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Subclinical left ventricular dysfunction revealed by circumferential 2D strain imaging in patients with coronary artery disease and fragmented QRS complex
Subclinical left ventricular dysfunction revealed by circumferential 2D strain imaging in patients with coronary artery disease and fragmented QRS complex Guo-Hui Yan, MD, PhD,*† Mei Wang, MD, PhD,*‡ Kai-Hang Yiu, MBBS,*‡ Chu-Pak Lau, MD,* Guang Zhi, MD,§ Stephen W.L. Lee, MD,* Chung-Wah Siu, MD,*‡ Hung-Fat Tse, MD, PhD*‡ From the *Department of Medicine, Division of Cardiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, †Ultrasound Department, Zhong Shan Hospital, Xiamen University, Xiamen, China, ‡Research Centre of Heart, Brain, Hormone & Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, and § Division of Cardiology, Chinese PLA General Hospital, Beijing, China. BACKGROUND Fragmented QRS (fQRS) complexes on a routine 12-lead electrocardiogram were associated with adverse cardiac events, including sudden death in patients with coronary artery disease (CAD). OBJECTIVE To investigate the relationship between the fQRS complex and global and regional left ventricular (LV) functions in patients with CAD. METHODS The study consisted of 176 patients (68 ⫾ 9 years; 145 [82%] men) with CAD with narrow QRS duration and preserved LV ejection fraction (⬎45%). All patients underwent detailed 2-dimensional speckle-tracking echocardiography to determine global and segmental (basal, middle, and apical) LV strains and strain rates and were prospectively followed-up in the outpatient clinic. RESULTS Fifty-five patients (31%) had fQRS complexes. Global, middle, and apical LV longitudinal, radial, and circumferential strains and strain rates were significantly lower in the fQRS group than in the non-fQRS group (all P ⬍.05). Multivariate logistic regression analysis revealed that the fQRS complex was associated with decreased global circumferential strain (odds ratio 1.19; 95%
Introduction The fragmented QRS (fQRS) complex identified on surface electrocardiogram (ECG) has been shown to occur in various cardiac conditions.1 In patients with coronary artery disease (CAD) with or without prior myocardial infarction (MI), the fQRS complex predicted the occurrence of adverse clinical outcomes and sudden cardiac death.2– 4 The presence of the fQRS complex in patients with CAD was associated with regional myocardial damage and had a greater sensitivity and negative predictive value than did Q
This study was supported by the General Research Fund of the Research Grant Council of Hong Kong (HKU 7777/07M and HKU 7775/08M). Address reprint requests and correspondence: Dr Hung-Fat Tse, MD, PhD, Department of Medicine, Cardiology Division, Queen Mary Hospital, The University of Hong Kong, Room 1928, Block K, Hong Kong. E-mail address: [email protected].
confidence interval 1.06⫺1.33; P ⫽ .003) and multivessel disease (odds ratio 3.69; 95% confidence interval 1.35⫺10.08; P ⫽ .011). Kaplan-Meier analysis revealed that event-free survival for cardiac events was significantly lower in the fQRS group than in the non-fQRS group (P ⫽ .036). CONCLUSIONS Our results demonstrated that the fQRS complex in patients with CAD with preserved LV ejection fraction was associated with subclinical global and regional LV dysfunctions as detected by 2-dimensional speckle-tracking imaging, and the results also predicted adverse cardiac events. KEYWORDS Fragmented QRS; Coronary artery disease; Strain; Strain rate ABBREVIATIONS CAD ⫽ coronary artery disease; ECG ⫽ electrocardiogram/electrocardiographic; fQRS ⫽ fragmented QRS; LV ⫽ left ventricular; LVEF ⫽ left ventricular ejection fraction; MI ⫽ myocardial infarction; WMSI ⫽ wall motion score index (Heart Rhythm 2012;9:928–935) © 2012 Heart Rhythm Society. All rights reserved.
waves on surface ECG for the detection of a myocardial scar.1,5,6 It has been postulated that a myocardial scar and/or ischemia in patients with CAD lead to heterogeneous ventricular activation, thus causing fragmentation of the QRS complex in ECG.7–9 In patients with nonischemic dilated cardiomyopathy and narrow QRS complex, the fQRS complex was associated with a significant intraventricular systolic dyssynchrony.10,11 However, the relationship between the fQRS complex and global and regional left ventricular (LV) functions in patients with CAD with preserved LV function is unknown. The purpose of this study was to investigate the relationship between the fQRS complex and the LV function as determined by a detailed echocardiographic examination, including 2-dimensional (2D) speckle-tracking imaging in patients with CAD with narrow QRS complex and preserved LV ejection fraction (LVEF) (⬎45%).
1547-5271/$ -see front matter © 2012 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2012.01.007
Yan et al
Ventricular Strain and Fragmented QRS
Methods Study population Consecutive patients with an established diagnosis of CAD in whom ⬎50% stenosis in at least 1 major coronary artery as documented by coronary angiogram were recruited from an outpatient clinic. All patients with significant and symptomatic CAD had received successful coronary revascularization before recruitment. All patients had stable CAD and received consistent medications for at least 12 months before enrollment. Patients who had a documented history of congestive heart failure, severe valvular heart disease, cardiomyopathy, persistent atrial fibrillation, permanent pacemaker or implantable cardioverter-defibrillator implantation, recent MI, unstable angina, coronary revascularization, or stroke within the last 6 months and LVEF ⱕ 45% as measured by echocardiogram were excluded. Furthermore, patients with coexisting ECG abnormalities, including typical or incomplete bundle branch block pattern and QRS duration ⱖ 120 ms that precluded the assessment of the fQRS complex, were also excluded. This study was approved by the local institutional review board, and informed consent was obtained from all participants.
ECG criteria for the assessment of the fQRS complex The resting 12-lead ECG (model Mac 5000; filter range 0.15–150 Hz; 25 mm/s; 10 mm/mV; GE Marquette, Milwaukee, WI) was analyzed by 2 independent readers blinded to the clinical and echocardiographic data. There was 98% concordance for the ECG signs. In case of disagreement, the final diagnosis was achieved by mutual agreement. In this study, the fQRS complex was defined by the presence of various RSR= patterns (QRS duration ⬍ 120 ms) with or without Q wave—which include an additional R wave (R=), notching of the R wave, and notching in the nadir of the S wave— or the presence of more than 1 R= (fragmentation) in 2 contiguous leads corresponding to a major coronary artery territory, as described previously.5 The presence of the fQRS complex in ⱖ2 contiguous anterior leads (V1-V5) corresponded to anterior myocardial segments or left anterior descending territory; the presence of
Figure 1
929 the fQRS complex in ⱖ2 contiguous lateral leads (I, aVL, and V6) corresponded to the lateral myocardial segments or left circumflex territory; and the presence of the fQRS complex in ⱖ2 contiguous inferior leads (II, III, and aVF) corresponded to the inferior myocardial segments or right coronary artery territory. The fQRS complex was also seen in ⬎1 coronary artery territory in the same patients (Figure 1). Patients with fQRS complexes in at least 1 major coronary artery territory on a resting 12-lead ECG were defined as the fQRS group, and the remaining patients without fQRS complex were defined as the non-fQRS group.
Echocardiographic examination Detailed echocardiography was performed in all patients to determine global and regional LV functions by using a commercially available system (Vivid 7, GE Vingmed-General Electric, Horton, Norway). LV dimensions were measured by 2D-guided M-mode echocardiography according to the guidelines of the American Society of Echocardiography,12 and LVEF was measured by using the modified biplane Simpson’s method from apical 4- and 2-chamber views. Mitral inflow E velocity and its deceleration time as well as mitral inflow A velocity were measured by using pulse wave Doppler, with the sample volume placed at the tips of the mitral valve from the apical 4-chamber view. The ratio of mitral inflow E velocity to septal wall myocardial e= velocity (E/e=sep) measured by using the pulsed tissue Doppler spectrum was calculated as an index of LV filling pressure.13 For speckle-tracking analysis, standard grayscale 2D images were acquired in the 4-chamber, 2-chamber, and apical views as well as the parasternal short-axis views at the mitral valve, papillary muscle, and apical levels with a frame rate of at least 60 frames/s. Data were stored in the cine-loop format and transferred to the workstation (EchoPac-PC, version 6.1.2, Vingmed-General Electric, Horton, Norway) for further off-line analysis. The endocardial border was manually traced, and the region-of-interest width was manually adjusted to include the entire myocardium. The software then automatically traced and analyzed (Figure 2). The left ventricle was divided into 18 segments (6 basal, 6 mid, and 6 apical), and
Example of a 12-lead electrocardiogram showing fragmented QRS complex over inferior leads and precordial lead V5.
