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Relationship Between Fragmented QRS and No-Reflow, Infarct Size, and Peri-Infarct Zone Assessed Using Cardiac Magnetic Resonance in Patients With Myocardial Infarction
Canadian Journal of Cardiology 30 (2014) 204e210
Clinical Research
Relationship Between Fragmented QRS and No-Reflow, Infarct Size, and Peri-Infarct Zone Assessed Using Cardiac Magnetic Resonance in Patients With Myocardial Infarction Luc Lorgis, MD, PhD,a,b Alexandre Cochet, MD, PhD,c Olivier Chevallier, MD,c Marion Angue, MD,a Aurelie Gudjoncik, MD,a,b Alain Lalande, PhD,c Marianne Zeller, PhD,b Philippe Buffet, MD,a François Brunotte, MD, PhD,c and Yves Cottin, MD, PhDa,b a b
Department of Cardiology, University Hospital, Dijon, France
Laboratory of Cardiometabolic Physiopathology and Pharmacology, INSERM U866, University of Burgundy, Dijon, France c
MRI Unit and LE2I UMR CNRS 6306, University Hospital, Dijon, France
ABSTRACT
RESUM E
Background: The relation between fragmented QRS complex (fQRS) and cardiac magnetic resonance parameters is poorly documented in ischemic cardiopathy. Methods: Among 209 consecutive patients, those with fQRS were compared with those without fQRS. Cardiac magnetic resonance studies with late gadolinium-enhanced sequences were done during the week after acute myocardial infarction. Results: fQRS was present in 113 (54%) patients, and associated with a significantly lower left ventricular ejection fraction, increased left ventricular volumes, a larger infarct size (IS), and a larger peri-infarct zone. Microvascular obstruction was more frequent in patients with fQRS (62% vs 45%; P ¼ 0.014) and the extent of the microvascular obstruction was significantly larger (1.6% [range, 0.0-4.4] vs 0.0 [range, 0.0-2.1]; P ¼ 0.004). Finally, the transmurality score in the 2 study populations was identical (48% vs 47%; P ¼ 0.895). In multivariate logistic regression analysis, only IS (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.03-1.09; P < 0.001), systolic blood pressure (OR, 1.02; 95% CI, 1.01-1.04; P < 0.001), and left ventricular endsystolic volume (OR, 1.02; 95% CI, 1.00-1.03; P ¼ 0.013) remained
(QRSf) et les Introduction : Le lien entre le complexe QRS fragmente sonance magne tique cardiaque est mal doparamètres de la re en matière de cardiopathie ische mique. cumente thodes : Parmi les 209 patients conse cutifs, ceux pre sentant un Me te compare s à ceux ne pre sentant pas un QRSf. Des e tudes QRSf ont e sonance magne tique cardiaque avec des se quences de de la re te re alise es rehaussement tardif après injection de gadolinium ont e durant la semaine après l’infarctus du myocarde aigu. sultats : Le QRSf e tait pre sent chez 113 (54 %) patients et associe Re jection ventriculaire gauche significativement plus à une fraction d’e faible, une augmentation du volume du ventricule gauche, une taille ri-infarctus plus grande. d’infarctus (TI) plus grande et une zone de pe tait plus fre quente chez les patients L’obstruction microvasculaire e sentant un QRSf (62 % vs 45 %; P ¼ 0,014), et l’e tendue de l’obpre tait significativement plus grande (1,6 % struction microvasculaire e tendue, 0,0-2,1]; P ¼ 0,004). Finalement, tendue, 0,0-4,4] vs 0,0 [e [e des 2 populations faisant l’objet de l’e tude le score de transmuralite tait identique (48 % vs 47 %; P ¼ 0,895). Dans l’analyse de e gression logistique multivarie e, seuls la TI (ratio d’incidence re
A twelve-lead electrocardiogram is an integral part of the evaluation of acute myocardial infarction (AMI). Fragmented QRS complexes (fQRSs), which include various RSR’ patterns without typical bundle-branch block on routine 12-lead electrocardiography (ECG), have recently been proposed as
a reliable and sensitive tool in this setting.1-4 fQRS is defined by the presence of an additional R wave or notching in the nadir of the S wave, or the presence of > 1 additional R wave (fragmentation) in 2 contiguous leads corresponding to a major coronary artery territory (Fig. 1).1 The fragmentation of QRS on the 12-lead surface electrocardiogram is a dynamic process, described in a number of cardiac diseases including ventricular aneurysm, idiopathic dilated cardiomyopathy, myocardial fibrosis, sarcoidosis, Brugada syndrome, arrhythmogenic right ventricular dysplasia, and myocarditis.5 Das et al. demonstrated that significant fragmentation of the QRS in coronary artery disease (CAD) was more sensitive and more specific than Q waves in detecting myocardial scarring in
Received for publication November 7, 2012. Accepted November 20, 2013. Corresponding author: Dr Luc Lorgis, Service de Cardiologie, CHU Dijon, Bd de Lattre de Tassigny, 21034 Dijon Cedex, France. Tel.: þ33 380293311; fax: þ33 380293333. E-mail: [email protected] See page 209 for disclosure information.
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.11.026
Lorgis et al. Fragmented QRS in MI: An MRI Study
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independent predictors of fQRS. Conclusions: This study revealed that fQRS was associated with increased IS, myocardial perfusion abnormalities, decreased left ventricular ejection fraction, and increased left heart volumes. These findings show that fQRS is a reliable marker of infarct size and acute ventricular remodelling.
[RIA], 1,06; intervalle de confiance [IC] à 95 %, 1,03-1,09; approche rielle systolique (RIA, 1,02; IC à 95 %, P < 0,001), la pression arte le systolique du ventricule gauche 1,01-1,04; P < 0,001) et le volume te (RIA, 1,02; IC à 95 %, 1,00-1,03; P ¼ 0,013) demeuraient des dicteurs inde pendants du QRSf. pre tude a re ve le que le QRSf e tait associe à une Conclusions : Cette e augmentation de la TI, à des anomalies de la perfusion myocardique, à jection ventriculaire gauche et à une une diminution de la fraction d’e sultats monaugmentation des volumes du « cœur gauche ». Ces re trent que le QRS est un marqueur fiable de la taille de l’infarctus et du remodelage ventriculaire à la phase aiguë.
patients with stable CAD.1 In patients with AMI, fQRS on the electrocardiogram during the acute phase (first 48 hours) or later (2 months) is a significant predictor of long-term mortality.2,3 However, the exact mechanisms of fQRS are still unknown. The widely accepted hypotheses are conduction abnormalities or peri-infarction conduction block due to myocardial necrosis or scarring,4,5 and Das et al. showed that the presence of fQRS was associated with significantly greater perfusion and function abnormalities assessed using cardiac single photon emission computed tomography compared with the presence of a Q wave in the 12-lead ECG.1 It is therefore important to improve our understanding of the pathophysiological correlates of fQRS. Cardiac magnetic resonance (CMR) with a gadoliniumbased contrast agent can allow the assessment of the extent of myocardial damage after infarction, and areas of hyperenhancement on late gadolinium-enhanced (LGE) images reflect infarct size.6 Moreover, regions of persistent hypoenhancement in the core of infarcted myocardium have been shown to reflect microvascular obstruction (MO).7 LGE images are used to measure the peri-infarct border zone, which is associated with cardiovascular events after infarction, in particular ventricular arrhythmia.8-10 We hypothesized that CMR assessment of myocardial damage due to ischemia or necrosis in patients with AMI would significantly improve our understanding of QRS fragmentation.
Electrocardiographic analysis
Methods Patients Data for the participants in this study were prospectively extracted from the observatoiRe des Infarctus de Côte-d’Or (RICO) database. RICO is a French regional survey of AMI.11 In this study, 223 patients admitted between January 1, 2005 and June 30, 2009 with a first AMI (ST segment elevation myocardial infarction [STEMI] or non-STEMI) within 12 hours after symptom onset were eligible. The diagnosis of AMI included symptoms of ischemia and at least 1 of the following: electrocardiogram changes in at least 2 contiguous leads consistent with acute coronary syndrome, and/or serial increases in serum biochemical markers of cardiac necrosis (eg, positive troponin > upper limit of the hospital’s reference range, creatine kinase (CK)-MB or CK > 2 times the upper limit of the hospital’s reference range). Data collection See Supplemental Appendix S1.
