.Automated QRS score and QRS-T angle werecalculated.7,21 Presence of LP was measured overan average of 350 beats using a 40-Hertz filter andwas defined as at least two positive findings among:filtered QRS duration >114 milliseconds; terminalQRS root mean square voltage <20 μV; and low-amplitude LP duration >38 milliseconds.

Ambulatory ECG Acquisition and Microvolt TWA Analy-sis

A 30-minute 12-lead ambulatory ECG recordingwas made with a SEER 12 digital ECG recorder(GE Healthcare) and included a 6-minute walktest. TWA magnitude was analyzed using themodified moving average method on a dedicatedMARS 8 workstation (GE Healthcare) by aninvestigator blinded to clinical status.22 TWA datawere measured as a continuous variable.

CMR Acquisition and Analysis

Patients underwent CMR with a 1.5-T scanner(Siemens Healthcare, Avanto, Erlangen, Germany)including cine and LGE study covering the wholeleft ventricle. Study protocol has been reportedpreviously.10

All CMR analyses were performed on dedicatedworkstations with Q-Mass (Medis, Leiden, TheNetherlands) for all measurements. All analyseswere performed by two experienced observersblinded to the results of the different ECG indices.

As presented in Figure 1, infarct core and greyzone were assessed on LGE images for eachpatient as reported previously.10 The scar patternwas classified as ischemic if its distribution wassubendocardial to transmural within a coronaryvascular territory and if scar was associated withsegmental systolic dysfunction on correspondingcine images. Scar was classified as nonischemic inall other cases.

Statistical Analysis

Continuous variables are expressed as mean± SD or median and interquartile range (IQR).Categorical data are summarized as frequenciesand percentages. Student’s t-test or Wilcoxon ranksum test were used to compare group differences incontinuous variables according to LGE-CMR scarstatus and size in grams, as well as according to LPor TWA alterations. For noncontinuous variables,Fisher’s exact test or chi-square were used. Normaldistribution was determined using Shapiro-Wilktest. ANOVA was performed to compare datafrom more than 2 groups of patients, and thecorresponding F-test result was reported.

The associations of different LV characteristicsby LGE-CMR with continuous ECG variables wereassessed with univariable and multivariable linearregressions. TWA level was analyzed as a depen-dent continuous outcome variable. The presence ofLP was analyzed as a dependent binary outcomevariable. Potential confounding factors for TWAand for LP by SAECG were ruled out by univariablefollowed by multivariable linear and logisticregression analyses, respectively. In multivariableanalyses, along with clinically relevant variablesthat were found to be associated with TWA or LPby univariable analysis, we systematically includedage, LVEF, LV end-diastolic volume (LVEDV), andtotal scar size as defined by the formula: total

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Figure 1. Mid-left ventricle short-axis late gadolinium enhanced cardiac magnetic resonance image (A) in a 67-year-oldAfrican American female patient with QRS score = 5 and QRS-T angle = 151° (B) showing an inferior and antero-septalinfarct. The gray zone was defined after placing a region of interest (ROI) in the remote (dark SI) healthy myocardiumand another ROI in the scarred hyperenhanced myocardium (high SI). The peak SI in the healthy myocardium (peak SI =14 in example shown) was used as the lower SI cutoff for the gray zone. The peak SI in the scarred hyperenhancedmyocardium (peak SI = 54 in example shown) was determined by the second ROI. The upper SI cutoff for the grayzone was calculated as 50% of peak hyper-enhanced SI (0.5 × 54 = 27 in example shown). The gray zone extent wasautomatically determined as the region (C, shown in yellow) with SI between peak healthy myocardium SI and 50% ofpeak hyperenhanced SI (between 14 and 27 in the example). The core region of dense scar (C, shown in red) was thearea with SI >50% of peak SI. For comparison, SI in a healthy myocardium is 9 ± 4 (mean ± SD), with maximum of14, while SI in a hyperenhanced myocardium is 45 ± 6 with maximum of 54. Core is an area with SI >27; gray zoneis an area with SI 14–27; and total scar size is an area with SI >14.

scar = core + gray zone, or core and gray zonesize separately and QRS score.

