Available online at www.sciencedirect.com
ScienceDirect Journal of Electrocardiology 48 (2015) 689 – 695 www.jecgonline.com
Effect of heart rate on the intrinsic and the ventricular-paced QRS duration John Chiladakis, MD,⁎ Andreas Kalogeropoulos, MD, Fani Zagkli, MD, Konstantinos Chouchoulis, MD Cardiology Department, Patras University Hospital, 26500 Rion, Patras, Greece
Abstract
Background: We evaluated the effect of heart rate on the intrinsic and the ventricular-paced QRS duration in implanted device recipients with normal or reduced left ventricular ejection fraction (EF). Methods: We studied 239 outpatients with preserved intrinsic ventricular activation and normal (n = 92) or reduced (n = 147) EF who had apical (RVA) or mid-septal (RVS) right ventricular lead position. The QRS duration was measured at baseline and during atrial-based pacing at increased heart rate to ensure intrinsic or ventricular-paced QRS activation. Results: The heart rate increase shortened the intrinsic QRS only in patients with normal EF, and further prolonged the ventricular-paced QRS in patients with reduced EF and either narrow or wide QRS (p b 0.001), irrespective of RVA or RVS pacing (p b 0.01). Conclusion: Heart rate increase is associated with further QRS prolongation in patients with reduced EF, regardless of RVA or RVS pacing site. © 2015 Elsevier Inc. All rights reserved.
Keywords:
Heart rate; QRS duration; Right ventricular apical vs septal pacing
Introduction The QRS duration is a dynamic component of the 12-lead electrocardiogram (ECG), subject to the influence of several factors, including the heart rate [1–3]. Still, assessment of the QRS duration is practically based on fixed measurements during resting heart rate. Little is known about the behavior of QRS duration in response to an increase in heart rate, which may occur even during resting conditions. This consideration largely applies also to cardiac device patients with ventricular-paced rhythm. Nonetheless, based primarily on QRS duration data derived from patients studied at rest, alternative right ventricular septal (RVS) pacing has been suggested in light of the deleterious consequences of traditional right ventricular apical (RVA) pacing [4,5]. The aim of the present study was to investigate the effect of heart rate on the intrinsic and the ventricular-paced QRS duration in implanted dual-chamber device recipients with normal or reduced left ventricular ejection function (EF) and in relation to RVA vs RVS pacing. Methods Patients We studied 239 outpatients (mean age 69 ± 10) who were chronically implanted with a dual-chamber pacemaker or ⁎ Corresponding author at: Agias Lavras, 26504 Platani, Patras, Greece. E-mail address: [email protected] http://dx.doi.org/10.1016/j.jelectrocard.2015.04.009 0022-0736/© 2015 Elsevier Inc. All rights reserved.
implantable cardioverter defibrillator (ICD) system due to symptomatic sinus bradycardia or ventricular tachyarrhythmias, respectively. Eligible patients were on sinus rhythm with preserved long-term intrinsic ventricular activation. The patients were classified into 4 subgroups on the basis of the underlying EF and the presence of narrow QRS complex (b 120 ms) or wide QRS complex (≥ 120 ms) at resting heart rate: normal EF/narrow QRS; normal EF/wide QRS; reduced EF/narrow QRS; reduced EF/wide QRS. Normal EF patients did not have apparent structural heart disease and had an EF ≥ 55%, whereas patients with reduced EF had ischemic or nonishemic cardiomyopathy based on history or objective assessment of coronary artery disease from coronary angiography. Standard two-dimensional echocardiographic measurements were performed to obtain cardiac dimensions and wall contraction abnormalities. The EF was measured using the Simpson's method. Patients were excluded if they had symptoms or signs of decompensated heart failure on the basis of physical examination and chest X-ray, or had recent history of atrial or ventricular tachyarrhythmia. In all patients, atrial screw-in leads were implanted in the right atrial appendage and ventricular leads were positioned either passive at the RVA or active at the RVS site. The left anterior oblique fluoroscopy view was used to confirm septal lead attachment at the lower portion of the right ventricular outflow tract, when possible, or mid-septal segment of the right ventricle [6]. The decision of ventricular lead position site was left to the discretion of the implanter. The stability of
690
J. Chiladakis et al. / Journal of Electrocardiology 48 (2015) 689–695
sinus rhythm and underlying atrioventricular conduction was documented by previous ECGs, and retrieved data from device event counters and histograms, when possible, at planned follow-up visits. Patients with an ICD were receiving long-term amiodarone. Study protocol The patients were studied in supine position under standardized conditions and continuous ECG monitoring. Dual-chamber devices had been programmed at implantation with a fixed long atrioventricular delay and all available algorithms activated to promote intrinsic ventricular activity. Resting baseline ECG measurements with the intrinsic narrow or wide QRS were taken during spontaneous sinus rhythm or at the lowest programmed pacing rate. Then, devices were programmed in DDD mode with long atrioventricular delay in order to allow with atrial-based pacing at 100 beats/min intrinsic atrioventricular QRS activation. For ventricular pacing, devices were programmed in DDD mode with the atrioventricular delay set short at 100 ms at the lowest heart rate, and then at 100 beats/min, in order to induce complete ventricular capture. ECG measurements at each pacing stage were obtained after approximately 30-sec of constant captured pacing. The ECG was continuously monitored to ensure constant and stable 1:1 atrioventricular conduction during the pacing tests, when possible. Electrocardiogram recordings showing atrioventricular conduction block or ventricular fusion were discarded, whereby careful attention was also paid to exclude intrinsic QRS patients with an initially narrow QRS if they developed a bundle-branch block during atrial pacing at 100 beats/min. Measurements were performed during routine follow-up visits in the context of assessing proper device function. ECG measurements Standard 12-lead ECGs were recorded throughout the study using a MAC-VU electrocardiograph (Marquette Medical Systems, Milwaukee, Wisconsin) at a paper speed of 25 mm/sec. The widest QRS duration was taken defined as the maximum QRS duration occurring in any of the 12 ECG leads and was determined as the interval between the initial QRS depolarization and the J point. The earliest onset and the latest offset were considered to define the lead with the widest QRS complex mostly from the three simultaneously precordial leads V1–V3 or alternatively from the leads I–III. The J point was taken at the beginning of the isoelectric ST segment, or if this landmark was not distinguishable, the tangent to the descending part of the R wave or the ascending part of the S wave and the isoelectric line was drawn through the ST segment. Standard ECG criteria were used to diagnose complete bundle branch block (BBB) of left BBB (LBBB) or right BBB (RBBB) morphology with QRS duration ≥ 120 ms. Patients with incomplete BBB were included in the narrow QRS patient group. Measurements of RR and PR intervals and QRS duration were performed manually by two independent experienced cardiologists using an electronic digitizer
(Mitutoyo Digimatic Caliber, Aurora IL, USA), and if the calculations differed substantially (although generally the difference was b 5%), the mean value was taken. Representative examples of real QRS measurements in patients with normal or reduced EF showing narrow or wide QRS are shown in Figs. 1 and 2. Statistical analysis Descriptive statistics are presented as mean ± standard deviation for continuous variables and number (percentage) for categorical variables. The paired t test was used to assess the effect of heart rate (baseline, atrial-based pacing at 100 beats/min) on the intrinsic and the ventricular-paced QRS duration and other continuous parameters. We compared the responses of QRS duration between subgroups of interest using the independent-samples t test on the responses (differences). Receiver-operating characteristic (ROC) curves were used to detect the best cut-off point of change in intrinsic or ventricular-paced QRS duration (ΔQRS) in response to heart rate increase that optimized classification of underlying reduced EF. A p ≤ 0.05 was considered statistically significant.