The standard 12-lead electrocardiograms (model ECG1550K, Nihon Kohden Corporation, Tokyo, Japan; filter range, 0.15-150 Hz, 25 mm/s, 10 mm/mV) recorded on the day of the CMR exam were retrospectively analyzed by 2 independent readers (M.A., L.L.) blinded to the levels of cardiac biomarkers, the cardiac catheterization results, and clinical data. There was 97% agreement between the 2 readers in defining fQRS. Any disagreement was adjudicated by a third reviewer (Y.C.). The intraobserver variability was 96%. Electrocardiograms were compared with previous electrocardiograms if available to confirm that fQRS or pathological Q waves were of new onset. Unfortunately, a previous ECG was available for only 12 (5%) patients. Fragmented QRS was defined by the presence of various RSR’ patterns with or without a Q wave and included an additional R wave, notching of the R wave, notching of the downstroke or upstroke of the S wave, or the presence of > 1 additional R wave in 2 contiguous leads corresponding to a major coronary artery territory.1 The location of the fQRS was defined according to Das et al.1 We excluded 14 patients with complete or incomplete bundle branch block. ST segment and T-wave abnormalities and Q waves were defined according to standard definitions recommended by consensus documents of the Joint European Society of Cardiology/American College of Cardiology Committee and the universal definition of myocardial infarction (MI).12 Patients with fQRS on the 12-lead ECG recorded the day of the CMR exam were put into the fQRS group (n ¼ 113). Patients without fQRS were included in the no fQRS group (n ¼ 96). To determine the value of the fQRS compared with Q waves in the assessment of MI, we dichotomized our population according the presence or absence of Q waves: thus, 40 patients had Q waves and no fQRS and 45 patients had fQRS and no Q waves. CMR protocol See Supplemental Appendix S1. CMR data analysis See Supplemental Appendix S1. Statistical analysis Continuous data were expressed as medians (25th-75th percentile) and dichotomous data as numbers (percentages). The normal distribution of continuous data was tested with the Kolmogorov-Smirnov test. The categorical variables were
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Figure 1. A 12-lead electrocardiogram showing various RSR’ patterns in anterior leads in a patient admitted for ST elevation in the left anterior descending artery territory, 48 hours after revascularization using primary percutaneous coronary intervention.
analyzed using the c2 or Fisher test. Continuous variables were analyzed using the analysis of variance or Kruskal-Wallis test as appropriate. Logistic regression analysis was performed to test for predictors of fQRS. All covariates listed in Table 1 with a univariate P value 0.15 were eligible for inclusion in the multivariate regression models. The data expression (log-transformed or not) with the best fit of linearity was introduced into the model. The variables included in the multivariate models were male sex, anterior wall location, the presence of a Q wave, stenting of the culprit lesion, and infarct size (IS) and systolic blood pressure as continuous variables. All the tests were 2-sided and a P value less than 0.01 was considered significant. All analyses were performed using SPSS 13.0 (SPSS Inc, IBM). Results
demographic and clinical presentations. Demographic characteristics, except the sex ratio, risk factors, and chronic medications before MI (aspirin, b-blockers) were similar in the 2 groups. Two-thirds of the patients in both groups were diagnosed with STEMI. The median ischemic time and anterior wall location were the same in both groups. Systolic and diastolic blood pressure were higher in the fQRS group (145 vs 130 mm Hg, P ¼ 0.001 and 83 vs 80 mm Hg, P ¼ 0.019, respectively), but the clinical presentation was similar for the 2 groups, especially acute heart failure defined by an admission Killip class > 1. Finally, the reperfusion strategies (lysis or percutaneous coronary intervention), the final Thrombolysis in Myocardial Infarction (TIMI) 3 flow in the culprit artery, and the drugs used during the acute phase were also similar in the 2 groups. No difference was found between the groups for adverse outcomes at 1 year (Table 1).
Clinical and angiographic data
Fragmentation, IS, and peri-infarct zone
Among the 209 consecutive patients included in the study, 96 (46%) did not have fQRS on the 12-lead ECG (no fQRS group), whereas 113 (54%) did (fQRS group). Baseline demographic and clinical characteristics, and CMR data categorized according to the presence or absence of fQRS are shown in Table 1. Patients from both groups had similar
As expected, the fragmentation was mostly found in the inferior territory and did not correlate with the location of the infarct on CMR. Regarding the other electrocardiographic signs, the incidence of a Q wave was significantly greater in the fQRS group than in the no fQRS group (62% vs 43%, P ¼ 0.005). QRS fragmentation was associated with greater
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Table 1. Characteristics of the 2 study groups (n ¼ 209) Characteristic
No fQRS (n ¼ 96)
Age, years 55 (48-69) Male sex 73 (76) Hypertension 39 (41) Diabetes 13 (14) Hypercholesterolemia 40 (42) Smoker 35 (37) BMI 27 (24-29) Clinical characteristics Anterior wall location 36 (38) STEMI 71 (74) Killip Class > 1 11 (11) Ischemic time, minutes 202 (140-535) Heart rate, bpm 72 (62-85) SBP, mm Hg 130 (118-155) DBP, mm Hg 80 (70-90) Previous medications Aspirin 13 (14) b-Blocker 16 (17) ACE inhibitor 10 (10) Statin 14 (15) ECG data Anterior fQRS * Inferior fQRS * Lateral fQRS * Q wave 40 (43) T wave inversion 23 (27) Acute treatments (< 48 hours) Aspirin 95 (99) Clopidogrel 82 (85) b-Blocker 78 (81) Statin 61 (64) Lysis 27 (28) PCI 74 (77) Final TIMI 3 flow 84 (88) Biological data Log Peak CK, IU/L 3.1 (2.9-3.5) Creatinine clearance, mL/min 90 (67-113) CRP, mg/L 4.2 (2.2-11.8) NT-proBNP, pg/mL 709 (169-1755) 1 year MACE CV deaths 4 (4) Recurrent MI 10 (10) Episode of heart failure 13 (13) Ventricular arrhythmia 9 (9)
fQRS (n ¼ 113) 57 98 45 14 48 46 27
Fragmentation, MO, and transmurality P
(49-66) (87) (40) (12) (43) (41) (25-30)
0.891 0.046 0.906 0.805 0.862 0.530 0.340
(48) (81) (12) (150-622) (65-88) (130-162) (76-99)
0.134 0.195 0.836 0.457 0.562 0.001 0.019
13 19 10 14
(12) (17) (9) (12)
0.657 0.977 0.701 0.643
63 68 17 68 27
(56) (60) (15) (62-44) (25)
* * * 0.005 0.905
111 97 98 76 41 97 98
(98) (86) (87) (67) (36) (86) (87)
0.659 0.931 0.279 0.573 0.210 0.102 0.868
3.5 94 3.8 695
(2.9-3.7) (73-114) (2.0-12.5) (170-1513)
0.012 0.450 0.380 0.940
(7) (16) (16) (12)
0.239 0.154 0.576 0.216
54 92 14 225 77 145 83
8 18 18 14
Data are presented as n (%) or median (25th-75th). ACE, angiotensin converting enzyme; BMI, body mass index; bpm, beats per minute; CRP, C-reactive protein; CV, cardiovascular; DBP, diastolic blood pressure; ECG, electrocardiographic; fQRS, fragmented QRS complex; MACE, major adverse cardiac events; MI, myocardial infarction; NTproBNP, NT-terminal pro B-type natriuretic peptide; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; STEMI, ST segment elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction; * No data available.
infarct size (shown by the higher median log peak CK [3.5 IU/L (2.9-3.7) vs 3.1 IU/L (2.9-3.5); P ¼ 0.012]) (Table 1) and the CMR data: IS (25.7% [15.3-34.8] in the fQRS group vs 16.6% [9.3-25.1]; P < 0.001), and a larger peri-infarct zone (8% [5-11.3] vs 7% [4-9]; P ¼ 0.031) (Table 2). Even when present alone (ie, without Q wave), fQRS was associated with worse left ventricular remodelling indexes after AMI, reflected by the greater end-diastolic/end-systolic volumes and a significantly lower left ventricular ejection fraction (LVEF) (48% [39-57] in the fQRS group vs 55% [44-60]; P ¼ 0.014).