We further analyzed electrocardiographic andimaging results independently according to QRSscore distribution categories (three categories: firstquartile, IQR, and last quartile).

Analyses were performed using STATA versionSE 13 (StataCorp, College Station, TX, USA). Atwo-tail probability value <0.05 defined statisticalsignificance.

All authors have read and agree to themanuscript as written.

RESULTS

Patient Population

All ECGs acquired and stored in the JHH entire12-lead ECG database including outpatient clinicsbetween October 1, 2009 and March 31, 2010,

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from patients age 21 to 100 years (n = 69088)were exported and analyzed. Patients whose ECGswere obtained in hospital areas with high riskof mortality were excluded from the study (n =19,829 ECGs from 5590 patients). After this review,19,750 eligible ECGs remained, of which 3217(8.0%) had QRS score �5 and/or QRS-T angle�105º. After screening and selecting patients basedupon predefined clinical screening characteristics,we contacted 800 eligible patients via mail andphone.

Consent to participate was received from 89 pa-tients. Further exclusions included 10 patients whorefused the CMR study because of claustrophobiaand two whose morbid obesity precluded CMRstudy. Thus, 77 patients underwent the LGE-CMRstudy.

The screening ECG was performed during aroutine cardiology consultation in 45 (58%) ofthese patients, in an emergency department in four(5%) and other medical or surgical consultations in28 (37%).

The basic clinical characteristics of our popula-tion are reported in Table 1. The mean age of thisstudy population was 60 ± 10, and 52 (68%) weremale with 54 (70%) Caucasians and 23 (30%) Afro-Americans. There was no known structural heartdisease in 43% of the study population.

Of these participants 47 (61%) had aspirin,31 (40%) had beta-blockers, 34 (44%) had an-giotensin converting enzyme inhibitors or an-giotensin II receptor blockers, 41 (53%) had statinsand 4 (5%) had anti-arrhythmic medication otherthan beta-blockers.

CMR Variables

Figure 2 demonstrates the LGE-CMR resultsfrom a representative participant of our studypopulation with an ischemic scar pattern.

Of the 77 patients enrolled, 41 (53%) hadevidence of myocardial scar on LGE-CMR (Table2). Of these, 22 (54%) patients had a nonischemicpattern on LGE-CMR and 19 (46%) exhibited atypical ischemic scar pattern. The median scarextent in patients with positive LGE-CMR was 8%of the LV, IQR (4; 15% LV) with a median core scarextent of 5% LV IQR (3; 8% LV), and a median grayzone extent of 2% LV IQR (1; 7%LV). The medianLVEF in the entire group of patients was 58% IQR(54; 65%), the median LVEDV was 144 mL, IQR

(118; 163 mL), and the median LV mass was 131 g,IQR (113; 152 g).

In the 19 patients with an ischemic scar pattern,13 (68%) had history of coronary heart diseaseor prior MI and six (32%) had none. As reportedin Table 1, 12 patients had a prior documentedMI history, of which 10 (83%) had an evidentmyocardial scar with ischemic pattern on LGE-CMR.

The different CMR and ECG characteristicsaccording to presence of scar and scar pattern arereported in Table 2. Patients with ischemic scarpattern had significantly larger total scar size (P =0.006), higher QRS score (P = 0.004), greater spatialQRS-T (P = 0.02) angle, and greater QRS duration(P = 0.03).

ECG Characteristics Correlation withLGE-CMR

As shown in Figure 3, QRS score was associatedwith the total myocardial scar size in grams (R2 =0.12; P = 0.002), with myocardial gray zone size(R2 = 0.17; P < 0.001) as defined by LGE-CMR anda with core scar size (R2 = 0.07; P = 0.02).

