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Original Articles |
From the Krannert Institute of Cardiology (M.K.D., H.S., W.M., M.A.M., J.P., G.D., J.M.), Indiana University School of Medicine; and Division of Biostatistics (C.S.), Department of Medicine, Indiana University School of Medicine, Indianapolis.
Correspondence to Mithilesh K. Das, MD, MRCP, FACC, Associate Professor of Clinical Medicine, Krannert Institute of Cardiology, Chief, Cardiac Electrophysiology, Roudebush VA Medical Center, Indiana University School of Medicine, 1800 North Capitol Avenue, Indianapolis, IN 46202. E-mail midas{at}iupui.edu
Received January 3, 2008; accepted July 2, 2008.
| Abstract |
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120 ms). We postulate that fragmented wQRS (f-wQRS) due to bundle branch block, premature ventricular complexes, or paced rhythms (f-pQRS) signify myocardial scar and higher mortality.
Methods and Results— Patients who underwent cardiac evaluation with nuclear stress imaging or cardiac catheterization and had wQRS (bundle branch block, premature ventricular complex, or pQRS) were studied. f-wQRS was defined by the presence of >2 notches on the R wave or the S wave and had to be present in
2 contiguous inferior (II, III, aVF), lateral (I, aVL, V6) or anterior (V1 to V5) leads. ECG analyses of 879 patients (age, 66.7±11.4 years; male, 97%; mean follow-up, 29±18 months) with bundle branch block (n=310), premature ventricular complex (n=301), and pQRS (n=268) revealed f-wQRS in 415 (47.2%) patients. Myocardial scar was present in 440 (50%) patients. The sensitivity, specificity, positive predictive value, and negative predictive value of f-wQRS for myocardial scar were 86.8%, 92.5%, 92.0%, and 87.5%, respectively. The sensitivity and specificity for diagnosing myocardial scar were 88.6% and 94.4%, 81.4% and 88.4%, and 89.8% and 95.7% for f-bundle branch block, f-premature ventricular complex, and f-pQRS, respectively. f-wQRS was associated with mortality after adjusting for age, ejection fraction, and diabetes (P=0.017).
Conclusions— f-wQRS on a standard 12-lead ECG is a moderately sensitive and highly specific sign for myocardial scar in patients with known or suspected coronary artery disease. f-wQRS is also an independent predictor of mortality.
Key Words: coronary disease electrocardiography scintigraphy fragmented QRS myocardial scar
| Introduction |
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110 ms) not related to bundle branch block (BBB) also represents myocardial scar.5 We have earlier defined fQRS in the presence of a narrow QRS (QRS duration <120 ms) only, and therefore, fragmentation of QRS has not been defined in the presence of a wide QRS (wQRS, QRS duration
120 ms), such as BBB, premature ventricular complex (PVC), or paced QRS (pQRS).
Clinical Perspective see p 258
Typical BBB is associated with a RSR' pattern due to partial transmyocardial depolarization of the ventricle due to relatively slow or absent conduction of the ipsilateral bundle branch. Typically, QRS complexes due to BBB have only 1 additional R' (or 2 notches on the wave). We postulated that myocardial scar alters the QRS morphology similar to that encountered in narrow QRS complexes and results in an additional R' or notch in the R wave or the S wave. These different fQRS morphologies probably represent intramyocardial conduction abnormalities and peri-infarction conduction block due to myocardial necrosis or scar.6 We, therefore, defined fragmentation of QRS with BBB morphology (QRS
120 ms) as the presence of >2 notches (at least 1 notch more than the typical BBB) or multiple notches of the R wave or >2 notches in the nadir of the S wave. Myocardial depolarization during a PVC or paced rhythm occurs due to intramyocardial conduction of impulses, which typically results in a wide QRS. Several smaller studies have shown that notching and qR pattern in the contour of BBB, PVC, and paced rhythm are associated with an old MI. The main aim of the study was to identify the predictive value of fragmentation of wide QRS complexes (f-wQRS) for myocardial scar. f-wQRS on a standard 12-lead included fragmented BBB (f-BBB), fragmented PVC (f-PVC), and fragmented paced QRS (f-pQRS). We also postulated that f-wQRS is associated with a significantly increased all-cause mortality when compared with wide QRS without fragmentation (wQRS).
| Methods |
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The inclusion criteria are as follows:
The exclusion criteria are as follows:
Wide QRS Complexes and Fragmented Wide QRS Complexes
wQRS (duration
120 ms) included QRS complexes due to BBB, PVC, and pQRS. f-wQRS (QRS duration
120 ms) was defined to be present if fragmented wQRS (f-BBB, f-PVC, and f-pQRS) were recorded in
2 contiguous anterior leads (V1 toV5) or in
2 lateral (I, aVL, and V6) or in
2 inferior leads (II, III, and aVF).