MO on the LGE images was more frequent (62% vs 45%; P ¼ 0.014), and the extent of the MO was significantly greater (1.6% [0.0-4.4] vs 0.0% [0.0-2.1]; P ¼ 0.004) in patients with fQRS. The subgroup analysis found a linear progression of the incidence of the MO, with only 28% in patients with neither Q waves nor fQRS, 51% in the group of patients with isolated fQRS, and 70% in patients with Q waves (with or without fQRS). Interestingly, although the extent of MO was significantly less in patients with isolated fQRS than in those with Q waves, the infarct size was similar in the 2 groups. Finally, the transmurality index assessed according to the number of segments with transmural scarring 1 was identical in both groups (Table 2). In multivariate logistic regression analysis (Table 3), only IS (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.03-1.09; P < 0.001), systolic blood pressure (OR, 1.02; 95% CI, 1.01-1.04; P < 0.001), and left ventricular end-systolic volume (OR, 1.02; 95% CI, 1.00-1.03; P ¼ 0.013) remained independent predictors of fQRS.
Discussion QRS fragmentation appears to be a dynamic process, associated with myocardial scarring,1 and the determinants of this phenomenon in a “real-life” population are unknown. The hypothesis that depolarization abnormalities would predict ventricular arrhythmia and sudden death has never been demonstrated with strong clinical evidence.13,14 We recently highlighted, however, that fQRS patients had an increased risk of death, of hospitalization for nonfatal recurrent MI, and of heart failure.15 With 54% of patients presenting fragmented QRS, our study confirmed that fQRS is frequent in patients with AMI. Our data further highlighted the finding that fQRS is mostly located in the inferior territory, which is in keeping with a previous study.2 The significant relationship between systolic blood pressure and fQRS found in our study is surprising, but convincing data in the literature demonstrated that a reduction in blood pressure in hypertensive or normotensive patients or animals significantly limits infarct size and myocardial ischemia reperfusion injury.16 Our results showed a relationship between fQRS and regional fixed perfusion defects that probably result from acute structural alterations within and outside of the area of infarction. Infarct size and left ventricular end-systolic volume were independent predictors of QRS fragmentation in our population, whereas transmurality and peri-infarct size indexes were not. Previous magnetic resonance imaging (MRI) studies have shown that myocardial scarring after AMI was related to the extent of endocardial and transmural necrosis. The extent of necrosis in the endocardium is characterized by the flatness of late enhancement in the vascular bed of the culprit coronary artery.17 The transmurality of the infarction, defined by the extension of necrosis from the endocardium to the epicardium, is mainly related to ischemic time.18 Our MRI data were consistent with biological data, because peak CK in the first 48 hours (usually used to assess the infarcted mass)19 was greater in the group with fQRS. Moreover, in these patients, left ventricular volumes and LVEF modifications were consistent with the peak CK. There are few data about the
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Table 2. CMR data in the 2 study groups (n ¼ 209) No fQRS (n ¼ 96) Variable
No Q wave (n ¼ 56)
Overall
LVEF, % EDV index, mL ESV index, mL Presence of MO Extent of MO, % IS, % Segments with transmural scar 1 Peri-infarct zone, %
55 135 61 44 0.0 16.6 45 7
fQRS (n ¼ 113)
(44-60) (113-169) (50-83) (45) (0.0-2.1) (9.3-25.1) (47) (4-9)
50 135 68 16 0.0 13.2 29 5
Q wave (n ¼ 40)
(41-56) (108-169) (52-95) (28) (0.0-0.85) (7.5-19.9) (52) (4-9)
56 127 57 28 1.5 21.4 16 8
(50-62)* (116-170)* (49-75)* (70)* (0.0-3.4)* (15.5-27.9) (40) (5-10)
Overall 48 157 78 71 1.6 25.7 54 8
(39-57) (133-191) (60-105) (62) (0.0-4.4) (15.3-34.8) (48) (5-11.3)
No Q wave (n ¼ 45) 52 153 69 23 0.6 21.9 20 7
(42-59) (127-191) (57-95) (51) (0.0-3.9) (11.2-31.5) (44) (4-11)
Q wave (n ¼ 68) 45 161 88 48 1.9 29.8 34 8
(39-54) (138-190) (72-108) (70) (0.0-4.4) (19.9-35.2) (50) (6-11.5)
P 0.014 <0.001 0.014 0.014 0.004 <0.001 0.895 0.031
Data are presented as n (%) or median (25th-75th). EDV, end-diastolic volume; ESV, end-systolic volume; IS, infarct size; LVEF, left ventricular ejection fraction; MO, microvascular obstruction. * Significant P value between patients with Q waves and no fQRS and patients with fQRS and no Q waves.
relationship between fragmentation and infarct extent. Carey et al.20 studied 138 patients with stable CAD using positron emission tomography with 13N-ammonia and found no relationship between infarct volume and QRS fragmentation. Our study failed to show any significant relationship between transmurality and the occurrence of fQRS. This result is consistent with other studies on Q waves. In a prospective MRI study, Engblom et al. dichotomized 29 patients with reperfused first-time MI according to the presence/absence of Q waves. They assessed infarct size, transmurality, and endocardial extent of MI using gadolinium enhancement MRI. Q waves and electrocardiographic MI size were estimated using QRS scoring of the ECG. They found a significant difference between patients with and without Q waves for MI size (P ¼ 0.03) and the endocardial extent of MI (P ¼ 0.01), but not for mean and maximum MI transmurality (P ¼ 0.09 and P ¼ 0.14). The extent of endocardial infarction was the only independent predictor of pathological Q waves. Of the MI variables tested, the extent of endocardial infarction correlated most strongly with the QRS score (r ¼ 0.86; P < 0.001).21 Our data therefore confirm previous work showing that the extent of infarction, but not transmurality, is a predictor of the presence of a Q wave.22 One can therefore hypothesize that QRS fragmentation is a marker of myocardial scarring and left ventricular remodelling after AMI. An alternative interpretation of our findings is that residual viable myocardium remains within the reperfused infarct zone and that the surviving myocytes are responsible for the fQRS phenomenon. The literature on the topic is inconsistent. Most reports suggest that enhanced zones on LGE sequences are Table 3. Predictors of fQRS in uni- and multivariate logistic regression analysis (n ¼ 209) Univariate analysis Variable
OR
IS, % Peri-infarct zone, % SBP, mm Hg Male sex Presence of Q wave EDV index, mL ESV index, mL LVEF, %
1.05 1.08 1.02 2.06 2.24 1.02 1.02 0.97
95% CI
P
Multivariate analysis OR
95% CI
P
1.03-1.08 < 0.001 1.06 1.03-1.09 < 0.001 1.01-1.16 0.025 d d d 1.01-1.03 0.001 1.02 1.01-1.04 < 0.001 1.00-4.22 0.049 d d d 1.28-3.93 0.005 d d d 1.00-1.02 < 0.001 d d d 1.00-1.03 < 0.001 1.02 1.00-1.03 0.013 0.95-0.99 0.015 d d d
EDV, end-diastolic volume; ESV, end-systolic volume; IS, infarct size; LVEF, left ventricular ejection fraction; SBP, systolic blood pressure.