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Figure 2 Examples of echocardiographic images of radial strain (A, D), circumferential strain (B, E), and longitudinal strain (C, F) measurements in patients with (left) or without (right) fragmented QRS complex.
each segment was analyzed individually.14 Two-dimensional longitudinal strain was assessed in 3 apical planes; 2D circumferential strain and radial strain were assessed in 3 parasternal short-axis planes. Systolic longitudinal strain rate, circumferential strain rate, and radial strain rate were assessed simultaneously. Peak systolic longitudinal strain and strain rate were calculated by averaging the peak systolic values of the 18 segments derived from the 6 segments of the 3 apical views (2- and 4-chamber and apical long-axis views). Peak systolic radial and circumferential strain and strain rate values were calculated by averaging the peak systolic values of the 18 segments from the 3 parasternal LV short-axis views. Interobserver measurement variability was determined by a second independent, blinded observer who measured LV strain parameters in 10 randomly selected patients. The intraobserver variability was determined by repeating the LV strain measurements by the first observer in another group of 10 randomly selected patients 1 month later. The
interobserver and intraobserver variabilities for measuring longitudinal, radial, and circumferential strains determined by using 2D speckle-tracking imaging were 6.5% and 2.6%, 10.4% and 7.6%, 4.9% and 2.4%, respectively. Wall motion was assessed semiquantitatively by an experienced observer by using a 16-segment, 4-point scale model of the left ventricle, where 1 ⫽ normal motion, 2 ⫽ hypokinesia, 3 ⫽ akinesia, and 4 ⫽ dyskinesia.15 The wall motion score index (WMSI) for each patient was calculated as the ratio between the sum of scores and the number of visualized segments.
Follow-up All patients were prospectively followed-up in our outpatient clinics or until they left the cohort through death. Information on deaths during the follow-up period after recruitment was retrieved from medical records and discharge summaries from our hospital as well as other institutions. The presence of a major adverse cardiac event was
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Ventricular Strain and Fragmented QRS
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Table 1 Comparison of demographic characteristics between patients with and without fQRS complex
Age (y) Sex male, n (%) Body mass index (kg/m2) Smoking, n (%) Hypertension, n (%) Diabetes mellitus, n (%) Myocardial infarction, n (%) PCI, n (%) CABG, n (%) Diseased vessel, n (%) Single vessel Multivessel Mean systolic BP (mm Hg) Mean diastolic BP (mm Hg) Mean QRS duration (ms) Total cholesterol (mmol/L) LDL-C (mmol/L) HDL-C (mmol/L) Triglycerides (mmol/L) Fasting glucose (mmol/L) Hb A1c (mmol/L) Medications, n (%) Diuretics Long-acting nitrates Beta-blocker Calcium-channel blocker ACEI or ARB Statins Aspirin Clopidogrel
fQRS group (n ⫽ 55)
Non-fQRS group (n ⫽ 121)
68 ⫾ 11 50 (91) 25.5 ⫾ 3.4 36 (67) 30 (55) 19 (35) 19 (35)
68 ⫾ 9 95 (79) 24.9 ⫾ 2.8 61 (51) 82 (68) 48 (40) 34 (29)
.76 .055 .21 .070 .095 .62 .48
42 (76) 7 (13)
86 (71) 11 (9)
.58 .59
15 (27) 40 (73) 142 ⫾ 18 83 ⫾ 8
63 (52) 58 (48) 145 ⫾ 19 82 ⫾ 8
.003 .003 .37 .80
97 ⫾ 12 4.14 ⫾ 0.64
91 ⫾ 10 4.12 ⫾ 0.70
.001 .87
2.30 1.19 1.48 6.04 6.79
⫾ ⫾ ⫾ ⫾ ⫾
.82 .66 .95 .50 .43
18 62 91 34 76 113 113 7
(15) (52) (76) (28) (63) (94) (94) (6)
2.28 1.17 1.50 6.27 7.00 15 30 43 7 44 52 54 7
⫾ ⫾ ⫾ ⫾ ⫾
(27) (55) (78) (13) (80) (95) (98) (13)
0.54 0.28 0.60 1.97 1.51
0.56 0.33 1.33 2.02 1.59
P
.063 .87 .85 .033 .035 1.00 .44 .14
ACEI ⫽ angiotensin-converting enzyme inhibitor; ARB ⫽ angiotensinreceptor blocker; BP ⫽ blood pressure; CABG ⫽ coronary artery bypass surgery; fQRS ⫽ fragmented QRS; Hb A1c ⫽ hemoglobin A1c; HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; PCI ⫽ percutaneous coronary intervention.
defined as deaths due to cardiac causes, acute coronary event, or symptom-driven coronary revascularization procedures. Deaths due to cardiac causes were defined as deaths due to lethal cardiac arrhythmias, MI, heart failure, or unexplained sudden deaths.
Statistical analysis Continuous variables are expressed as mean ⫾ SD and categorical variables as frequencies and percentages. Comparisons of continuous variables were performed by using 2-sample Student t tests, and comparisons of dichotomous variables were performed by using 2 tests. Multivariate logistic regression analysis was performed to determine the association of the fQRS complex with clinical and echocardiographic parameters. Survival curves were constructed according to the Kaplan-Meier method with comparison by the log-rank test. Furthermore, Cox regression analysis was
performed to determine the predictors of clinical outcomes. All analyses were performed by using SPSS statistical software (version 15.0 for Windows, SPSS, Inc, Chicago, IL). A P value of ⬍.05 was considered statistically significant.
Results Study population Of the 193 consecutive CAD patients recruited, 17 (9%) patients were excluded because of complete or incomplete right bundle branch block (n ⫽ 12), left bundle branch block (n ⫽ 4), and Wolff-Parkinson-White syndrome (n ⫽ 1). As a result, the analysis included a total of 176 patients (mean age 68 ⫾ 9 years; 145 [82%] men). The fQRS complex was detected in at least 1 coronary artery territory in 55 (31%) patients. The baseline clinical characteristics of patients with CAD in the fQRS group and the non-fQRS group are shown in Table 1. There were no significant differences in age, the prevalence of man, hypertension, smoking, diabetes mellitus, and history of MI and coronary revascularization between the 2 groups (all P ⬎.05). However, patients in the fQRS group were more likely to have multivessel CAD than those in the non-fQRS group (78% vs 48%; P ⫽ .003). Furthermore, the fQRS group had significantly longer mean QRS duration and more likely to receive angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker but less likely to treat with calcium-channel blockers as compared with the non-fQRS group (all P ⬍.05; Table 1).
Echocardiographic findings All patients had preserved LVEF, and their mean LVEF was 57% ⫾ 12%. As shown in Table 2, the fQRS group had Table 2 Conventional echocardiographic parameters in patients with and without fQRS complex fQRS group (n ⫽ 55) LV end-diastolic diameter (cm) LV end-systolic diameter (cm) LV end-diastolic volume (mL) LV end-systolic volume (mL) LVEF (%) Left atrial dimension (cm) Mitral inflow E (cm/s) Deceleration time (ms) Mitral inflow A (cm/s) E/A ratio IVRT (ms) TR pressure (mm Hg) WMSI
Non-fQRS group (n ⫽ 121)
5.09 ⫾ 0.89 4.76 ⫾ 0.56
P .003
3.68 ⫾ 1.07 3.15 ⫾ 0.72 ⬍.001 98.3 ⫾ 35.4 81.1 ⫾ 29.3
.001
51.5 ⫾ 27.9 35.4 ⫾ 22.4 ⬍.001 52 3.88 69 230 83 0.90 97 22 1.26
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
12 59 ⫾ 12 ⬍.001 0.56 3.77 ⫾ 0.51 .24 24 67 ⫾ 17 .44 69 230 ⫾ 62 .96 18 83 ⫾ 20 .99 0.53 0.86 ⫾ 0.40 .60 21 95 ⫾ 20 .56 9 22 ⫾ 9 .79 0.44 1.10 ⫾ 0.23 .002
E/A ⫽ the ratio of mitral E velocity to mitral A velocity; fQRS ⫽ fragmented QRS; IVRT ⫽ isovolumic relaxation time; LV ⫽ left ventricular; LVEF ⫽ left ventricular ejection fraction; TR ⫽ tricuspid regurgitation; WMSI ⫽ wall motion score index.