Results Clinical and electrocardiographic characteristics We enrolled a total of 239 patients (190 men and 49 women), aged 69 ± 10 years (range, 38 to 92 years), 92 (38.5%) with normal EF and 147 (61.5%) with reduced EF. Baseline characteristics are summarized in Table 1. Significantly more patients with reduced EF compared to patients with normal EF were receiving long-term amiodarone (96% vs 0, p b 0.001) as well as β-blockers (97% vs 12%, p b 0.001) and ACE inhibitors (97% vs 20%, p b 0.001). Patients with normal EF had no significant structural heart disease, whereas more patients with reduced EF had ischemic compared to non-ischemic etiology of left ventricular dysfunction (76.5% and 24.5%, respectively). All patients (100%) with normal EF had received pacemakers, whereas the majority of patients (97.3%) with reduced EF had received an ICD. Patients with reduced EF were more likely to have wide QRS complex compared to those with normal EF (54.4% vs 22.8%, p b 0.001) as well as LBBB (33.3% versus 4.3%, p b 0.001). In patients with normal EF, the ventricular lead was more often implanted at the apex (67.4%) vs the septum (32.6%) compared to reduced EF patients (31.3% and 68.7% for apical and septal placement, respectively, p b 0.001 for the difference between groups). Overall, patients with reduced EF had similar age (69 ± 9 vs 69 ± 11 years, p = 0.76) and resting heart rate (63 ± 10 vs 63 ± 9 beats/min, p = 0.98) compared to those with normal EF, but longer PR interval (205 ± 40 vs 190 ± 37, p = 0.003). The intrinsic PR interval increased significantly during atrial pacing at 100 beats/min pacing in patients with both normal EF and reduced EF (from 189 ± 38 ms to 248 ± 47 ms and from 199 ± 34 ms to 263 ± 48 ms, respectively, both p b 0.001).
J. Chiladakis et al. / Journal of Electrocardiology 48 (2015) 689–695
691
Fig. 1. Representative QRS measurements in patients with normal EF and narrow (upper panel) or wide QRS (lower panel) at baseline heart rate (BL-IC, BL-VP) as well as at 100 beats/min (100-IC, 100-VP). BL = baseline, IC = intrinsic, VP = ventricular paced.
Intrinsic QRS duration changes
Ventricular-paced QRS duration changes
Patients with normal EF and either narrow or wide baseline QRS had shorter QRS duration compared to their reduced-EF counterparts (p b 0.0001 and p b 0.05, respectively) (Table 2). Following pacing-induced heart rate increase, the QRS duration decreased in patients with normal EF/narrow QRS (p b 0.001), but it did not significantly change in patients with normal EF/wide QRS as well as in patients with reduced EF and either narrow or wide QRS (p = NS). The increased heart rate induced ΔQRS decreased in patients with normal EF/narrow QRS as compared to ΔQRS increases in patients with reduced EF/narrow QRS (− 3.6 ± 5.9 vs 1.0 ± 6.8 ms, p b 0.001), whereas the differences in ΔQRS between patients with normal EF/wide QRS and patients with reduced EF/wide QRS were not significant (− 1.7 ± 8.3 vs 0.8 ± 8.6 ms, p = 0.24) (Fig. 3). ROC analysis demonstrated that following heart rate increase, for patients with narrow QRS, a ΔQRS ≥ 0 ms predicted reduced EF with 58% sensitivity and 70% specificity (C statistic 0.67; 95% CI 0.58–0.57; p b 0.001), whereas for patients with wide QRS, the best ΔQRS ≥ − 1 ms indicated reduced EF with poor sensitivity and specificity of 54% and 62%, respectively (C statistic 0.59; 95% CI 0.45–0.73; p = 0.21).
At the baseline rate, ventricular pacing increased significantly both the narrow and wide QRS complex both in patients with normal and reduced EF (p b 0.05) (Table 2). However, patients with normal EF and either narrow QRS or wide QRS had shorter QRS compared to the corresponding subgroups of patients with reduced EF (153 ± 16 vs 164 ± 25 ms, p = 0.004, and 165 ± 20 vs 189 ± 28 ms, p b 0.001, respectively). Normal-EF patients had also shorter QRS duration when pacing at RVA or RVS compared to patients with reduced EF (159 ± 18 vs 174 ± 34, p = 0.008, and 150 ± 16 vs 179 ± 27 ms, p b 0.001, respectively). Within-group comparisons showed that RVS pacing compared to RVA pacing produced shorter QRS only in patients with normal EF (159 ± 18 vs 150 ± 16 ms, p = 0.022) and not in patients with reduced EF (174 ± 34 vs 179 ± 27 ms, p = 0.34, respectively). Following heart rate increase, the ventricular-paced QRS duration increased significantly in patients with normal or reduced EF and narrow QRS as well as in those patients with reduced EF/wide QRS, with either RVA or RVS pacing (p b 0.01), but not in patients with normal EF/wide QRS (p = NS). The increased heart rate induced higher QRS increases in both patient groups with reduced EF and narrow
692
J. Chiladakis et al. / Journal of Electrocardiology 48 (2015) 689–695
Fig. 2. Representative QRS measurements in patients with reduced EF and narrow (upper panel) or wide QRS (lower panel). Abbreviations as in Fig. 1.
or wide QRS as compared to the patients with normal EF and narrow or wide QRS, respectively (16.9 ± 19.7 vs 5.0 ± 11.4, p b 0.001 and 15.7 ± 21.9 vs 1.7 ± 11.2, p = 0.006, respectively) (Fig. 4). With both RVA and RVS pacing, the ΔQRS was significantly higher in patients with reduced EF and narrow or wide QRS as compared to patients with normal EF and narrow or wide QRS, respectively (15.2 ± 19.3 vs 4.4 ± 11.9, p b 0.001 and 16.7 ± 21.6 vs 4.0 ± 10.4, p = 0.002, respectively). ROC analysis indicated that following heart rate increase, for patients with baseline narrow QRS, a ΔQRS ≥ 4 ms predicted reduced EF with a sensitivity of 81% and specificity 54% (C statistic 0.71; 95% CI 0.62–0.80; p b 0.001), whereas for patients with baseline wide QRS, a ΔQRS ≥ 3 ms predicted reduced EF with 69% sensitivity and 71% specificity (C statistic 0.71; 95% CI 0.59–0.82; p b 0.001). By considering RVA pacing site, a ΔQRS ≥ 8 ms predicted patients with reduced EF with a sensitivity 63% and specificity of 71% (area under the ROC curve 0.694 [95% CI: 0.591–0.796]), whereas by considering RVS pacing, a ΔQRS ≥ 3 ms predicted reduced EF with a sensitivity 73.3% and specificity of 60% (area under the ROC curve 0.681 [95% CI: 0.584–0.779]).