entirely nonviable.19 However, enhancement on LGE CMR can overestimate infarct size, and viable, edematous border zones can show enhancement.23 Histological data suggested that preserved islands of viable myocytes exist within the infarct zone.24,25 These structural differences might lead to differential transmission of epicardial contraction and conduction into the infarct zone depending on the presence of MO. In a recent study, Kidambi et al.26 performed serial (2, 7, 30, and 90 days) CMR with LGE and T2 sequences in 39 AMI patients treated using primary percutaneous coronary intervention. Patients without MO showed recovery of strain in the endocardial, midmyocardial, and epicardial infarct borders, but in patients with MO (with or without intramyocardial hemorrhage [IMH]), there was no significant recovery in endocardial and midmyocardial areas. Furthermore, endocardial and midmyocardial contractile function in the 2 groups was significantly different at day 7, and there was no difference for the epicardial border until day 30. This is in keeping with the wavefront theory of infarction which states that MO and IMH principally develop in the endocardium and midmyocardium, and the epicardium is relatively spared from ischemia and infarction before reperfusion. Recent experimental work has provided new insights into this complex interplay. Using an in vivo porcine model of reperfused STEMI, Robbers et al.27 demonstrated: (1) that the infarct core on histology, the area of IMH on T2-weighted images, and the area of MO on LGE showed close correlations for size and location; and (2) the important role of hemorrhage in the development of myocardial reperfusion injury. Although we were unable to provide data on IMH, fQRS was associated with a greater infarct size and a larger peri-infarct zone. Even when present alone (ie, without Q wave), fQRS was associated with worse left ventricular remodelling indexes after AMI. The subgroup analysis showed that fQRS, in the presence or absence of Q waves, could be used to quickly identify patients with an increased risk of death. Further studies are needed to test the potential effect of fQRS to guide inpatient therapy to limit acute left ventricular remodelling, for example, by the early prescription of mineralocorticoid receptor antagonist receptors. Study limitations To analyze QRS fragmentation, we included only patients without previous MI. Because previous studies have clearly
Lorgis et al. Fragmented QRS in MI: An MRI Study
shown that infarct size varies according to the time between the acute event and the CMR exam,17 all of the patients were evaluated using MRI in a timely fashion (mean 6 3 days). Nonetheless, in our patients, infarct size might have varied depending on the time between the acute event and the MRI. Conclusion Our study showed that the systematic assessment of QRS fragmentation on a 12-lead electrocardiogram in patients with AMI is a simple, widely available, and inexpensive tool. fQRS is a useful parameter, but reflects infarct size and the left ventricular volume, rather than the transmural extent of the infarct. Acknowledgements The authors thank Edith Fusier, Anne Cecile Lagrost, and Juliane Berchoud for their research assistance, and Philip Bastable for editorial assistance. Funding Sources This work was supported by the University Hospital of Dijon, the Association de Cardiologie de Bourgogne, and by grants from the Union Régionale des Caisses d'Assurance Maladie de Bourgogne (URCAM), the Agence Regionale de Santé (ARS) de Bourgogne, the Conseil Régional de Bourgogne and the Fédération Française de Cardiologie (FFC). Disclosures The authors have no conflicts of interest to disclose. References 1. Das MK, Khan B, Jacob S, Kumar A, Mahenthiran J. Significance of a fragmented QRS complex vs a Q wave in patients with coronary artery disease. Circulation 2006;113:2495-501. 2. Das MK, Michael MA, Suradi H, et al. Usefulness of fragmented QRS on a 12-lead electrocardiogram in acute coronary syndrome for predicting mortality. Am J Cardiol 2009;104:1631-7. 3. Pietrasik G, Goldenberg I, Zdzienicka J, Moss AJ, Zareba W. Prognostic significance of fragmented QRS complex for predicting the risk of recurrent cardiac events in patients with Q-wave myocardial infarction. Am J Cardiol 2007;100:583-6. 4. Castle CH, Keane WM. Electrocardiographic “peri-infarction block.” A clinical and pathological correlation. Circulation 1965;31:403-8. 5. Shadaksharappa KS, Kalbfleisch JM, Conrad LL, Sarkar NK. Recognition and significance of intraventricular block due to myocardial infarction (peri-infarction block). Circulation 1968;37:20-6. 6. Fieno DS, Kim RJ, Chen EL, et al. Contrast-enhanced magnetic resonance imaging of myocardium at risk: distinction between reversible and irreversible injury throughout infarct healing. J Am Coll Cardiol 2000;36: 1985-91. 7. Lima JA, Judd RM, Bazille A, et al. Regional heterogeneity of human myocardial infarcts demonstrated by contrast-enhanced MRI. Potential mechanisms. Circulation 1995;92:1117-25.
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8. Roes SD, Borleffs CJ, van der Geest RJ, et al. Infarct tissue heterogeneity assessed with contrast-enhanced MRI predicts spontaneous ventricular arrhythmia in patients with ischemic cardiomyopathy and implantable cardioverter-defibrillator. Circ Cardiovasc Imaging 2009;2: 183-90. 9. Heidary S, Patel H, Chung J, et al. Quantitative tissue characterization of infarct core and border zone in patients with ischemic cardiomyopathy by magnetic resonance is associated with future cardiovascular events. J Am Coll Cardiol 2010;55:2762-8. 10. Dowsley T, Al-Mallah M, Ananthasubramaniam K, et al. The role of noninvasive imaging in coronary artery disease detection, prognosis, and clinical decision making. Can J Cardiol 2013;29:285-96. 11. Lorgis L, Zeller M, Dentan G, et al. Prognostic value of N-terminal probrain natriuretic peptide in elderly people with acute myocardial infarction: prospective observational study. BMJ 2009;338:b1605. 12. Thygesen K, Alpert JS, White HD. Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Circulation 2007;116:2634-53. 13. Das MK, Saha C, El Masry H, et al. Fragmented QRS on a 12-lead ECG: a predictor of mortality and cardiac events in patients with coronary artery disease. Heart Rhythm 2007;4:1385-92. 14. Goldberger JJ, Greenstein E. Fragmented QRS for risk prediction: picking up the pieces. Heart Rhythm 2007;4:1393-4. 15. Lorgis L, Jourda F, Hachet O, et al. Prognostic value of fragmented QRS on a 12-lead ECG in patients with acute myocardial infarction. Heart Lung 2013;42:326-31. 16. Yamazaki KG, Taub PR, Barraza-Hidalgo M, et al. Effects of ()epicatechin on myocardial infarct size and left ventricular remodeling after permanent coronary occlusion. J Am Coll Cardiol 2010;55:2869-76. 17. Lee JT, Ideker RE, Reimer KA. Myocardial infarct size and location in relation to the coronary vascular bed at risk in man. Circulation 1981;64:526-8. 18. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation 1977;56:786-8. 19. Jansen DE, Corbett JR, Wolfe CL, et al. Quantification of myocardial infarction: a comparison of single photon-emission computed tomography with pyrophosphate to serial plasma MB-creatine kinase measurements. Circulation 1985;72:327-33. 20. Carey MG, Luisi AJ, Baldwa S, et al. The Selvester QRS Score is more accurate than Q waves and fragmented QRS complexes using the MasonLikar configuration in estimating infarct volume in patients with ischemic cardiomyopathy. J Electrocardiol 2010;43:318-37. 21. Engblom H, Carlsson MB, Hedström E, et al. The endocardial extent of reperfused first-time myocardial infarction is more predictive of pathologic Q waves than is infarct transmurality: a magnetic resonance imaging study. Clin Physiol Funct Imaging 2007;27:101-7. 22. Moon JC, De Arenaza DP, Elkington AG, et al. The pathologic basis of Q-wave and non-Q-wave myocardial infarction: a cardiovascular magnetic resonance study. J Am Coll Cardiol 2004;44:554-6. 23. Arai AE. The cardiac magnetic resonance (CMR) approach to assessing myocardial viability. J Nucl Cardiol 2011;18:1095-102. 24. Dall’Armellina E, Karia N, Lindsay AC, et al. Dynamic changes of edema and late gadolinium enhancement after acute myocardial infarction and their relationship to functional recovery and salvage index. Circ Cardiovasc Imaging 2011;4:228-36.
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25. Factor SM, Sonnenblick EH, Kirk ES. The histologic border zone of acute myocardial infarctioneislands or peninsulas? Am J Pathol 1978;92:111-24. 26. Kidambi AJ, Mather AN, Motwani M, et al. The effect of microvascular obstruction and intramyocardial hemorrhage on contractile recovery in reperfused myocardial infarction: insights from cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2013;15:58. 27. Robbers LF, Eerenberg ES, Teunissen PF, et al. Magnetic resonance imaging-defined areas of microvascular obstruction after acute myocardial
Canadian Journal of Cardiology Volume 30 2014 infarction represent microvascular destruction and haemorrhage. Eur Heart J 2013;34:2346-53.
Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2013.11.026.
Clinical Research
Relationship Between Fragmented QRS and No-Reflow, Infarct Size, and Peri-Infarct Zone Assessed Using Cardiac Magnetic Resonance in Patients With Myocardial Infarction Luc Lorgis, MD, PhD,a,b Alexandre Cochet, MD, PhD,c Olivier Chevallier, MD,c Marion Angue, MD,a Aurelie Gudjoncik, MD,a,b Alain Lalande, PhD,c Marianne Zeller, PhD,b Philippe Buffet, MD,a François Brunotte, MD, PhD,c and Yves Cottin, MD, PhDa,b a b
Department of Cardiology, University Hospital, Dijon, France
Laboratory of Cardiometabolic Physiopathology and Pharmacology, INSERM U866, University of Burgundy, Dijon, France c
MRI Unit and LE2I UMR CNRS 6306, University Hospital, Dijon, France
ABSTRACT
RESUM E
Background: The relation between fragmented QRS complex (fQRS) and cardiac magnetic resonance parameters is poorly documented in ischemic cardiopathy. Methods: Among 209 consecutive patients, those with fQRS were compared with those without fQRS. Cardiac magnetic resonance studies with late gadolinium-enhanced sequences were done during the week after acute myocardial infarction. Results: fQRS was present in 113 (54%) patients, and associated with a significantly lower left ventricular ejection fraction, increased left ventricular volumes, a larger infarct size (IS), and a larger peri-infarct zone. Microvascular obstruction was more frequent in patients with fQRS (62% vs 45%; P ¼ 0.014) and the extent of the microvascular obstruction was significantly larger (1.6% [range, 0.0-4.4] vs 0.0 [range, 0.0-2.1]; P ¼ 0.004). Finally, the transmurality score in the 2 study populations was identical (48% vs 47%; P ¼ 0.895). In multivariate logistic regression analysis, only IS (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.03-1.09; P < 0.001), systolic blood pressure (OR, 1.02; 95% CI, 1.01-1.04; P < 0.001), and left ventricular endsystolic volume (OR, 1.02; 95% CI, 1.00-1.03; P ¼ 0.013) remained
(QRSf) et les Introduction : Le lien entre le complexe QRS fragmente sonance magne tique cardiaque est mal doparamètres de la re en matière de cardiopathie ische mique. cumente thodes : Parmi les 209 patients conse cutifs, ceux pre sentant un Me te compare s à ceux ne pre sentant pas un QRSf. Des e tudes QRSf ont e sonance magne tique cardiaque avec des se quences de de la re te re alise es rehaussement tardif après injection de gadolinium ont e durant la semaine après l’infarctus du myocarde aigu. sultats : Le QRSf e tait pre sent chez 113 (54 %) patients et associe Re jection ventriculaire gauche significativement plus à une fraction d’e faible, une augmentation du volume du ventricule gauche, une taille ri-infarctus plus grande. d’infarctus (TI) plus grande et une zone de pe tait plus fre quente chez les patients L’obstruction microvasculaire e sentant un QRSf (62 % vs 45 %; P ¼ 0,014), et l’e tendue de l’obpre tait significativement plus grande (1,6 % struction microvasculaire e tendue, 0,0-2,1]; P ¼ 0,004). Finalement, tendue, 0,0-4,4] vs 0,0 [e [e des 2 populations faisant l’objet de l’e tude le score de transmuralite tait identique (48 % vs 47 %; P ¼ 0,895). Dans l’analyse de e gression logistique multivarie e, seuls la TI (ratio d’incidence re
A twelve-lead electrocardiogram is an integral part of the evaluation of acute myocardial infarction (AMI). Fragmented QRS complexes (fQRSs), which include various RSR’ patterns without typical bundle-branch block on routine 12-lead electrocardiography (ECG), have recently been proposed as
a reliable and sensitive tool in this setting.1-4 fQRS is defined by the presence of an additional R wave or notching in the nadir of the S wave, or the presence of > 1 additional R wave (fragmentation) in 2 contiguous leads corresponding to a major coronary artery territory (Fig. 1).1 The fragmentation of QRS on the 12-lead surface electrocardiogram is a dynamic process, described in a number of cardiac diseases including ventricular aneurysm, idiopathic dilated cardiomyopathy, myocardial fibrosis, sarcoidosis, Brugada syndrome, arrhythmogenic right ventricular dysplasia, and myocarditis.5 Das et al. demonstrated that significant fragmentation of the QRS in coronary artery disease (CAD) was more sensitive and more specific than Q waves in detecting myocardial scarring in
Received for publication November 7, 2012. Accepted November 20, 2013. Corresponding author: Dr Luc Lorgis, Service de Cardiologie, CHU Dijon, Bd de Lattre de Tassigny, 21034 Dijon Cedex, France. Tel.: þ33 380293311; fax: þ33 380293333. E-mail: [email protected] See page 209 for disclosure information.
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.11.026
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independent predictors of fQRS. Conclusions: This study revealed that fQRS was associated with increased IS, myocardial perfusion abnormalities, decreased left ventricular ejection fraction, and increased left heart volumes. These findings show that fQRS is a reliable marker of infarct size and acute ventricular remodelling.
[RIA], 1,06; intervalle de confiance [IC] à 95 %, 1,03-1,09; approche rielle systolique (RIA, 1,02; IC à 95 %, P < 0,001), la pression arte le systolique du ventricule gauche 1,01-1,04; P < 0,001) et le volume te (RIA, 1,02; IC à 95 %, 1,00-1,03; P ¼ 0,013) demeuraient des dicteurs inde pendants du QRSf. pre tude a re ve le que le QRSf e tait associe à une Conclusions : Cette e augmentation de la TI, à des anomalies de la perfusion myocardique, à jection ventriculaire gauche et à une une diminution de la fraction d’e sultats monaugmentation des volumes du « cœur gauche ». Ces re trent que le QRS est un marqueur fiable de la taille de l’infarctus et du remodelage ventriculaire à la phase aiguë.
patients with stable CAD.1 In patients with AMI, fQRS on the electrocardiogram during the acute phase (first 48 hours) or later (2 months) is a significant predictor of long-term mortality.2,3 However, the exact mechanisms of fQRS are still unknown. The widely accepted hypotheses are conduction abnormalities or peri-infarction conduction block due to myocardial necrosis or scarring,4,5 and Das et al. showed that the presence of fQRS was associated with significantly greater perfusion and function abnormalities assessed using cardiac single photon emission computed tomography compared with the presence of a Q wave in the 12-lead ECG.1 It is therefore important to improve our understanding of the pathophysiological correlates of fQRS. Cardiac magnetic resonance (CMR) with a gadoliniumbased contrast agent can allow the assessment of the extent of myocardial damage after infarction, and areas of hyperenhancement on late gadolinium-enhanced (LGE) images reflect infarct size.6 Moreover, regions of persistent hypoenhancement in the core of infarcted myocardium have been shown to reflect microvascular obstruction (MO).7 LGE images are used to measure the peri-infarct border zone, which is associated with cardiovascular events after infarction, in particular ventricular arrhythmia.8-10 We hypothesized that CMR assessment of myocardial damage due to ischemia or necrosis in patients with AMI would significantly improve our understanding of QRS fragmentation.
Electrocardiographic analysis
Methods Patients Data for the participants in this study were prospectively extracted from the observatoiRe des Infarctus de Côte-d’Or (RICO) database. RICO is a French regional survey of AMI.11 In this study, 223 patients admitted between January 1, 2005 and June 30, 2009 with a first AMI (ST segment elevation myocardial infarction [STEMI] or non-STEMI) within 12 hours after symptom onset were eligible. The diagnosis of AMI included symptoms of ischemia and at least 1 of the following: electrocardiogram changes in at least 2 contiguous leads consistent with acute coronary syndrome, and/or serial increases in serum biochemical markers of cardiac necrosis (eg, positive troponin > upper limit of the hospital’s reference range, creatine kinase (CK)-MB or CK > 2 times the upper limit of the hospital’s reference range). Data collection See Supplemental Appendix S1.