QRS-T angle was not associated with totalmyocardial scar size, core of scar and gray zonesize in grams by LGE-CMR (P = 0.13; P = 0.14;P = 0.15, respectively) even after adjustment forQRS duration.

As reported in Table 2, patients with a my-ocardial ischemic scar had significantly greaterQRS duration as compared with patients withnonischemic scar and patients without myocardialscar (P = 0.03).

There were significant differences in electro-cardiographic and LGE-CMR characteristics whendividing patients according to three different QRSscore categories (QRS score �2, between 3 and5, and � 6). There was a significant increase inmyocardial scar features and LVEDV for increasingQRS scores (Table 3). Patients with a QRS score�6 had significantly greater LVEDV compared topatients with a QRS score �2 (162 ± 46 mL vs.137 ± 37 mL, respectively; P = 0.02).

There were also significant electrocardiographicdifferences when dividing patients according tothree different QRS-T angle categories (QRS-Tangle � 82°, between 83 and 135°, and �136°) butthere were not any significant differences in termsof LGE-CMR characteristics (data not shown).

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Table 1. Basic Clinical Characteristics in the Whole Study Sample and According to Presence of Scar on LGE-CMR

All Patients With Scar Without Scar(n = 77) (n = 41) (n = 36) P Value

Age (years) 60 ± 10 62 ± 10 57 ± 10 0.02Female 25(32) 9(22) 16(44) 0.035Body mass index (kg/m2) 31 ± 6 31 ± 6 31 ± 7 0.85Hypertension 47(61) 27(66) 20(56) 0.35Diabetes 17(22) 7(17) 10(28) 0.26Hypercholesterolemia 39(51) 26(63) 13(36) 0.02Current smoker 28(36) 19(46) 9(25) 0.052History of CAD 24(31) 19(46) 5(15) 0.002History of MI 12(16) 10(24) 2(8) 0.02History of atrial fibrillation 21(27) 12(16) 9(25) 0.49ECG characteristicsHeart rate (bpm) 66 ± 12 65 ± 8 67 ± 15 0.43QRS duration (milliseconds) 107 ± 24 112 ± 25 102 ± 23 0.06QT interval corrected (milliseconds) 432 ± 31 434 ± 30 431 ± 31 0.48QRS-T angle (°) 102 ± 41 108 ± 40 95 ± 41 0.2QRS score 3.7 ± 2.8 4.4 ± 2.9 2.9 ± 2.4 0.03

Continuous data are expressed as means ± SD and categorical data as n (%). CAD = coronary artery disease; MI = myocardialinfarction; NYHA = New York Heart Association; bpm = beats per minute. P values are obtained by t-test and Wilcoxon rank-sumtest depending on data distribution, performed between patients with and without scar.

Figure 2. Late-gadolinium enhanced CMR vertical long-axis (left panel) andbasal short-axis (right panel) views of a representative case of our studypopulation. This patient was a Caucasian male patient with hypertension,current smoking and previous history of inferior myocardial infarction. Thispatient had a QRS-score of 12 and QRS-T angle of 139° on 12-lead ECG at rest.The patient also had late potentials on SA-ECG and T-wave alternans on Holter-ECG (TWA of 47 μV). There was an ischemic transmural chronic scar of theLV basal inferior wall (white arrows), associated with LV enlargement (LVEDV =150 mL) and decreased LVEF at 43%.

Associations with TWATWA level could be analyzed in 53 (69%) patients

after exclusion of nine patients with current AFand three patients in whom the ECG signal wasdistorted. The median TWA level was 31 μV, IQR(22; 57μV).

The scar core size was 3.8 ± 5.3 g in patientswithout TWA versus 8.2 ± 9.4 g in patients withTWA (P = 0.035) but gray zone size did notsignificantly differ (2.7 ±4.2 g vs. 4.3 ± 5.3 g,respectively; P = 0.22). By univariate linear

regression analysis myocardial scar core size (R2 =0.21; P = 0.001), total scar size (R2 = 0.18; P =0.001), and gray zone size (R2 = 0.11; P = 0.01)were all significantly associated with TWA.