Discussion This study provides several new insights on how the heart rate affects the intrinsic and the ventricular-paced QRS duration. The main findings indicate that following heart rate increase: (1) the intrinsic QRS duration decreases in patients with normal EF and increases slightly in patients with reduced EF; (2) the ventricular-paced QRS duration increases in patients with normal or reduced EF irrespective of baseline intrinsic narrow or wide QRS complex as well as of RVA or RVS pacing site; (3) RVS pacing prolongs the ventricular-paced QRS duration particularly in patients with reduced EF; and (4) the extent of the intrinsic and the ventricular-paced ΔQRS may be useful in identifying patients with reduced EF. Prolongation of QRS duration is often associated with LV dysfunction and heart failure, and signifies unfavorable prognosis even in individuals without apparent structural heart disease [7,8]. The inclusion of a wide QRS complex as a guideline-mandated prerequisite for cardiac resynchronization therapy in patients with systolic heart failure highlights the clinical importance of severe conduction delay [9]. Intraventricular conduction delays are associated with
J. Chiladakis et al. / Journal of Electrocardiology 48 (2015) 689–695
693
Table 1 Patient characteristics. Normal EF (n = 92)
Age, years Male, n (%) Cardiomyopathy, n (%) Ischemic Nonischemic BBB, n (%) LBBB RBBB Devices, n (%) PM ICD Pacing site, n (%) Septum Apex EF, % LVEDD, mm Heart rate, beats/min PR, ms QRS, ms
Reduced EF (n = 147)
Narrow QRS (n = 71)
Wide QRS (n = 21)
P Value
Narrow QRS (n = 67)
Wide QRS (n = 80)
P-value
69 ± 11 36 (51)
72 ± 10 18 (86)
0.24 0.005
68 ± 9 63 (94)
69 ± 10 73 (91)
0.56 0.76 0.44
-
-
53 (79) 14 (21)
58 (72.5) 22 (27.5)
-
4 (19) 17 (81)
-
49 (61) 31 (39)
71 (100) -
21 (100) -
67 (100)
4 (5) 76 (95)
24 (34) 47 (66) 61.0 (3.2) 48.2 ± 3.6 63.2 ± 9.8 188 ± 34 101 ± 12
6 (29) 15 (71) 60.0 (4) 50.6 ± 4 63.2 ± 8 198 ± 48 153 ± 13
42 (63) 25 (37) 37.9 (10) 60.1 ± 76 62.8 ± 11 201 ± 42 110 ± 9
59 (73.8) 21 (26.2) 31.5 (8) 64.3 ± 8 63.5 ± 9 209 ± 38 166 ± 26
0.014
0.79
0.27 0.022 0.99 0.30 -a
0.16
b 0.001 0.001 0.67 0.27 -a
BBB = bundle branch block, ICD = implantable cardioverter defibrillator, LBBB = left bundle branch block, LVDD = left ventricular end-diastolic diameter, EF = left ventricular ejection fraction, PM = pacemaker, RBBB = right bundle branch block. Continuous variables are expressed as mean ± SD. a Different by design.
worsening myocardial performance, impaired systolic and diastolic function, adversed myocyte remodeling with ventricular dilatation, altered myocardial metabolism, and functional mitral regurgitation [9–11]. Still, this indication is based primarily on QRS duration data derived at rest. There is currently no information available on the possible dynamic interactions between the heart rate and the QRS duration.
Specifically, increased sympathetic activity due to common stress conditions or through exercise, in proportion to myocardial oxygen demand, causes the heart rate to increase, which may affect QRS duration. In this study, we used a within-patient, atrial-based pacing protocol to achieve heart rate increase and thereby determine the isolated effect of increased heart rate on QRS duration. Advantages of this
Table 2 QRS duration responses to heart rate according to ventricular activation and pacing site. Patient groups Normal EF/narrow QRS (n = 71) QRS, ms Normal EF/wide QRS (n = 21) QRS, ms Normal EF/narrow QRS, RVA (n = 47) QRS, ms Normal EF/narrow QRS, RVS (n = 24) QRS, ms Normal EF/Wide QRS, RVA (n = 15) QRS, ms Normal EF/Wide QRS, RVS (n = 6) QRS, ms Reduced EF/Narrow QRS (n = 67) QRS, ms Reduced EF/Wide QRS (n = 80) QRS, ms Reduced EF/narrow QRS, RVA (n = 25) QRS, ms Reduced EF/narrow QRS, RVS (n = 42) QRS, ms Reduced EF/wide QRS, RVA (n = 21) QRS, ms Reduced EF/narrow QRS, RVS (n = 59) QRS, ms
BL-IC-QRS
100-IC-QRS
P-value
BL-VP-QRS
100-VP-QRS
P-value
101 ± 12
97 ± 13
b0.001
153 ± 16
159 ± 15
b0.001
153 ± 13
151 ± 16
0.37
165 ± 20
167 ± 19
0.47
100 ± 11
97 ± 12
b0.001
157 ± 16
161 ± 14
0.007
101 ± 13
97 ± 15
0.038
146 ± 15
154 ± 16
0.003
153 ± 14
150 ± 15
0.23
165 ± 22
169 ± 21
0.36
153 ± 13
153 ± 21
0.99
165 ± 12
163 ± 14
0.17
110 ± 9
112 ± 13
0.16
164 ± 25
180 ± 29
b0.001
166 ± 26
165 ± 26
0.43
189 ± 28
209 ± 41
b0.001
108 ± 9
109 ± 13
0.48
159 ± 24
174 ± 27
b0.001
111 ± 8
114 ± 13
0.23
166 ± 25
183 ± 30
b0.001
165 ± 29
164 ± 33
0.53
192 ± 37
207 ± 32
0.005
166 ± 25
165 ± 24
0.61
189 ± 24
210 ± 44
b0.001
BL = baseline heart rate, BL-IC-QRS = BL intrinsic QRS, BL-VP-QRS = BL ventricular-paced QRS, EF = left ventricular ejection fraction, RVA = right ventricular apex, RVS = right ventricular septum, 100 = 100 beats/min. Values are expressed as mean ± SD.
694
J. Chiladakis et al. / Journal of Electrocardiology 48 (2015) 689–695
Ventricular-paced QRS duration changes
Fig. 3. Intrinsic QRS duration response to increased heart rate.
method include avoidance of extraneous confounding influences, minimization of bias related to inter-subject variability as a result of autonomic, neurohumoral, pathologic, or pharmacologic influences, and increased reliability to evaluate QRS duration on repeated measurements. Intrinsic QRS duration changes In our study, the baseline intrinsic narrow and wide QRS complex in patients with normal EF was shorter than in those patients with reduced EF. This agrees with previous observations that a prolonged QRS duration in patients with or without BBB is associated with decreased EF [7,12]. Data on the effect of heart rate on QRS duration are available only from studies using exercise stress testing, indicating a differential QRS duration change according to underlying heart disease status. In contrast to the small exercise-induced QRS duration shortening observed in normal subjects, moderate QRS duration prolongations during exercise seem to indicate coronary artery disease and risk for ischemia-related ventricular tachycardia [2,3]. The current results show that the extent of QRS duration responses closely resembles those described above following exercise. We documented that the elevation of heart rate decreased the QRS duration only in patients with normal EF and in particular those with narrow QRS, and produced subtle QRS prolongation in patients with reduced EF. Analysis of the extend of intrinsic ΔQRS following heart rate increase showed that a ΔQRS ≥ 0 ms in patients with narrow QRS provided the optimal balance between sensitivity (58%) and specificity (70%) to predict reduced EF. However, for patients with wide QRS, the best ΔQRS of ≥ − 1 ms was of limited value for detecting patients with reduced EF.
Fig. 4. Ventricular-paced QRS duration response to increased heart rate.