The standard 12-lead electrocardiograms (model ECG1550K, Nihon Kohden Corporation, Tokyo, Japan; filter range, 0.15-150 Hz, 25 mm/s, 10 mm/mV) recorded on the day of the CMR exam were retrospectively analyzed by 2 independent readers (M.A., L.L.) blinded to the levels of cardiac biomarkers, the cardiac catheterization results, and clinical data. There was 97% agreement between the 2 readers in defining fQRS. Any disagreement was adjudicated by a third reviewer (Y.C.). The intraobserver variability was 96%. Electrocardiograms were compared with previous electrocardiograms if available to confirm that fQRS or pathological Q waves were of new onset. Unfortunately, a previous ECG was available for only 12 (5%) patients. Fragmented QRS was defined by the presence of various RSR’ patterns with or without a Q wave and included an additional R wave, notching of the R wave, notching of the downstroke or upstroke of the S wave, or the presence of > 1 additional R wave in 2 contiguous leads corresponding to a major coronary artery territory.1 The location of the fQRS was defined according to Das et al.1 We excluded 14 patients with complete or incomplete bundle branch block. ST segment and T-wave abnormalities and Q waves were defined according to standard definitions recommended by consensus documents of the Joint European Society of Cardiology/American College of Cardiology Committee and the universal definition of myocardial infarction (MI).12 Patients with fQRS on the 12-lead ECG recorded the day of the CMR exam were put into the fQRS group (n ¼ 113). Patients without fQRS were included in the no fQRS group (n ¼ 96). To determine the value of the fQRS compared with Q waves in the assessment of MI, we dichotomized our population according the presence or absence of Q waves: thus, 40 patients had Q waves and no fQRS and 45 patients had fQRS and no Q waves. CMR protocol See Supplemental Appendix S1. CMR data analysis See Supplemental Appendix S1. Statistical analysis Continuous data were expressed as medians (25th-75th percentile) and dichotomous data as numbers (percentages). The normal distribution of continuous data was tested with the Kolmogorov-Smirnov test. The categorical variables were
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Figure 1. A 12-lead electrocardiogram showing various RSR’ patterns in anterior leads in a patient admitted for ST elevation in the left anterior descending artery territory, 48 hours after revascularization using primary percutaneous coronary intervention.
analyzed using the c2 or Fisher test. Continuous variables were analyzed using the analysis of variance or Kruskal-Wallis test as appropriate. Logistic regression analysis was performed to test for predictors of fQRS. All covariates listed in Table 1 with a univariate P value 0.15 were eligible for inclusion in the multivariate regression models. The data expression (log-transformed or not) with the best fit of linearity was introduced into the model. The variables included in the multivariate models were male sex, anterior wall location, the presence of a Q wave, stenting of the culprit lesion, and infarct size (IS) and systolic blood pressure as continuous variables. All the tests were 2-sided and a P value less than 0.01 was considered significant. All analyses were performed using SPSS 13.0 (SPSS Inc, IBM). Results
demographic and clinical presentations. Demographic characteristics, except the sex ratio, risk factors, and chronic medications before MI (aspirin, b-blockers) were similar in the 2 groups. Two-thirds of the patients in both groups were diagnosed with STEMI. The median ischemic time and anterior wall location were the same in both groups. Systolic and diastolic blood pressure were higher in the fQRS group (145 vs 130 mm Hg, P ¼ 0.001 and 83 vs 80 mm Hg, P ¼ 0.019, respectively), but the clinical presentation was similar for the 2 groups, especially acute heart failure defined by an admission Killip class > 1. Finally, the reperfusion strategies (lysis or percutaneous coronary intervention), the final Thrombolysis in Myocardial Infarction (TIMI) 3 flow in the culprit artery, and the drugs used during the acute phase were also similar in the 2 groups. No difference was found between the groups for adverse outcomes at 1 year (Table 1).
Clinical and angiographic data
Fragmentation, IS, and peri-infarct zone
Among the 209 consecutive patients included in the study, 96 (46%) did not have fQRS on the 12-lead ECG (no fQRS group), whereas 113 (54%) did (fQRS group). Baseline demographic and clinical characteristics, and CMR data categorized according to the presence or absence of fQRS are shown in Table 1. Patients from both groups had similar
As expected, the fragmentation was mostly found in the inferior territory and did not correlate with the location of the infarct on CMR. Regarding the other electrocardiographic signs, the incidence of a Q wave was significantly greater in the fQRS group than in the no fQRS group (62% vs 43%, P ¼ 0.005). QRS fragmentation was associated with greater
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Table 1. Characteristics of the 2 study groups (n ¼ 209) Characteristic
No fQRS (n ¼ 96)
Age, years 55 (48-69) Male sex 73 (76) Hypertension 39 (41) Diabetes 13 (14) Hypercholesterolemia 40 (42) Smoker 35 (37) BMI 27 (24-29) Clinical characteristics Anterior wall location 36 (38) STEMI 71 (74) Killip Class > 1 11 (11) Ischemic time, minutes 202 (140-535) Heart rate, bpm 72 (62-85) SBP, mm Hg 130 (118-155) DBP, mm Hg 80 (70-90) Previous medications Aspirin 13 (14) b-Blocker 16 (17) ACE inhibitor 10 (10) Statin 14 (15) ECG data Anterior fQRS * Inferior fQRS * Lateral fQRS * Q wave 40 (43) T wave inversion 23 (27) Acute treatments (< 48 hours) Aspirin 95 (99) Clopidogrel 82 (85) b-Blocker 78 (81) Statin 61 (64) Lysis 27 (28) PCI 74 (77) Final TIMI 3 flow 84 (88) Biological data Log Peak CK, IU/L 3.1 (2.9-3.5) Creatinine clearance, mL/min 90 (67-113) CRP, mg/L 4.2 (2.2-11.8) NT-proBNP, pg/mL 709 (169-1755) 1 year MACE CV deaths 4 (4) Recurrent MI 10 (10) Episode of heart failure 13 (13) Ventricular arrhythmia 9 (9)
fQRS (n ¼ 113) 57 98 45 14 48 46 27
Fragmentation, MO, and transmurality P
(49-66) (87) (40) (12) (43) (41) (25-30)
0.891 0.046 0.906 0.805 0.862 0.530 0.340
(48) (81) (12) (150-622) (65-88) (130-162) (76-99)
0.134 0.195 0.836 0.457 0.562 0.001 0.019
13 19 10 14
(12) (17) (9) (12)
0.657 0.977 0.701 0.643
63 68 17 68 27
(56) (60) (15) (62-44) (25)
* * * 0.005 0.905
111 97 98 76 41 97 98
(98) (86) (87) (67) (36) (86) (87)
0.659 0.931 0.279 0.573 0.210 0.102 0.868
3.5 94 3.8 695
(2.9-3.7) (73-114) (2.0-12.5) (170-1513)
0.012 0.450 0.380 0.940
(7) (16) (16) (12)
0.239 0.154 0.576 0.216
54 92 14 225 77 145 83
8 18 18 14
Data are presented as n (%) or median (25th-75th). ACE, angiotensin converting enzyme; BMI, body mass index; bpm, beats per minute; CRP, C-reactive protein; CV, cardiovascular; DBP, diastolic blood pressure; ECG, electrocardiographic; fQRS, fragmented QRS complex; MACE, major adverse cardiac events; MI, myocardial infarction; NTproBNP, NT-terminal pro B-type natriuretic peptide; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; STEMI, ST segment elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction; * No data available.
infarct size (shown by the higher median log peak CK [3.5 IU/L (2.9-3.7) vs 3.1 IU/L (2.9-3.5); P ¼ 0.012]) (Table 1) and the CMR data: IS (25.7% [15.3-34.8] in the fQRS group vs 16.6% [9.3-25.1]; P < 0.001), and a larger peri-infarct zone (8% [5-11.3] vs 7% [4-9]; P ¼ 0.031) (Table 2). Even when present alone (ie, without Q wave), fQRS was associated with worse left ventricular remodelling indexes after AMI, reflected by the greater end-diastolic/end-systolic volumes and a significantly lower left ventricular ejection fraction (LVEF) (48% [39-57] in the fQRS group vs 55% [44-60]; P ¼ 0.014).