932 Table 3
Heart Rhythm, Vol 9, No 6, June 2012 Echocardiographic strain and strain rate parameters in patients with and without fQRS complex
Global longitudinal strain (%) Segmental longitudinal strain (%) Basal level Middle level Apical level Global radial strain (%) Segmental radial strain (%) Basal level Middle level Apical level Global circumferential strain (%) Segmental circumferential strain (%) Basal level Middle level Apical level Global longitudinal systolic strain rate (s⫺1) Segmental longitudinal systolic strain rate (s⫺1) Basal level Middle level Apical level Global radial systolic strain rate (s⫺1) Segmental radial systolic strain rate (s⫺1) Basal level Middle level Apical level Global circumferential systolic strain rate (s⫺1) Segmental circumferential systolic strain rate (s⫺1) Basal level Middle level Apical level
fQRS group (n ⫽ 55)
Non-fQRS group (n ⫽ 121)
P
⫺14.9 ⫾ 4.1
⫺17.8 ⫾ 4.2
⬍.001
⫺14.1 ⫺14.2 ⫺13.9 27.2
⫾ ⫾ ⫾ ⫾
3.9 3.9 8.1 10.8
⫺15.8 ⫺16.9 ⫺19.0 33.4
⫾ ⫾ ⫾ ⫾
3.3 4.1 8.5 13.1
.004 ⬍.001 ⬍.001 .005
29.7 31.5 19.9 ⫺16.4
⫾ ⫾ ⫾ ⫾
13.2 15.0 15.4 3.7
34.7 38.3 27.6 ⫺20.0
⫾ ⫾ ⫾ ⫾
17.6 17.8 19.7 4.9
.08 .02 .01 ⬍.001
⫺13.3 ⫺16.3 ⫺19.5 ⫺1.00
⫾ ⫾ ⫾ ⫾
4.2 5.4 6.7 0.26
⫺16.3 ⫺19.1 ⫺24.5 ⫺1.15
⫾ ⫾ ⫾ ⫾
4.9 6.0 7.8 0.25
.002 .02 .001 .003
⫺1.05 ⫺0.90 ⫺1.06 1.67
⫾ ⫾ ⫾ ⫾
0.28 0.23 0.40 0.43
⫺1.13 ⫺1.02 ⫺1.29 1.83
⫾ ⫾ ⫾ ⫾
0.23 0.21 0.39 0.44
.09 .003 .003 .08
1.85 1.72 1.44 ⫺1.33
⫾ ⫾ ⫾ ⫾
0.52 0.51 0.84 0.33
2.01 1.83 1.67 ⫺1.49
⫾ ⫾ ⫾ ⫾
0.82 0.50 0.72 0.37
.29 .26 .13 .04
⫺1.30 ⫾ 0.42 ⫺1.31 ⫾ 0.49 ⫺1.41 ⫾ 0.47
⫺1.36 ⫾ 0.53 ⫺1.44 ⫾ 0.46 ⫺1.72 ⫾ 0.55
.57 .19 .004
fQRS ⫽ fragmented QRS.
significantly larger LV systolic and diastolic dimension and volume, lower LVEF, and higher WMSI as compared with the non-fQRS group (all P ⬍.05). However, there were no significant differences in atrial dimension, E wave, A wave, and the ratio of mitral E velocity to mitral A velocity between the 2 groups (all P ⬎ .05). As shown in Table 3, the global longitudinal, radial, and circumferential peak systolic strains were markedly reduced in the fQRS group than in the non-fQRS group (all P ⬍.01; Figure 2). Furthermore, the global strain rate was significantly reduced in the fQRS group than in the non-fQRS group, with the exception of the radial strain rate (all P ⬍.05). Segmental analysis revealed that the longitudinal, radial, and circumferential peak systolic strains and strain rates in the middle and apical LV segments were significantly lower in the fQRS group than in the non-fQRS group. In addition, all global strain and strain rate indices were significantly positive with regard to LVEF but negative with regard to WMSI (all P ⬍.01; Table 4).
Relationships between the fQRS complex and clinical and echocardiographic parameters Univariate logistic regression showed that multivessel lesion, QRS duration, treatment with calcium-channel blocker and angiotensin-converting enzyme inhibitor/angiotensin-
receptor blocker, LV dimension, LV volume, LVEF, WMSI, and global strain and strain rate indices were associated with the fQRS complex. However, multivariate loTable 4 Correlations of echocardiographic deformation parameters with left ventricular ejection fraction and wall motion scores index
Global longitudinal strain Global radial strain Global circumferential strain Global longitudinal systolic strain rate Global radial systolic strain rate Global circumferential systolic strain rate
Left ventricular ejection fraction
Wall motion scores index
Correlation coefficient (r)
P
Correlation coefficient (r)
P
.76
⬍.001
⫺.47
⬍.001
.63 .70
⬍.001 ⬍.001
⫺.33 ⫺.37
⬍.001 ⬍.001
.61
⬍.001
⫺.41
⬍.001
.39
⬍.001
⫺.23
.01
.55
⬍.001
⫺.27
.003
Yan et al Table 5
Ventricular Strain and Fragmented QRS
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Relationship between clinical and echocardiographic parameters and the fQRS complex Univariate regression
Age Sex male Myocardial infarction Diabetes mellitus Hypertension Multivessel lesion QRS duration Calcium-channel blocker ACEI or ARB LV end-diastolic diameter LV end-systolic diameter LV end-diastolic volume LV end-systolic volume LVEF WMSI E/A ratio IVRT Deceleration time Global longitudinal strain Global radial strain Global circumferential strain Global longitudinal systolic strain rate Global radial systolic strain rate Global circumferential systolic strain rate
Multivariate regression
Odds ratio, 95% CI
P
Odds ratio, 95% CI
P
0.99,0.96–1.03 0.37,0.13–1.01 1.32,0.67–2.61 0.80,0.41–1.56 0.57,0.30–1.10 2.90,1.45–5.79 1.05,1.02–1.09 0.37,0.15–0.89 2.32,1.08–4.94 1.07,1.02–1.12 1.07,1.03–1.11 1.02,1.01–1.03 1.03,1.01–1.04 0.95,0.93–0.98 4.33,1.59–11.82 1.21,0.60–2.43 1.01,0.99–1.02 1.00,0.99–1.01 1.17,1.08–1.27 0.96,0.93–0.99 1.18,1.07–1.30 9.43,2.03–43.88 0.38,0.13–1.10 3.34,1.05–10.65
.753 .052 .427 .517 .093 .003 .001 .028 .030 .004 .000 .002 .000 .000 .004 .59 .56 .96 .000 .007 .001 .004 .075 .041
— — — — — 3.69,1.35–10.08 — — — — — — — — — — — — — — 1.19,1.06–1.33 — — —
— — — — — .011 — — — — — — — — — — — — — — .003 — — —
ACEI ⫽ angiotensin-converting enzyme inhibitor; ARB ⫽ angiotensin-receptor blocker; CI ⫽ confidence interval; E/A ⫽ the ratio of mitral E velocity to mitral A velocity; fQRS ⫽ fragmented QRS; IVRT ⫽ isovolumic relaxation time; LV ⫽ left ventricular; LVEF ⫽ left ventricular ejection fraction; WMSI ⫽ wall motion score index.
gistic regression analysis after adjusting for all significant variables in univariate analysis revealed that only decreased global circumferential strain (odds ratio 1.19; 95% confidence interval [CI] 1.06 –1.33; P ⫽ .003) and multivessel disease (odds ratio 3.69; 95% CI 1.35–10.08; P ⫽ .011) were associated with the fQRS complex independent of regional wall motion abnormality and LV systolic and diastolic functions (Table 5). Furthermore, receiver operating characteristic analysis was performed for all global deformation indices to assess their sensitivity and specificity for the detection of the fQRS complex. Among all indices, circumferential strain measured by using 2D speckle-tracking imaging was also shown to have the highest sensitivity and specificity for the association with the fQRS complex (area under curve ⫽ 0.73; P ⬍.001).
Clinical outcomes After a mean follow-up of 36 ⫾ 11 months, cardiac events were observed in 40 (22.7%) patients, including cardiac death (n ⫽ 5), acute coronary event (n ⫽ 12), or symptomdriven coronary revascularization procedures (n ⫽ 23), and 9 (5.1%) patients died. Patients with fQRS complex had a significantly higher incidence of cardiac events during follow-up as compared with those without fQRS complex (32.7% vs 18.2%; P ⫽ .036; Figure 3A). However, there was no significant difference in all-cause mortality between the 2 groups (1.8% vs 6.6%; P ⫽ .19; Figure 3B). Multivariate Cox regression analysis revealed that the fQRS com-
plex (hazards ratio 2.69; 95% CI 1.26 –5.75; P ⫽ .01) and LVEF (hazards ratio 0.34; 95% CI 0.12– 0.98; P ⫽ .04) were independent predictors of major cardiac events.