Fragmented BBB
Right BBB (RBBB) and left BBB (LBBB) were defined by the standard ECG criteria (QRS duration
120 ms) (Figures 1 and 2
). Incomplete BBB (QRS duration of <120 ms) were not included in f-BBB group. f-BBB was defined as various RSR' patterns with or without a Q wave, with >2 R waves (R') or >2 notches in the R wave, or >2 notches in the downstroke or upstroke of the S wave, in 2 contiguous leads corresponding to a major coronary artery territory.
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Cardiac Catheterization
Some of the patients underwent stress test as well as cardiac catheterization. During cardiac catheterization, the left ventriculography in RAO 30° projection was studied for akinesia or dyskinesia of at least one of the segments (basal anterior, anterolateral, apical, inferior, posterobasal) of the LV wall, suggestive of myocardial scar in patients who underwent cardiac catheterization for evaluation or treatment of CAD.
Echocardiography
Myocardial scar was confirmed by echocardiography in patients who did not have left ventriculography performed during cardiac catheterization. Wall motion and thickening were assessed using a standard 16-segment LV model from digitally stored images and a previously validated 6-grade scoring system.10 Myocardial coronary segments were assigned according to standard nomenclature. The presence of regional akinesia was determined by
2 akinetic segments corresponding to a major epicardial coronary artery.
Myocardial Scar
Myocardial scar was defined by the presence of either of the following 2 findings:
1 segment) of respective LV wall as demonstrated by the left ventriculography or echocardiography (>2 segments).
Mortality Data
Mortality data were obtained from the hospital medical records and social security death indices from the Web site available to the public.
Statistical Analysis
Continuous variables were expressed as the mean±SD, and categorical variables were expressed as frequency and percentage. Comparison of continuous variables and dichotomous variables was performed with t test and Fisher exact test. Survival curves for fragmented and nonfragmented w-QRS groups were estimated by the Kaplan-Meier estimator and compared by log-rank test. Cox proportional hazard model was used to model the association between mortality and fragmented w-QRS by adjusting for potential confounders. The assumption of proportional hazard was tested by the method proposed by Lin et al11 All analyses were performed by SAS 9.1 (SAS Inc., Cary, NC).
| Results |
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PVC group (n=310)
f-PVC was present in 125 (41.5%) patients (Figure 3). Myocardial scar was present in 129 (42.9%) patients. Sensitivity and specificity of f-PVC for myocardial scar was 81.4% and 88.4%, respectively.
pQRS group (n=268)
The pQRS included 120 patients with an ICD and 148 patients with a pacemaker. Nuclear imaging in Figure 4 shows f-pQRS with myocardial scar (upper panels) and pQRS without fragmentation and no myocardial scar (lowest panel). f-pQRS was present in 120 (44.8%) patients and myocardial scar was present in 127 (47.4%) patients. Sensitivity and specificity of f-pQRS for myocardial scar was 89.8% and 95.7%, respectively.
f-wQRS as a Predictor of Mortality
Kaplan-Meier survival analysis revealed a significantly higher mortality in the f-wQRS group when compared with the wQRS group (P<0.001; Figure 5). The subgroup analysis also revealed that f-BBB, f-PVC, and f-pQRS were associated with a significantly reduced time to death compared with nonfragmented fBBB, PVC, and pQRS, respectively (P=0.05, 0.001 and 0.008, respectively; Figures 6 and 7
). Further analysis of the fBBB group revealed that f-LBBB but not f-RBBB was associated with a significantly reduced time to death compared with nonfragmented LBBB (P=0.003) and RBBB (P=0.88), respectively. Cox proportional hazard regression model revealed that age, diabetes, ejection fraction (ejection factor), and f-wQRS were univariate predictors of mortality, whereas sex, history of coronary revascularization, aspirin therapy, β-blocker therapy, and angiotensin-converting enzyme inhibitor therapy were not predictors of mortality (Table 3). The multivariable regression model revealed that f-wQRS is associated with mortality after adjusting for age, ejection fraction, and diabetes.
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| Discussion |
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Fragmentation of QRS
Normal ventricular depolarization occurs in 3 phases, involving the interventricular septum (phase 1), free wall of right ventricle (phase 2), and free wall of left ventricle (phase 3).13 Phases 2 and 3 normally occur simultaneously and are in almost opposite directions. As a result, only the net vector is registered on the surface ECG. In the presence of RBBB, phase 2 is delayed occurring after phase 3 resulting in prolongation of the QRS duration. Additionally, the right ventricular depolarization produces a higher voltage potential on the surface ECG, due to the absence of the opposing effect of simultaneous LV depolarization. This vectorially unopposed activation of right ventricle leads to a diminished S wave depth in V1, which may even disappear completely depending on the severity of the conduction abnormality. Therefore, ECG changes in RBBB are mainly a prolongation of QRS duration and a delayed terminal depolarization manifested as an R' wave along with reduced S waves in V1 and V2 as well as a prominent slurred S wave in I, V5, and V6. A similar but vectorially opposite phenomenon occurs in LBBB and is manifested as RSR' pattern in the left precordial leads. Similarly, the PVC morphology also depends on the site of origin and the physiology of intramyocardial conduction. PVCs in patients with structurally normal hearts have a wide QRS with a smooth contour of the R wave or a narrow notch <40 ms in the R wave.7 Likewise, right ventricular pacing is usually from the right ventricular apex and, therefore, it depolarizes the left ventricle similar to a PVC (LBBB, left superior axis) originating from that area.