MO on the LGE images was more frequent (62% vs 45%; P ¼ 0.014), and the extent of the MO was significantly greater (1.6% [0.0-4.4] vs 0.0% [0.0-2.1]; P ¼ 0.004) in patients with fQRS. The subgroup analysis found a linear progression of the incidence of the MO, with only 28% in patients with neither Q waves nor fQRS, 51% in the group of patients with isolated fQRS, and 70% in patients with Q waves (with or without fQRS). Interestingly, although the extent of MO was significantly less in patients with isolated fQRS than in those with Q waves, the infarct size was similar in the 2 groups. Finally, the transmurality index assessed according to the number of segments with transmural scarring 1 was identical in both groups (Table 2). In multivariate logistic regression analysis (Table 3), only IS (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.03-1.09; P < 0.001), systolic blood pressure (OR, 1.02; 95% CI, 1.01-1.04; P < 0.001), and left ventricular end-systolic volume (OR, 1.02; 95% CI, 1.00-1.03; P ¼ 0.013) remained independent predictors of fQRS.
Discussion QRS fragmentation appears to be a dynamic process, associated with myocardial scarring,1 and the determinants of this phenomenon in a “real-life” population are unknown. The hypothesis that depolarization abnormalities would predict ventricular arrhythmia and sudden death has never been demonstrated with strong clinical evidence.13,14 We recently highlighted, however, that fQRS patients had an increased risk of death, of hospitalization for nonfatal recurrent MI, and of heart failure.15 With 54% of patients presenting fragmented QRS, our study confirmed that fQRS is frequent in patients with AMI. Our data further highlighted the finding that fQRS is mostly located in the inferior territory, which is in keeping with a previous study.2 The significant relationship between systolic blood pressure and fQRS found in our study is surprising, but convincing data in the literature demonstrated that a reduction in blood pressure in hypertensive or normotensive patients or animals significantly limits infarct size and myocardial ischemia reperfusion injury.16 Our results showed a relationship between fQRS and regional fixed perfusion defects that probably result from acute structural alterations within and outside of the area of infarction. Infarct size and left ventricular end-systolic volume were independent predictors of QRS fragmentation in our population, whereas transmurality and peri-infarct size indexes were not. Previous magnetic resonance imaging (MRI) studies have shown that myocardial scarring after AMI was related to the extent of endocardial and transmural necrosis. The extent of necrosis in the endocardium is characterized by the flatness of late enhancement in the vascular bed of the culprit coronary artery.17 The transmurality of the infarction, defined by the extension of necrosis from the endocardium to the epicardium, is mainly related to ischemic time.18 Our MRI data were consistent with biological data, because peak CK in the first 48 hours (usually used to assess the infarcted mass)19 was greater in the group with fQRS. Moreover, in these patients, left ventricular volumes and LVEF modifications were consistent with the peak CK. There are few data about the
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Table 2. CMR data in the 2 study groups (n ¼ 209) No fQRS (n ¼ 96) Variable
No Q wave (n ¼ 56)
Overall
LVEF, % EDV index, mL ESV index, mL Presence of MO Extent of MO, % IS, % Segments with transmural scar 1 Peri-infarct zone, %
55 135 61 44 0.0 16.6 45 7
fQRS (n ¼ 113)
(44-60) (113-169) (50-83) (45) (0.0-2.1) (9.3-25.1) (47) (4-9)
50 135 68 16 0.0 13.2 29 5
Q wave (n ¼ 40)
(41-56) (108-169) (52-95) (28) (0.0-0.85) (7.5-19.9) (52) (4-9)
56 127 57 28 1.5 21.4 16 8
(50-62)* (116-170)* (49-75)* (70)* (0.0-3.4)* (15.5-27.9) (40) (5-10)
Overall 48 157 78 71 1.6 25.7 54 8
(39-57) (133-191) (60-105) (62) (0.0-4.4) (15.3-34.8) (48) (5-11.3)
No Q wave (n ¼ 45) 52 153 69 23 0.6 21.9 20 7
(42-59) (127-191) (57-95) (51) (0.0-3.9) (11.2-31.5) (44) (4-11)
Q wave (n ¼ 68) 45 161 88 48 1.9 29.8 34 8
(39-54) (138-190) (72-108) (70) (0.0-4.4) (19.9-35.2) (50) (6-11.5)
P 0.014 <0.001 0.014 0.014 0.004 <0.001 0.895 0.031
Data are presented as n (%) or median (25th-75th). EDV, end-diastolic volume; ESV, end-systolic volume; IS, infarct size; LVEF, left ventricular ejection fraction; MO, microvascular obstruction. * Significant P value between patients with Q waves and no fQRS and patients with fQRS and no Q waves.
relationship between fragmentation and infarct extent. Carey et al.20 studied 138 patients with stable CAD using positron emission tomography with 13N-ammonia and found no relationship between infarct volume and QRS fragmentation. Our study failed to show any significant relationship between transmurality and the occurrence of fQRS. This result is consistent with other studies on Q waves. In a prospective MRI study, Engblom et al. dichotomized 29 patients with reperfused first-time MI according to the presence/absence of Q waves. They assessed infarct size, transmurality, and endocardial extent of MI using gadolinium enhancement MRI. Q waves and electrocardiographic MI size were estimated using QRS scoring of the ECG. They found a significant difference between patients with and without Q waves for MI size (P ¼ 0.03) and the endocardial extent of MI (P ¼ 0.01), but not for mean and maximum MI transmurality (P ¼ 0.09 and P ¼ 0.14). The extent of endocardial infarction was the only independent predictor of pathological Q waves. Of the MI variables tested, the extent of endocardial infarction correlated most strongly with the QRS score (r ¼ 0.86; P < 0.001).21 Our data therefore confirm previous work showing that the extent of infarction, but not transmurality, is a predictor of the presence of a Q wave.22 One can therefore hypothesize that QRS fragmentation is a marker of myocardial scarring and left ventricular remodelling after AMI. An alternative interpretation of our findings is that residual viable myocardium remains within the reperfused infarct zone and that the surviving myocytes are responsible for the fQRS phenomenon. The literature on the topic is inconsistent. Most reports suggest that enhanced zones on LGE sequences are Table 3. Predictors of fQRS in uni- and multivariate logistic regression analysis (n ¼ 209) Univariate analysis Variable
OR
IS, % Peri-infarct zone, % SBP, mm Hg Male sex Presence of Q wave EDV index, mL ESV index, mL LVEF, %
1.05 1.08 1.02 2.06 2.24 1.02 1.02 0.97
95% CI
P
Multivariate analysis OR
95% CI
P
1.03-1.08 < 0.001 1.06 1.03-1.09 < 0.001 1.01-1.16 0.025 d d d 1.01-1.03 0.001 1.02 1.01-1.04 < 0.001 1.00-4.22 0.049 d d d 1.28-3.93 0.005 d d d 1.00-1.02 < 0.001 d d d 1.00-1.03 < 0.001 1.02 1.00-1.03 0.013 0.95-0.99 0.015 d d d
EDV, end-diastolic volume; ESV, end-systolic volume; IS, infarct size; LVEF, left ventricular ejection fraction; SBP, systolic blood pressure.