Discussion Our results demonstrated that the fQRS complex in patients with CAD with preserved LVEF and narrow QRS complex was associated with abnormal regional and global 2D circumferential strains. In this study, patients with CAD with fQRS complex had a significantly decreased mechanical deformation function measured by using 2D speckle-tracking imaging, including longitudinal, radial, circumferential strains and strain rates. Furthermore, 2D circumferential strain was significantly associated with the fQRS complex, independent of history of MI and other echocardiographic parameters, including LV systolic and diastolic functions and regional wall motion abnormalities. In addition, the fQRS complex was an independent predictor of increased cardiac events in patients with CAD. Recent studies have shown that the presence of the fQRS complex on a 12-lead ECG predicts cardiac events in several populations. The fQRS complex has been associated with an increased mortality risk in patients with acute coronary syndrome16 and higher rates of spontaneous ventricular tachyarrhythmias among patients with Brugada syndrome17 and arrhythmogenic right ventricular dysplasia.18 Although the underlying mechanism remains unclear, it has been proposed that the fQRS complex might represent in-
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Figure 3 Kaplan-Meier analysis of event-free survival for (A) cardiac events (myocardial infarction, need for revascularization, or cardiac death) and (B) all-cause mortality in patients with fragmented QRS complex (fQRS group) and without fragmented QRS complex (non-fQRS group).
homogeneous activation7 and conduction abnormalities17 within a relatively large area of pathological (scar) or physiologically abnormal (ischemia) myocardium. The presence of a myocardial scar or ischemia is associated with a poor prognosis because of an increased risk for ventricular tachyarrhythmias and heart failure.5–7,19,20 Therefore, the presence of the fQRS complex on a routine 12-lead ECG has been proposed as a potential novel marker of depolarization abnormality and myocardial scar in patients with known or suspected cardiac diseases, which is associated with increased adverse cardiac events and mortality. Recent studies also suggested that segmented LV wall abnormalities were associated with increased arrhythmic events presumably because of patchy myocardial scars.21 However, the relationship between the fQRS complex and regional LV wall abnormalities, especially in patients with preserved LVEF and narrow QRS complex, remains unclear. The movement or deformation of the LV myocardium is 3D, which can be expressed in the 3 coordinates as longitudinal shortening, circumferential compression, and radial thickening. These myocardial shortening can be measured from strain and strain rate measurements by using echocardiography.22,23 Recent studies24 –27 have demonstrated that the measurement of strains and strain rates with speckletracking imaging can detect more subtle regional changes as compared with conventional echocardiographic measurements of LV systolic function in various cardiac diseases. Indeed, our results showed that most of the global strain and strain rate indices have only weak to moderate correlation with conventional echocardiographic index of LV function using LVEF and WMSI, as they measure intrinsic myocardial contractility rather than a semiquantitative assessment of LV function. In this study, we hypothesized that the fQRS complex is associated with subclinical regional LV abnormalities as detected by 2D speckle-tracking imaging in
patients with CAD with preserved LVEF and narrow QRS complex. The results of this study showed that up to 30% of patients with CAD with preserved LV function had the fQRS complex. Those patients with CAD with fQRS complex had more dilated LV dimension, lower LVEF, higher WMSI, and reduced regional and global 2D strains as compared with those without fQRS complex. Nevertheless, there were no significant differences in the conventional indexes of diastolic function between patients with or without fQRS complex. This reflects that conventional indexes of diastolic function are semiquantitative and rather insensitive to distinguish patients with subtle LV dysfunction. Furthermore, among different echocardiographic parameters, decreased global circumferential strain had the highest sensitivity and specificity with respect to the association with the fQRS complex independent of regional wall motion abnormality. In this study, patients with CAD with fQRS complex had decreased circumferential but not radial strain and strain rate indices. Previous studies28 have shown that the level of contribution of circumferential fibers to LV myocardial thickening is greater than that of longitudinal fibers. As a result, circumferential myocardial shortening deteriorates to a greater extent during myocardial ischemia among 3-dimensional deformations. Therefore, changes in circumferential strain and strain rate indices are more sensitive and closely related with prognosis than are longitudinal strain measurements in patients with heart failure.29 On the other hand, as a transmural infarct or scar is associated with a reduction in both long-axis and short-axis functions, the lack of difference in the radial strain and strain rate suggested that the fQRS complex in patients with CAD with preserved LVEF is likely related to nonhomogeneous intraventricular activation and uncoordinated depolarization in ischemic rather than infarcted myocardium.
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Indeed, the higher adverse cardiac events in patients with fQRS complex were mainly attributed to an increased acute coronary event or symptom-driven coronary revascularization procedures. These results provide further evidences to show that the fQRS complex was associated with subclinical regional LV abnormalities revealed by 2D circumferential strain and the presence of multivessel diseases even in stable patients with CAD with preserved LVEF. In addition, our results confirmed the previous findings2– 4,20 and showed that the fQRS complex predicted the occurrence of adverse cardiac events in these patients. Thus, the fQRS complex can be used as a simple and noninvasive marker to identify a high-risk subgroup of patients with stable CAD for more aggressive medical therapy, including coronary revascularization.
Study limitations In this study, patients with stable CAD with preserved LVEF were included. As a result, the numbers of hard clinical outcomes were limited in these relatively low-risk patients and other less hard clinical end points including acute coronary event or symptom-driven coronary revascularization procedures were included.
Conclusions Our results demonstrated that the fQRS complex was observed in up to 30% of the patients with CAD with preserved LVEF and narrow QRS complex as well as predicted increased adverse cardiac events. Patients with fQRS complex have significantly more global and regional impairments of LV function as detected by conventional and 2D speckle-tracking echocardiographic imaging as compared with patients without fQRS complex. Furthermore, among different echocardiographic parameters, 2D circumferential strain had the strongest association with the predictor of the occurrence of the fQRS complex in patients with CAD. These findings suggest that the fQRS complex can be used as a simple and noninvasive marker to identify a high-risk subgroup of patients with stable CAD with subclinical global and regional LV dysfunction and increased adverse cardiac events.
References 1. Chatterjee S, Changawala N. Fragmented QRS complex: a novel marker of cardiovascular disease. Clin Cardiol 2010;33:68 –71. 2. 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;100:583–586. 3. 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;4:1385–1392. 4. Das MK, Maskoun W, Shen C, et al. Fragmented QRS on twelve-lead electrocardiogram predicts arrhythmic events in patients with ischemic and nonischemic cardiomyopathy. Heart Rhythm 2010;7:74 – 80. 5. Das MK, Khan B, Jacob S, Kumar A, Mahenthiran J. Significance of a fragmented QRS complex versus a Q wave in patients with coronary artery disease. Circulation 2006;113:2495–2501. 6. Mahenthiran J, Khan BR, Sawada SG, Das MK. Fragmented QRS complexes not typical of a bundle branch block: a marker of greater myocardial perfusion tomography abnormalities in coronary artery disease. J Nucl Cardiol 2007;14: 347–353.