In multivariable analysis including age, QRSscore, QRS-T angle, LVEF, LVEDV, total myocar-dial scar size and myocardial scar pattern, LVEDV(β = 0.17; 95%CI [0.02–0.32]; P = 0.02) and totalmyocardial scar size (β = 1.16; 95%CI [0.25–2.07];P = 0.01) remained significantly associated withTWA (Fig. 4).

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Table 2. Principal CMR Variables According to Presence of Myocardial Scar and Scar Classification

No Scar Nonischemic Scar Pattern Ischemic Scar Pattern(n = 36) (n = 22) (n = 19) F-Test

LVEF (%) 60 ± 7 58.5 ± 10 54 ± 8 0.01LVEDV (mL) 146 ± 42 145 ± 41 154 ± 49 0.58LV mass (grams) 136 ± 37 145 ± 49 134 ± 28 0.94LV MVR (g/mL) 0.96 ± 0.20 1.04 ± 0.36 0.91 ± 0.21 0.73RVEF (%) 48 ± 6 50 ± 9 48 ± 9 0.74RVEDV (mL) 164 ± 49 162 ± 45 168 ± 42 0.79Total scar size (grams) – 9.5 ± 9.2 17.9 ± 10.9 0.006*Core size (grams) – 5.9 ± 5.5 11.6 ± 7.1 0.002*Gray zone size (grams) – 3.6 ± 4.1 6.4 ± 4.8 0.03*QRS duration (milliseconds) 102 ± 23 107 ± 23 117 ± 27 0.03QRS score 2.9 ± 2.4 3.7 ± 2.8 5.2 ± 2.8 0.004QRS-T angle (°) 95 ± 40 95 ± 42 123 ± 31 0.02

All values are means ± SD. *Comparison by t-test or Wilcoxon rank-sum test of nonischemic and ischemic scar subgroups. LV= left ventricular; LVEDV = LV end-diastolic volume; LV MVR = LV mass to volume ratio (calculated as the LV mass over LVEDVratio); LVEF = LV ejection fraction; RVEF = right ventricular ejection fraction; RVEDV = right ventricular end-diastolic volume.

Figure 3. Box-and-whiskers plots showing total scar size as a percentageof left ventricular mass per QRS score category. There was a significantscar size difference between QRS score �6 and QRS score = 0 and therewas a trend toward greater scar size between QRS score within 1 to 5 andQRS score = 0.

Association with LP Presence by SAECG

Of the 77 patients studied, 33 (43%) exhibited LPwith TWA �47 μV in nine (37%). By univariatelogistic regression analysis myocardial scar coremass (OR = 1.07; 95%CI [0.99–1.15]; P = 0.09)and gray zone mass (OR = 1.08; 95%CI [0.97–1.21]; P = 0.17) were not significantly associatedwith the presence of LP, but there was a significantassociation with LVEF (OR = 0.88; 95%CI [0.82–0.95]; P < 0.001 and LVEDV(OR = 1.01; 95%CI[1.00–1.03]; P = 0.02).

DISCUSSIONIn this study, we demonstrate the myocardial

scar features among patients with preserved LVsystolic function screened according to standard12-lead ECG indices: the QRS score and QRS-Tangle. We found that in a diverse multiethnic hos-pital population (1) myocardial scar by LGE-CMRwas present in 53% of patients and was correlatedwith QRS score but not with QRS-T angle; (2) therewere significant increase in electrocardiographicabnormalities, LVEF alteration, and myocardial

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Table 3. Underlying Electrocardiographic and Myocardial Substrate According to QRS Score DistributionCategory

QRS Score � 2 QRS Score between 3 and 5 QRS Score � 6(n = 29) (n = 27) (n = 21) P Value