Conventional RVA pacing creates prolonged QRS duration due to the heterogeneity in electrical activation and mechanical dyssynchrony, with resultant detrimental hemodynamic, structural and left ventricular remodeling changes [13–15]. These adverse effects likely explain the risk for developing heart failure, which grows with increasing cumulative percentage of RVA pacing and prolonged spontaneous or ventricular-paced QRS duration, particularly in the presence of substrate of left ventricular dysfunction [15,16]. Of the various alternative right ventricular pacing sites, RVS pacing has been advocated as the most practical and reliable. There is a general agreement that RVS pacing creates shorter ventricular-paced QRS duration than RVA pacing [4,5]. However, much uncertainty exists as to whether RVS pacing improves hemodynamics and prevents adverse left ventricular remodeling compared to RVA pacing [4,5,16,17]. In our study more patients with already reduced EF had the ventricular pacing lead positioned in the mid-septal site in order to avoid further detrimental effects of pacing on the left ventricular function. The opposite strategy was intended in patients with normal EF. The present results demonstrated that pacing from either RVA or RVS site at the baseline rate increased, as expected, the ventricular-paced QRS duration in patients with baseline intrinsic narrow QRS complex regardless of normal or reduced EF. We add the novel observation that a similar QRS duration response applies also to patients with baseline intrinsic wide QRS. Furthermore, our results confirm previous reports indicating that RVS pacing creates narrower ventricular-paced QRS duration compared to RVA pacing in patients with preserved EF [4,5,18]. However, extending our findings to patients with preexisting left ventricular dysfunction, we emphasize that this does not occur in patients with reduced EF. This is consistent with previous observations of an acute hemodynamic study indicating broadening of QRS in patients with low EF as a result of RVS pacing, in comparison not only to RVA pacing but also to patients with preserved EF [19]. The elevation of heart rate elicited parallel changes in the ventricular-paced QRS duration that have not been described before. We observed a significant widening of the QRS duration following heart rate increase in patients with either normal or reduced EF and intrinsic narrow QRS complex, irrespective of the ventricular pacing site. For patients with intrinsic wide QRS, a similar ventricular-paced QRS complex broadening was demonstrated in patients with reduced EF, albeit not in those with normal EF. Our data emphasize the greater ventricular-paced QRS prolongation in already highrisk patients with reduced EF compared to patients with normal EF, suggesting avoidance of ventricular pacing as much as possible irrespective of the intrinsic QRS duration. We also note that in patients with reduced EF, RVS pacing may not be considered superior to RVA pacing in regard to the effect of heart rate on the ventricular-paced QRS duration. This study also highlights the challenge of identifying patients with reduced EF by considering the value of the
J. Chiladakis et al. / Journal of Electrocardiology 48 (2015) 689–695
ventricular-paced ΔQRS following heart rate increase. In patients with baseline narrow QRS, the best ΔQRS ≥ 4 ms identified reduced-EF with 81% sensitivity and only 54% specificity, but in patients in patients with baseline wide QRS, a ΔQRS ≥ 3 ms performed better reaching sensitivity 69% and specificity 71%. In evaluating the impact of ventricular-paced ΔQRS from the different ventricular pacing sites to classify patients with reduced EF, a ΔQRS ≥ 8 ms with RVA pacing, or of ≥ 3 ms with RVS pacing, could be used as diagnostic tools with reasonable sensitivity (63% and 73%, respectively), and specificity (71% and 60%, respectively). Limitations The applicability of our findings may be limited by the fact that our study patients were pacemaker recipients. Nevertheless, our data may be also applied to the general population since the atrial-based increase in heart rate particularly in the patients who maintained intrinsic ventricular activation might mimic what happens in real life. In addition, our ROC analysis is confounded by the fact that patients had already been classified according to EF. Therefore, our ROC analysis results should not be interpreted in the context of a prospective diagnostic test validation, but rather as indicative of the capacity of pacing-induced QRS changes to discriminate the presence of underlying structural heart disease. Another limitation relates to our method of QRS measurement, whereby QRS assessment based on the first QRS onset in any lead to the latest QRS termination in any lead, or computer-calculated automatic QRS measurements would have been preferable, although international guidelines do not specify a preferred/ standard measurement technique [9]. We also acknowledge that we did not consider separately patients with incomplete BBB as well as patients with wide QRS patients and IVCD morphology since a left bundle branch block-like QRS morphology that is categorized as intraventricular conduction delay may be difficult to define.
Conclusions We demonstrated a heart rate-dependent prolonging effect on the ventricular-paced QRS duration, particularly in patients with reduced EF. Our study also suggests that at increased heart rate the alternative RVS pacing has a similar broadening effect on the QRS duration to RVA pacing in patients with reduced EF. Management with ventricular pacing strategies that preserve the intrinsic ventricular activation sequence as much as possible appears to be even more necessary to reduce unfavorable effects that could be attributed to the further prolongation of the ventricular-paced QRS duration during increased heart rate. On the other hand, since current guidelines take no cognizance of the effect of heart rate, cardiac resynchronization therapy indications need to consider patients with broadening QRS during increased heart rate with particular focus to patients with reduced EF and narrow QRS complex at rest.
695
References [1] Michaelides A, Ryan JM, VanFossen D, Pozderac R, Boudoulas H. Exercise-induced QRS prolongation in patients with coronary artery disease: a marker of myocardial ischemia. Am Heart J 1993;126:1320–5. [2] Berntsen RF, Gjestvang FT, Rasmussen K. QRS prolongation as an indicator of risk of ischemia-related ventricular tachycardia and fibrillation induced by exercise. Am Heart J 1995;129:542–8. [3] Takaki H, Tahara N, Miyazaki S, Sugimachi M, Sunagawa K. Exercise-induced QRS prolongation in patients with mild coronary artery disease: computer analysis of the digitized multilead ECGs. J Electrocardiol 1999;32:206–11. [4] Tse HF, Wong KK, Siu CW, Zhang XH, Ho WY, Lau CP. Upgrading pacemaker patients with right ventricular apical pacing to right ventricular septal pacing improves left ventricular performance and functional capacity. J Cardiovasc Electrophysiol 2009;20:901–5. [5] Wang F, Shi H, Sun Y, Wang J, Yan Q, Jin W, et al. Right ventricular outflow pacing induces less regional wall motion abnormalities in the left ventricle compared with apical pacing. Europace 2012;14:351–7. [6] Lieberman R, Grenz D, Mond HG, Gammage MD. Selective site pacing: defining and reaching the selected site. Pacing Clin Electrophysiol 2004;27:883–6. [7] Murkofsky RL, Dangas G, Diamond JA, Mehta D, Schaffer A, Ambrose JA. A prolonged QRS duration on surface electrocardiogram is a specific indicator of left ventricular dysfunction. J Am Coll Cardiol 1998;32:476–82. [8] Kurl S, Mäkikallio TH, Rautaharju P, Kiviniemi V, Laukkanen JA. Duration of QRS complex in resting electrocardiogram is a predictor of sudden cardiac death in men. Circulation 2012;125:2588–94. [9] Epstein AE, DiMarco JP, Ellenbogen KA, Estes III NA, Freedman RA, Gettes LS, et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2013;127:283–352. [10] Dhingra R, Ho Nam B, Benjamin EJ, Wang TJ, Larson MG, D'Agostino Sr RB, et al. Cross-sectional relations of electrocardiographic QRS duration to left ventricular dimensions: the Framingham Heart Study. J Am Coll Cardiol 2005;45:685–9. [11] Bryant AR, Wilton SB, Lai MP, Exner DV. Association between QRS duration and outcome with cardiac resynchronization therapy: a systematic review and meta-analysis. J Electrocardiol 2013;46:147–55. [12] Caso P, D'Andrea A, Martiniello AR, Severino S, Cioppa C, Iengo R, et al. Myocardial systolic activation delay in patients with left bundle branch block and either normal or impaired left ventricular function. Echocardiography 2006;23:14–23. [13] Chen S, Yin Y, Lan X, Liu Z, Ling Z, Su L, et al. PREDICT-Heart Failure study international group. Eur J Heart Fail 2013;15:352–9. [14] Zhang XH, Chen H, Siu CW, Yiu KH, Chan WS, Lee KL, et al. Newonset heart failure after permanent right ventricular apical pacing in patients with acquired high-grade atrioventricular block and normal left ventricular function. J Cardiovasc Electrophysiol 2008;19:136–41. [15] Sweeney MO, Hellkamp AS. Heart failure during cardiac pacing. Circulation 2006;113:2082–8. [16] Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial.; Dual Chamber and VVI Implantable Defibrillator Trial Investigators. JAMA 2002;288:3115–23. [17] Kypta A, Steinwender C, Kammler J, Leisch F, Hofmann R. Longterm outcomes in patients with atrioventricular block undergoing septal ventricular lead implantation compared with standard apical pacing. Europace 2008;10:574–9. [18] Domenichini G, Sunthorn H, Fleury E, Foulkes H, Stettler C, Burri H. Pacing of the interventricular septum versus the right ventricular apex: a prospective, randomized study. Eur J Intern Med 2012;23:621–7. [19] Lieberman R, Padeletti L, Schreuder J, Jackson K, Michelucci A, Colella A, et al. Ventricular pacing lead location alters systemic hemodynamics and left ventricular function in patients with and without reduced ejection fraction. J Am Coll Cardiol 2006;48: 1634–41.