935 7. Flowers NC, Horan LG, Thomas JR, Tolleson WJ. The anatomic basis for highfrequency components in the electrocardiogram. Circulation 1969;39:531–539. 8. Gardner PI, Ursell PC, Fenoglio JJ Jr, Wit AL. Electrophysiologic and anatomic basis for fractionated electrograms recorded from healed myocardial infarcts. Circulation 1985;72:596 – 611. 9. Lesh MD, Spear JF, Simson MB. A computer model of the electrogram: what causes fractionation? J Electrocardiol 1988;21:S69 –S73. 10. Tigen K, Karaahmet T, Gurel E, et al. The utility of fragmented QRS complexes to predict significant intraventricular dyssynchrony in nonischemic dilated cardiomyopathy patients with a narrow QRS interval. Can J Cardiol 2009;25:517–522. 11. Basaran Y, Tigen K, Karaahmet T, et al. Fragmented QRS complexes are associated with cardiac fibrosis and significant intraventricular systolic dyssynchrony in nonischemic dilated cardiomyopathy patients with a narrow QRS interval. Echocardiography 2011;28:62– 68. 12. Schiller NB. Two-dimensional echocardiographic determination of left ventricular volume, systolic function, and mass: summary and discussion of the 1989 recommendations of the American Society of Echocardiography. Circulation 1991;84:1280 –1287. 13. Yan GH, Wang M, Yue WS, et al. Elevated pulmonary artery systolic pressure in patients with coronary artery disease and left ventricular dyssynchrony. Eur J Heart Fail 2010;12:1067–1075. 14. Suffoletto MS, Dohi K, Cannesson M, Saba S, Gorcsan J III. Novel speckletracking radial strain from routine black-and-white echocardiographic images to quantify dyssynchrony and predict response to cardiac resynchronization therapy. Circulation 2006;113:960 –968. 15. Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2:358 –367. 16. 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;104:1631–1637. 17. Morita H, Kusano KF, Miura D, et al. Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome. Circulation 2008;118:1697–1704. 18. Peters S, Trümmel M, Koehler B. QRS fragmentation in standard ECG as a diagnostic marker of arrhythmogenic right ventricular dysplasia-cardiomyopathy. Heart Rhythm 2008;5:1417–1421. 19. Varriale P, Chryssos BE. The RSR’ complex not related to right bundle branch block: diagnostic value as a sign of myocardial infarction scar. Am Heart J 1992;123:369 –376. 20. Das MK, Suradi H, Maskoun W, et al. Fragmented wide QRS on a 12-lead ECG: a sign of myocardial scar and poor prognosis. Circ Arrhythm Electrophysiol 2008;1:258 –268. 21. Gaitonde RS, Subbarao R, Michael MA, et al. Segmental wall-motion abnormalities of the left ventricle predict arrhythmic events in patients with nonischemic cardiomyopathy. Heart Rhythm 2010;7:1390 –1395. 22. Perk G, Tunick PA, Kronzon I. Non-Doppler two-dimensional strain imaging by echocardiography—from technical considerations to clinical applications. J Am Soc Echocardiogr 2007;20:234 –243. 23. Götte MJ, Germans T, Rüssel IK, et al. Myocardial strain and torsion quantified by cardiovascular magnetic resonance tissue tagging: studies in normal and impaired left ventricular function. J Am Coll Cardiol 2006;48:2002–2011. 24. Vartdal T, Brunvand H, Pettersen E, et al. Early prediction of infarct size by strain Doppler echocardiography after coronary reperfusion. J Am Coll Cardiol 2007;49:1715–1721. 25. Gjesdal O, Hopp E, Vartdal T, et al. Global longitudinal strain measured by two-dimensional speckle tracking echocardiography is closely related to myocardial infarct size in chronic ischaemic heart disease. Clin Sci (Lond) 2007; 113:287–296. 26. Gjesdal O, Helle-Valle T, Hopp E, et al. Noninvasive separation of large, medium, and small myocardial infarcts in survivors of reperfused ST-elevation myocardial infarction: a comprehensive tissue Doppler and speckle-tracking echocardiography study. Circ Cardiovasc Imaging 2008;1:189 –196. 27. Narayanan A, Aurigemma GP, Chinali M, Hill JC, Meyer TE, Tighe DA. Cardiac mechanics in mild hypertensive heart disease: a speckle-strain imaging study. Circ Cardiovasc Imaging 2009;2:382–390. 28. Tanaka H, Oishi Y, Mizuguchi Y, et al. Three-dimensional evaluation of dobutamine-induced changes in regional myocardial deformation in ischemic myocardium using ultrasonic strain measurements: the role of circumferential myocardial shortening. J Am Soc Echocardiogr 2007;20:1294 –1299. 29. Cho GY, Marwick TH, Kim HS, Kim MK, Hong KS, Oh DJ. Global 2-dimensional strain as a new prognosticator in patients with heart failure. J Am Coll Cardiol 2009;54:618 – 624.
Introduction The fragmented QRS (fQRS) complex identified on surface electrocardiogram (ECG) has been shown to occur in various cardiac conditions.1 In patients with coronary artery disease (CAD) with or without prior myocardial infarction (MI), the fQRS complex predicted the occurrence of adverse clinical outcomes and sudden cardiac death.2– 4 The presence of the fQRS complex in patients with CAD was associated with regional myocardial damage and had a greater sensitivity and negative predictive value than did Q
This study was supported by the General Research Fund of the Research Grant Council of Hong Kong (HKU 7777/07M and HKU 7775/08M). Address reprint requests and correspondence: Dr Hung-Fat Tse, MD, PhD, Department of Medicine, Cardiology Division, Queen Mary Hospital, The University of Hong Kong, Room 1928, Block K, Hong Kong. E-mail address: [email protected].
confidence interval 1.06⫺1.33; P ⫽ .003) and multivessel disease (odds ratio 3.69; 95% confidence interval 1.35⫺10.08; P ⫽ .011). Kaplan-Meier analysis revealed that event-free survival for cardiac events was significantly lower in the fQRS group than in the non-fQRS group (P ⫽ .036). CONCLUSIONS Our results demonstrated that the fQRS complex in patients with CAD with preserved LV ejection fraction was associated with subclinical global and regional LV dysfunctions as detected by 2-dimensional speckle-tracking imaging, and the results also predicted adverse cardiac events. KEYWORDS Fragmented QRS; Coronary artery disease; Strain; Strain rate ABBREVIATIONS CAD ⫽ coronary artery disease; ECG ⫽ electrocardiogram/electrocardiographic; fQRS ⫽ fragmented QRS; LV ⫽ left ventricular; LVEF ⫽ left ventricular ejection fraction; MI ⫽ myocardial infarction; WMSI ⫽ wall motion score index (Heart Rhythm 2012;9:928–935) © 2012 Heart Rhythm Society. All rights reserved.
waves on surface ECG for the detection of a myocardial scar.1,5,6 It has been postulated that a myocardial scar and/or ischemia in patients with CAD lead to heterogeneous ventricular activation, thus causing fragmentation of the QRS complex in ECG.7–9 In patients with nonischemic dilated cardiomyopathy and narrow QRS complex, the fQRS complex was associated with a significant intraventricular systolic dyssynchrony.10,11 However, the relationship between the fQRS complex and global and regional left ventricular (LV) functions in patients with CAD with preserved LV function is unknown. The purpose of this study was to investigate the relationship between the fQRS complex and the LV function as determined by a detailed echocardiographic examination, including 2-dimensional (2D) speckle-tracking imaging in patients with CAD with narrow QRS complex and preserved LV ejection fraction (LVEF) (⬎45%).
1547-5271/$ -see front matter © 2012 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2012.01.007
Yan et al
Ventricular Strain and Fragmented QRS
Methods Study population Consecutive patients with an established diagnosis of CAD in whom ⬎50% stenosis in at least 1 major coronary artery as documented by coronary angiogram were recruited from an outpatient clinic. All patients with significant and symptomatic CAD had received successful coronary revascularization before recruitment. All patients had stable CAD and received consistent medications for at least 12 months before enrollment. Patients who had a documented history of congestive heart failure, severe valvular heart disease, cardiomyopathy, persistent atrial fibrillation, permanent pacemaker or implantable cardioverter-defibrillator implantation, recent MI, unstable angina, coronary revascularization, or stroke within the last 6 months and LVEF ⱕ 45% as measured by echocardiogram were excluded. Furthermore, patients with coexisting ECG abnormalities, including typical or incomplete bundle branch block pattern and QRS duration ⱖ 120 ms that precluded the assessment of the fQRS complex, were also excluded. This study was approved by the local institutional review board, and informed consent was obtained from all participants.
ECG criteria for the assessment of the fQRS complex The resting 12-lead ECG (model Mac 5000; filter range 0.15–150 Hz; 25 mm/s; 10 mm/mV; GE Marquette, Milwaukee, WI) was analyzed by 2 independent readers blinded to the clinical and echocardiographic data. There was 98% concordance for the ECG signs. In case of disagreement, the final diagnosis was achieved by mutual agreement. In this study, the fQRS complex was defined by the presence of various RSR= patterns (QRS duration ⬍ 120 ms) with or without Q wave—which include an additional R wave (R=), notching of the R wave, and notching in the nadir of the S wave— or the presence of more than 1 R= (fragmentation) in 2 contiguous leads corresponding to a major coronary artery territory, as described previously.5 The presence of the fQRS complex in ⱖ2 contiguous anterior leads (V1-V5) corresponded to anterior myocardial segments or left anterior descending territory; the presence of
Figure 1
929 the fQRS complex in ⱖ2 contiguous lateral leads (I, aVL, and V6) corresponded to the lateral myocardial segments or left circumflex territory; and the presence of the fQRS complex in ⱖ2 contiguous inferior leads (II, III, and aVF) corresponded to the inferior myocardial segments or right coronary artery territory. The fQRS complex was also seen in ⬎1 coronary artery territory in the same patients (Figure 1). Patients with fQRS complexes in at least 1 major coronary artery territory on a resting 12-lead ECG were defined as the fQRS group, and the remaining patients without fQRS complex were defined as the non-fQRS group.