entirely nonviable.19 However, enhancement on LGE CMR can overestimate infarct size, and viable, edematous border zones can show enhancement.23 Histological data suggested that preserved islands of viable myocytes exist within the infarct zone.24,25 These structural differences might lead to differential transmission of epicardial contraction and conduction into the infarct zone depending on the presence of MO. In a recent study, Kidambi et al.26 performed serial (2, 7, 30, and 90 days) CMR with LGE and T2 sequences in 39 AMI patients treated using primary percutaneous coronary intervention. Patients without MO showed recovery of strain in the endocardial, midmyocardial, and epicardial infarct borders, but in patients with MO (with or without intramyocardial hemorrhage [IMH]), there was no significant recovery in endocardial and midmyocardial areas. Furthermore, endocardial and midmyocardial contractile function in the 2 groups was significantly different at day 7, and there was no difference for the epicardial border until day 30. This is in keeping with the wavefront theory of infarction which states that MO and IMH principally develop in the endocardium and midmyocardium, and the epicardium is relatively spared from ischemia and infarction before reperfusion. Recent experimental work has provided new insights into this complex interplay. Using an in vivo porcine model of reperfused STEMI, Robbers et al.27 demonstrated: (1) that the infarct core on histology, the area of IMH on T2-weighted images, and the area of MO on LGE showed close correlations for size and location; and (2) the important role of hemorrhage in the development of myocardial reperfusion injury. Although we were unable to provide data on IMH, fQRS was associated with a greater infarct size and a larger peri-infarct zone. Even when present alone (ie, without Q wave), fQRS was associated with worse left ventricular remodelling indexes after AMI. The subgroup analysis showed that fQRS, in the presence or absence of Q waves, could be used to quickly identify patients with an increased risk of death. Further studies are needed to test the potential effect of fQRS to guide inpatient therapy to limit acute left ventricular remodelling, for example, by the early prescription of mineralocorticoid receptor antagonist receptors. Study limitations To analyze QRS fragmentation, we included only patients without previous MI. Because previous studies have clearly
Lorgis et al. Fragmented QRS in MI: An MRI Study
shown that infarct size varies according to the time between the acute event and the CMR exam,17 all of the patients were evaluated using MRI in a timely fashion (mean 6 3 days). Nonetheless, in our patients, infarct size might have varied depending on the time between the acute event and the MRI. Conclusion Our study showed that the systematic assessment of QRS fragmentation on a 12-lead electrocardiogram in patients with AMI is a simple, widely available, and inexpensive tool. fQRS is a useful parameter, but reflects infarct size and the left ventricular volume, rather than the transmural extent of the infarct. Acknowledgements The authors thank Edith Fusier, Anne Cecile Lagrost, and Juliane Berchoud for their research assistance, and Philip Bastable for editorial assistance. Funding Sources This work was supported by the University Hospital of Dijon, the Association de Cardiologie de Bourgogne, and by grants from the Union Régionale des Caisses d'Assurance Maladie de Bourgogne (URCAM), the Agence Regionale de Santé (ARS) de Bourgogne, the Conseil Régional de Bourgogne and the Fédération Française de Cardiologie (FFC). Disclosures The authors have no conflicts of interest to disclose. References 1. Das MK, Khan B, Jacob S, Kumar A, Mahenthiran J. Significance of a fragmented QRS complex vs a Q wave in patients with coronary artery disease. Circulation 2006;113:2495-501. 2. Das MK, Michael MA, Suradi H, et al. Usefulness of fragmented QRS on a 12-lead electrocardiogram in acute coronary syndrome for predicting mortality. Am J Cardiol 2009;104:1631-7. 3. Pietrasik G, Goldenberg I, Zdzienicka J, Moss AJ, Zareba W. Prognostic significance of fragmented QRS complex for predicting the risk of recurrent cardiac events in patients with Q-wave myocardial infarction. Am J Cardiol 2007;100:583-6. 4. Castle CH, Keane WM. Electrocardiographic “peri-infarction block.” A clinical and pathological correlation. Circulation 1965;31:403-8. 5. Shadaksharappa KS, Kalbfleisch JM, Conrad LL, Sarkar NK. Recognition and significance of intraventricular block due to myocardial infarction (peri-infarction block). Circulation 1968;37:20-6. 6. Fieno DS, Kim RJ, Chen EL, et al. Contrast-enhanced magnetic resonance imaging of myocardium at risk: distinction between reversible and irreversible injury throughout infarct healing. J Am Coll Cardiol 2000;36: 1985-91. 7. Lima JA, Judd RM, Bazille A, et al. Regional heterogeneity of human myocardial infarcts demonstrated by contrast-enhanced MRI. Potential mechanisms. Circulation 1995;92:1117-25.
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8. Roes SD, Borleffs CJ, van der Geest RJ, et al. Infarct tissue heterogeneity assessed with contrast-enhanced MRI predicts spontaneous ventricular arrhythmia in patients with ischemic cardiomyopathy and implantable cardioverter-defibrillator. Circ Cardiovasc Imaging 2009;2: 183-90. 9. Heidary S, Patel H, Chung J, et al. Quantitative tissue characterization of infarct core and border zone in patients with ischemic cardiomyopathy by magnetic resonance is associated with future cardiovascular events. J Am Coll Cardiol 2010;55:2762-8. 10. Dowsley T, Al-Mallah M, Ananthasubramaniam K, et al. The role of noninvasive imaging in coronary artery disease detection, prognosis, and clinical decision making. Can J Cardiol 2013;29:285-96. 11. Lorgis L, Zeller M, Dentan G, et al. Prognostic value of N-terminal probrain natriuretic peptide in elderly people with acute myocardial infarction: prospective observational study. BMJ 2009;338:b1605. 12. Thygesen K, Alpert JS, White HD. Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Circulation 2007;116:2634-53. 13. Das MK, Saha C, El Masry H, et al. Fragmented QRS on a 12-lead ECG: a predictor of mortality and cardiac events in patients with coronary artery disease. Heart Rhythm 2007;4:1385-92. 14. Goldberger JJ, Greenstein E. Fragmented QRS for risk prediction: picking up the pieces. Heart Rhythm 2007;4:1393-4. 15. Lorgis L, Jourda F, Hachet O, et al. Prognostic value of fragmented QRS on a 12-lead ECG in patients with acute myocardial infarction. Heart Lung 2013;42:326-31. 16. Yamazaki KG, Taub PR, Barraza-Hidalgo M, et al. Effects of ()epicatechin on myocardial infarct size and left ventricular remodeling after permanent coronary occlusion. J Am Coll Cardiol 2010;55:2869-76. 17. Lee JT, Ideker RE, Reimer KA. Myocardial infarct size and location in relation to the coronary vascular bed at risk in man. Circulation 1981;64:526-8. 18. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation 1977;56:786-8. 19. Jansen DE, Corbett JR, Wolfe CL, et al. Quantification of myocardial infarction: a comparison of single photon-emission computed tomography with pyrophosphate to serial plasma MB-creatine kinase measurements. Circulation 1985;72:327-33. 20. Carey MG, Luisi AJ, Baldwa S, et al. The Selvester QRS Score is more accurate than Q waves and fragmented QRS complexes using the MasonLikar configuration in estimating infarct volume in patients with ischemic cardiomyopathy. J Electrocardiol 2010;43:318-37. 21. Engblom H, Carlsson MB, Hedström E, et al. The endocardial extent of reperfused first-time myocardial infarction is more predictive of pathologic Q waves than is infarct transmurality: a magnetic resonance imaging study. Clin Physiol Funct Imaging 2007;27:101-7. 22. Moon JC, De Arenaza DP, Elkington AG, et al. The pathologic basis of Q-wave and non-Q-wave myocardial infarction: a cardiovascular magnetic resonance study. J Am Coll Cardiol 2004;44:554-6. 23. Arai AE. The cardiac magnetic resonance (CMR) approach to assessing myocardial viability. J Nucl Cardiol 2011;18:1095-102. 24. Dall’Armellina E, Karia N, Lindsay AC, et al. Dynamic changes of edema and late gadolinium enhancement after acute myocardial infarction and their relationship to functional recovery and salvage index. Circ Cardiovasc Imaging 2011;4:228-36.
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25. Factor SM, Sonnenblick EH, Kirk ES. The histologic border zone of acute myocardial infarctioneislands or peninsulas? Am J Pathol 1978;92:111-24. 26. Kidambi AJ, Mather AN, Motwani M, et al. The effect of microvascular obstruction and intramyocardial hemorrhage on contractile recovery in reperfused myocardial infarction: insights from cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2013;15:58. 27. Robbers LF, Eerenberg ES, Teunissen PF, et al. Magnetic resonance imaging-defined areas of microvascular obstruction after acute myocardial
Canadian Journal of Cardiology Volume 30 2014 infarction represent microvascular destruction and haemorrhage. Eur Heart J 2013;34:2346-53.
Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2013.11.026.