ScienceDirect Journal of Electrocardiology 48 (2015) 689 – 695 www.jecgonline.com
Effect of heart rate on the intrinsic and the ventricular-paced QRS duration John Chiladakis, MD,⁎ Andreas Kalogeropoulos, MD, Fani Zagkli, MD, Konstantinos Chouchoulis, MD Cardiology Department, Patras University Hospital, 26500 Rion, Patras, Greece
Abstract
Background: We evaluated the effect of heart rate on the intrinsic and the ventricular-paced QRS duration in implanted device recipients with normal or reduced left ventricular ejection fraction (EF). Methods: We studied 239 outpatients with preserved intrinsic ventricular activation and normal (n = 92) or reduced (n = 147) EF who had apical (RVA) or mid-septal (RVS) right ventricular lead position. The QRS duration was measured at baseline and during atrial-based pacing at increased heart rate to ensure intrinsic or ventricular-paced QRS activation. Results: The heart rate increase shortened the intrinsic QRS only in patients with normal EF, and further prolonged the ventricular-paced QRS in patients with reduced EF and either narrow or wide QRS (p b 0.001), irrespective of RVA or RVS pacing (p b 0.01). Conclusion: Heart rate increase is associated with further QRS prolongation in patients with reduced EF, regardless of RVA or RVS pacing site. © 2015 Elsevier Inc. All rights reserved.
Keywords:
Heart rate; QRS duration; Right ventricular apical vs septal pacing
Introduction The QRS duration is a dynamic component of the 12-lead electrocardiogram (ECG), subject to the influence of several factors, including the heart rate [1–3]. Still, assessment of the QRS duration is practically based on fixed measurements during resting heart rate. Little is known about the behavior of QRS duration in response to an increase in heart rate, which may occur even during resting conditions. This consideration largely applies also to cardiac device patients with ventricular-paced rhythm. Nonetheless, based primarily on QRS duration data derived from patients studied at rest, alternative right ventricular septal (RVS) pacing has been suggested in light of the deleterious consequences of traditional right ventricular apical (RVA) pacing [4,5]. The aim of the present study was to investigate the effect of heart rate on the intrinsic and the ventricular-paced QRS duration in implanted dual-chamber device recipients with normal or reduced left ventricular ejection function (EF) and in relation to RVA vs RVS pacing. Methods Patients We studied 239 outpatients (mean age 69 ± 10) who were chronically implanted with a dual-chamber pacemaker or ⁎ Corresponding author at: Agias Lavras, 26504 Platani, Patras, Greece. E-mail address: [email protected] http://dx.doi.org/10.1016/j.jelectrocard.2015.04.009 0022-0736/© 2015 Elsevier Inc. All rights reserved.
implantable cardioverter defibrillator (ICD) system due to symptomatic sinus bradycardia or ventricular tachyarrhythmias, respectively. Eligible patients were on sinus rhythm with preserved long-term intrinsic ventricular activation. The patients were classified into 4 subgroups on the basis of the underlying EF and the presence of narrow QRS complex (b 120 ms) or wide QRS complex (≥ 120 ms) at resting heart rate: normal EF/narrow QRS; normal EF/wide QRS; reduced EF/narrow QRS; reduced EF/wide QRS. Normal EF patients did not have apparent structural heart disease and had an EF ≥ 55%, whereas patients with reduced EF had ischemic or nonishemic cardiomyopathy based on history or objective assessment of coronary artery disease from coronary angiography. Standard two-dimensional echocardiographic measurements were performed to obtain cardiac dimensions and wall contraction abnormalities. The EF was measured using the Simpson's method. Patients were excluded if they had symptoms or signs of decompensated heart failure on the basis of physical examination and chest X-ray, or had recent history of atrial or ventricular tachyarrhythmia. In all patients, atrial screw-in leads were implanted in the right atrial appendage and ventricular leads were positioned either passive at the RVA or active at the RVS site. The left anterior oblique fluoroscopy view was used to confirm septal lead attachment at the lower portion of the right ventricular outflow tract, when possible, or mid-septal segment of the right ventricle [6]. The decision of ventricular lead position site was left to the discretion of the implanter. The stability of
690
J. Chiladakis et al. / Journal of Electrocardiology 48 (2015) 689–695
sinus rhythm and underlying atrioventricular conduction was documented by previous ECGs, and retrieved data from device event counters and histograms, when possible, at planned follow-up visits. Patients with an ICD were receiving long-term amiodarone. Study protocol The patients were studied in supine position under standardized conditions and continuous ECG monitoring. Dual-chamber devices had been programmed at implantation with a fixed long atrioventricular delay and all available algorithms activated to promote intrinsic ventricular activity. Resting baseline ECG measurements with the intrinsic narrow or wide QRS were taken during spontaneous sinus rhythm or at the lowest programmed pacing rate. Then, devices were programmed in DDD mode with long atrioventricular delay in order to allow with atrial-based pacing at 100 beats/min intrinsic atrioventricular QRS activation. For ventricular pacing, devices were programmed in DDD mode with the atrioventricular delay set short at 100 ms at the lowest heart rate, and then at 100 beats/min, in order to induce complete ventricular capture. ECG measurements at each pacing stage were obtained after approximately 30-sec of constant captured pacing. The ECG was continuously monitored to ensure constant and stable 1:1 atrioventricular conduction during the pacing tests, when possible. Electrocardiogram recordings showing atrioventricular conduction block or ventricular fusion were discarded, whereby careful attention was also paid to exclude intrinsic QRS patients with an initially narrow QRS if they developed a bundle-branch block during atrial pacing at 100 beats/min. Measurements were performed during routine follow-up visits in the context of assessing proper device function. ECG measurements Standard 12-lead ECGs were recorded throughout the study using a MAC-VU electrocardiograph (Marquette Medical Systems, Milwaukee, Wisconsin) at a paper speed of 25 mm/sec. The widest QRS duration was taken defined as the maximum QRS duration occurring in any of the 12 ECG leads and was determined as the interval between the initial QRS depolarization and the J point. The earliest onset and the latest offset were considered to define the lead with the widest QRS complex mostly from the three simultaneously precordial leads V1–V3 or alternatively from the leads I–III. The J point was taken at the beginning of the isoelectric ST segment, or if this landmark was not distinguishable, the tangent to the descending part of the R wave or the ascending part of the S wave and the isoelectric line was drawn through the ST segment. Standard ECG criteria were used to diagnose complete bundle branch block (BBB) of left BBB (LBBB) or right BBB (RBBB) morphology with QRS duration ≥ 120 ms. Patients with incomplete BBB were included in the narrow QRS patient group. Measurements of RR and PR intervals and QRS duration were performed manually by two independent experienced cardiologists using an electronic digitizer
(Mitutoyo Digimatic Caliber, Aurora IL, USA), and if the calculations differed substantially (although generally the difference was b 5%), the mean value was taken. Representative examples of real QRS measurements in patients with normal or reduced EF showing narrow or wide QRS are shown in Figs. 1 and 2. Statistical analysis Descriptive statistics are presented as mean ± standard deviation for continuous variables and number (percentage) for categorical variables. The paired t test was used to assess the effect of heart rate (baseline, atrial-based pacing at 100 beats/min) on the intrinsic and the ventricular-paced QRS duration and other continuous parameters. We compared the responses of QRS duration between subgroups of interest using the independent-samples t test on the responses (differences). Receiver-operating characteristic (ROC) curves were used to detect the best cut-off point of change in intrinsic or ventricular-paced QRS duration (ΔQRS) in response to heart rate increase that optimized classification of underlying reduced EF. A p ≤ 0.05 was considered statistically significant.