Echocardiographic examination Detailed echocardiography was performed in all patients to determine global and regional LV functions by using a commercially available system (Vivid 7, GE Vingmed-General Electric, Horton, Norway). LV dimensions were measured by 2D-guided M-mode echocardiography according to the guidelines of the American Society of Echocardiography,12 and LVEF was measured by using the modified biplane Simpson’s method from apical 4- and 2-chamber views. Mitral inflow E velocity and its deceleration time as well as mitral inflow A velocity were measured by using pulse wave Doppler, with the sample volume placed at the tips of the mitral valve from the apical 4-chamber view. The ratio of mitral inflow E velocity to septal wall myocardial e= velocity (E/e=sep) measured by using the pulsed tissue Doppler spectrum was calculated as an index of LV filling pressure.13 For speckle-tracking analysis, standard grayscale 2D images were acquired in the 4-chamber, 2-chamber, and apical views as well as the parasternal short-axis views at the mitral valve, papillary muscle, and apical levels with a frame rate of at least 60 frames/s. Data were stored in the cine-loop format and transferred to the workstation (EchoPac-PC, version 6.1.2, Vingmed-General Electric, Horton, Norway) for further off-line analysis. The endocardial border was manually traced, and the region-of-interest width was manually adjusted to include the entire myocardium. The software then automatically traced and analyzed (Figure 2). The left ventricle was divided into 18 segments (6 basal, 6 mid, and 6 apical), and
Example of a 12-lead electrocardiogram showing fragmented QRS complex over inferior leads and precordial lead V5.
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Heart Rhythm, Vol 9, No 6, June 2012
Figure 2 Examples of echocardiographic images of radial strain (A, D), circumferential strain (B, E), and longitudinal strain (C, F) measurements in patients with (left) or without (right) fragmented QRS complex.
each segment was analyzed individually.14 Two-dimensional longitudinal strain was assessed in 3 apical planes; 2D circumferential strain and radial strain were assessed in 3 parasternal short-axis planes. Systolic longitudinal strain rate, circumferential strain rate, and radial strain rate were assessed simultaneously. Peak systolic longitudinal strain and strain rate were calculated by averaging the peak systolic values of the 18 segments derived from the 6 segments of the 3 apical views (2- and 4-chamber and apical long-axis views). Peak systolic radial and circumferential strain and strain rate values were calculated by averaging the peak systolic values of the 18 segments from the 3 parasternal LV short-axis views. Interobserver measurement variability was determined by a second independent, blinded observer who measured LV strain parameters in 10 randomly selected patients. The intraobserver variability was determined by repeating the LV strain measurements by the first observer in another group of 10 randomly selected patients 1 month later. The
interobserver and intraobserver variabilities for measuring longitudinal, radial, and circumferential strains determined by using 2D speckle-tracking imaging were 6.5% and 2.6%, 10.4% and 7.6%, 4.9% and 2.4%, respectively. Wall motion was assessed semiquantitatively by an experienced observer by using a 16-segment, 4-point scale model of the left ventricle, where 1 ⫽ normal motion, 2 ⫽ hypokinesia, 3 ⫽ akinesia, and 4 ⫽ dyskinesia.15 The wall motion score index (WMSI) for each patient was calculated as the ratio between the sum of scores and the number of visualized segments.
Follow-up All patients were prospectively followed-up in our outpatient clinics or until they left the cohort through death. Information on deaths during the follow-up period after recruitment was retrieved from medical records and discharge summaries from our hospital as well as other institutions. The presence of a major adverse cardiac event was
Yan et al
Ventricular Strain and Fragmented QRS
931
Table 1 Comparison of demographic characteristics between patients with and without fQRS complex
Age (y) Sex male, n (%) Body mass index (kg/m2) Smoking, n (%) Hypertension, n (%) Diabetes mellitus, n (%) Myocardial infarction, n (%) PCI, n (%) CABG, n (%) Diseased vessel, n (%) Single vessel Multivessel Mean systolic BP (mm Hg) Mean diastolic BP (mm Hg) Mean QRS duration (ms) Total cholesterol (mmol/L) LDL-C (mmol/L) HDL-C (mmol/L) Triglycerides (mmol/L) Fasting glucose (mmol/L) Hb A1c (mmol/L) Medications, n (%) Diuretics Long-acting nitrates Beta-blocker Calcium-channel blocker ACEI or ARB Statins Aspirin Clopidogrel
fQRS group (n ⫽ 55)
Non-fQRS group (n ⫽ 121)
68 ⫾ 11 50 (91) 25.5 ⫾ 3.4 36 (67) 30 (55) 19 (35) 19 (35)
68 ⫾ 9 95 (79) 24.9 ⫾ 2.8 61 (51) 82 (68) 48 (40) 34 (29)
.76 .055 .21 .070 .095 .62 .48
42 (76) 7 (13)
86 (71) 11 (9)
.58 .59
15 (27) 40 (73) 142 ⫾ 18 83 ⫾ 8
63 (52) 58 (48) 145 ⫾ 19 82 ⫾ 8
.003 .003 .37 .80
97 ⫾ 12 4.14 ⫾ 0.64
91 ⫾ 10 4.12 ⫾ 0.70
.001 .87
2.30 1.19 1.48 6.04 6.79
⫾ ⫾ ⫾ ⫾ ⫾
.82 .66 .95 .50 .43
18 62 91 34 76 113 113 7
(15) (52) (76) (28) (63) (94) (94) (6)
2.28 1.17 1.50 6.27 7.00 15 30 43 7 44 52 54 7
⫾ ⫾ ⫾ ⫾ ⫾
(27) (55) (78) (13) (80) (95) (98) (13)
0.54 0.28 0.60 1.97 1.51
0.56 0.33 1.33 2.02 1.59
P
.063 .87 .85 .033 .035 1.00 .44 .14
ACEI ⫽ angiotensin-converting enzyme inhibitor; ARB ⫽ angiotensinreceptor blocker; BP ⫽ blood pressure; CABG ⫽ coronary artery bypass surgery; fQRS ⫽ fragmented QRS; Hb A1c ⫽ hemoglobin A1c; HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; PCI ⫽ percutaneous coronary intervention.
defined as deaths due to cardiac causes, acute coronary event, or symptom-driven coronary revascularization procedures. Deaths due to cardiac causes were defined as deaths due to lethal cardiac arrhythmias, MI, heart failure, or unexplained sudden deaths.
Statistical analysis Continuous variables are expressed as mean ⫾ SD and categorical variables as frequencies and percentages. Comparisons of continuous variables were performed by using 2-sample Student t tests, and comparisons of dichotomous variables were performed by using 2 tests. Multivariate logistic regression analysis was performed to determine the association of the fQRS complex with clinical and echocardiographic parameters. Survival curves were constructed according to the Kaplan-Meier method with comparison by the log-rank test. Furthermore, Cox regression analysis was
performed to determine the predictors of clinical outcomes. All analyses were performed by using SPSS statistical software (version 15.0 for Windows, SPSS, Inc, Chicago, IL). A P value of ⬍.05 was considered statistically significant.
Results Study population Of the 193 consecutive CAD patients recruited, 17 (9%) patients were excluded because of complete or incomplete right bundle branch block (n ⫽ 12), left bundle branch block (n ⫽ 4), and Wolff-Parkinson-White syndrome (n ⫽ 1). As a result, the analysis included a total of 176 patients (mean age 68 ⫾ 9 years; 145 [82%] men). The fQRS complex was detected in at least 1 coronary artery territory in 55 (31%) patients. The baseline clinical characteristics of patients with CAD in the fQRS group and the non-fQRS group are shown in Table 1. There were no significant differences in age, the prevalence of man, hypertension, smoking, diabetes mellitus, and history of MI and coronary revascularization between the 2 groups (all P ⬎.05). However, patients in the fQRS group were more likely to have multivessel CAD than those in the non-fQRS group (78% vs 48%; P ⫽ .003). Furthermore, the fQRS group had significantly longer mean QRS duration and more likely to receive angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker but less likely to treat with calcium-channel blockers as compared with the non-fQRS group (all P ⬍.05; Table 1).