QRS-T angle (°) 90 ± 40 103 ± 38 119 ± 41 0.009QRS duration (milliseconds) 96 ± 16 109 ± 25 123 ± 26 <0.0001TWA (μV) 36.4 ± 22.0 39 ± 21.2 44.4 ± 24.4 0.28Presence of LP, n (%) 7(24) 10(38) 16(76) 0.001LVEF (%) 62 ± 9 57 ± 8 55 ± 8 0.007LVEDV (mL) 137 ± 37 147 ± 47 162 ± 46 0.04Total scar mass (grams) 4.4 ± 8.9 6.7 ± 8.1 11.5 ± 13.3 0.02Scar core (grams) 3.1 ± 6.0 4.3 ± 5.3 6.8 ± 8.2 0.05Scar gray zone (grams) 1.3 ± 2.9 2.4 ± 3.3 4.7 ± 5.7 0.005Ischemic scar pattern, n (%) 4(14) 8(29) 7(33) 0.21

Continuous data are expressed as means ± SD and categorical data as n (%). QRS duration by standard 12-leadelectrocardiogram; TWA = T-wave alternans; Presence of LP = presence of late potentials by signal average ECG; LVEF =left ventricle ejection fraction; LVEDV = LV end-diastolic volume. P values are obtained by F-test for continuous variables andchi-square tests for categorical variables.

Figure 4. Association of T-wave alternans with total myocardial scar coresize based on multivariable linear regression adjusting for age, LVEF,LVEDV, QRS-score, QRS-T angle, and myocardial scar pattern. In this plotthe regression line represents the effect of total scar size in grams on T-wave alternans amplitude after adjustment for all previously cited variable.There was a significant residual positive relationship between total scar sizeand T-wave alternans (β = 1.16; 95%CI [0.25–2.07]; P = 0.01).

scar size with increasing QRS scores, while thiswas not as clear for increasing QRS-T angles; (3)myocardial scar by LGE-CMR was independentlyassociated with TWA, a feature of ventriculararrhythmogenesis. These findings support theconcept that LGE-defined scars are associated witha certain degree of electrical instability in patientswithout severe LV dysfunction identified among

those who had an ECG as part of a nonspecificclinical evaluation.

Myocardial Scar in Patients withPreserved LVEF and 12-Lead ECG

Current risk stratification strategies to predictSCD fail to identify the large number of patients

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with preserved or normal ventricular functionwho experience the vast majority of reportedSCDs.23 The current study is part of a globaleffort to address this issue by proposing simpleECG screening tools to select patients withpotentially increased risk of SCD and is the first toexplore the underlying myocardial anatomical andstructural characteristics determined by 12-leadECG indices of myocardial damage and/or abnor-mal repolarization.

Prior studies in selected groups of ischemicand nonischemic patients with advanced stagesof myocardial disease and LVEF <35% reportedthat myocardial scar assessed by LGE-CMR pre-dicts ventricular arrhythmias and cardiovasculardeath.10,12,13,24 These studies hypothesized thatthe presence of scar forms the substrate formalignant reentrant arrhythmias and suggestedthat heterogeneous scar border zones createareas of slowed conduction that are necessaryto induce lethal reentrant arrhythmia.10,24,25 Theindependent prognostic value of myocardial scarby LGE-CMR on cardiac death and ventriculararrhythmias has also been shown in other typesof cardiomyopathies and multicenter trials.26,27

These findings have recently been pushed furtherin broader groups of patients setting the pathfor the first clinical trials stratifying candidatesto ICD implantation based upon myocardial scarfeatures.14,28

In this study, we used a sequential approachcombining electrical and structural markers to-gether in a diverse group of hospital patients, andwe found that more than half of electrical positives(QRS score or QRS-T angle above thresholds),also had structural pathology. The combinationof electrical and structural markers together mayprovide a more efficient means of detecting riskthan protocols in general use, based on a singledimension.