Results Clinical and electrocardiographic characteristics We enrolled a total of 239 patients (190 men and 49 women), aged 69 ± 10 years (range, 38 to 92 years), 92 (38.5%) with normal EF and 147 (61.5%) with reduced EF. Baseline characteristics are summarized in Table 1. Significantly more patients with reduced EF compared to patients with normal EF were receiving long-term amiodarone (96% vs 0, p b 0.001) as well as β-blockers (97% vs 12%, p b 0.001) and ACE inhibitors (97% vs 20%, p b 0.001). Patients with normal EF had no significant structural heart disease, whereas more patients with reduced EF had ischemic compared to non-ischemic etiology of left ventricular dysfunction (76.5% and 24.5%, respectively). All patients (100%) with normal EF had received pacemakers, whereas the majority of patients (97.3%) with reduced EF had received an ICD. Patients with reduced EF were more likely to have wide QRS complex compared to those with normal EF (54.4% vs 22.8%, p b 0.001) as well as LBBB (33.3% versus 4.3%, p b 0.001). In patients with normal EF, the ventricular lead was more often implanted at the apex (67.4%) vs the septum (32.6%) compared to reduced EF patients (31.3% and 68.7% for apical and septal placement, respectively, p b 0.001 for the difference between groups). Overall, patients with reduced EF had similar age (69 ± 9 vs 69 ± 11 years, p = 0.76) and resting heart rate (63 ± 10 vs 63 ± 9 beats/min, p = 0.98) compared to those with normal EF, but longer PR interval (205 ± 40 vs 190 ± 37, p = 0.003). The intrinsic PR interval increased significantly during atrial pacing at 100 beats/min pacing in patients with both normal EF and reduced EF (from 189 ± 38 ms to 248 ± 47 ms and from 199 ± 34 ms to 263 ± 48 ms, respectively, both p b 0.001).
J. Chiladakis et al. / Journal of Electrocardiology 48 (2015) 689–695
691
Fig. 1. Representative QRS measurements in patients with normal EF and narrow (upper panel) or wide QRS (lower panel) at baseline heart rate (BL-IC, BL-VP) as well as at 100 beats/min (100-IC, 100-VP). BL = baseline, IC = intrinsic, VP = ventricular paced.
Intrinsic QRS duration changes
Ventricular-paced QRS duration changes
Patients with normal EF and either narrow or wide baseline QRS had shorter QRS duration compared to their reduced-EF counterparts (p b 0.0001 and p b 0.05, respectively) (Table 2). Following pacing-induced heart rate increase, the QRS duration decreased in patients with normal EF/narrow QRS (p b 0.001), but it did not significantly change in patients with normal EF/wide QRS as well as in patients with reduced EF and either narrow or wide QRS (p = NS). The increased heart rate induced ΔQRS decreased in patients with normal EF/narrow QRS as compared to ΔQRS increases in patients with reduced EF/narrow QRS (− 3.6 ± 5.9 vs 1.0 ± 6.8 ms, p b 0.001), whereas the differences in ΔQRS between patients with normal EF/wide QRS and patients with reduced EF/wide QRS were not significant (− 1.7 ± 8.3 vs 0.8 ± 8.6 ms, p = 0.24) (Fig. 3). ROC analysis demonstrated that following heart rate increase, for patients with narrow QRS, a ΔQRS ≥ 0 ms predicted reduced EF with 58% sensitivity and 70% specificity (C statistic 0.67; 95% CI 0.58–0.57; p b 0.001), whereas for patients with wide QRS, the best ΔQRS ≥ − 1 ms indicated reduced EF with poor sensitivity and specificity of 54% and 62%, respectively (C statistic 0.59; 95% CI 0.45–0.73; p = 0.21).
At the baseline rate, ventricular pacing increased significantly both the narrow and wide QRS complex both in patients with normal and reduced EF (p b 0.05) (Table 2). However, patients with normal EF and either narrow QRS or wide QRS had shorter QRS compared to the corresponding subgroups of patients with reduced EF (153 ± 16 vs 164 ± 25 ms, p = 0.004, and 165 ± 20 vs 189 ± 28 ms, p b 0.001, respectively). Normal-EF patients had also shorter QRS duration when pacing at RVA or RVS compared to patients with reduced EF (159 ± 18 vs 174 ± 34, p = 0.008, and 150 ± 16 vs 179 ± 27 ms, p b 0.001, respectively). Within-group comparisons showed that RVS pacing compared to RVA pacing produced shorter QRS only in patients with normal EF (159 ± 18 vs 150 ± 16 ms, p = 0.022) and not in patients with reduced EF (174 ± 34 vs 179 ± 27 ms, p = 0.34, respectively). Following heart rate increase, the ventricular-paced QRS duration increased significantly in patients with normal or reduced EF and narrow QRS as well as in those patients with reduced EF/wide QRS, with either RVA or RVS pacing (p b 0.01), but not in patients with normal EF/wide QRS (p = NS). The increased heart rate induced higher QRS increases in both patient groups with reduced EF and narrow
692
J. Chiladakis et al. / Journal of Electrocardiology 48 (2015) 689–695
Fig. 2. Representative QRS measurements in patients with reduced EF and narrow (upper panel) or wide QRS (lower panel). Abbreviations as in Fig. 1.
or wide QRS as compared to the patients with normal EF and narrow or wide QRS, respectively (16.9 ± 19.7 vs 5.0 ± 11.4, p b 0.001 and 15.7 ± 21.9 vs 1.7 ± 11.2, p = 0.006, respectively) (Fig. 4). With both RVA and RVS pacing, the ΔQRS was significantly higher in patients with reduced EF and narrow or wide QRS as compared to patients with normal EF and narrow or wide QRS, respectively (15.2 ± 19.3 vs 4.4 ± 11.9, p b 0.001 and 16.7 ± 21.6 vs 4.0 ± 10.4, p = 0.002, respectively). ROC analysis indicated that following heart rate increase, for patients with baseline narrow QRS, a ΔQRS ≥ 4 ms predicted reduced EF with a sensitivity of 81% and specificity 54% (C statistic 0.71; 95% CI 0.62–0.80; p b 0.001), whereas for patients with baseline wide QRS, a ΔQRS ≥ 3 ms predicted reduced EF with 69% sensitivity and 71% specificity (C statistic 0.71; 95% CI 0.59–0.82; p b 0.001). By considering RVA pacing site, a ΔQRS ≥ 8 ms predicted patients with reduced EF with a sensitivity 63% and specificity of 71% (area under the ROC curve 0.694 [95% CI: 0.591–0.796]), whereas by considering RVS pacing, a ΔQRS ≥ 3 ms predicted reduced EF with a sensitivity 73.3% and specificity of 60% (area under the ROC curve 0.681 [95% CI: 0.584–0.779]).