Several studies have suggested that fragmentation of QRS occurs due to an alteration of the normal depolarization of the ventricles. Autopsies of patients with MI and LV aneurysm have confirmed significant myocardial necrosis, with "islands" of viable myocardial tissue interspersed in abundant fibrous tissue.14 The islands of chronically ischemic myocardium display slow activation as a result of partially depolarized and depressed action potential upstroke velocities. This feature is responsible for inhomogeneous activation of the ventricles. This alters ventricular depolarization patterns, as shown by endocardial mapping and computer models, probably represent fragmentation in the QRS complex on the surface 12-lead ECG.15,16 We postulate that the fragmentations or fractionations in the presence of MI recorded in computer models, high-frequency ECG recordings, and magnetocardiography represents fQRS on a routine 12-lead ECG.17–19
Fragmented BBB
Remote MIs in patients with a BBB are diagnosed by the presence of pathological Q waves. A Q-wave or T-wave inversion with LBBB in lead aVF signifies old inferior MI (sensitivity, 86% and specificity, 91%).20 However, other than the Q wave, there is no diagnostic sign of an old anterior or lateral wall MI in the presence of LBBB. Furthermore, with the recent improvements in the management of acute MI, including aggressive medical therapy, the use of thrombolytic agents, and early coronary revascularization, the incidence of Q-wave MI has decreased from 66.6% to 37.5%, and the incidence of non-Q-wave MI has increased reciprocally.21 This trend has made the recognition of an old MI in the presence of a BBB more difficult. Multiple Center Investigation of the Limit of Infarction Study demonstrated that late notching of the S wave in V1 to V4 as one of the specific ECG signs of MI in the presence of LBBB.22 The notching of the S wave in addition to the R waves in LBBB qualifies for the definition of f-BBB in our study because there are already 2 notches or an additional R' wave. Our findings are also consistent with another smaller ECG study related to the MI scar. The RSR' complex associated with a wide QRS (
110 ms), unrelated to RBBB or LBBB was identified in 26 patients with an old MI.5 In these patients, the RSR' pattern was present in the precordial leads, inferior leads, or both. Severe segmental wall motion abnormalities (akinetic in 16 and dyskinetic in 10 patients) consistent with MI scar were detected using the equilibrium radionuclide study and the 2-dimensional echocardiogram in these patients. The major difference of our study with the above-mentioned study is that they did not include a typical BBB, paced rhythm, or PVC. A pathological study confirmed that the Q wave and notches in the S wave upstroke or nadir represents MI scar.23 In our study, f-RBBB was not associated with significantly reduced time to death when compared with RBBB. It may be because RBBB may represent myocardial scar predominantly in the right ventricle or inferior wall, which is associated with a relatively better prognosis than LBBB. Furthermore, unlike LBBB, a RBBB does not significantly increase mortality on long-term follow-up.24 Therefore, RBBB represents a relatively low-risk group of patients, and f-RBBB does not represent a significantly higher risk for mortality when compared with RBBB, whereas f-LBBB is a significant predictor of myocardial scar and mortality.
Fragmented PVC
Notching of the PVC represents myocardial scar and Moulton et al7 have shown that PVC with a normal contour or notching of QRS with a separation of <40 ms is associated with no myocardial disease, whereas notching (or selves) of the QRS with a separation of >40 ms was associated with significant myocardial disease. In another study, 12-lead ECGs and 2-minute multiple-lead rhythm strips revealed PVCs in 58 of 515 patients who underwent cardiac catheterization. Twenty-one patients with PVCs had prior MI diagnosed by regional akinesia or dyskinesia on left ventriculography.25 Standard criteria were used to diagnose prior MI from the sinus beats of the ECG. MI was diagnosed when a PVC had a QR or QRS pattern with Q wave
0.04 seconds. Morphological analysis of PVCs had a low sensitivity (29%) but high specificity (97%) and high predictive value (86%) for the diagnosis of MI, whereas a Q wave in sinus rhythm had a sensitivity of 52% and specificity of 97%. Our study has shown that f-PVC has a much higher predictive value for diagnosing MI scar.