Detection of myocardial scar by the modified12-lead ECG Selvester scoring criteria, afteradjustment for the presence of ECG confounders(hypertrophy and conduction defects), has beenvalidated in several studies from our group.5,9,21

Our results show a lower diagnostic accuracyof QRS score for scar detection in our studypopulation. These findings can be explained inpart by the heterogeneous character of our studypopulation, the lower median scar size detectedon LGE-CMR (8% of the LV, IQR [4; 15%LV]), a selection bias preventing the diagnostic

performance assessment over a full range of QRSscores and the lower degree of disease severity inthis selected group of patients. Our results showthat the QRS score is related to LV structuraldamage in a hospital population with preservedejection fraction and an a priori low to intermediaterisk of SCD.

This further extends the results of prior reportsin large cohorts of post-myocardial infarctionpatients29 and more heterogenous groups ofpatients19,30 showing that the QRS score was astrong independent predictor of all-cause mortality.These results suggest that QRS score carries moreinformation than as a simple structural parameterof myocardial scar, as confirmed in the prior citedstudy in the SCD-HeFT in which QRS score was anindependent predictor of ventricular arrhythmias.9

Myocardial Scar by LGE-CMR, TWAand LP Presence

This is the first study to show an independentrelationship of myocardial scar with TWA levels.Prior imaging studies revealed that patients withidiopathic dilated cardiomyopathy displayed TWAduring increased sympathetic nerve activity.31

In patients with hypertrophic cardiomyopathy,myocardial fiber disarray and/or fibrosis wereassociated with positive TWA test results32 Ina recent publication, no association was reportedbetween TWA level and scar size33 This might beexplained because TWA level was not quantifiedbut was analyzed as positive or negative.

Limitations

Our results on the predictive capacity of simpleand inexpensive clinical ECG-derived indices forLGE-CMR indicators of myocardial scar must beinterpreted in the face of certain methodologiclimitations. First, the small sample size limits thestatistical power to detect discrete but significantrelationships between clinical, ECG, and LGE-CMR variables especially after the subdivision indifferent scar categories. Second, patient selectionbias is possible related to the 11% of enrolledpatients relative to the potentially eligible patientsfrom the entire ECG database at one health caresystem over a 6-month period. A prior studyin this population demonstrated that the patientswith highest QRS scores and QRS-T angles diedbefore they could be assessed during the clinic

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visit for this study and patients with elevated QRSscores or QRS-T angle that had LVEF �35% wereexcluded.19 Also, 10 (12%) patients did not undergoCMR study. Fourth, LGE-CMR may be limited inquantifying diffuse microscopic nonfocal scar thatmay affect ECG indices. This limitation may beovercome in the near future with the advent ofnew T1 mapping and T2 mapping sequences thathave been shown to provide direct quantificationof diffuse myocardial fibrosis and myocardialedema.34

CONCLUSION

In this study designed to explore the underlyingmyocardial substrate of patients identified bystandard 12-lead ECG markers but with preservedLVEF, we found that myocardial scar by LGE-CMRwas correlated with 12-lead electrocardiographicfeatures of arrhythmogenesis. Future studies areneeded to refine the screening algorithm in largercohorts of patients and to assess its predictive valuefor arrhythmic outcomes in the general population.

Acknowledgments: The authors wish to express their sincereacknowledgements to Anita Bacher, Rosalie Cosgriff, MeredithDobrosielski and Jeanette Walker for their help on thescreening, enrollment and data collection of participants.

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Supporting Information

Additional Supporting Information may be foundin the online version of this article at the publisher’sweb site:

Figure S1. QRS Scoring Criteria. Abbreviations:LAFB = left anterior fascicular block; LBBB = leftbundle branch block; LV = left ventricle; LVH =left ventricular hypertrophy; NchInIt40 = Notch ininitial 40 milliseconds; RAO = right atrial overload;RBBB = right bundle branch block.