Discussion This study provides several new insights on how the heart rate affects the intrinsic and the ventricular-paced QRS duration. The main findings indicate that following heart rate increase: (1) the intrinsic QRS duration decreases in patients with normal EF and increases slightly in patients with reduced EF; (2) the ventricular-paced QRS duration increases in patients with normal or reduced EF irrespective of baseline intrinsic narrow or wide QRS complex as well as of RVA or RVS pacing site; (3) RVS pacing prolongs the ventricular-paced QRS duration particularly in patients with reduced EF; and (4) the extent of the intrinsic and the ventricular-paced ΔQRS may be useful in identifying patients with reduced EF. Prolongation of QRS duration is often associated with LV dysfunction and heart failure, and signifies unfavorable prognosis even in individuals without apparent structural heart disease [7,8]. The inclusion of a wide QRS complex as a guideline-mandated prerequisite for cardiac resynchronization therapy in patients with systolic heart failure highlights the clinical importance of severe conduction delay [9]. Intraventricular conduction delays are associated with
J. Chiladakis et al. / Journal of Electrocardiology 48 (2015) 689–695
693
Table 1 Patient characteristics. Normal EF (n = 92)
Age, years Male, n (%) Cardiomyopathy, n (%) Ischemic Nonischemic BBB, n (%) LBBB RBBB Devices, n (%) PM ICD Pacing site, n (%) Septum Apex EF, % LVEDD, mm Heart rate, beats/min PR, ms QRS, ms
Reduced EF (n = 147)
Narrow QRS (n = 71)
Wide QRS (n = 21)
P Value
Narrow QRS (n = 67)
Wide QRS (n = 80)
P-value
69 ± 11 36 (51)
72 ± 10 18 (86)
0.24 0.005
68 ± 9 63 (94)
69 ± 10 73 (91)
0.56 0.76 0.44
-
-
53 (79) 14 (21)
58 (72.5) 22 (27.5)
-
4 (19) 17 (81)
-
49 (61) 31 (39)
71 (100) -
21 (100) -
67 (100)
4 (5) 76 (95)
24 (34) 47 (66) 61.0 (3.2) 48.2 ± 3.6 63.2 ± 9.8 188 ± 34 101 ± 12
6 (29) 15 (71) 60.0 (4) 50.6 ± 4 63.2 ± 8 198 ± 48 153 ± 13
42 (63) 25 (37) 37.9 (10) 60.1 ± 76 62.8 ± 11 201 ± 42 110 ± 9
59 (73.8) 21 (26.2) 31.5 (8) 64.3 ± 8 63.5 ± 9 209 ± 38 166 ± 26
0.014
0.79
0.27 0.022 0.99 0.30 -a
0.16
b 0.001 0.001 0.67 0.27 -a
BBB = bundle branch block, ICD = implantable cardioverter defibrillator, LBBB = left bundle branch block, LVDD = left ventricular end-diastolic diameter, EF = left ventricular ejection fraction, PM = pacemaker, RBBB = right bundle branch block. Continuous variables are expressed as mean ± SD. a Different by design.
worsening myocardial performance, impaired systolic and diastolic function, adversed myocyte remodeling with ventricular dilatation, altered myocardial metabolism, and functional mitral regurgitation [9–11]. Still, this indication is based primarily on QRS duration data derived at rest. There is currently no information available on the possible dynamic interactions between the heart rate and the QRS duration.
Specifically, increased sympathetic activity due to common stress conditions or through exercise, in proportion to myocardial oxygen demand, causes the heart rate to increase, which may affect QRS duration. In this study, we used a within-patient, atrial-based pacing protocol to achieve heart rate increase and thereby determine the isolated effect of increased heart rate on QRS duration. Advantages of this
Table 2 QRS duration responses to heart rate according to ventricular activation and pacing site. Patient groups Normal EF/narrow QRS (n = 71) QRS, ms Normal EF/wide QRS (n = 21) QRS, ms Normal EF/narrow QRS, RVA (n = 47) QRS, ms Normal EF/narrow QRS, RVS (n = 24) QRS, ms Normal EF/Wide QRS, RVA (n = 15) QRS, ms Normal EF/Wide QRS, RVS (n = 6) QRS, ms Reduced EF/Narrow QRS (n = 67) QRS, ms Reduced EF/Wide QRS (n = 80) QRS, ms Reduced EF/narrow QRS, RVA (n = 25) QRS, ms Reduced EF/narrow QRS, RVS (n = 42) QRS, ms Reduced EF/wide QRS, RVA (n = 21) QRS, ms Reduced EF/narrow QRS, RVS (n = 59) QRS, ms
BL-IC-QRS
100-IC-QRS
P-value
BL-VP-QRS
100-VP-QRS
P-value
101 ± 12
97 ± 13
b0.001
153 ± 16
159 ± 15
b0.001
153 ± 13
151 ± 16
0.37
165 ± 20
167 ± 19
0.47
100 ± 11
97 ± 12
b0.001
157 ± 16
161 ± 14
0.007
101 ± 13
97 ± 15
0.038
146 ± 15
154 ± 16
0.003
153 ± 14
150 ± 15
0.23
165 ± 22
169 ± 21
0.36
153 ± 13
153 ± 21
0.99
165 ± 12
163 ± 14
0.17
110 ± 9
112 ± 13
0.16
164 ± 25
180 ± 29
b0.001
166 ± 26
165 ± 26
0.43
189 ± 28
209 ± 41
b0.001
108 ± 9
109 ± 13
0.48
159 ± 24
174 ± 27
b0.001
111 ± 8
114 ± 13
0.23
166 ± 25
183 ± 30
b0.001
165 ± 29
164 ± 33
0.53
192 ± 37
207 ± 32
0.005
166 ± 25
165 ± 24
0.61
189 ± 24
210 ± 44
b0.001
BL = baseline heart rate, BL-IC-QRS = BL intrinsic QRS, BL-VP-QRS = BL ventricular-paced QRS, EF = left ventricular ejection fraction, RVA = right ventricular apex, RVS = right ventricular septum, 100 = 100 beats/min. Values are expressed as mean ± SD.
694
J. Chiladakis et al. / Journal of Electrocardiology 48 (2015) 689–695
Ventricular-paced QRS duration changes
Fig. 3. Intrinsic QRS duration response to increased heart rate.
method include avoidance of extraneous confounding influences, minimization of bias related to inter-subject variability as a result of autonomic, neurohumoral, pathologic, or pharmacologic influences, and increased reliability to evaluate QRS duration on repeated measurements. Intrinsic QRS duration changes In our study, the baseline intrinsic narrow and wide QRS complex in patients with normal EF was shorter than in those patients with reduced EF. This agrees with previous observations that a prolonged QRS duration in patients with or without BBB is associated with decreased EF [7,12]. Data on the effect of heart rate on QRS duration are available only from studies using exercise stress testing, indicating a differential QRS duration change according to underlying heart disease status. In contrast to the small exercise-induced QRS duration shortening observed in normal subjects, moderate QRS duration prolongations during exercise seem to indicate coronary artery disease and risk for ischemia-related ventricular tachycardia [2,3]. The current results show that the extent of QRS duration responses closely resembles those described above following exercise. We documented that the elevation of heart rate decreased the QRS duration only in patients with normal EF and in particular those with narrow QRS, and produced subtle QRS prolongation in patients with reduced EF. Analysis of the extend of intrinsic ΔQRS following heart rate increase showed that a ΔQRS ≥ 0 ms in patients with narrow QRS provided the optimal balance between sensitivity (58%) and specificity (70%) to predict reduced EF. However, for patients with wide QRS, the best ΔQRS of ≥ − 1 ms was of limited value for detecting patients with reduced EF.
Fig. 4. Ventricular-paced QRS duration response to increased heart rate.