Fragmented pQRS
The usefulness of the 12-lead resting ECG is limited for diagnosing an old MI in paced ventricular rhythms.26 Our results are concordant with the findings of several smaller studies of patients with paced rhythms.27 In a study of 45 patients with MI (anterior 23, inferior 22) and 26 healthy controls, pacing was applied from the right ventricular apex after coronary angiography.28 The sensitivity, specificity, and average diagnostic accuracy of the 5 known criteria for MI scar in the presence of paced ECG were assessed. These include (1) notching (0.04 second in duration) in the ascending limb of the S wave of leads V3, V4, or V5 (Cabreras sign); (2) notching of the upstroke of the R wave in lateral leads (I, aVL, or V6, Chapmans sign); (3) Q waves >0.03 second in duration in lateral leads; (4) notching of the first 0.04 second of the QRS complex in inferior leads (II, III, and aVF); (5) Q wave >0.03 second in duration in inferior leads. The most sensitive criteria, for anterior and inferior MI were Cabreras and Chapmans (91.1% and 86.6%, respectively). All criteria had a low specificity (range, 42.3% to 69.2%). The combination of Cabreras and Chapmans sign decreased the sensitivity to 77.7%, but increased the specificity to 82.2%. A recent study (n=107) revealed that Cabreras sign (63.6%) was a moderately sensitive sign for MI scar but other known ECG signs had a poor sensitivity (9.1% to 40.9%).27 However, the specificity (81.6% to 100%) was relatively high for all ECG. In our study, both the above-mentioned signs were included in the definition of f-pPVC (>2 QRS notches), with a sensitivity of 89.7% and a specificity of 95.7%. Additionally, our study involved a larger population with documented myocardial scar and unlike other studies did not include patients with nonischemic cardiomyopathy. Our definition of the f-pQRS (as well as f-BBB and f-PVC) is simple, easily interpretable, and more importantly has a higher predictive value than all the above-mentioned criteria combined.
f-wQRS as a Predictor of Mortality
Our study showed that wQRS is associated with a significantly higher mortality when compared with its absence (P=0.017) during a mean follow-up of 29 months. The study results are in concordance with the mortality rates reported in patients with a narrow fQRS (<120 ms).12,29 A large-scale study involving 46,933 veterans revealed that BBB and paced QRS were predictors of cardiovascular mortality.30 Similarly, many other studies have shown that wQRS itself is a predictor of mortality in patients with CAD, but our study further identifies f-wQRS as a marker of the higher risk population (f-BBB, f-PVC, and f-QRS) in the wQRS group.31–33 Our study does not provide the mechanism of death in patients with f-wQRS. One of the possible mechanisms of death may be myocardial scar–related heart failure or a coronary events in this high-risk population.34 fQRS is also associated with significantly higher arrhythmic events in patients with an ICD.35 Therefore, it is possible that f-wQRS, which represents abnormalities of impulse conduction, may create a milieu for malignant reentrant ventricular arrhythmias and death.
Limitations
Our study population comprised of patients with at least a low-to-moderate risk for CAD, and therefore, the data cannot be applied to the general population as well as to patients with various non-CAD diseases and cardiomyopathy such as dilated cardiomyopathy or infiltrative heart diseases. The other limitation of our study population is predominantly male veterans. Cardiac MRI (CMR) is considered to be the gold standard for defining myocardial scar, whereas our data for myocardial scar was collected from 2 different diagnostic modalities (cardiac catheterization and stress nuclear imaging). However, these modalities are used more commonly in practice than CMR. Furthermore, CMR is expensive and cannot be used in patients with a pacemaker or an ICD.
| Conclusions |
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| Acknowledgments |
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None.
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Related Article
CLINICAL PERSPECTIVE
We previously found that fragmented QRS complexes are a marker for myocardial scar and a greater risk for cardiac events in patients with known or suspected coronary artery disease who have a QRS duration <120 ms. Traditional measures of ECG detection of scar, such as prior infarct, are more difficult when the QRS duration is prolonged by bundle branch block, pacing, or ectopic ventricular activation. This study evaluated the relation of fragmentation of wide QRS complexes (f-wQRS) to myocardial scar. Nearly half of the patients with wide QRS complexes in this study had f-wQRS as defined as >2 notches on R wave or S wave in
2 contiguous inferior (II, III, aVF), lateral (I, aVL, V6), or anterior (V1 to V5) leads. f-wQRS had a sensitivity of 87% and a specificity of 93% for myocardial scar. Patients with f-wQRS had greater mortality when compared with patients without fragmentation of QRS (36% vs. 18%) during a 29-month follow-up, and f-wQRS was an independent predictor of mortality. Fragmentation of wide QRS complexes is a simple ECG sign that identifies a high-risk group of patients with myocardial scar.
Circ Arrhythm Electrophysiol 2008 1: 258-268.
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