Cardiac resynchronization therapy (CRT) is an effective option in the treatment of patients with heart failure (HF) and wide QRS. Fragmented QRS (fQRS) on 12-lead electrocardiography has been shown to predict cardiac events in several patient populations. However, the relationship between the number of leads with fQRS and response to CRT has not been investigated.
The number of leads with fQRS may predict response to CRT.
One hundred five patients with HF undergoing CRT were prospectively studied. The presence of fQRS was assessed using standardized criteria. Echocardiographic response to CRT was defined by a ≥15% reduction in left ventricular end-systolic volume at 6 months follow-up.
Seventy-four patients (71%) had CRT response after 6 months of follow-up. In multivariate analysis, significant associates of response to CRT were evaluated adjusting for gender, etiology of cardiomyopathy, QRS width, baseline left ventricular ejection fraction, and the number of leads with fQRS. The number of leads with fQRS was the only predictor of response to CRT (odds ratio: 0.61, 95% confidence interval: 0.48-0.77, P < 0.001).
The more leads with fQRS predicts nonresponse to CRT and may help in the selection of CRT candidates. Clin. Cardiol. 2011 DOI: 10.1002/clc.22061
The authors have no funding, financial relationships, or conflicts of interest to disclose.
Cardiac resynchronization therapy (CRT) has been established as an important therapy for patients with symptomatic heart failure (HF), prolonged QRS duration, and reduced ejection fraction. CRT has been proven to reduce symptoms and hospitalizations for HF, improve exercise capacity and quality of life, and reduce mortality.1
Fragmented QRS (fQRS), defined by unexpected deviations in the QRS morphology on 12-lead electrocardiography (ECG), has been shown to predict cardiac events in patients with coronary artery disease, acute coronary syndrome, and ischemic and nonischemic cardiomyopathy.2–5 fQRS was also found to be a predictor of sudden cardiac death in patients with arrhythmogenic right ventricular dysplasia and Brugada syndrome.4,6 Recently, fQRS was not found to be a predictor of ventricular remodeling or mortality in HF patients undergoing CRT.7 However, whether the number of leads with fQRS has a predictive value in patients undergoing CRT remains unknown. We aimed to investigate the relationship between the number of leads with fQRS and response to CRT.
We prospectively studied 105 HF patients who underwent CRT at our institution. The indications for CRT were severe HF (New York Heart Association class III or IV) despite optimal medical therapy, left ventricular ejection fraction (LVEF) ≤35%, QRS duration ≥120 ms. All of the patients had left bundle branch block (LBBB). Patients with non-LBBB morphology were excluded from the study. The etiology of HF was considered ischemic in the presence of significant coronary artery disease (>50% stenosis in ≥1 of the major coronary arteries) and/or a history of myocardial infarction or previous revascularization. All patients received optimal pharmacological treatment before and after pacemaker implantation.
Written informed consent was obtained from all patients. The study was approved by the local ethics committee.
The resting 12-lead ECGs (0.5–150 Hz, 25 mm/s, 10 mm/ mV) were analyzed by 2 independent clinicians blinded to study design, echocardiographic findings, and follow-up data. The fQRS with bundle branch block (BBB) morphology was defined as the presence of >2 notches (at least 1 notch more than the typical BBB) or multiple notches of the R wave, or >2 notches in the nadir of the S wave (Figure 1).8 There was a 99% of concordance for fQRS and nonfragmented QRS. In case of disagreement, the final diagnosis was achieved by mutual consent.
All pacemaker implantations were performed by left infraclavicular approach. Right atrial and right ventricular leads were implanted using a transvenous approach. Left ventricular leads were positioned by a transvenous approach through the coronary sinus in a lateral, posterior, or posterolateral cardiac vein. The atrioventricular delay was optimized using Doppler echocardiographic measurements of transmitral flow 1 week after implantation.
All patients underwent transthoracic echocardiography before and 6 months after CRT implantation. Patients were imaged in the left lateral decubitus position with a commercially available system (VIVID 7; General Electric-Vingmed Ultrasound, Horten, Norway). Images were obtained with a 2.5-MHz broadband transducer at a depth of 16 cm in the parasternal and apical views (standard long-axis, 2- and 4-chamber images). Standard 2-dimensional and color Doppler data triggered to the QRS complex were saved in cine-loop format. Left ventricular volumes were calculated using the Teicholz method, and left ventricular ejection fraction (LVEF) was calculated from the conventional apical 2- and 4-chamber images using the biplane Simpson technique.9 All echocardiographic measurements after CRT implantation were made with the device in active pacing mode. Echocardiographic response to CRT was defined by a ≥15% reduction in left ventricular end-systolic volume (LVESV) at 6 months follow-up.10
All analyses were performed with the statistical software program SPSS version 13.0 (IBM, Armonk, NY). Continuous data were expressed as mean (standard deviation). Categorical variables were compared by the χ2 or Fisher exact test. The Mann-Whitney U test was used to assess differences in clinical and baseline echocardiographic findings between responder and nonresponder patients. A comparison of the echocardiographic variables before and after CRT was performed by paired sample t test or Wilcoxon signed rank test. Variables associated with CRT response in univariate analysis were entered into a forward stepwise logistic regression model. A receiver operating characteristic curve was used to determine the best cutoff number of the leads with fQRS. The best cutoff number was defined as the point with the highest sum of sensitivity and specificity. A value of P < 0.05 was considered statistically significant.