Conventional RVA pacing creates prolonged QRS duration due to the heterogeneity in electrical activation and mechanical dyssynchrony, with resultant detrimental hemodynamic, structural and left ventricular remodeling changes [13–15]. These adverse effects likely explain the risk for developing heart failure, which grows with increasing cumulative percentage of RVA pacing and prolonged spontaneous or ventricular-paced QRS duration, particularly in the presence of substrate of left ventricular dysfunction [15,16]. Of the various alternative right ventricular pacing sites, RVS pacing has been advocated as the most practical and reliable. There is a general agreement that RVS pacing creates shorter ventricular-paced QRS duration than RVA pacing [4,5]. However, much uncertainty exists as to whether RVS pacing improves hemodynamics and prevents adverse left ventricular remodeling compared to RVA pacing [4,5,16,17]. In our study more patients with already reduced EF had the ventricular pacing lead positioned in the mid-septal site in order to avoid further detrimental effects of pacing on the left ventricular function. The opposite strategy was intended in patients with normal EF. The present results demonstrated that pacing from either RVA or RVS site at the baseline rate increased, as expected, the ventricular-paced QRS duration in patients with baseline intrinsic narrow QRS complex regardless of normal or reduced EF. We add the novel observation that a similar QRS duration response applies also to patients with baseline intrinsic wide QRS. Furthermore, our results confirm previous reports indicating that RVS pacing creates narrower ventricular-paced QRS duration compared to RVA pacing in patients with preserved EF [4,5,18]. However, extending our findings to patients with preexisting left ventricular dysfunction, we emphasize that this does not occur in patients with reduced EF. This is consistent with previous observations of an acute hemodynamic study indicating broadening of QRS in patients with low EF as a result of RVS pacing, in comparison not only to RVA pacing but also to patients with preserved EF [19]. The elevation of heart rate elicited parallel changes in the ventricular-paced QRS duration that have not been described before. We observed a significant widening of the QRS duration following heart rate increase in patients with either normal or reduced EF and intrinsic narrow QRS complex, irrespective of the ventricular pacing site. For patients with intrinsic wide QRS, a similar ventricular-paced QRS complex broadening was demonstrated in patients with reduced EF, albeit not in those with normal EF. Our data emphasize the greater ventricular-paced QRS prolongation in already highrisk patients with reduced EF compared to patients with normal EF, suggesting avoidance of ventricular pacing as much as possible irrespective of the intrinsic QRS duration. We also note that in patients with reduced EF, RVS pacing may not be considered superior to RVA pacing in regard to the effect of heart rate on the ventricular-paced QRS duration. This study also highlights the challenge of identifying patients with reduced EF by considering the value of the
J. Chiladakis et al. / Journal of Electrocardiology 48 (2015) 689–695
ventricular-paced ΔQRS following heart rate increase. In patients with baseline narrow QRS, the best ΔQRS ≥ 4 ms identified reduced-EF with 81% sensitivity and only 54% specificity, but in patients in patients with baseline wide QRS, a ΔQRS ≥ 3 ms performed better reaching sensitivity 69% and specificity 71%. In evaluating the impact of ventricular-paced ΔQRS from the different ventricular pacing sites to classify patients with reduced EF, a ΔQRS ≥ 8 ms with RVA pacing, or of ≥ 3 ms with RVS pacing, could be used as diagnostic tools with reasonable sensitivity (63% and 73%, respectively), and specificity (71% and 60%, respectively). Limitations The applicability of our findings may be limited by the fact that our study patients were pacemaker recipients. Nevertheless, our data may be also applied to the general population since the atrial-based increase in heart rate particularly in the patients who maintained intrinsic ventricular activation might mimic what happens in real life. In addition, our ROC analysis is confounded by the fact that patients had already been classified according to EF. Therefore, our ROC analysis results should not be interpreted in the context of a prospective diagnostic test validation, but rather as indicative of the capacity of pacing-induced QRS changes to discriminate the presence of underlying structural heart disease. Another limitation relates to our method of QRS measurement, whereby QRS assessment based on the first QRS onset in any lead to the latest QRS termination in any lead, or computer-calculated automatic QRS measurements would have been preferable, although international guidelines do not specify a preferred/ standard measurement technique [9]. We also acknowledge that we did not consider separately patients with incomplete BBB as well as patients with wide QRS patients and IVCD morphology since a left bundle branch block-like QRS morphology that is categorized as intraventricular conduction delay may be difficult to define.
Conclusions We demonstrated a heart rate-dependent prolonging effect on the ventricular-paced QRS duration, particularly in patients with reduced EF. Our study also suggests that at increased heart rate the alternative RVS pacing has a similar broadening effect on the QRS duration to RVA pacing in patients with reduced EF. Management with ventricular pacing strategies that preserve the intrinsic ventricular activation sequence as much as possible appears to be even more necessary to reduce unfavorable effects that could be attributed to the further prolongation of the ventricular-paced QRS duration during increased heart rate. On the other hand, since current guidelines take no cognizance of the effect of heart rate, cardiac resynchronization therapy indications need to consider patients with broadening QRS during increased heart rate with particular focus to patients with reduced EF and narrow QRS complex at rest.
695
References [1] Michaelides A, Ryan JM, VanFossen D, Pozderac R, Boudoulas H. Exercise-induced QRS prolongation in patients with coronary artery disease: a marker of myocardial ischemia. Am Heart J 1993;126:1320–5. [2] Berntsen RF, Gjestvang FT, Rasmussen K. QRS prolongation as an indicator of risk of ischemia-related ventricular tachycardia and fibrillation induced by exercise. Am Heart J 1995;129:542–8. [3] Takaki H, Tahara N, Miyazaki S, Sugimachi M, Sunagawa K. Exercise-induced QRS prolongation in patients with mild coronary artery disease: computer analysis of the digitized multilead ECGs. J Electrocardiol 1999;32:206–11. [4] Tse HF, Wong KK, Siu CW, Zhang XH, Ho WY, Lau CP. Upgrading pacemaker patients with right ventricular apical pacing to right ventricular septal pacing improves left ventricular performance and functional capacity. J Cardiovasc Electrophysiol 2009;20:901–5. [5] Wang F, Shi H, Sun Y, Wang J, Yan Q, Jin W, et al. Right ventricular outflow pacing induces less regional wall motion abnormalities in the left ventricle compared with apical pacing. Europace 2012;14:351–7. [6] Lieberman R, Grenz D, Mond HG, Gammage MD. Selective site pacing: defining and reaching the selected site. Pacing Clin Electrophysiol 2004;27:883–6. [7] Murkofsky RL, Dangas G, Diamond JA, Mehta D, Schaffer A, Ambrose JA. A prolonged QRS duration on surface electrocardiogram is a specific indicator of left ventricular dysfunction. J Am Coll Cardiol 1998;32:476–82. [8] Kurl S, Mäkikallio TH, Rautaharju P, Kiviniemi V, Laukkanen JA. Duration of QRS complex in resting electrocardiogram is a predictor of sudden cardiac death in men. Circulation 2012;125:2588–94. [9] Epstein AE, DiMarco JP, Ellenbogen KA, Estes III NA, Freedman RA, Gettes LS, et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2013;127:283–352. [10] Dhingra R, Ho Nam B, Benjamin EJ, Wang TJ, Larson MG, D'Agostino Sr RB, et al. Cross-sectional relations of electrocardiographic QRS duration to left ventricular dimensions: the Framingham Heart Study. J Am Coll Cardiol 2005;45:685–9. [11] Bryant AR, Wilton SB, Lai MP, Exner DV. Association between QRS duration and outcome with cardiac resynchronization therapy: a systematic review and meta-analysis. J Electrocardiol 2013;46:147–55. [12] Caso P, D'Andrea A, Martiniello AR, Severino S, Cioppa C, Iengo R, et al. Myocardial systolic activation delay in patients with left bundle branch block and either normal or impaired left ventricular function. Echocardiography 2006;23:14–23. [13] Chen S, Yin Y, Lan X, Liu Z, Ling Z, Su L, et al. PREDICT-Heart Failure study international group. Eur J Heart Fail 2013;15:352–9. [14] Zhang XH, Chen H, Siu CW, Yiu KH, Chan WS, Lee KL, et al. Newonset heart failure after permanent right ventricular apical pacing in patients with acquired high-grade atrioventricular block and normal left ventricular function. J Cardiovasc Electrophysiol 2008;19:136–41. [15] Sweeney MO, Hellkamp AS. Heart failure during cardiac pacing. Circulation 2006;113:2082–8. [16] Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial.; Dual Chamber and VVI Implantable Defibrillator Trial Investigators. JAMA 2002;288:3115–23. [17] Kypta A, Steinwender C, Kammler J, Leisch F, Hofmann R. Longterm outcomes in patients with atrioventricular block undergoing septal ventricular lead implantation compared with standard apical pacing. Europace 2008;10:574–9. [18] Domenichini G, Sunthorn H, Fleury E, Foulkes H, Stettler C, Burri H. Pacing of the interventricular septum versus the right ventricular apex: a prospective, randomized study. Eur J Intern Med 2012;23:621–7. [19] Lieberman R, Padeletti L, Schreuder J, Jackson K, Michelucci A, Colella A, et al. Ventricular pacing lead location alters systemic hemodynamics and left ventricular function in patients with and without reduced ejection fraction. J Am Coll Cardiol 2006;48: 1634–41.