Echocardiographic findings All patients had preserved LVEF, and their mean LVEF was 57% ⫾ 12%. As shown in Table 2, the fQRS group had Table 2 Conventional echocardiographic parameters in patients with and without fQRS complex fQRS group (n ⫽ 55) LV end-diastolic diameter (cm) LV end-systolic diameter (cm) LV end-diastolic volume (mL) LV end-systolic volume (mL) LVEF (%) Left atrial dimension (cm) Mitral inflow E (cm/s) Deceleration time (ms) Mitral inflow A (cm/s) E/A ratio IVRT (ms) TR pressure (mm Hg) WMSI
Non-fQRS group (n ⫽ 121)
5.09 ⫾ 0.89 4.76 ⫾ 0.56
P .003
3.68 ⫾ 1.07 3.15 ⫾ 0.72 ⬍.001 98.3 ⫾ 35.4 81.1 ⫾ 29.3
.001
51.5 ⫾ 27.9 35.4 ⫾ 22.4 ⬍.001 52 3.88 69 230 83 0.90 97 22 1.26
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
12 59 ⫾ 12 ⬍.001 0.56 3.77 ⫾ 0.51 .24 24 67 ⫾ 17 .44 69 230 ⫾ 62 .96 18 83 ⫾ 20 .99 0.53 0.86 ⫾ 0.40 .60 21 95 ⫾ 20 .56 9 22 ⫾ 9 .79 0.44 1.10 ⫾ 0.23 .002
E/A ⫽ the ratio of mitral E velocity to mitral A velocity; fQRS ⫽ fragmented QRS; IVRT ⫽ isovolumic relaxation time; LV ⫽ left ventricular; LVEF ⫽ left ventricular ejection fraction; TR ⫽ tricuspid regurgitation; WMSI ⫽ wall motion score index.
932 Table 3
Heart Rhythm, Vol 9, No 6, June 2012 Echocardiographic strain and strain rate parameters in patients with and without fQRS complex
Global longitudinal strain (%) Segmental longitudinal strain (%) Basal level Middle level Apical level Global radial strain (%) Segmental radial strain (%) Basal level Middle level Apical level Global circumferential strain (%) Segmental circumferential strain (%) Basal level Middle level Apical level Global longitudinal systolic strain rate (s⫺1) Segmental longitudinal systolic strain rate (s⫺1) Basal level Middle level Apical level Global radial systolic strain rate (s⫺1) Segmental radial systolic strain rate (s⫺1) Basal level Middle level Apical level Global circumferential systolic strain rate (s⫺1) Segmental circumferential systolic strain rate (s⫺1) Basal level Middle level Apical level
fQRS group (n ⫽ 55)
Non-fQRS group (n ⫽ 121)
P
⫺14.9 ⫾ 4.1
⫺17.8 ⫾ 4.2
⬍.001
⫺14.1 ⫺14.2 ⫺13.9 27.2
⫾ ⫾ ⫾ ⫾
3.9 3.9 8.1 10.8
⫺15.8 ⫺16.9 ⫺19.0 33.4
⫾ ⫾ ⫾ ⫾
3.3 4.1 8.5 13.1
.004 ⬍.001 ⬍.001 .005
29.7 31.5 19.9 ⫺16.4
⫾ ⫾ ⫾ ⫾
13.2 15.0 15.4 3.7
34.7 38.3 27.6 ⫺20.0
⫾ ⫾ ⫾ ⫾
17.6 17.8 19.7 4.9
.08 .02 .01 ⬍.001
⫺13.3 ⫺16.3 ⫺19.5 ⫺1.00
⫾ ⫾ ⫾ ⫾
4.2 5.4 6.7 0.26
⫺16.3 ⫺19.1 ⫺24.5 ⫺1.15
⫾ ⫾ ⫾ ⫾
4.9 6.0 7.8 0.25
.002 .02 .001 .003
⫺1.05 ⫺0.90 ⫺1.06 1.67
⫾ ⫾ ⫾ ⫾
0.28 0.23 0.40 0.43
⫺1.13 ⫺1.02 ⫺1.29 1.83
⫾ ⫾ ⫾ ⫾
0.23 0.21 0.39 0.44
.09 .003 .003 .08
1.85 1.72 1.44 ⫺1.33
⫾ ⫾ ⫾ ⫾
0.52 0.51 0.84 0.33
2.01 1.83 1.67 ⫺1.49
⫾ ⫾ ⫾ ⫾
0.82 0.50 0.72 0.37
.29 .26 .13 .04
⫺1.30 ⫾ 0.42 ⫺1.31 ⫾ 0.49 ⫺1.41 ⫾ 0.47
⫺1.36 ⫾ 0.53 ⫺1.44 ⫾ 0.46 ⫺1.72 ⫾ 0.55
.57 .19 .004
fQRS ⫽ fragmented QRS.
significantly larger LV systolic and diastolic dimension and volume, lower LVEF, and higher WMSI as compared with the non-fQRS group (all P ⬍.05). However, there were no significant differences in atrial dimension, E wave, A wave, and the ratio of mitral E velocity to mitral A velocity between the 2 groups (all P ⬎ .05). As shown in Table 3, the global longitudinal, radial, and circumferential peak systolic strains were markedly reduced in the fQRS group than in the non-fQRS group (all P ⬍.01; Figure 2). Furthermore, the global strain rate was significantly reduced in the fQRS group than in the non-fQRS group, with the exception of the radial strain rate (all P ⬍.05). Segmental analysis revealed that the longitudinal, radial, and circumferential peak systolic strains and strain rates in the middle and apical LV segments were significantly lower in the fQRS group than in the non-fQRS group. In addition, all global strain and strain rate indices were significantly positive with regard to LVEF but negative with regard to WMSI (all P ⬍.01; Table 4).
Relationships between the fQRS complex and clinical and echocardiographic parameters Univariate logistic regression showed that multivessel lesion, QRS duration, treatment with calcium-channel blocker and angiotensin-converting enzyme inhibitor/angiotensin-
receptor blocker, LV dimension, LV volume, LVEF, WMSI, and global strain and strain rate indices were associated with the fQRS complex. However, multivariate loTable 4 Correlations of echocardiographic deformation parameters with left ventricular ejection fraction and wall motion scores index
Global longitudinal strain Global radial strain Global circumferential strain Global longitudinal systolic strain rate Global radial systolic strain rate Global circumferential systolic strain rate
Left ventricular ejection fraction
Wall motion scores index
Correlation coefficient (r)
P
Correlation coefficient (r)
P
.76
⬍.001
⫺.47
⬍.001
.63 .70
⬍.001 ⬍.001
⫺.33 ⫺.37
⬍.001 ⬍.001
.61
⬍.001
⫺.41
⬍.001
.39
⬍.001
⫺.23
.01
.55
⬍.001
⫺.27
.003
Yan et al Table 5
Ventricular Strain and Fragmented QRS
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Relationship between clinical and echocardiographic parameters and the fQRS complex Univariate regression
Age Sex male Myocardial infarction Diabetes mellitus Hypertension Multivessel lesion QRS duration Calcium-channel blocker ACEI or ARB LV end-diastolic diameter LV end-systolic diameter LV end-diastolic volume LV end-systolic volume LVEF WMSI E/A ratio IVRT Deceleration time Global longitudinal strain Global radial strain Global circumferential strain Global longitudinal systolic strain rate Global radial systolic strain rate Global circumferential systolic strain rate
Multivariate regression
Odds ratio, 95% CI
P
Odds ratio, 95% CI
P
0.99,0.96–1.03 0.37,0.13–1.01 1.32,0.67–2.61 0.80,0.41–1.56 0.57,0.30–1.10 2.90,1.45–5.79 1.05,1.02–1.09 0.37,0.15–0.89 2.32,1.08–4.94 1.07,1.02–1.12 1.07,1.03–1.11 1.02,1.01–1.03 1.03,1.01–1.04 0.95,0.93–0.98 4.33,1.59–11.82 1.21,0.60–2.43 1.01,0.99–1.02 1.00,0.99–1.01 1.17,1.08–1.27 0.96,0.93–0.99 1.18,1.07–1.30 9.43,2.03–43.88 0.38,0.13–1.10 3.34,1.05–10.65
.753 .052 .427 .517 .093 .003 .001 .028 .030 .004 .000 .002 .000 .000 .004 .59 .56 .96 .000 .007 .001 .004 .075 .041
— — — — — 3.69,1.35–10.08 — — — — — — — — — — — — — — 1.19,1.06–1.33 — — —
— — — — — .011 — — — — — — — — — — — — — — .003 — — —
ACEI ⫽ angiotensin-converting enzyme inhibitor; ARB ⫽ angiotensin-receptor blocker; CI ⫽ confidence interval; E/A ⫽ the ratio of mitral E velocity to mitral A velocity; fQRS ⫽ fragmented QRS; IVRT ⫽ isovolumic relaxation time; LV ⫽ left ventricular; LVEF ⫽ left ventricular ejection fraction; WMSI ⫽ wall motion score index.