A total of 105 patients (65 male; mean age, 63 ± 12 years) were included in the study. Baseline data of the study population are outlined in Table 1. The baseline clinical and echocardiographic findings of patients with responders and nonresponders showed no statistically significant difference, except the number of leads with fQRS (Table 2). A fQRS was found in ≥1 lead(s) in 48 (46%) patients. The distribution of the number of leads with fQRS is shown in Figure 2. Nine patients were hospitalized for decompensated HF during follow-up.
Table 1. Patient Characteristics (n = 105)
63 ± 12
Abbreviations: ACE, angiotensin-converting enzyme; ARB; angiotensin receptor blocker; fQRS, fragmented QRS; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.
Atrial fibrillation (n/%)
3.1 ± 0.3
No. of leads with fQRS
1.6 ± 2.4
146 ± 18
23 ± 6
Use of ACE-inhibitors or ARB (n/%)
Use of β-blocker
Use of diuretic
Table 2. Baseline Clinical and Echocardiographic Parameters of Responder and Nonresponder Patients
Responders (n = 74)
Nonresponders (n = 31)
Abbreviations: CMP, cardiomyopathy; fQRS, fragmented QRS; LAD, left atrial diameter; LVEDD, left ventricular end-diastolic diameter; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic diameter; LVESV, left ventricular end-systolic volume; NYHA, New York Heart Association; RVD, right ventricular diameter.
63 ± 11
64 ± 13
3 ± 0.4
3.1 ± 0.3
Ischemic CMP (n/%)
66 ± 8
68 ± 10
53 ± 10
54 ± 15
44 ± 7
45 ± 6
25 ± 3
26 ± 3
23.2 ± 5.8
21.5 ± 5.3
219 ± 65
227 ± 83
144 ± 53
147 ± 75
147 ± 19
150 ± 18
Number of leads with fQRS
0.9 ± 1.5
3.4 ± 3
Seventy-four patients (71%) had response to CRT. After 6 months, LVESV had significantly decreased from 144 ± 53 to 92 ± 38 in responders (P = 0.001). There was no significant decrease in LVESV in nonresponders at 6 months follow-up (147 ± 75 vs 144 ± 60, P = 0.56). LVEF had increased from 23.2 ± 5.8 to 34.3 ± 10.1 in responders (P = 0.001). There was no significant change in LVEF in nonresponders at 6 months follow-up (21.5 ± 5.3 vs 23.0 ± 4.7, P = 0.07).
In multivariate analysis, significant associates of response to CRT was evaluated adjusting for gender, etiology of cardiomyopathy, QRS width, baseline LVEF, and the number of leads with fQRS. The number of leads with fQRS was the only predictor of response to CRT (odds ratio 0.61, 95% confidence interval: 0.48-0.77, P < 0.001).
The best cutoff number of leads with fQRS to distinguish between responder and nonresponder patients was 1 (Figure 3). This cutoff number yielded a sensitivity and specificity of 68.9% and 81.6%, respectively.
To the best of our knowledge, our study is the first study that investigates the prognostic significance of the number of leads with fQRS in HF patients who underwent CRT. Cardiac resynchronization therapy is considered an important treatment option for patients with wide QRS and advanced CHF who are on optimal medical treatment. However, an important proportion of patients do not respond to CRT, although they are selected according to current patient selection criteria.11,12 Therefore, additional selection criteria for CRT are needed to increase the likelihood of response.
Fragmentation in the QRS complex is a result of myocardial scar that causes heterogeneous ventricular activation and dyssynchronous contraction.13 It has been previously shown that fQRS is associated with adverse events in patients with ischemic and nonischemic cardiomyopathy.7 fQRS is associated with the presence of myocardial scar, cardiac death, need for revascularization, arrhythmic events, and all-cause mortality in patients with coronary artery disease.7,14 fQRS is associated with the presence of scar on cardiac magnetic resonance imaging, increased arrhythmic events, and higher rates of all-cause mortality in patients with nonischemic cardiomyopathy.15 Both number of maxima and the duration of the fQRS complex have been shown to have an inverse relationship with LVEF in patients with idiopathic dilated cardiomyopathy.6
In our study, approximately one-third (29%) of patients were nonresponders. Although QRS duration was longer in nonresponder patients, the difference between responder and nonresponder patients was not significant. The only significant parameter between responder and nonresponder patients was the number of leads with fQRS. The mean number for fQRS was significantly higher in nonresponder patients. This finding supports that there are other electrocardiographic signs, such as number of leads with fQRS, besides QRS duration and QRS morphology on ECG that could give information about the disease extent and response to CRT.
The importance of baseline cardiac dimensions in the prognosis and response to CRT has been reported.16,17 The mean left ventricular end-diastolic diameter (LVEDD) in nonresponder patients is larger than responder patients. Although the difference is statistically not significant, larger LVEDD in patients with nonresponse may relate to more progressive disease, extensive scar tissue, and impaired contraction.
The increased number of leads with fQRS in our patients with nonresponse may relate to reduced LVEF, increased LVEDD, and the presence of more progressive disease and extensive scar tissue. Our data suggest that the number of leads with fQRS may provide useful information for predicting response to CRT.
We acknowledge that there were limitations in this study. One limitation of our study was the single-center nonrandomized design. Second, we had not assessed the presence of myocardial scar. Third, we had not investigated the intraventricular dyssynchrony in our patients. However, our data reflect a real-life situation in many cardiology departments where CRT guidelines are used. Fourth, we had excluded patients with non-LBBB undergoing CRT. A larger study population that includes CRT patients with all QRS morphologies might bring more significance to the presented data. Further studies are needed to confirm our findings.
The more leads with fQRS predicts nonresponse to CRT and may help in the selection of CRT candidates.