gistic regression analysis after adjusting for all significant variables in univariate analysis revealed that only decreased global circumferential strain (odds ratio 1.19; 95% confidence interval [CI] 1.06 –1.33; P ⫽ .003) and multivessel disease (odds ratio 3.69; 95% CI 1.35–10.08; P ⫽ .011) were associated with the fQRS complex independent of regional wall motion abnormality and LV systolic and diastolic functions (Table 5). Furthermore, receiver operating characteristic analysis was performed for all global deformation indices to assess their sensitivity and specificity for the detection of the fQRS complex. Among all indices, circumferential strain measured by using 2D speckle-tracking imaging was also shown to have the highest sensitivity and specificity for the association with the fQRS complex (area under curve ⫽ 0.73; P ⬍.001).
Clinical outcomes After a mean follow-up of 36 ⫾ 11 months, cardiac events were observed in 40 (22.7%) patients, including cardiac death (n ⫽ 5), acute coronary event (n ⫽ 12), or symptomdriven coronary revascularization procedures (n ⫽ 23), and 9 (5.1%) patients died. Patients with fQRS complex had a significantly higher incidence of cardiac events during follow-up as compared with those without fQRS complex (32.7% vs 18.2%; P ⫽ .036; Figure 3A). However, there was no significant difference in all-cause mortality between the 2 groups (1.8% vs 6.6%; P ⫽ .19; Figure 3B). Multivariate Cox regression analysis revealed that the fQRS com-
plex (hazards ratio 2.69; 95% CI 1.26 –5.75; P ⫽ .01) and LVEF (hazards ratio 0.34; 95% CI 0.12– 0.98; P ⫽ .04) were independent predictors of major cardiac events.
Discussion Our results demonstrated that the fQRS complex in patients with CAD with preserved LVEF and narrow QRS complex was associated with abnormal regional and global 2D circumferential strains. In this study, patients with CAD with fQRS complex had a significantly decreased mechanical deformation function measured by using 2D speckle-tracking imaging, including longitudinal, radial, circumferential strains and strain rates. Furthermore, 2D circumferential strain was significantly associated with the fQRS complex, independent of history of MI and other echocardiographic parameters, including LV systolic and diastolic functions and regional wall motion abnormalities. In addition, the fQRS complex was an independent predictor of increased cardiac events in patients with CAD. Recent studies have shown that the presence of the fQRS complex on a 12-lead ECG predicts cardiac events in several populations. The fQRS complex has been associated with an increased mortality risk in patients with acute coronary syndrome16 and higher rates of spontaneous ventricular tachyarrhythmias among patients with Brugada syndrome17 and arrhythmogenic right ventricular dysplasia.18 Although the underlying mechanism remains unclear, it has been proposed that the fQRS complex might represent in-
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Heart Rhythm, Vol 9, No 6, June 2012
Figure 3 Kaplan-Meier analysis of event-free survival for (A) cardiac events (myocardial infarction, need for revascularization, or cardiac death) and (B) all-cause mortality in patients with fragmented QRS complex (fQRS group) and without fragmented QRS complex (non-fQRS group).
homogeneous activation7 and conduction abnormalities17 within a relatively large area of pathological (scar) or physiologically abnormal (ischemia) myocardium. The presence of a myocardial scar or ischemia is associated with a poor prognosis because of an increased risk for ventricular tachyarrhythmias and heart failure.5–7,19,20 Therefore, the presence of the fQRS complex on a routine 12-lead ECG has been proposed as a potential novel marker of depolarization abnormality and myocardial scar in patients with known or suspected cardiac diseases, which is associated with increased adverse cardiac events and mortality. Recent studies also suggested that segmented LV wall abnormalities were associated with increased arrhythmic events presumably because of patchy myocardial scars.21 However, the relationship between the fQRS complex and regional LV wall abnormalities, especially in patients with preserved LVEF and narrow QRS complex, remains unclear. The movement or deformation of the LV myocardium is 3D, which can be expressed in the 3 coordinates as longitudinal shortening, circumferential compression, and radial thickening. These myocardial shortening can be measured from strain and strain rate measurements by using echocardiography.22,23 Recent studies24 –27 have demonstrated that the measurement of strains and strain rates with speckletracking imaging can detect more subtle regional changes as compared with conventional echocardiographic measurements of LV systolic function in various cardiac diseases. Indeed, our results showed that most of the global strain and strain rate indices have only weak to moderate correlation with conventional echocardiographic index of LV function using LVEF and WMSI, as they measure intrinsic myocardial contractility rather than a semiquantitative assessment of LV function. In this study, we hypothesized that the fQRS complex is associated with subclinical regional LV abnormalities as detected by 2D speckle-tracking imaging in
patients with CAD with preserved LVEF and narrow QRS complex. The results of this study showed that up to 30% of patients with CAD with preserved LV function had the fQRS complex. Those patients with CAD with fQRS complex had more dilated LV dimension, lower LVEF, higher WMSI, and reduced regional and global 2D strains as compared with those without fQRS complex. Nevertheless, there were no significant differences in the conventional indexes of diastolic function between patients with or without fQRS complex. This reflects that conventional indexes of diastolic function are semiquantitative and rather insensitive to distinguish patients with subtle LV dysfunction. Furthermore, among different echocardiographic parameters, decreased global circumferential strain had the highest sensitivity and specificity with respect to the association with the fQRS complex independent of regional wall motion abnormality. In this study, patients with CAD with fQRS complex had decreased circumferential but not radial strain and strain rate indices. Previous studies28 have shown that the level of contribution of circumferential fibers to LV myocardial thickening is greater than that of longitudinal fibers. As a result, circumferential myocardial shortening deteriorates to a greater extent during myocardial ischemia among 3-dimensional deformations. Therefore, changes in circumferential strain and strain rate indices are more sensitive and closely related with prognosis than are longitudinal strain measurements in patients with heart failure.29 On the other hand, as a transmural infarct or scar is associated with a reduction in both long-axis and short-axis functions, the lack of difference in the radial strain and strain rate suggested that the fQRS complex in patients with CAD with preserved LVEF is likely related to nonhomogeneous intraventricular activation and uncoordinated depolarization in ischemic rather than infarcted myocardium.
Yan et al
Ventricular Strain and Fragmented QRS
Indeed, the higher adverse cardiac events in patients with fQRS complex were mainly attributed to an increased acute coronary event or symptom-driven coronary revascularization procedures. These results provide further evidences to show that the fQRS complex was associated with subclinical regional LV abnormalities revealed by 2D circumferential strain and the presence of multivessel diseases even in stable patients with CAD with preserved LVEF. In addition, our results confirmed the previous findings2– 4,20 and showed that the fQRS complex predicted the occurrence of adverse cardiac events in these patients. Thus, the fQRS complex can be used as a simple and noninvasive marker to identify a high-risk subgroup of patients with stable CAD for more aggressive medical therapy, including coronary revascularization.
Study limitations In this study, patients with stable CAD with preserved LVEF were included. As a result, the numbers of hard clinical outcomes were limited in these relatively low-risk patients and other less hard clinical end points including acute coronary event or symptom-driven coronary revascularization procedures were included.
Conclusions Our results demonstrated that the fQRS complex was observed in up to 30% of the patients with CAD with preserved LVEF and narrow QRS complex as well as predicted increased adverse cardiac events. Patients with fQRS complex have significantly more global and regional impairments of LV function as detected by conventional and 2D speckle-tracking echocardiographic imaging as compared with patients without fQRS complex. Furthermore, among different echocardiographic parameters, 2D circumferential strain had the strongest association with the predictor of the occurrence of the fQRS complex in patients with CAD. These findings suggest that the fQRS complex can be used as a simple and noninvasive marker to identify a high-risk subgroup of patients with stable CAD with subclinical global and regional LV dysfunction and increased adverse cardiac events.
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